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![1. Before study initiation, or
2. Concomitantly according to written standard operating procedures,
which provide for periodic analysis of each batch.
C. Each storage container for a test or control article shall be labeled by
name, chemical abstract number or code number, batch number,
expiration date, if any, and, where appropriate, storage conditions
necessary to maintain the identity, strength, purity, and composition of
the test or control article. Storage containers shall be assigned to a
particular test article for the duration of the study.
D. For studies of more than 4 weeks' duration, reserve samples from each
batch of test and control articles shall be retained for the period of time
provided by §58.195.
Test and control article handling
Procedures shall be established for a system for the handling of the test and
control articles to ensure that:
a. There is proper storage.
b. Distribution is made in a manner designed to preclude the possibility of
contamination, deterioration, or damage.
c. Proper identification is maintained throughout the distribution process.
d. The receipt and distribution of each batch is documented. Such
documentation shall include the date and quantity of each batch
distributed or returned.
Mixtures of articles with carriers
A. For each test or control article that is mixed with a carrier, tests by
appropriate analytical methods shall be conducted:
1. To determine the uniformity of the mixture and to determine,
periodically, the concentration of the test or control article in the
mixture.
2. To determine the stability of the test and control articles in the mixture
as required by the conditions of the study either:
a. Before study initiation, or
b. Concomitantly according to written standard operating procedures
which provide for periodic analysis of the test and control articles in the
mixture.
B. [Reserved].
C. Where any of the components of the test or control article carrier
mixture has an expiration date, that date shall be clearly shown on the
container. If more than one component has an expiration date, the
earliest date shall be show.
Subpart G - Protocol for and Conduct of a Nonclinical Laboratory Study
Protocol
A. Each study shall have an approved written protocol that clearly
indicates the objectives and all methods for the conduct of the study.
The protocol shall contain, as applicable, the following information:
1. A descriptive title and statement of the purpose of the study.
2. Identification of the test and control articles by name, chemical abstract
number, or code number.](https://image.slidesharecdn.com/qaqc-231118170635-5161d858/75/QA-QC-pdf-14-2048.jpg)
![entry, shall indicate the reason for change, shall be dated, and the
responsible individual shall be identified.
Subparts H - I [Reserved]
Subpart J - Records and Reports
Reporting of nonclinical laboratory study results
A. A final report shall be prepared for each nonclinical laboratory study
and shall include, but not necessarily be limited to, the following:
1. Name and address of the facility performing the study and the dates on
which the study was initiated and completed.
2. Objectives and procedures stated in the approved protocol, including
any changes in the original protocol.
3. Statistical methods employed for analyzing the data.
4. The test and control articles identified by name, chemical abstracts
number or code number, strength, purity, and composition or other
appropriate characteristics.
5. Stability of the test and control articles under the conditions of
administration.
6. A description of the methods used.
7. A description of the test system used. Where applicable, the final report
shall include the number of animals used, sex, body weight range,
source of supply, species, strain and substrain, age, and procedure used
for identification.
8. A description of the dosage, dosage regimen, route of administration,
and duration.
9. A description of all circumstances that may have affected the quality or
integrity of the data.
10. The name of the study director, the names of other scientists or
professionals, and the names of all supervisory personnel, involved in
the study.
11. A description of the transformations, calculations, or operations
performed on the data, a summary and analysis of the data, and a
statement of the conclusions drawn from the analysis.
12. The signed and dated reports of each of the individual scientists or other
professionals involved in the study.
13. The locations where all specimens, raw data, and the final report are to
be stored.
14. The statement prepared and signed by the quality assurance unit as
described in §58.35(b)(7).
B. The final report shall be signed and dated by the study director.
C. Corrections or additions to a final report shall be in the form of an
amendment by the study director. The amendment shall clearly identify
that part of the final report that is being added to or corrected and the
reasons for the correction or addition, and shall be signed and dated by
the person responsible storage and retrieval of records and data.
a. All raw data, documentation, protocols, final reports, and specimens
(except those specimens obtained from mutagenicity tests and wet](https://image.slidesharecdn.com/qaqc-231118170635-5161d858/75/QA-QC-pdf-16-2048.jpg)
![2
DRUG AND COSMETIC ACT IN INDIA
• In 1937 a Bill was introduced in the Central Legislative Assembly to give
effect to the recommendations of the Drugs Enquiry Committee to
regulate the import of drugs into British India.
• Provincial Governments got the resolution passed from the Provincial
Legislatures and sent them to the Central Government for getting
through the Bill to regulate the import, manufacture, distribution and
sale of Drugs and Cosmetics. There upon the Drugs and Cosmetics Bill
was introduced in the Central Legislative Assembly.
• The Drugs and Cosmetics Bill was passed by the Central Legislative
Assembly and it received the assent of the Governor General on 10th
April, 1940 and thus became the Drugs and Cosmetics Act, 1940 (23 of
1940).
• An Act to regulate the import, manufacture, distribution and sale of
drugs [(Note: Ins. by Act 21 of 1962, sec.2 (w.e.f. 27-7-1964)) and
cosmetics].
DRUG AND COSMETIC ACT 1940
SCHEDULE M
1. General Requirements :
a) Location and surroundings- The factory building(s) for manufacture of
drugs shall be so situated that it avoid risk of contamination from
external environmental including open sewage, drain, public lavatory.
b) Building and premises- They shall conform to the conditions laid down in
the Factories Act, 1948 (63 of 1948)
The premises used for manufacturing, processing, warehousing,
packaging labelling and testing purposes shall be:
i. compatible with other drug manufacturing operations.
ii. adequately working space to avoid the risk of mix-up between
different (b) avoid the possibilities of contamination and cross
contamination.
iii. designed / constructed / maintained to prevent entry of insects,
pests, birds, and rodents.
iv. well lighted, effectively ventilated, with proper Air Handling Units.
c) Water System-](https://image.slidesharecdn.com/qaqc-231118170635-5161d858/75/QA-QC-pdf-28-2048.jpg)
More Related Content
QA &QC.pdf
- 1. CONCEPT AND EVOLUTIONOF QUALITY CONTROL AND QUALITY ASSURANCE Quality assurance Quality control Definitions QA is a set of activities for ensuring quality in the process by which products are developed. Definitions QC is a set of activities for ensuring quality in products. The activities focus on identifying defects in the actual products produced. Focus on QA aims to prevent defects with a focus on the process used to make the product. It is a “proactive quality” process Focus on QC aims to identify defects in the finished product. Quality control is a “reactive” process. Goals The goal of QA is to improve development and test process so that defects do not arise when the product is being developed. Goals The goal of QC is to identify defects after a product is developed and before its released. How Establish a good quality management system and the assessment of its adequacy periodic conformance audits of the operations of the system. How Finding and eliminating sources of quality problems through tools customers requirements are continually met. What Prevention of quality problems through planned and systematic activities including documentation. What The activities or techniques used to achieve and maintain the product quality, process and service. Responsibility Everyone on the team involved in developing the product is responsible for quality assurance. • QA is process oriented. • Verification is an example of QA. Responsibility Quality control is usually the responsibility of a specific team that tests the product for defects. • Validation/software testing is an example of QC. • QC is product oriented.
- 2. ICH The international councilfor harmonization of technical requirements for pharmaceuticals for human use is unique in bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceuticals and develop ICH guidelines Quality guidelines Safety guidelines Efficacy guidelines Multidisciplinary Quality guidelines: Harmonization achievements in the quality area include pivotal milestones such as conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on good manufacturing practice (GMP) risk management. 𝐐𝟏𝐀 - 𝐐𝟏𝐅 Stability:- 𝑸𝟏𝑨 (𝑹𝟐) - Stability testing of new drug substances and products. 𝑸𝟏𝑩 - Stability testing: photo stability 𝑸𝟏𝑪 - Stability testing for new dosage forms 𝑸𝟏𝑫 - Bracketing and matrixing designs for stability 𝑸𝟏𝑬 - Evaluation of stability data 𝑸𝟏𝑭 - Stability data package for registration applications in climatic zones iii and iv 𝑸𝟐- Analytical validation (𝑹𝟏) − Validation of analytical procedures: text and methodology (𝑹𝟐)/𝑸𝟏𝟒 EWG - Analytical procedure development and revision of (𝑹𝟏) analytical validation 𝑸𝟑𝑨 − 𝑸𝟑𝑫 Impurities (𝑹𝟐) − Impurities in new drug substances (𝑹𝟐) − Impurities in new drug products (𝑹𝟔) − Maintenance of the guidelines for residual solvents
- 3. (𝑹𝟖) − MaintenanceEWG maintenance of the guideline for residual solvents (𝑹𝟏) − Guidelines for elemental impurities (𝑹𝟐) − EWG maintenance revision of 𝑸𝟑(𝑹𝟏)for cutaneous and transdermal products 𝑸𝟑𝑫 − Training implementation of guidelines for elemental impurities 𝑸𝟑𝑬 𝑰𝒏𝒇𝒐𝒓𝒎𝒂𝒍 𝑾𝑮 − Impurity: Assessment and control of extractables and leachables for pharmaceuticals and biological 𝑸𝟒𝑨 − 𝑸𝟒𝑩 Pharmacopoeias 𝑸𝟒𝑨 − Pharmacopoeial harmonization 𝑸𝟒𝑩 − Evaluation and recommendation of pharmacopoeial texts for use in the ICH regions 𝑸𝟒𝑩Annex 1(𝑹𝟏) − Residue on ignition/ sulphated ash general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Test for extractable volume of parenteral preparations general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Test for particulate contamination: sub- visible particles general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Microbiological examination of non- sterile products: Microbiological enumeration tests general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Microbiological examination of non- sterile products: tests for specified micro-organisms general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Microbiological examination of non- sterile products: Acceptance criteria for pharmaceutical preparation and substances for pharmaceutical use general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Disintegration test general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟔 − Uniformity of dosage unit’s general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟐) − Dissolution test general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟖 (𝑹𝟏) − Sterility test general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 (𝑹𝟏) − Tablet friability general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟏𝟎 (𝑹𝟏) − Polyacrylamide gel electrophoresis general chapter
- 4. 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟏𝟏− Capillary electrophoresis general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟏𝟐 − Analytical sieving general chapter 𝑸𝟒𝑩 𝑨𝒏𝒏𝒆𝒙 𝟏𝟑 − Bulk density and tapped density of powders general chapter 𝑸𝟒𝑩 𝑨𝑵𝑵𝑬𝑿: 𝟏𝟒 − Bacterial endotoxins test general chapter 𝐐𝟒𝐁 FAQS - Frequently asked questions 𝑸𝟓𝑨 − 𝑸𝟓 𝑬 Quality of biotechnologicalproducts 𝑸𝟓𝑨 (𝑹𝟏) - Viral safety evaluation of biotechnology products derived from cell lines of human (or) animal origin 𝑸𝟓𝑨 (𝑹𝟐) EWG - Viral safety evaluation of biotechnology products derived from cell lines of human (or) animal origin 𝑸𝟓𝑩 - Analysis of the expression construct in cells used for production of r- DNA derived protein products 𝑸𝟓𝑪 - Quality of biotechnological products: Stability testing of biotechnological/biological products 𝑸𝟓𝑫 - Derivation and characterization of cell substances used for production of biotechnological/biological products 𝑸𝟓𝑬 - Comparability of biotechnological/biological products subject to changes in their manufacturing process 𝑸𝟔𝑨 − 𝑸𝟔𝑩- Specifications 𝑸𝟔𝑨 - Specifications: Test procedures and acceptance criteria for new drug substances and new drug product: chemical substances. 𝑸𝟔𝑩 - Specifications: Test procedures and acceptance criteria for biotechnological/biological products 𝑸𝟕 - Good manufacturing practice 𝑸𝟕 - Good manufacturing practice guidelines for active pharmaceutical ingredients 𝐐𝟕 Q&AS - Questions and answers: Good manufacturing practice for active pharmaceutical ingredients 𝑸𝟖 - Pharmaceutical development
- 5. (𝑹𝟐) - Pharmaceuticaldevelopment 𝐐𝟖/𝐐𝟗/𝐐𝟏𝟎Q&AS (𝑹𝟒) 𝑸𝟖/𝑸𝟗/ 𝑸𝟏𝟎 - Implementation 𝑸𝟗-Quality Risk management 𝐐𝟖/𝐐𝟗/ 𝐐𝟏𝟎 Q&AS (𝑹𝟒)/𝐐𝟗/𝐐𝟏𝟎 – Implementation 𝑸𝟏𝟎 – Pharmaceutical quality system 𝑸𝟖/𝑸𝟗/(𝑹𝟒) − Implementation 𝐐𝟏𝟏 - Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) 𝐐𝟏𝟐 − Life cyclemanagement 𝐐𝟏𝟐 EWG – Technical and regulatory considerations for pharmaceutical product life cycle management 𝐐𝟏𝟑 - Continuous manufacturing of drug substances and drug products 𝐐𝟏𝟑 EWG - Continuous manufacturing of drug substances and drug products 𝑸𝟏𝟒 - Analytical proceduredevelopment 𝑸𝟐 (𝑹𝟐) /𝑸𝟏𝟒 EWG - Analytical procedure development and revision of analytical validation Good laboratory practices Definition: GLP is a set of principles that provides a frame work intended to assure the quality and clinical laboratory studies that are planned, performed, monitored, archived, and reported to support research or marketing permits for products regulated by Government agencies. The term GLP is most commonly associated with the pharmaceutical industry and the required non clinical animal testing that must be performed prior to approval of new drug products However, GLP applies to many other non-pharmaceutical agents such as food additives, color additives, food contamination limits, food packaging and medical device. This GLP comes under code of federal regulations by USFDA in title 21 which means it is for food and drugs under this part 58 is GLP. • GLP under part 58 have subparts from A to K. • Subpart A- General provisions • Subpart B- Organization and personnel
- 6. • Subpart C-Facilities • Subpart D- Equipment • Subpart E- Testing facilitiesoperation • Subpart F- Test and control articles • Subpart G- Protocol for and conduct of a nonclinical laboratory study • Subpart H-I- Reserved • Subpart J- Records and Reports • Subpart K- Disqualification of testing facilities. Subpart- A General provisions: Scope Definitions Applicability to studies performed under grants and contracts Inspection of a testing facility. Scope: This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products. Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant to sections 406, 408, 409, 502, 503, 505, 506, 510, 512-516, 518-520, 721, and 801 of the Federal Food, Drug, and Cosmetic Act and sections 351 and 354-360F of the Public Health Service Act. Definitions: Test article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any other article subject to regulation under the act or under sections 351 and 354-360F of the Public Health Service Act. Control article means any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed, or water that is administered to the test system in the course of a nonclinical laboratory study for the purpose of establishing a basis for comparison with the test article. Nonclinical laboratory study means in vivo and in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article. Sponsor means: 1. A person who initiates and supports, by provision of financial or other
- 7. resources, a nonclinicallaboratory study; 2. A person who submits a nonclinical study to the Food and Drug Administration in support of an application for a research or marketing permit. • Testing facility means a person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system. • Test system means any animal, plant, microorganism, or subparts thereof to which the test or control article is administered or added for study. • Specimen means any material derived from a test system for examination or analysis • Raw data means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. • Quality assurance unit means any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to quality assurance of nonclinical laboratory studies. • Study director means the individual responsible for the overall conduct of a nonclinical laboratory study. • Batch means a specific quantity or lot of a test or control article that has been characterized. • Study initiation date means the date the protocol is signed by the study director. • Study completion date means the date the final report is signed by the study director. Applicabilityto studies performed under grants and contracts: When a sponsor conducting a nonclinical laboratory study intended to be submitted to or reviewed by the Food and Drug Administration utilizes the services of a consulting laboratory, contractor, or grantee to perform an analysis or other service, it shall notify the consulting laboratory, contractor, or grantee that the service is part of a nonclinical laboratory study that must be conducted in compliance with the provisions of this part. Inspection of a testing facility A testing facility shall permit an authorized employee of the Food and Drug Administration, at reasonable times and in a reasonable manner, to inspect the facility and to inspect (and in the case of records also to copy) all records and specimens required to be maintained regarding studies within the scope of this part. The records inspection and copying requirements shall not apply to quality assurance unit records of findings and problems, or to actions recommended and taken. Subpart – B organization and personnel Each individual engaged in the conduct of or responsible for the
- 8. supervision of anonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions. Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study. There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems. Personnel engaged in a nonclinical laboratory study shall wear clothing appropriate for the duties they perform. Such clothing shall be changed as often as necessary to prevent microbiological, radiological, or chemical contamination of test systems and test and control articles. Any individual found at any time to have an illness that may adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with test systems, test and control articles and any other operation or function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a nonclinical laboratory study. Testing facility management For each nonclinical laboratory study, testing facility management shall: a. Designate a study director as described in §58.33, before the study is initiated. b. Replace the study director promptly if it becomes necessary to do so during the conduct of a study. c. Assure that there is a quality assurance unit as described in §58.35. d. Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. e. Assure that personnel, resources, facilities, equipment, materials, and methodologies are available as scheduled. f. Assure that personnel clearly understand the functions they are to perform. g. Assure that any deviations from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented. Study director For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director. The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control. The study director shall assure that:
- 9. a. The protocol,including any change, is approved as provided by §58.120 and is followed. b. All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified. c. Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. d.Test systems are as specified in the protocol. e. All applicable good laboratory practice regulations are followed. f. All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study. Quality assurance unit A. A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. B. The quality assurance unit shall: 1. Maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director. 2. Maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible. Inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for re inspection. Any problems found during the course of an inspection which are likely to affect study integrity shall be brought to the attention of the study director and management immediately. 3. Periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken. 4. Determine that no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation. 5. Review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study. 6. Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director.
- 10. C. The responsibilitiesand procedures applicable to the quality assurance unit, the records maintained by the quality assurance unit, and the method of indexing such records shall be in writing and shall be maintained. These items including inspection dates, the study inspected, the phase or segment of the study inspected, and the name of the individual performing the inspection shall be made available for inspection to authorized employees of the Food and Drug Administration. D. A designated representative of the Food and Drug Administration shall have access to the written procedures established for the inspection and may request testing facility management to certify that inspections are being implemented, performed, documented, and followed-up in accordance with this paragraph. Subpart C-Facilities General Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study. Animal care facilities A. A testing facility shall have a sufficient number of animal rooms or areas, as needed, to assure proper: 1. Separation of species or test systems. 2. Isolation of individual projects. 3. Quarantine of animals. 4. Routine or specialized housing of animals. B. A testing facility shall have a number of animal rooms or areas separate from those described in paragraph (a) of this section to ensure isolation of studies being done with test systems or test and control articles known to be biohazardous, including volatile substances, aerosols, radioactive materials, and infectious agents. C. Separate areas shall be provided, as appropriate, for the diagnosis, treatment, and control of laboratory animal diseases. These areas shall provide effective isolation for the housing of animals either known or suspected of being diseased, or of being carriers of disease, from other animals. D. When animals are housed, facilities shall exist for the collection and disposal of all animal waste and refuse or for safe sanitary storage of waste before removal from the testing facility. Disposal facilities shall be so provided and operated as to minimize vermin infestation, odors, disease hazards, and environmental contamination. Animal supply facilities There shall be storage areas, as needed, for feed, bedding, supplies, and equipment. Storage areas for feed and bedding shall be separated from areas housing the test systems and shall be protected against infestation or
- 11. contamination. Perishable suppliesshall be preserved by appropriate means. Facilities for handling test and control articles A. As necessary to prevent contamination or mixups, there shall be separate areas for: 1. Receipt and storage of the test and control articles. 2. Mixing of the test and control articles with a carrier, e.g., feed. 3. Storage of the test and control article mixtures. B. Storage areas for the test and/or control article and test and control mixtures shall be separate from areas housing the test systems and shall be adequate to preserve the identity, strength, purity, and stability of the articles and mixtures. Laboratory operation areas Separate laboratory space shall be provided, as needed, for the performance of the routine and specialized procedures required by nonclinical laboratory studies. Specimen and data storage facilities Space shall be provided for archives, limited to access by authorized personnel only, for the storage and retrieval of all raw data and specimens from completed studies. Subpart D - Equipment Equipment design Equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance. Maintenance and calibration of equipment A. Equipment shall be adequately inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and/or standardized. B. The written standard operating procedures required under §58.81(b)(11) shall set forth in sufficient detail the methods, materials, and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration, and/or standardization of equipment, and shall specify, when appropriate, remedial action to be taken in the event of failure or malfunction of equipment. The written standard operating procedures shall designate the person responsible for the performance of each operation. C. Written records shall be maintained of all inspection, maintenance, testing, calibrating and/or standardizing operations. These records, containing the date of the operation, shall describe whether the
- 12. maintenance operations wereroutine and followed the written standard operating procedures. Written records shall be kept of non-routine repairs performed on equipment as a result of failure and malfunction. Such records shall document the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect. Subpart E - Testing Facilities Operation Standard operating procedures A. A testing facility shall have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study. All deviations in a study from standard operating procedures shall be authorized by the study director and shall be documented in the raw data. Significant changes in established standard operating procedures shall be properly authorized in writing by management. B. Standard operating procedures shall be established for, but not limited to, the following: 1. Animal room preparation. 2. Animal care. 3. Receipt, identification, storage, handling, mixing, and method of sampling of the test and control articles. 4. Test system observations. 5. Laboratory tests. 6. Handling of animals found moribund or dead during study. 7. Necropsy of animals or postmortem examination of animals. 8. Collection and identification of specimens. 9. Histopathology. 10. Data handling, storage, and retrieval. 11. Maintenance and calibration of equipment. 12. Transfer, proper placement, and identification of animals. C. Each laboratory area shall have immediately available laboratory manuals and standard operating procedures relative to the laboratory procedures being performed. Published literature may be used as a supplement to standard operating procedures. D. A historical file of standard operating procedures, and all revisions thereof, including the dates of such revisions, shall be maintained. Reagents and solutions All reagents and solutions in the laboratory areas shall be labeled to indicate identity, titer or concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and solutions shall not be used. Animal care A. There shall be standard operating procedures for the housing, feeding, handling, and care of animals.
- 13. B. All newlyreceived animals from outside sources shall be isolated and their health status shall be evaluated in accordance with acceptable veterinary medical practice. C. At the initiation of a nonclinical laboratory study, animals shall be free of any disease or condition that might interfere with the purpose or conduct of the study. If, during the course of the study, the animals contract such a disease or condition, the diseased animals shall be isolated, if necessary. These animals may be treated for disease or signs of disease provided that such treatment does not interfere with the study. The diagnosis, authorizations of treatment, description of treatment, and each date of treatment shall be documented and shall be retained. D. Warm-blooded animals, excluding suckling rodents, used in laboratory procedures that require manipulations and observations over an extended period of time or in studies that require the animals to be removed from and returned to their home cages for any reason (e.g., cage cleaning, treatment, etc.), shall receive appropriate identification. All information needed to specifically identify each animal within an animal-housing unit shall appear on the outside of that unit. E. Animals of different species shall be housed in separate rooms when necessary. Animals of the same species, but used in different studies, should not ordinarily be housed in the same room when inadvertent exposure to control or test articles or animal mixup could affect the outcome of either study. If such mixed housing is necessary, adequate differentiation by space and identification shall be made. F. Animal cages, racks and accessory equipment shall be cleaned and sanitized at appropriate intervals. G. Feed and water used for the animals shall be analyzed periodically to ensure that contaminants known to be capable of interfering with the study and reasonably expected to be present in such feed or water are not present at levels above those specified in the protocol. Documentation of such analyses shall be maintained as raw data. H. Bedding used in animal cages or pens shall not interfere with the purpose or conduct of the study and shall be changed as often as necessary to keep the animals dry and clean. I. If any pest control materials are used, the use shall be documented. Cleaning and pest control materials that interfere with the study shall not be used. Subpart F - Test and Control Articles Test and control article characterization A. The identity, strength, purity, and composition or other characteristics which will appropriately define the test or control article shall be determined for each batch and shall be documented. Methods of synthesis, fabrication, or derivation of the test and control articles shall be documented by the sponsor or the testing facility. In those cases where marketed products are used as control articles, such products will be characterized by their labeling. B. The stability of each test or control article shall be determined by the testing facility or by the sponsor either:
- 14. 1. Before studyinitiation, or 2. Concomitantly according to written standard operating procedures, which provide for periodic analysis of each batch. C. Each storage container for a test or control article shall be labeled by name, chemical abstract number or code number, batch number, expiration date, if any, and, where appropriate, storage conditions necessary to maintain the identity, strength, purity, and composition of the test or control article. Storage containers shall be assigned to a particular test article for the duration of the study. D. For studies of more than 4 weeks' duration, reserve samples from each batch of test and control articles shall be retained for the period of time provided by §58.195. Test and control article handling Procedures shall be established for a system for the handling of the test and control articles to ensure that: a. There is proper storage. b. Distribution is made in a manner designed to preclude the possibility of contamination, deterioration, or damage. c. Proper identification is maintained throughout the distribution process. d. The receipt and distribution of each batch is documented. Such documentation shall include the date and quantity of each batch distributed or returned. Mixtures of articles with carriers A. For each test or control article that is mixed with a carrier, tests by appropriate analytical methods shall be conducted: 1. To determine the uniformity of the mixture and to determine, periodically, the concentration of the test or control article in the mixture. 2. To determine the stability of the test and control articles in the mixture as required by the conditions of the study either: a. Before study initiation, or b. Concomitantly according to written standard operating procedures which provide for periodic analysis of the test and control articles in the mixture. B. [Reserved]. C. Where any of the components of the test or control article carrier mixture has an expiration date, that date shall be clearly shown on the container. If more than one component has an expiration date, the earliest date shall be show. Subpart G - Protocol for and Conduct of a Nonclinical Laboratory Study Protocol A. Each study shall have an approved written protocol that clearly indicates the objectives and all methods for the conduct of the study. The protocol shall contain, as applicable, the following information: 1. A descriptive title and statement of the purpose of the study. 2. Identification of the test and control articles by name, chemical abstract number, or code number.
- 15. 3. The nameof the sponsor and the name and address of the testing facility at which the study is being conducted. 4. The number, body weight range, sex, source of supply, species, strain, substrain, and age of the test system. 5. The procedure for identification of the test system. 6. A description of the experimental design, including the methods for the control of bias. 7. A description and/or identification of the diet used in the study as well as solvents, emulsifiers, and/or other materials used to solubilize or suspend the test or control articles before mixing with the carrier. The description shall include specifications for acceptable levels of contaminants that are reasonably expected to be present in the dietary materials and are known to be capable of interfering with the purpose or conduct of the study if present at levels greater than established by the specifications. 8. Each dosage level, expressed in milligrams per kilogram of body weight or other appropriate units, of the test or control article to be administered and the method and frequency of administration. 9. The type and frequency of tests, analyses, and measurements to be made. 10. The records to be maintained. 11. The date of approval of the protocol by the sponsor and the dated signature of the study director. 12. A statement of the proposed statistical methods to be used. B. All changes in or revisions of an approved protocol and the reasons therefore shall be documented, signed by the study director, dated, and maintained with the protocol. Conduct of a nonclinical laboratory study A. The nonclinical laboratory study shall be conducted in accordance with the protocol. B. The test systems shall be monitored in conformity with the protocol. C. Specimens shall be identified by test system, study, nature, and date of collection. This information shall be located on the specimen container or shall accompany the specimen in a manner that precludes error in the recording and storage of data. D. Records of gross findings for a specimen from postmortem observations should be available to a pathologist when examining that specimen histo pathologically. E. All data generated during the conduct of a nonclinical laboratory study, except those that are generated by automated data collection systems, shall be recorded directly, promptly, and legibly in ink. All data entries shall be dated on the date of entry and signed or initialed by the person entering the data. Any change in entries shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall be dated and signed or identified at the time of the change. In automated data collection systems, the individual responsible for direct data input shall be identified at the time of data input. Any change in automated data entries shall be made so as not to obscure the original
- 16. entry, shall indicatethe reason for change, shall be dated, and the responsible individual shall be identified. Subparts H - I [Reserved] Subpart J - Records and Reports Reporting of nonclinical laboratory study results A. A final report shall be prepared for each nonclinical laboratory study and shall include, but not necessarily be limited to, the following: 1. Name and address of the facility performing the study and the dates on which the study was initiated and completed. 2. Objectives and procedures stated in the approved protocol, including any changes in the original protocol. 3. Statistical methods employed for analyzing the data. 4. The test and control articles identified by name, chemical abstracts number or code number, strength, purity, and composition or other appropriate characteristics. 5. Stability of the test and control articles under the conditions of administration. 6. A description of the methods used. 7. A description of the test system used. Where applicable, the final report shall include the number of animals used, sex, body weight range, source of supply, species, strain and substrain, age, and procedure used for identification. 8. A description of the dosage, dosage regimen, route of administration, and duration. 9. A description of all circumstances that may have affected the quality or integrity of the data. 10. The name of the study director, the names of other scientists or professionals, and the names of all supervisory personnel, involved in the study. 11. A description of the transformations, calculations, or operations performed on the data, a summary and analysis of the data, and a statement of the conclusions drawn from the analysis. 12. The signed and dated reports of each of the individual scientists or other professionals involved in the study. 13. The locations where all specimens, raw data, and the final report are to be stored. 14. The statement prepared and signed by the quality assurance unit as described in §58.35(b)(7). B. The final report shall be signed and dated by the study director. C. Corrections or additions to a final report shall be in the form of an amendment by the study director. The amendment shall clearly identify that part of the final report that is being added to or corrected and the reasons for the correction or addition, and shall be signed and dated by the person responsible storage and retrieval of records and data. a. All raw data, documentation, protocols, final reports, and specimens (except those specimens obtained from mutagenicity tests and wet
- 17. specimens of blood,urine, feces, and biological fluids) generated as a result of a nonclinical laboratory study shall be retained. b. There shall be archives for orderly storage and expedient retrieval of all raw data, documentation, protocols, specimens, and interim and final reports. Conditions of storage shall minimize deterioration of the documents or specimens in accordance with the requirements for the time period of their retention and the nature of the documents or specimens. A testing facility may contract with commercial archives to provide a repository for all material to be retained. Raw data and specimens may be retained elsewhere provided that the archives have specific reference to those other location. c. An individual shall be identified as responsible for the archives. d. Only authorized personnel shall enter the archives. e. Material retained or referred to in the archives shall be indexed to permit expedient retrieval. Retention of records A. Record retention requirements set forth in this section do not supersede the record retention requirements of any other regulations in this chapter. B. Except as provided in paragraph C of this section, documentation records, raw data and specimens pertaining to a nonclinical laboratory study and required to be made by this part shall be retained in the archive(s) for whichever of the following periods is shortest: 1. A period of at least 2 years following the date on which an application for a research or marketing permit, in support of which the results of the nonclinical laboratory study were submitted, is approved by the Food and Drug Administration. This requirement does not apply to studies supporting investigational new drug applications (IND's) or applications for investigational device exemptions (IDE's), records of which shall be governed by the provisions of paragraph A (2) of this section. 2. A period of at least 5 years following the date on which the results of the nonclinical laboratory study are submitted to the Food and Drug Administration in support of an application for a research or marketing permit. 3. In other situations (e.g., where the nonclinical laboratory study does not result in the submission of the study in support of an application for a research or marketing permit), a period of at least 2 years following the date on which the study is completed, terminated, or discontinued. C. Wet specimens (except those specimens obtained from mutagenicity tests and wet specimens of blood, urine, feces, and biological fluids), samples of test or control articles, and specially prepared material, which are relatively fragile and differ markedly in stability and quality during storage, shall be retained only as long as the quality of the preparation affords evaluation. In no case shall retention be required for longer periods than those set forth in paragraphs A and B of this section. D. The master schedule sheet, copies of protocols, and records of quality assurance inspections, as required by §58.35(c) shall be maintained by the quality assurance unit as an easily accessible system of records for
- 18. the period oftime specified in paragraphs A and B of this section. E. Summaries of training and experience and job descriptions required to be maintained by §58.29 B may be retained along with all other testing facility employment records for the length of time specified in paragraphs A and B of this section. F. Records and reports of the maintenance and calibration and inspection of equipment, as required by §58.63 B and C, shall be retained for the length of time specified in paragraph B of this section. G. Records required by this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. H. If a facility conducting nonclinical testing goes out of business, all raw data, documentation, and other material specified in this section shall be transferred to the archives of the sponsor of the study. The Food and Drug Administration shall be notified in writing of such a transfer. Subpart K - Disqualification of Testing Facilities Purpose A. The purposes of disqualification are: 1. To permit the exclusion from consideration of completed studies that were conducted by a testing facility which has failed to comply with the requirements of the good laboratory practice regulations until it can be adequately demonstrated that such noncompliance did not occur during, or did not affect the validity or acceptability of data generated by, a particular study; and 2. To exclude from consideration all studies completed after the date of disqualification until the facility can satisfy the Commissioner that it will conduct studies in compliance with such regulations. a. The determination that a nonclinical laboratory study may not be considered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulation to submit the results of the study to the Food and Drug Administration. Grounds for disqualification The Commissioner may disqualify a testing facility upon finding all of the following: A. The testing facility failed to comply with one or more of the regulations set forth in this part (or any other regulations regarding such facilities in this chapter); B. The noncompliance adversely affected the validity of the nonclinical laboratory studies; and C. Other lesser regulatory actions (e.g., warnings or rejection of individual studies) have not been or will probably not be adequate to achieve compliance with the good laboratory practice regulations. Notice of and opportunity for hearing on proposed disqualification A. Whenever the Commissioner has information indicating that grounds exist under §58.202 which in his opinion justify disqualification of a
- 19. testing facility, hemay issue to the testing facility a written notice proposing that the facility be disqualified. B. A hearing on the disqualification shall be conducted in accordance with the requirements for a regulatory hearing set forth in part 16 of this chapter. Final order on disqualification A. If the Commissioner, after the regulatory hearing, or after the time for requesting a hearing expires without a request being made, upon an evaluation of the administrative record of the disqualification proceeding, makes the findings required in §58.202, he shall issue a final order disqualifying the facility. Such order shall include a statement of the basis for that determination. Upon issuing a final order, the Commissioner shall notify (with a copy of the order) the testing facility of the action. B. If the Commissioner, after a regulatory hearing or after the time for requesting a hearing expires without a request being made, upon an evaluation of the administrative record of the disqualification proceeding, does not make the findings required in §58.202, he shall issue a final order terminating the disqualification proceeding. Such order shall include a statement of the basis for that determination. Upon issuing a final order the Commissioner shall notify the testing facility and provide a copy of the order. Actions upon disqualification A. Once a testing facility has been disqualified, each application for a research or marketing permit, whether approved or not, containing or relying upon any nonclinical laboratory study conducted by the disqualified testing facility may be examined to determine whether such study was or would be essential to a decision. If it is determined that a study was or would be essential, the Food and Drug Administration shall also determine whether the study is acceptable, notwithstanding the disqualification of the facility. Any study done by a testing facility before or after disqualification may be presumed to be unacceptable, and the person relying on the study may be required to establish that the study was not affected by the circumstances that led to the disqualification, e.g., by submitting validating information. If the study is then determined to be unacceptable, such data will be eliminated from consideration in support of the application; and such elimination may serve as new information justifying the termination or withdrawal of approval of the application. B. No nonclinical laboratory study begun by a testing facility after the date of the facility's disqualification shall be considered in support of any application for a research or marketing permit, unless the facility has
- 20. been reinstated under§58.219.The determination that a study may not be considered in support of an application for a research or marketing permit does not, however, relieve the applicant for such a permit of any obligation under any other applicable regulation to submit the results of the study to the Food and Drug Administration. Public disclosure of information regarding disqualification A. Upon issuance of a final order disqualifying a testing facility under §58.206(a), the Commissioner may notify all or any interested persons. Such notice may be given at the discretion of the Commissioner whenever he believes that such disclosure would further the public interest or would promote compliance with the good laboratory practice regulations set forth in this part. Such notice, if given, shall include a copy of the final order issued under §58.206(a) and shall state that the disqualification constitutes a determination by the Food and Drug Administration that nonclinical laboratory studies performed by the facility will not be considered by the Food and Drug Administration in support of any application for a research or marketing permit. If such notice is sent to another Federal Government agency, the Food and Drug Administration will recommend that the agency also consider whether or not it should accept nonclinical laboratory studies performed by the testing facility. If such notice is sent to any other person, it shall state that it is given because of the relationship between the testing facility and the person being notified and that the Food and Drug Administration is not advising or recommending that any action be taken by the person notified. B. A determination that a testing facility has been disqualified and the administrative record regarding such determination are disclosable to the public under part 20 of this chapter. Alternative or additional actions to disqualification A. Disqualification of a testing facility under this subpart is independent of, and neither in lieu of nor a precondition to, other proceedings or actions authorized by the act. The Food and Drug Administration may, at any time, institute against a testing facility and/or against the sponsor of a nonclinical laboratory study that has been submitted to the Food and Drug Administration any appropriate judicial proceedings (civil or criminal) and any other appropriate regulatory action, in addition to or in lieu of, and prior to, simultaneously with, or subsequent to, disqualification. The Food and Drug Administration may also refer the matter to another Federal, State, or local government law enforcement or regulatory agency for such action as that agency deems appropriate. B. The Food and Drug Administration may refuse to consider any particular nonclinical laboratory study in support of an application for a research or marketing permit, if it finds that the study was not
- 21. conducted in accordancewith the good laboratory practice regulations set forth in this part, without disqualifying the testing facility that conducted the study or undertaking other regulatory action. Suspension or termination of a testing facility by a sponsor Termination of a testing facility by a sponsor is independent of, and neither in lieu of nor a precondition to, proceedings or actions authorized by this subpart. If a sponsor terminates or suspends a testing facility from further participation in a nonclinical laboratory study that is being conducted as part of any application for a research or marketing permit that has been submitted to any Center of the Food and Drug Administration (whether approved or not), it shall notify that Center in writing within 15 working days of the action; the notice shall include a statement of the reasons for such action. Suspension or termination of a testing facility by a sponsor does not relieve it of any obligation under any other applicable regulation to submit the results of the study to the Food and Drug Administration. Reinstatement of a disqualified testing facility A testing facility that has been disqualified may be reinstated as an acceptable source of nonclinical laboratory studies to be submitted to the Food and Drug Administration if the Commissioner determines, upon an evaluation of the submission of the testing facility, that the facility can adequately assure that it will conduct future nonclinical laboratory studies in compliance with the good laboratory practice regulations set forth in this part and, if any studies are currently being conducted, that the quality and integrity of such studies have not been seriously compromised. A disqualified testing facility that wishes to be so reinstated shall present in writing to the Commissioner reasons why it believes it should be reinstated and a detailed description of the corrective actions it has taken or intends to take to assure that the acts or omissions which led to its disqualification will not recur. The Commissioner may condition reinstatement upon the testing facility being found in compliance with the good laboratory practice regulations upon an inspection. If a testing facility is reinstated, the Commissioner shall so notify the testing facility and all organizations and persons who were notified, under §58.213 of the disqualification of the testing facility. A determination that a testing facility has been reinstated is disclosable to the public under part 20 of this chapter. Good manufacturing practices Introduction: This document (Guide) is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity that they purport or are represented to possess. In this Guide “manufacturing” is defined to include all operations
- 22. of receipt ofmaterials, production, packaging, repackaging, labelling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this Guide the term “should” indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance. For the purposes of this Guide, the terms “current good manufacturing practices” and “good manufacturing practices” are equivalent. Scope: This Guide applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidelines for drug (medicinal) products as defined by local authorities. This Guide covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, by recovery from natural sources, or by any combination of these processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18. This Guide excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. An “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structure. Quality management Principles: Quality should be the responsibility of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
- 23. The personsauthorized to release intermediates and APIs should be specified. All quality related activities should be recorded at the time they are performed. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation). Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related complaints, recalls, regulatory actions, etc.). Responsibilities of the Quality Unit(s) The quality unit(s) should be involved in all quality-related matters. The quality unit(s) should review and approve all appropriate quality- related documents. The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include but not necessarily be limited to: 1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company; 2. Establishing a system to release or reject raw materials, intermediates, packaging and labelling materials; 3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution; 4. Making sure that critical deviations are investigated and resolved; 5. Approving all specifications andmaster production instructions; 6. Approving all procedures impacting the quality of intermediates or APIs; 7. Making sure that internal audits (self-inspections) are performed; 8. Approving intermediate and API contract manufacturers; 9. Approving changes that potentially impact intermediate or API quality; 10. Reviewing and approving validation protocols and reports; 11. Making sure that quality related complaints are investigated and resolved; 12. Making sure that effective systems are used for maintaining and calibrating critical equipment; 13. Making sure that materials are appropriately tested and the results are reported; 14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where
- 24. appropriate; and 15. Performingproduct quality reviews (as defined in Section 2.5). Responsibility for Production Activities The responsibility for production activities should be described in writing, and should include but not necessarily be limited to: 1. Preparing, reviewing, approving and distributing the instructions for the production of intermediates or APIs according to written procedures; 2. Producing APIs and, when appropriate, intermediates according to preapproved instructions; 3. Reviewing all production batch records and ensuring that these are completed and signed; 4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded; 5. Making sure that production facilities are clean and when appropriate disinfected 6. Making sure that the necessary calibrations are performed and records kept; 7. Making sure that the premises and equipment are maintained and records kept; 8. Making sure that validation protocols and reports are reviewed and approved; 9. Evaluating proposed changes in product, process or equipment; and 10. Making sure that new and, when appropriate, modified facilities and equipment are qualified. Internal Audits (Self Inspection) In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner Product Quality Review Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: A review of critical in-process control and critical API test results A review of all batches that failed to meet established specification(s); A review of all critical deviations or non- conformances and related investigations; A review of any changes carried out to the processes or analytical methods; A review of results of the stability monitoring program; A review of all quality-related returns, complaints and recalls; and
- 25. A reviewof adequacy of corrective actions. Personnel: There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs. The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed. Personnel Hygiene Personnel should practice good sanitation and health habits Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination. Personnel should avoid direct contact with intermediates or APIs. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs. Building and facilities Design and Construction: Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stageof manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination. Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.
- 26. The flowof materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination. There should be defined areas or other control systems for the following activities: Receipt, identification, sampling, and quarantine of incoming materials, pending release or rejection; Quarantine before release or rejection of intermediates and APIs; Sampling of intermediates and APIs Holding rejected materials before further disposition (e.g., return, reprocessing or destruction); Storage of released materials; Production operations; Packaging and labelling operations; and Laboratory operations.
- 27. 1 cGMP GUIDELINES ACCORDINGTO SCHEDULE M, USFDA (INCLUSIVE OF CDER AND CBER) PHARMACEUTICAL INSPECTION CONVENTION (PIC), WHO AND EMEA GMP GUIDELINES AS PER SCHEDULE M GMP: • GMP is that part of Quality assurance which ensures that the products are consistently manufactured and controlled to the Quality standards appropriate to their intended use. • "GMP" - A set of principles and procedures which, when followed by manufacturers for therapeutic goods, helps ensure that the products manufactured will have the required quality. CGMP : • Usually see “cGMP” – where c = current, to emphasize that the expectations are dynamic . GMP COVERS.. • GMPs ➢ Organisation and Personnel ➢ Buildings and Facilities ➢ Equipment ➢ Control of Components, Containers and Closures ➢ Production and Process control ➢ Holding and Distribution ➢ Laboratory Controls ➢ Records and Reports ➢ Returned and salvaged products • All aspects of production; from the starting materials, premises and equipment to the training and personal hygiene of staff . • Detailed, written procedures are essential for each process that could affect the quality of the finished product. • There must be systems to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process - every time a product is made.
- 28. 2 DRUG AND COSMETICACT IN INDIA • In 1937 a Bill was introduced in the Central Legislative Assembly to give effect to the recommendations of the Drugs Enquiry Committee to regulate the import of drugs into British India. • Provincial Governments got the resolution passed from the Provincial Legislatures and sent them to the Central Government for getting through the Bill to regulate the import, manufacture, distribution and sale of Drugs and Cosmetics. There upon the Drugs and Cosmetics Bill was introduced in the Central Legislative Assembly. • The Drugs and Cosmetics Bill was passed by the Central Legislative Assembly and it received the assent of the Governor General on 10th April, 1940 and thus became the Drugs and Cosmetics Act, 1940 (23 of 1940). • An Act to regulate the import, manufacture, distribution and sale of drugs [(Note: Ins. by Act 21 of 1962, sec.2 (w.e.f. 27-7-1964)) and cosmetics]. DRUG AND COSMETIC ACT 1940 SCHEDULE M 1. General Requirements : a) Location and surroundings- The factory building(s) for manufacture of drugs shall be so situated that it avoid risk of contamination from external environmental including open sewage, drain, public lavatory. b) Building and premises- They shall conform to the conditions laid down in the Factories Act, 1948 (63 of 1948) The premises used for manufacturing, processing, warehousing, packaging labelling and testing purposes shall be: i. compatible with other drug manufacturing operations. ii. adequately working space to avoid the risk of mix-up between different (b) avoid the possibilities of contamination and cross contamination. iii. designed / constructed / maintained to prevent entry of insects, pests, birds, and rodents. iv. well lighted, effectively ventilated, with proper Air Handling Units. c) Water System-
- 29. 3 ➢ There shallbe validated system for treatment of water in accordance with standards specified by the Bureau of Indian Standards or Local Municipality or Pharmacopoeial specification. ➢ Water shall be stored in tanks, which do not adversely affect quality of water and ensure freedom from microbiological growth. ➢ The tank shall be cleaned periodically and records maintained by the licensee in this behalf. d) Disposal of Waste- i. The disposal of sewage and effluents (solid, liquid and gas) be in conformity with the requirements of Environment Pollution Control Board. ii. All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 1996. iii. Records shall be maintained for all disposal of waste. iv. Provisions shall be made for the proper and safe storage of waste materials awaiting disposal. 2. Warehousing Area : • Adequate areas to allow orderly warehousing of various categories of materials. • Good storage conditions. • There shall be a separate sampling area in the warehousing area for active raw materials and excipients. • Segregation shall be provided for the storage of rejected, recalled or returned materials or products. • Highly hazardous, poisonous and explosive materials shall be stored in safe and secure areas. 3. Production Area : • Separate dedicated and self-contained facilities shall be made available for the production of sensitive pharmaceutical products. • Orderly and logical positioning of equipment and materials and movement of personnel and to minimize risk of omission or wrong application of any manufacturing and control measures. • Services lines shall preferably be identified by colours and the nature of the supply and direction of the flow shall be marked/indicated.
- 30. 4 4. Ancillary Areas: • Ancillary Areas 4.1 Rest and refreshment rooms shall be separate from other areas. Facilities for changing, storing clothes and for washing and toilet purposes shall be adequate for the number of users. • Animal houses shall be those as prescribed in Rule 150-C(3) of the Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes. 5. Quality Control Area : • QC Lab. shall be independent of the production areas. Separate areas each for physico-chemical, biological, microbiological or radio-isotope analysis. • Adequate space shall be provided to avoid mix-ups and proper storage for test samples, retained samples, reference standards, reagents and records. 6. Personnel : • Qualifications and practical experience in the relevant field. • Written duties of technical and Quality Control personnel shall be laid and following strictly. • Number of personnel employed shall be adequate and in direct proportion to the workload. 7. Health, Clothing and Sanitation of Workers : • Prior to employment, all personnel, shall undergo medical examination and a periodically examination is carried out, records are also maintained. • Proper training shall be given to all employees to maintain personnel hygiene and adequate facilities for personal cleanliness. • Smoking, eating, drinking, chewing , food, drink and personal medicines not permitted in production, laboratory, storage area. 8. Manufacturing Operations and Controls : • All manufacturing operations shall be carried out under the supervision of technical staff approved by the Licensing Authority. • Precautions against mix-up and cross-contamination-
- 31. 5 i. By properair handling system, pressure differential, segregation, status labelling and cleaning. Proper records and SOP there of shall be maintained. ii. Processing of sensitive drugs and cytotoxic substances in segregated areas. iii. Proper labelling of materials and equipments. iv. Packaging lines shall be independent and adequately segregated. v. All printing and overprinting shall be authorized in writing. vi. The manufacturing environment maintained at the required levels of temperature, humidity and cleanliness. 9. Sanitation in the Manufacturing Premises : • The manufacturing premises shall be cleaned and in an orderly manner. • The manufacturing areas shall not be used for other operations. • A routine sanitation program shall be drawn up which shall be properly recorded and which indicate- i. specific areas to be cleaned and cleaning intervals. ii. cleaning procedure to be followed. iii. personnel assigned to and responsible for the cleaning operation. 10. Raw Materials : • Keeping an inventory of all raw materials to be used and maintain records as per Schedule U. • Authorized staff who examine each consignment for its integrity. • Labelling with the following information: i. name of the product and the internal code reference and analytical reference number. ii. manufacturer’s name, address and batch number. iii. the status of the contents (e.g. quarantine, under test, released, approved, rejected); and iv. the manufacturing date, expiry date and re-test date. 11. Equipment : • Equipment shall be located, designed, constructed, adapted to suit the operations and logbook is maintained.
- 32. 6 • Equipment shallbe calibrated and checked on a scheduled basis in accordance to SOP and maintain records. • Equipment shall be inert and defective are removed and labelled. 12. Documentation and Records : Documentation and Records. Documentation is an essential part of the Quality assurance system and Its aim is to define the specifications for all materials, method of manufacture and control to release a batch of drug for sale. • Documents shall be approved, signed and dated by authorized persons. • Documents shall specify : the title, nature and purpose laid out in an orderly fashion kept up to date. • SOP shall be retained for at least one year after the expiry date of the finished product. • Data may be recorded by electronic data processing systems but Master Formulae and detailed operating procedures relating to the system in use shall also be available in a hard copy to facilitate checking of the accuracy of the records. 13. Labels and Other Printed Materials : Labels are necessary for identification of the drugs and their use. The Printing shall be done in bright colours and in a legible manner. The label shall carry all the prescribed details about the product. • All containers and equipment shall bear appropriate labels. • Prior to release, all labels for containers shall be examined by the QC Department. • Records of receipt of all labelling and packaging materials shall be maintained and unused coded and damaged labels and packaging materials shall be destroyed and recorded. 14. Quality Assurance : It is a wide-ranging concept concerning all matters that individually or collectively influence the quality of a product. It shall ensure that: • the pharmaceutical products are designed and developed in a way that takes account of the requirement of GMP ,GLP and GCP. • adequate controls on starting materials, intermediate products, and other in-process controls, calibrations, and validations are carried out. • products are released after authorized persons have certified.
- 33. 7 15. Self-inspection andQuality Audit : It is for the assessment of all or part of a system with the specific purpose of improving it. • The program is designed to detect shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections shall be performed routinely and on specific occasions. The team responsible for self-inspection shall consist of independent, experienced, qualified persons from within or outside the company who can evaluate the implementation of GMP objectively; all recommendations for corrective action shall be implemented. • The procedure for self-inspection shall be documented indicating self- inspection results; evaluation, conclusions and recommended corrective actions with effective follow up program. 16. Quality Control System : Quality control shall be concerned with sampling, specifications, testing, documentation, release procedures. Materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory. • QC lab should have qualified and experience staff. • QC lab. may be divided into Chemical, Instrumentation, Microbiological and Biological testing. • The QC department shall conduct stability studies of the products to ensure and assign their shell life . All records of such studies shall be maintained. • All instruments shall be calibrated and validated before adopted for routine testing. • Pharmacopoeia, reference standards, working standards, references spectra, other reference materials and technical books, as required, shall be available in the QC Laboratory. 17. Specification : • For raw materials and packaging materials. They shall include: i. the designated name and internal code reference. ii. reference, if any, to a pharmacopoeial monograph. iii. qualitative and quantitative requirements with acceptance limits. iv. name and address of manufacturer or supplier and original manufacturer of the material.
- 34. 8 v. specimen ofprinted material. vi. directions for sampling and testing or reference to procedures. vii. storage conditions and viii. maximum period of storage before re-testing. • For Finished Products: Appropriate specifications for finished products shall include: - i. the designated name of the product and the code reference. ii. the formula or a reference to the formula and the pharmacopoeial reference. iii. directions for sampling and testing or a reference to procedures. iv. a description of the dosage form and package details. v. the storage conditions and precautions, where applicable. vi. the shelf-life. 18. Master Formula Records : There shall be Master Formula records relating to all manufacturing procedures for each product and batch size. These shall be prepared and endorsed by head of production and quality control. The Master Formula shall include: • the name of the product together with product reference code relating to its specifications. • the patent or proprietary name of the product along with the generic name, a description of the dosage form, strength, composition of the product and batch size. • name, quantity, and reference number of all the starting materials to be used. • A statement of the processing location and the principal equipment to be used. • detailed stepwise processing instructions and the time taken for each step. • the instructions for in-process control with their limits. • the requirements for storage conditions of the products, including the container, labelling and special storage conditions where applicable. • any special precautions to be observed; and • packing details and specimen labels. 19. Packing Records : There shall be authorised packaging instructions for each product, pack size and type . These shall include or have a reference to the following: -
- 35. 9 • name ofthe product. • description of the dosage form, strength and composition. • the pack size expressed in terms of the number of doses, weight or volume of the product in the final container. • special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before the operations begin. 20. Batch Processing Records : A batch packaging record shall be kept for each batch or part batch processed. It shall be based on the relevant parts of the packaging instructions, and the method of preparation of such records shall be designed to avoid transcription errors. 21. Batch Processing Records: There shall be Batch Processing Record for each product. It shall be based on the relevant parts of the currently approved Master Formula. The method of preparation of such records included in the Master Formula shall be designed to avoid transcription errors. 22. Standard Operating Procedures (SOPs) : There shall be written SOP and records for the: • Receipt of each delivery of raw, primary and printed material. • Internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate. • For each instrument and equipment. • Sampling which include the person(s) authorized to take the samples. • Describing the details of the batch numbering which ensure that each batch of intermediate, bulk or finished product is identified with a specific batch number. • Testing materials and products at different stages of manufacture, describing the methods and equipment to be used. 23. Reference Samples : • Each lot of every active ingredient, in a quality sufficient to carryout all the tests, except sterility and pyrogens / Bacterial Endotoxin Test, shall be retained for a period of 3 months after the date of expiry of the last batch produced from that active ingredient.
- 36. 10 • Samples offinished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed. 24. Reprocessing and Recoveries : • When reprocessing is necessary, written procedures shall be established and approved by quality assurance department. • Recovery of product residue may be carried out, if permitted, in the master production. 25. Distribution Records : Records of distribution shall be maintained in a manner such that finished batch of a drug can be traced to the retain level to facilitate prompt and complete recall of the batch, if and when necessary. 26. Validation and Process Validation : • Validation studies shall be an essential part of GMP and shall be conducted as per the pre-defined protocols. • A written report summarizing recorded results and conclusions shall be prepared, documented and maintained. • When any new Master Formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. • Significant changes to the manufacturing process, including any changes in equipment or materials shall be validated. 27. Product Recalls : • A prompt and effective product recall system of defective products shall be devised for timely information of al concerned stockist, wholesalers, suppliers, up to the retail level within the shortest period. • The license may make use of both print and electronic media in this regard. 28. Complaints and Adverse Reactions : • All complaints there of concerning product quality shall be carefully reviewed and recorded according to written procedures. • Each complaint shall be investigated /evaluated by the designated personnel of the company and records of investigation and remedial action taken thereof shall be maintained.
- 37. 11 • Reports ofserious adverse drug reactions resulting from the use of a drug shall be forthwith reported to the concerned licensing authority. 29. Site Master File : The licensee shall prepare a succinct document in the form of Site Master File containing specific and factual GMP about the production and/or control of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following: - • General information • Personnel. • Premises. • Equipment. • Sanitation. • Documentation. • Production. • Quality Control. • Loan licence manufacture and licensee. • Distribution, complaints and product recall. • Export of drugs. cGMPs According to US FDA INTRODUCTION: Good Manufacturing Practice (GMP) ensures that quality is built into the organisation and processes involved in manufacture GMP covers all aspects of “manufacture” including collection, transportation, processing, storage, quality control and delivery of the finished product. • It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product Protect the integrity and quality of manufactured product intended for human use. PRINCIPLES OF cGMP: • Design and construct the facilities and equipments properly
- 38. 12 •Follow written proceduresand Instructions •Document work •Validate work • Monitor facilities and equipment •Write step by step operating procedures and work on instructions •Design, develop and demonstrate job competence •Protect against contamination •Control components and product related processes •Conduct planned and periodic audits LIST OF IMPORTANT DOCUMENTS IN cGMP: •Policies •SOPs •Specifications •MFR (Master Formula Record) •Batch Package Records (BMR) •Manuals •Master plans/ files •Validation protocols •Forms and Formats •Records What are CGMP?
- 39. 13 • c GMPscover a broad range of methods, practices and principles that are implemented and documented during product development to ensure consistent manufacture of quality products •the cGMP assures the identity, strength, quality, and purity of drug products is built into the design and manufacturing process at every step. •" GMP is a dynamic concept and practice. Staying “current” is driven by technology, improved practices and regulatory issues. USFDA REGULATIONS : •The requirements for compliance to cGMP are lain down in the following code of Federal Regulation (21CFR). •21 CFR Part 210 cGMP in manufacturing, processing, packing, or holding of the drugs; General 210.1 Status of current good manufacturing practice regulations. 210.2 Applicability of current good manufacturing practice regulations. 210.3 Definitions. •21 CFR Part 211 cGMP for finished pharmaceutical. •21 CFR Part 610 – Current Good Manufacture of Biological Products •21 CFR Part 820 – Current Good Manufacturing Practices for Devices Why are cGMPs so important? •A consumer usually cannot detect that a drug product is safe. While cGMPs require testing, testing alone is not adequate to ensure quality. •FDA will often use these reports to identify sites for which an inspection or investigation is needed.
- 40. 14 Essential elements ofcGMP are: •Good Documentation Practices •Training •Facilities and Equipment Management •Change Control Systems •Operations Oversight and Management CGMP for finished pharmaceuticals: part 211 •Subpart A - General Provision •Subpart B - Organization & Personnel •Subpart C - Building & Facilities •Subpart D – Equipment •Subpart E - Control of Components & Drug Product Containers & Closures •Subpart F - Production & Process Control •Subpart G - Packaging & Labeling Control •Subpart H - Handling & Distribution •Subpart I - Laboratory Control •Subpart J - Records & Reports •Subpart K - Returned & Salvaged Drugs Subpart A-General Provisions 211.1 Scope: (a) The minimum cGMP for preparation of drug products for administration to humans or animals.
- 41. 15 (b) The requirementsin this part shall not be enforced for OTC drug products and all their ingredients are ordinarily marketed and consumed as human foods. 211.3 Definitions: The definitions and interpretations contained in section 201 of the act shall be applicable to such terms when used in this part and in Parts 211 Subpart B-Organization and Personnel 211.22 Responsibilities of quality control unit: (a) There shall be a QC unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling . And records. (b) The responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product. 211.25 Personnel qualifications: (a) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it is represented to possess. 211.28 Personnel responsibilities: (a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. (b) Personnel shall practice good sanitation and health habits. 211.34 Consultants: It advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide. Subpart C-Buildings and Facilities
- 42. 16 211.42 Design andconstruction features: (a) Building shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. (b) adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling , in-process materials, or drug products, and to prevent contamination. 211.44 Lighting: Adequate lighting shall be provided in all areas. 211.46 Ventilation, air filtration, air heating and cooling: (a) Adequate ventilation shall be provided. (b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided (c) Air filtration systems, including pre-filters and particulate matter air filters, shall be used. 211.48 Plumbing: Potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. 211.50 Sewage and refuse: Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner. 211.52 Washing and toilet facilities. 211.56 Sanitation. 211.58 Maintenance. 211.52-211.58 should be neat, clean and good
- 43. 17 Subpart D-Equipment 211.63 Equipmentdesign, size, and location: Equipment shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. 211.65 Equipment construction: Equipment shall be constructed so that surfaces that contact components, in- process materials, or drug products shall not be reactive, additive, so as to alter the safety, identity, strength, quality, or purity of the drug product 211.67 Equipment cleaning and maintenance: •Equipment shall be cleaned, maintained, to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product. •Inspection of equipment for cleanliness before use. •Records shall be kept of maintenance, cleaning. 211.68 Automatic, mechanical, and electronic equipment: (a) Equipments including computers, or related systems that will perform a function satisfactorily. (b) They shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. (c)Written records of those calibration checks and inspections shall be maintained. 211.72 Filter: (a) Fiber -releasing filters may not be used for injectable drug products unless it is not possible to manufacture such drug products without the use of such filters. (b) If use of a fiber -releasing filter is necessary, an additional non- fiber - releasing filter of 0.22 micron maximum mean porosity shall subsequently be used to reduce the content of particles in the injectable drug product. Use of an asbestos-containing filter.
- 44. 18 Subpart E-Control ofComponents and Drug Product Containers and Closures 211.80 General requirement: There shall be written procedures in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures. 211.82 Receipt and storage of untested components, drug product containers, and closures: (a) They shall be examined visually for appropriate labeling as to contents, container damage or broken seals, and contamination. (b) They shall be stored under quarantine until they have been tested or examined, as appropriate, and released. 211.84 Testing and approval or rejection of components, drug product containers, and closures: (a) The lot has been sampled, tested, as appropriate, and released for use by the quality control unit. (b) Representative samples of each shipment of each lot shall be collected for testing or examination. 211.86 Use of approved components, drug product containers, and closures: They shall be rotated so that the oldest approved stock is used first. 211.87 Retesting of approved components, drug product containers, and closures: They shall be retested, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit. Subpart F-Production and Process Controls 211.100 Written procedures; deviations: There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. 211.101 Charge-in of components:
- 45. 19 Components for drugproduct manufacturing shall be weighed, measured. If a component is removed from the original container to another, the new container shall be identified with the following information: (1) Component name (2) Receiving or control number; (3) Weight or measure in new container; (4) Batch for which component was dispensed, including its product name, strength, and lot number. 211.103 Calculation of yield: Actual yields and % of theoretical yield shall be determined at manufacturing, processing, packaging, or holding of the drug product. 211.105 Equipment identification: (a) Major equipment properly identified during production. (b) Major equipment shall be identified by a distinctive identification number that shall be recorded in the batch production record to show the specific equipment used in the manufacture. 211.110 Sampling and testing of in-process materials and drug products: (a) To assure batch uniformity and integrity of drug products, (b) Written procedures shall be established that describe the in-process controls, and tests, to be conducted on appropriate samples of in-process materials of each batch. 211.111 Time limitations on production: To assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. 211.113 Control of microbiological contamination: Written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile. Such procedures shall include validation 211.115 Reprocessing: Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform to all established standards, specifications, and characteristics.
- 46. 20 Subpart G-Packaging andLabeling Control 211.122 Materials examination and usage criteria: There shall be written procedures describing in detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials ,materials that do not meet such specifications shall be rejected to prevent their use 211.125 Labeling issuance: Labeling materials issued for a batch shall be carefully examined for identity and conformity to the labeling specified in the master or batch production records. 211.130 Packaging and labeling operations: (a) Prevention of mix-ups and cross-contamination by physical separation from operations on other drug products. (b) Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch. 211.132 Tamper-resistant packaging requirements for over-the-counter (OTC) human drug products: 211.134 Drug product inspection: 211.137 Expiration dating: (a) To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use. (b) It shall be related to any storage conditions stated on the labeling, as determined by stability studies Subpart H-Holding and Distribution 211.142 Warehousing procedures: (a) Quarantine of drug products before release by the quality control unit. (b) Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected.
- 47. 21 (c)Written procedures arenecessary. 211.150 Distribution procedures: (a) A procedure whereby the oldest approved stock of a drug product is distributed first. Subpart I-Laboratory Controls 211.160 General requirements: (a) They shall include the establishment of, standards, sampling plans, and test procedures etc to confirm appropriate standards of identity, strength, quality, and purity. (b)The calibration of instruments, apparatus, and recording devices at suitable intervals in accordance to written program 211.165 Testing and release for distribution: (a) The sterility and/or Pyrogen testing are conducted on specific batches of short lived radiopharmaceuticals, 211.166 Stability testing: (a) Stability testing shall be used in determining appropriate storage conditions and expiration dates. (b)Accelerated studies, combined with basic stability information on the components, drug products. 211.167 Special testing requirements: For each batch purporting to be sterile and/or Pyrogen -free, there shall be appropriate laboratory testing to determine conformance to such requirements. 211.173 Laboratory animals: Animals used in testing components, in-process materials, or drug products for compliance with established specifications shall be maintained .They shall be identified, and adequate records shall be maintained showing the history of their use. 211.176 Penicillin contamination:
- 48. 22 (a)If a non-penicillindrug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin. (b) Such drug product shall not be marketed if detectable levels are found when tested according to procedures. Subpart J-Records and Reports 211.182 Equipment cleaning and use log: A written record of major equipment cleaning, maintenance and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. 211.184 Component, drug product container, closure, and labeling records: (a) The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier. 211.186 Master production and control records: To assure uniformity from batch to batch and including each batch size thereof, shall be prepared, dated, and signed by one person and independently checked, dated, and signed by a second person. 211.188 Batch production and control records: Batch production and control records shall be prepared for each batch produced and shall include complete information relating to the production and control of each batch. (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed; (b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished 211.192 Production record review: All drug product, production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.
- 49. 23 211.194 Laboratory records: Itshall include complete data derived from all tests 211.196 Distribution records: It shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. 211.198 Complaint files: All written and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications Subpart K-Returned and Salvaged Drug Products 211.204 Returned drug product: (a) Products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return (b) if the condition of the drug product, its container, carton, or labeling , as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product 211.208 Drug product salvaging: Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, equipment failures shall not be salvaged and returned to the marketplace.
- 50. 24 CENTRE FOR DRUGEVALUATION AND RESEARCH (CDER) CDER : The Center for Drug Evaluation and Research (CDER) is a division of the U.S. Food and Drug Administration (FDA) that monitors most drugs as defined in the Food, Drug, and Cosmetic Act. CDER Mission : ➢ CDER’s mission is to protect and promote public health by helping to ensure that human drugs are safe and effective for their intended use. ➢ To protect public health by promoting the safe use of marketed drugs and by helping to ensure the quality and integrity of marketed drug products. DEPARTMENT OF HEALTH AND HUMAN SERIVICES FOOD AND DRUG ADMINISTRATION (FDA) Center for Drug Evaluation & Research (CDER) Center for Biologics Evaluation & Research (CBER) Center for Devices & Radiological Health (CDRH) Center for Food Safety & Applied Nutrition (CFSAN) Center for Veterinary Medicine (CVM) National Center for Toxicological Research Office of Regulatory Affairs Office of the Commissioner
- 51. 25 FUNDAMENTAL GOALS ANDOBJECTIVES : • Promote public health by ensuring the availability of safe and effective drugs : Promote patient and health professional awareness of drug benefits and risks through effective communication of drug information • Protect public health by promoting the safe use of marketed drugs: Oversee drug promotion and marketing to help ensure that marketed drug labeling and advertising are truthful and not misleading • Protect public health by ensuring the quality and integrity of marketed drug products Current CDER Activity : ➢ To oversee new drug development and review of drug marketing applications. ➢ To oversee post-marketing drug safety, to help ensure safe use of approved medicines. ➢ To oversee drug manufacturing and quality. Other Roles : ✓ CDER assures that all prescription and over-the- counter drugs are safe and effective. ✓ Efficient risk management. ✓ Provides health professionals and consumers information to use drugs appropriately and safely.(ads, communication media). ✓ Remove barriers to innovation in drug development and to facilitate the modernization of drug manufacturing. Work of CDER : ➢ CDER Drug Product Applications. ➢ CDER Small Business Assistance Program. ➢ Small business guide to FDA. ➢ CDER Handbook describes the Center's processes and activities. ❖ New Drug Development and Review - IND, NDA. ❖ Generic Drug Review –ANDA. ❖ Over-the-Counter Drug Review . ❖ Post Drug Approval Activities. ❖ Communicating with CDER. ❖ Other activities.
- 52. 26 THE NEW DRUGDEVELOPMENT PROCESS
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- 55. 29 GENERIC DRUG REVIEWPROCESS
- 56. 30 Regulatory Guidances : •Regulatory & Scientific Guidances • Submitting applications for New Drug Products • International activities • CDER polices and procedures • Compliance Activities • Useful resources Current Guidance Agenda : Home/Drugs/Guidance, Compliance & Regulatory Information/Guidances(Drugs)/Newly Added Guidance Documents Topic Guidance Status Date Genetics Competitive Generic Therapies Guidance for Industry Final 3/13/2020 Rare Diseases Slowly Progressive, Low- Prevalence Rare Diseases With Substrate Deposition That Results From Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies Guidance for Industry Final 3/13/2020 ICH - Quality Q3D(R1) Elemental Impurities Guidance for Industry Final 3/10/2020 Electronic Submissions Providing Regulatory Submissions in Alternate Draft 3/10/2020
- 57. 31 Topic Guidance StatusDate Electronic Format Clinical / Medical Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Draft 3/9/2020 Clinical / Medical Contact Dermatitis From Topical Drug Products for Cutaneous Application: Human Safety Assessment Guidance for Industry Draft 3/6/2020 Pharmacology / Toxicology Safety Testing of Drug Metabolites Guidance for Industry Final, Revision 2 3/5/2020 Procedural The “Deemed to be a License” Provision of the BPCI Act: Questions and Answers Final 3/4/2020 Electronic Submissions Providing Regulatory Submissions in Electronic Format--Certain Human Pharmaceutical Product Applications and Related Submissions Using the Electronic Common Technical Document Specifications Revision 7 Final 2/21/2020 Pharm / Tox Nonclinical Safety Evaluation of the Immunotoxic Potential of Drugs and Biologics Guidance for Industry Revised Draft 2/19/2020 Biosimilarity Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Draft 2/06/2020
- 58. 32 Topic Guidance StatusDate Conditions of Use for Which the Reference Product Has Been Licensed Guidance for Industry Clinical / Medical Mucopolysaccharidosis Type III (Sanfilippo Syndrome):Developing Drugs for Treatment Guidance for Industry Draft 2/04/2020 Advertising Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products Questions and Answers Guidance for Industry Draft 2/03/2020 Clinical/ Medical Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment Guidance for Industry Final 1/24/2020
- 59. 33 CENTER FOR BIOLOGICSEVALUATION AND RESEARCH (CBER) CBER is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. CBER's mission is to protect and enhance the public health through the regulation of biological and related products including blood, vaccines, allergenics, tissues, and cellular and gene therapies. CBER : • One of 6 main centers of USFDA. • Regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. • Responsible for assuring the safety, purity, potency, and effectiveness of biologics and related products (such as vaccines, live biotherapeutics (probiotics), blood products, and cell, tissue, and gene therapies). • Monoclonal antibodies and other therapeutic proteins are regulated by the FDA Center for Drug Evaluation and Research (CDER). Biological Products : • Derived from human, animals, plants and microorganism sources. • This includes blood and blood components, tissues allergenic extracts, vaccines, drugs derived using biotechnology and certain diagnostic products. Regulating the Products : Activities include: ✓ Monitoring the pre-clinical and clinical testing of new biological products, and evaluating their safety and effectiveness before marketing. ✓ Licensing biological products and manufacturing establishments, including blood banks. ✓ Research on aids medication, diagnostic tests and vaccines. ✓ Compliance monitoring, lot releasing, and post market surveillance.
- 60. 34 Approval : • CBERstaff reviews clinical research and laboratory testing data to determine if the biologic is safe and effective for its intended use. • In order for a biological product to be approved for marketing in the U.S., an applicant must submit a Biologics License Application (BLA). Biologics License Application : • Animal studies and human clinical trials performed. • How the biologic is manufactured, processed, and packaged, including information on the quality control methods used during its manufacture. • Labeling that will be used with the product Once a biological product is approved, its identity and manufacturing process cannot change without prior FDA approval. Blood Supply : Assuring the safety of, and the public confidence in, the nation’s blood supply is one of CBER’s main priorities. There are five overlapping safeguards in place to help protect the safety of blood. • Quarantine of untested blood • Donor screening • Donor deferral registries • Blood testing • Investigations of problems • Some of the products regulated by CBER are devices. • These include products used in the collection and processing of blood products, such as blood bags, centrifuges, and test kits that are used to screen donated blood for infections diseases such as HIV and hepatitis. Authority : Resides in section 351 and 361 of the Public Health Service Act. Section 351: ✓ Licensing the biological products that travel in the interstate commerce of the United States. ✓ Deny or suspend or cancel any current license if the manufacturer does not comply with the requirements.
- 61. 35 Section 361: ✓ Makeand enforce the regulations to control the interstate speed of communicable diseases. PHARMACEUTICAL INSPECTION CONVENTION (PIC) Introduction : • PIC/S is a combine term used for the execution of activities of Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme. • PIC/S was established to harmonize, educate, and update aspects relating to Good Manufacturing Practice among member countries. PIC/S is also a body that even harmonized relation among regulatory authorities and governments. • The presentation helps in understanding the origin, purpose, objective, role and functions of PIC/S. Origin and Purpose : • In 1995, PIC/S was established as a provision to streamline with long back established Pharmaceutical Inspection Convention of 1970 with some flexibility. Initially, European Commission is the body permitted to sign agreements with countries outside Europe. • Since, European Commission is not a member of Pharmaceutical Inspection Convention of 1970, there was some incompatibility among European Law and PIC. This incompatibility did not allow EU countries that were members of PIC to have agreement with countries that are seeking to join PIC. • Formation of a PIC Scheme, less formal, more flexible, with no legal status that in turn brings understanding between health authorities. • Thus PIC/S is a parallel scheme of both Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme. PIC/S has brought understanding among health and led to joint execution of activities among health authorities and governments. History, Members of PIC and PIC/S : • Pharmaceutical Inspection Convention was established in 1970 by European Foreign Trade Association under the title “The Convention for
- 62. 36 the Mutual Recognitionof Inspections in respect of the Manufacture of Pharmaceutical Products”. • Initial ten members of EFTA i.e. Austria, Denmark, Finland, Iceland, Liechtenstein, Norway, Portugal, Sweden, Switzerland and United Kingdom were later members of PIC. • Membership of PIC was subsequently expanded to include Argentina, Canada, Chinese Taipei, Croatia, Cyprus, Hungary, Ireland, Romania, Germany, Italy, Belgium, France, Australia, Canada, Czech Republic and Estonia etc., (Total no.of members 47) • It was later the PIC scheme established in 1995 that in turn led to PIC/S. Presently, 39 regulatory authorities are members and partners of PIC/S. Objective and Role of PIC and PIC/S : • The main objective is to harmonize Good Manufacturing Practice requirements, bring about uniform-mutual recognition inspections, educate and exchange information, among different countries and attain mutual confidence of drug regulatory authorities. • The key issues like duplication of inspections, licensing procedures, expenditure and licensing can be overcome by one time procedures. • The role of PIC scheme is to safe guard public health by providing good quality medicines by bringing a harmonization in Good Manufacturing Practice among countries. • To achieve this harmonization, regular awareness along with training, sharing information and experience, implementing procedures to be followed relating to manufacture and quality control of medicinal products so that equivalent standards among countries can be implemented. • To meet the objective, PIC/S has to thoroughly assess the status of regulatory process of a drug regulatory authority of a country and make necessary changes if necessary in the protocols of manufacturing and quality control of drugs so as to harmonize Good Manufacturing Practice among the member countries. Administrative Structure of PIC/S : • PIC/S is constituted with a permanent committee and executes meetings with representative of participating authorities. • The meetings are held at least twice a year by the committee. The PIC/S committee is assisted by a secretariat in coordinating, documenting and implementing the objectives of PIC/S.
- 63. 37 Functioning of PIC/SCommittee : • To meet the objectives of PIC/S in terms of harmonisation of GMP • • The committee makes recommendations, update and improve GMP, promote cooperation relating to quality assurance of inspections and quality systems of inspectorate, educate the authorities by means of training and exchange of information and helps in bringing out new guidelines relating to manufacturing and quality control of medicinal products. • The committee also assesses the system being practiced by a country for medicinal products in terms of manufacture, quality control along with protocols followed for corresponding regulatory inspections/inspectors • • Decides suggestions and changes necessary for the country to become a member of PIC/S. Advantages with PIC/S : • PIC/S brings about an international harmonization among countries with relating to Good Manufacturing Practice, quality maintenance systems of medicinal products. • In addition to this, implementation of high standards of quality along with mutual understanding among members is achieved. • PIC/S brings about a single network system relating to GMP of medicinal products. • It helps member regulatory authorities in sharing, facilitating, recalling, concluding aspects relating to manufacture, quality and inspection systems among inspectorates, pharmaceutical industries. • Aspects relating to duplication of inspections and other regulatory become cost effective. • PIC/S also brings about single window export facilitation to enhance marketing of the medicinal products. • As a whole, PIC/S brings about uniform licensing decisions among member countries. • Several countries like Colombia that is a non-PIC/S authority do accept GMP certification from PIC/S member countries for import of the medicinal product which is a benefit.
- 64. 38 Difference Between PICScheme and PIC : PIC Scheme PIC 1. Scheme Convention 2. An informal arrangement A formal treaty 3. Has no legal status Has legal status 4. Between health authorities Between countries 5. Exchange of information Mutual recognition of inspections PIC/S GMP Guide : All Reference Category Section 2ND TARGETED CONSULTATION DOCUMENT ON REVISION OF ANNEX 1 (MANUFACTURE OF STERILE MEDICINAL PRODUCTS) 2nd Targeted Consultation Document on Revision of Annex 1 Documents for Industry PIC/S GMP Guide CONSULTATION NOTICE ON REVISION ANNEX 2 PS INF 24 2019 Documents for Industry PIC/S GMP Guide DRAFT ANNEX 2A (MANUFACTURE OF ATMP) TO PICS GMP GUIDE FOR PUBLIC CONSULTATION PS INF 25 2019 (Rev. 1) Draft Documents for Industry PIC/S GMP Guide DRAFT ANNEX 2B (MANUFACTURE OF BIOLOGICAL MEDICINALS) TO PIC/S GMP GUIDE FOR PUBLIC CONSULTATION PS INF 26 2019 (Rev. 1) Draft Documents for Industry PIC/S GMP Guide JOINT PIC/S-EMA CONCEPT PAPER ON THE REVISION OF ANNEX 1 (MANUFACTURE OF STERILE MEDICINAL PRODUCTS) PS W 01 2015 Documents for Industry PIC/S GMP Guide
- 65. 39 All Reference CategorySection PIC/S GMP GUIDE (INTRODUCTION) PE 009-14 (Intro) Documents for Industry PIC/S GMP Guide PIC/S GMP GUIDE (PART I: BASIC REQUIREMENTS FOR MEDICINAL PRODUCTS) PE 009-14 (Part I) Documents for Industry PIC/S GMP Guide PIC/S GMP GUIDE (PART II: BASIC REQUIREMENTS FOR ACTIVE PHARMACEUTICAL INGREDIENTS) PE 009-14 (Part II) Documents for Industry PIC/S GMP Guide PIC/S GMP GUIDE (RELATED ANNEXES) PE 009-14 (Annexes) Documents for Industry PIC/S GMP Guide PIC/S GMP GUIDE (ZIP) PE 009-14 Documents for Industry PIC/S GMP Guide List of PIC/S Guide Lines : • PIC/S provides guide lines for industry, inspectorates and inspectors as mentioned below: Guidance to Industry: • PE 009-9 : Good Manufacturing Practice for Medicinal Products (Part I, II, Annexes) • PI 010-4 : Procedure for Handling Rapid Alerts and Recalls Arising from Quality Defects Guidance to Inspectorate: • PIC Convention • PIC/S Scheme • Participating Authorities & Partners • PI 002-3 : Quality System Requirement for Pharmaceutical Inspectorate • PI 013-3 : Standard Operating Procedure PIC/S Inspection Report Format
- 66. 40 Guidance to Inspectors: •PI 009-3 : Aide-Memoire Inspection of Utilities • PI 021-2 : Aide-Memoire on GMP Particularities for Clinical Trial Products • PI 023-2 : Aide-Memoire on Inspection of Quality Control Laboratories • PI 024-2 : Aide-Memoire on Inspection of Biotech • PI 025-2 : Aide-Memoire on Medicinal Gases • PI 028-1 : Aide-Memoire on Packaging • PI 030-1 : Aide-Memoire on the Inspection of APIS • PE 005-3 : PIC/S GMP Guide for Blood Establishments Guidance to Inspectors: • PE 010-3 : Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments • PI 005-3 : Guidance on Parametric Release • PI 006-3 : Validation Master Plan Installation and Operational Qualification Non-Sterile Process Clening Validation: • PI 007-6 : Validation of Aseptic Processes • PI 008-3 : PIC/S Guide to Inspections of Source Plasma Establishments and Plasma Warehouses (Inspection Guide): • PI 011-3 : Good Practices for Computerized Systems in Regulated GXP Environments • PI 012-3 : Recommendation on Sterility Testing • PI 014-3 : Isolators used for Aseptic processing and Sterility Testing • PI 032-2 : Technical Interpretation of Revised Annex 1 to PIC/S GMP Guide Conclusion : • Implementation of PIC/S has brought a harmony among PIC and PIC Scheme. • It has brought a uniform understanding among member countries regarding Good Manufacturing Practices for medicinal products.
- 67. 41 • PIC/S hasbrought an understanding among drug regulatory authorities in bringing high standard, uniform acceptable quality standard medicines that can be permitted into the member countries. As a whole PIC/S has benefited the pharmaceutical manufacturers, inspectors, inspectorate and governments in saving time, cost for drug approval procedures and enhance the pharmaceutical market. Members & Partners of PIC/S : A)Participating Authorities: 1. Argentina-National Institute of Drugs Instituto Nacional de Medicamentos (INAME) 2. Australia-Therapeutic Goods Administration (TGA) 3. Austria-Austrian Agency for Health and Food Safety (AGES) 4. Belgium-Federal Agency for Medicines and Health Products 5. Canada-Health Canada / Santé Canada 6. Chinese Taipei-Taiwan Food and Drug Administration (TFDA) 7. Croatia-Agency for Medicinal Products and Medical Devices of Croatia 8. Cyprus-Pharmaceutical Services (CyPHS) 9. Czech Republic-State Institute for Drug Control 10.Czech Republic-Institute for State Control of Veterinary Biologicals and Medicines (ISCVBM) 11.Denmark-Danish Medicines Agency (DKMA) 12.Estonia-State Agency of Medicines (SAM) 13.Finland-Finnish Medicines Agency (FIMEA) 14.France-French National Agency for Medicines and Health Products Safety 15.France-Agency for Food, Environmental & Occupational Health Safety 16.Central Authority of the Laender for Health Protection regarding Medicinal Products and Medical Devices * 17.Greece-Greek National Organisation for Medicine 18.Hong Kong SAR, China 19.Pharmacy and Poisons Board of Hong Kong (PPBHK) 20.Hungary-National Institute of Pharmacy and Nutrition (NIPN)
- 68. 42 21.Iceland-Icelandic Medicines Agency(IMA) 22.Indonesia-National Agency for Drug and Food Control (NADFC) 23.Iran-Iran Food and Drug Administration (IFDA) 24.Ireland-Health Products Regulatory Authority (HPRA) 25.Israel-Institute for Standardization and Control of Pharmaceuticals (ISCP) 26.Italy-Italian Medicines Agency 27.Italy (Veterinary Agency)-Directorate General for Animal Health and Veterinary Medicinal Products 28.Japan-Ministry of Health, Labour and Welfare (MHLW) * 29.Pharmaceuticals and Medical Devices Agency (PMDA) * 30.Korea (Republic of)-Ministry of Food and Drug Safety (MFDS) 31.Latvia-State Agency of Medicines 32.Liechtenstein-Office of Healthcare 33.Lithuania-State Medicines Control Agency (SMCA) 34.Malaysia-National Pharmaceutical Regulatory Agency (NPRA) 35.Malta-Malta Medicines Authority (MMA) 36.Mexico-Federal Commission for the Protection Against Sanitary Risks (COFEPRIS) 37.Netherlands-Health and Youth Care Inspectorate* 38.New Zealand-Medicines and Medical Devices Safety Authority (Medsafe) 39.Norway-Norwegian Medicines Agency (NOMA) 40.Poland-Chief Pharmaceutical Inspectorate (CPI) 41.Portugal-National Authority of Medicines and Health Products, IP 42.Romania-National Agency for Medicines and Medical Devices(NAMMD) 43.Singapore-Health Sciences Authority (HSA) 44.Slovak Republic-State Institute for Drug Control (SIDC) 45.Slovenia-Agency for Medicinal Products and Medical Devices 46.South Africa-South African Health Products Regulatory Authority (SAHPRA) 47.Spain-Spanish Agency of Medicines and Medical Devices*
- 69. 43 48.Sweden-Swedish Medical ProductsAgency (MPA) 49.Switzerland-Swiss Agency for Therapeutic Products (Swissmedic) 50.Thailand-Food and Drug Administration (Thai FDA) 51.Turkey-Turkish Medicines and Medical Devices Agency (TMMDA) 52.Ukraine-State Service of Ukraine on Medicines and Drugs Control (SMDC) 53.United Kingdom-Medicines & Healthcare Products Regulatory Agency (MHRA) 54.United Kingdom-Veterinary Medicines Directorate (VMD) B)Partners to PIC/S: 1. European Directorate for the Quality of Medicines & Healthcare 2. European Medicines Agency 3. United Nations International Children’s Emergency Fund 4. World Health Organisation cGMP GUIDELINES ACCORDING TO WHO Introduction : • cGMP is defined as “it is a part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate for their intended use and the legal requirements”. • cGMP is thus concerned with both production and quality control matters. • cGMP provides complete guidelines on designing material and product specifications, testing methods and reproducing methods for same. • The drug regulatory authorities all over world e.g. WHO, M.H.RA.(U.K),T.G.A(Australia),M.C.C(South Africa),U.S.F.D.A etc. Provides guidelines based on their requirements. Activities of cGMP : • cGMP expects that all the people should be trained. • It provides complete guidelines on requirements of facilities and equipments. • cGMP talks about how you should control the quality of materials at every stage. • It also further talks about quality , production systems and their control.
- 70. 44 Personnel : • Themanufacturer should have an adequate number of personal with the necessary qualification and practical experience. • Academic qualification required in various areas of specialization. o Production: B.Pharm ; M.Pharm; Ph.D. o Q.C/Q.A: B.Pharm ; M.Pharm , M.S.C o Stores: P.G. in material management o Finance :M.com, M.B.A, Chartered accountants • People in an origination are the main resource and as more value and importance than other resources like facilities ,equipment and materials. • A trained person generally has the knowledge, skill and attitude relevant to their job and that too in the appropriate levels. • Training improves human performance on job, working capacity. • Smoking ,drinking, chewing, food drinking material should not be permitted into manufacturing, production areas. Surroundings, Buildings and Facilities : • Premises must be located, designed, constructed, adapted ,maintained to suit the operation to be carried out. • Premise should be designed and equipment maximum protection against the entry of insects or other animals. • Washing and toilet facilities should be provided for each individuals in working areas, cupboards must be provided in change rooms for keeping cloths, other belongings. • Rest and refreshment rooms should be separate from other areas, animal houses should be well-isolated from other areas, with separate entrance. • Storage area should sufficient capacity to allow orderly storage of the various types of materials and products. • Temperature and humidity conditions should be maintained in storage areas. • Production area adequate space to prevent cross contamination, area should be effectively ventilated with air control facilities. Equipment : • Equipment design, size, and location. • Equipment construction. • Equipment cleaning and maintenance.
- 71. 45 • Balances andother measuring equipment shall be calibrated and checked on periodical basis in accordance with the SOP’s and records maintained. Material Management : • Stored properly and records maintained as per schedule U. • All incoming raw material shall be quarantined immediately after receipt or processing. • Stored in such a manner that FIRST IN FIRST OUT principle. • Purchased from approved sources under valid purchase voucher stored appropriately with labels. • Authorized staff shall be appointed by license in raw material department he/she may be from QC department. • If any product failed established specification or other relevant qualities should be rejected. • Reagents made up in the laboratory should be prepared according to written procedure and appropriately labeled. the label should indicate the concentration, standardization factor, shelf life. Quality Management : • The word “QUALITY” has its origin in a Latin word “Qualitas” means “general excellence”. • “quality should be built into the product, and testing alone cannot be relied onto ensure product quality”. • Each and every manufacturing unit should have its own QC laboratory with qualified and experienced staff. • It is concerned with sampling, specification, testing, documentation and release procedures. • S.O.P are maintained for each and every step in the process. • Each specification for raw materials, intermediates, final product ,packing materials shall be approved and maintained by Q.C department. • Should be independent of the production areas and divided in to separate sections. • Physico-chemical. • Biological. • Microbiological. • And radio-isotope analysis.
- 72. 46 • Space shallbe provided for test samples, retained samples, reference standard. • Suitable to construction materials and ventilation. Manufacturing Operational Control : • The main objective of the manufacturing is to produce a quality pharmaceutical product. • Production operation should follow manufacturing and marketing authorization. • Simultaneous operations should not performed in the same room to prevent cross contamination. • Cleaning, sanitation and disinfection of manufacturing premises falls under the category of achieving purity in the finished pharmaceutical by avoiding contamination. Pharmaceutical Validation : • “It is the documented evidence which provide a high degree of assurance that a specific process will consistently produce, a product meeting its pre -determined specifications and quality attributes”. • Components of a production process such as facilities and equipment must be validated before use. • In pharmaceutical industry cleaning validation of facility , equipment and apparatus is also considered. • Inspection of equipment for cleanliness immediately before use. Sterile Pharmaceutical Products : • Sterile pharmaceutical products are very critical and sensitive products. these products are free from living organisms , pyrogens and particulate matter. • The production of sterile preparations should be carried out in clean area. • The entry of personal and goods into sterile preparation rooms should be through air lock systems. • Only the minimum number of Persons should be present in Clean area. Site and Plant Security : • Site and plant security is an essential part of the pharmaceutical manufacturing operations.
- 73. 47 • This ismainly related to see that unauthorized persons are not entering in the plant, which may results into adulteration of product. Documentation and Records : • A document is any written ,printed or computer generated information that is going to provide some evidence. The method of making a document is called as a documentation. • It is part of QA and play an imp role in implementation of GMP. • Documents shall specify the title ,nature and purpose and arranged in such a manner that it should be easy to check. • There should be a separate record book shall be maintained for each batch and should include product name, batch no, size, etc Conclusion : • Inculcation of cGMP in the organization provides increased quality of products with less wastage , more profit and customer satisfaction.
- 74. 48 Europe, Middle East,and Africa (EMEA) EMEA is an acronym that stands for Europe, the Middle East, and Africa. As the name suggests, the EMEA region of the world encapsulates all of the countries found on the continents of Africa and Europe, as well as the countries that make up the Middle East. Human medicines: regulatory information Provides information on the regulation of medicines for human use in the European Union (EU). It particularly concerns the centralised procedure, where the European Medicines Agency (EMA) plays a key role. Introduction : ❖ The EMEA began its activities in 1995, when the European system for authorizing medicinal products was introduced. ❖ European Medicines Agency (EMEA) is a decentralized body of the European Union, headquarters in London. ❖ Its main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. ❖ The EMEA primarily involved in the centralized procedure. ❖ Where the centralized procedure is used, companies submit one single marketing authorization application to the EMEA. ❖ A single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP) or Committee for Medicinal Products for Veterinary Use (CVMP). ❖ In 2001, the Committee on Orphan Medicinal Products (COMP) was established, charged with reviewing designation applications from persons or companies who intend to develop medicines for rare diseases (so-called ‘orphan drugs’). ❖ The Committee on Herbal Medicinal Products (HMPC) was established in 2004 and provides scientific opinions on traditional herbal medicines. ❖ The main responsibility of the Pediatric Committee (PDCO) is to assess the content of pediatric investigation plans and adopt opinions on them in accordance with Regulation.
- 75. 49 EMEA ORGANISATION EMEA MissionStatement : ❖ Developing efficient and transparent procedures to allow rapid access by users to safe and effective innovative medicines and to generic and non- prescription medicines through a single European marketing authorization. ❖ Controlling the safety of medicines for humans and animals ▪ in particular through a pharmacovigilance network EXECUTIVE DIRECTOR Executive Support Integrated quality management and audit Legal Sector PRE-AUTHORIZATION EVALUATION OF MEDICINES FOR HUMAN USE POST-AUTHORIZATION EVALUATION OF MEDICINES FOR HUMAN USE VETERINARY MEDICINES AND INSPECTIONS ADMINISTRATION COMMUNICATIONS AND NETWORKING Scientific advice and orphan drugs Quality of Medicines Medical information Veterinary marketing authorizatio n procedures Regulatory affairs and organizational support Pharmacovigilance and post - authorization safety and efficacy of medicines Inspection Safety of veterinary medicines Information technology Project managemen t Meeting managemen t and conferences Document management and publishing Accountin g Infrastructur e services Personnel and budget Safety and efficacy of Medicines
- 76. 50 ▪ the establishmentof safe limits for residues in food- producing animals ❖ Facilitating innovation and stimulating research ❖ Mobilizing and coordinating scientific resources from throughout the EU ▪ to provide high-quality evaluation of medicinal products ▪ to advise on research and development programme EMEA Committee : Management Board ❖ CHMP ❖ CVMP ❖ COMP ❖ HMPC ❖ PDC ❖ CAT ❖ PRAC Board Management : ➢ A Chairman ➢ Two members of European parliament European commission ➢ Two representatives of Patients' organizations Doctors' organizations Veterinarians' organizations ➢ One representative of observer countries ➢ One representative of each member country 25 Membered Countries : 1.Austria 13.Italy 2.Belgium 14.Latvia
- 77. 51 3.Cyprus 15.Lithuania 4.Czech Republic16.Luxembourg 5.Denmark 17.Malta 6. Estonia 18.Netherlands 7.Finland 19.Poland 8.France 20.Portugal 9.Germany 21.Slovakia 10.Greece 22.Slovenia 11.Hungary 23.Spain 12.Ireland 24.Sweden 25.United Kingdom CHMP : Role and Responsibilities: ❖ Responsible for several post-authorization and maintenance activities ❖ Assessments conducted by the CHMP are based on purely scientific criteria and determine whether or not the products concerned meet the necessary quality, safety and efficacy requirements. ❖ These processes ensure that medicinal products have a positive risk- benefit balance in favour of patients/users of these products once they reach the marketplace. ❖ The CHMP plays an important role in this EU-wide ‘pharmacovigilance’ activity by closely monitoring reports of adverse drug reaction reports, making recommendations regarding changes to a product’s marketing authorization or the product’s suspension/withdrawal from the market. ❖ Can issue an ‘urgent safety restriction’ (USR) ❖ The CHMP publishes a European Public Assessment Report (EPAR) for every centrally authorized product that is granted a marketing authorization The EMEA’s integrated quality-management system ensures effective planning, operation and control of the CHMP’s processes and records.
- 78. 52 Other important activitiesof the CHMP : ❖ providing scientific advice to companies researching and developing new medicines ❖ preparing scientific guidelines and regulatory guidance to help pharmaceutical companies prepare marketing authorisation applications for human medicines ❖ cooperate with international partners on the harmonisation of regulatory requirements. CVMP : Role and Responsibilities: ❖ Establishment of MRLs: the 'maximum residue limits' of veterinary medicinal products permissible in food produced by or from animals for human consumption, including dairy products, meat, honey etc. ❖ These limits must be established for all pharmacologically active substances contained in a medicinal product before the product can be granted a marketing authorization. COMP : The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Role of COMP: ❖ The COMP is evaluating applications for orphan designation. ❖ This designation is for medicines to be developed for the diagnosis, prevention or treatment of rare diseases that are life-threatening or very serious. In the European Union (EU), a disease is defined as rare if it affects fewer than 5 in 10,000 people across the EU. The European Commission decides whether to grant an orphan designation for the medicine based on the COMP's opinion. ❖ An orphan designation allows a pharmaceutical company to benefit from incentives from the EU, such as reduced fees and protection from competition once the medicine is placed on the market.
- 79. 53 ❖ The COMPalso advises and assists the European Commission on matters related to orphan medicines, including: ➢ developing and establishing an EU-wide policy; ➢ drawing up detailed guidelines; ➢ liaising internationally. HMPC : The Committee on Herbal Medicinal Products (HMPC) is the European Medicines Agency's (EMA) committee responsible for compiling and assessing scientific data on herbal substances, preparations and combinations, to support the harmonisation of the European market. Role and Responsibilities: ❖ The HMPC's activities aim at assisting the harmonization of procedures and provisions concerning herbal medicinal products laid down in EU Member States, and further integrating herbal medicinal products in the European regulatory framework. ❖ The HMPC provides EU Member States and European institutions its scientific opinion on questions relating to herbal medicinal products. ❖ To support EU Member States, the HMPC focuses on two main tasks: ➢ establishing EU monographs covering the therapeutic uses and safe conditions of well-established and/or traditional use for herbal substances and preparations ➢ drafting an EU list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products. ❖ The HMPC and its working parties and other groups also: ➢ prepare scientific guidelines and regulatory guidance to help companies prepare marketing authorisation and registration applications for herbal medicines ➢ coordinate with other scientific committees at the Agency on the regulation and safe use of herbal medicines ➢ provide scientific and regulatory support to companies researching and developing herbal medicines ➢ provide advice and training to herbal assessors of national competent authorities PDCO :
- 80. 54 The Paediatric Committee(PDCO) is the European Medicines Agency’s (EMA) scientific committee responsible for activities on medicines for children and to support the development of such medicines in the European Union by providing scientific expertise and defining paediatric needs Role of PDCP: Pediatric Committee (PDCO) main role is to assess the content of pediatric investigation plans and adopt opinions on them in accordance with Regulation Committee other roles include: ❖ assessing data generated in accordance with agreed PIPs ❖ adopting opinions on the quality, safety or efficacy of a medicine for use in the paediatric population, at the request of the Committee for Medicinal Products for Human Use (CHMP) ❖ advising the Agency and the European Commission on how to communicate the arrangements available for conducting research into paediatric medicines. ❖ advising Member States on the content and format of data to be collected through surveys on the uses of medicines in children CAT : The Committee for Advanced Therapies (CAT) is the European Medicines Agency's (EMA) committee responsible for assessing the quality, safety and efficacy of advanced therapy medicinal products (ATMPs) and following scientific developments in the field. Role of the CAT: ❖ participates in certifying quality and non-clinical data for small and medium-sized enterprises developing ATMPs ❖ participates in providing scientific recommendations on the classification of ATMPs ❖ supports the work programmes of the CHMP working parties PRAC : The Pharmacovigilance Risk Assessment Committee (PRAC) is the European Medicines Agency's (EMA) committee responsible for assessing and monitoring the safety of human medicines.
- 81. 55 Role of PRAC: ❖The PRAC is responsible for assessing all aspects of risk management of human medicines, including: ➢ the detection, assessment, minimisation and communication of the risk of adverse reactions, while taking the therapeutic effect of the medicine into account ➢ design and evaluation of post-authorisation safety studies ➢ pharmacovigilance audit. Inspectors-Activities of the Sector ❖ Coordination of the verification of compliance with the principles of Good Manufacturing Practice (GMP), Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) ❖ PharmacovigilanceCo-coordinating any inspection requested by the CHMP or CVMP ❖ Pharmacovigilance ❖ Vaccine Antigen Master File (VAMF) and Plasma Master File (PMF) certification ❖ Sampling and Testing Programmed ❖ Communication and action by Member States in response to suspected Quality Defects ❖ Responsibility for issuing Certificates of Medicinal Products in accordance with WHO requirements While most scientific activities of the Agency are divided between medicinal products for human and for veterinary use, the tasks of the Inspections Sector are typically common to both types of products. Inspections : EMEA Certificates of Medicinal Products ❖ The EMEA certification scheme is based on World Health Organization (WHO) recommendations ❖ EMEA Certificates are issued by EMEA, on behalf of the European Commission, to confirm the Marketing Authorization status of products ❖ EMEA issues certificates within 10 working days following receipt of a valid application form. Good Clinical Practices-Human Medicinal Products
- 82. 56 ❖ Good ClinicalPractice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. ❖ Compliance with this standard provides public assurance that ➢ the rights, safety and well being of trial subjects are protected ➢ the clinical trial data are credible ❖ Clinical trials included in any marketing authorization application in the EU are required to be conducted in accordance with GCP ❖ The sector is involved in the preparation of new and revised guidance on GCP topics, co-ordination of advice on the interpretation of EU GCP requirements and related technical issues, and on the development of community-wide procedures relating to GCP inspections. ❖ Europe has adopted the ICH-GCP in July 1996 Good Laboratory Practice ❖ The principles of Good Laboratory Practice (GLP) define a set of rules and criteria for a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, reported and archived. ❖ The Procedure describes the co-ordination of GLP inspections of the non- clinical safety, toxicological and pharmacological studies proposed in human and veterinary applications for marketing authorizations under the centralized system. Product Defects and Recalls ❖ In order to protect public health and animal health, it may become necessary to implement urgent measures such as the recall of one or more defective batches of a medicinal product during its marketing period. ❖ Competent Authorities should ensure that information concerning the recall of medicinal products is notified rapidly to other Member States, if the nature of the defect presents a serious risk to public health. ❖ This information is communicated using the Rapid Alert Procedure Sampling and Testing of Centrally Authorized Products ❖ The EMEA implements every year a sampling and testing programme, aimed at supervising the quality of the Centrally Authorized Products (CAPs) available on the European market
- 83. 57 ❖ Annual reportson the outcome of the sampling and testing programme have been published starting with products submitted for testing in 2003. EMEA Implementation of the New EU Pharmaceutical Legislation ❖ These new provisions provide tools to speed up patients’ and healthcare professionals’ access to medicinal products in the Community. ❖ They also introduce measures for better safety monitoring of medicinal products for human and veterinary use New name for the EMEA ❖ As a consequence of the revised EU pharmaceutical legislation, the name of the EMEA changed from the 'European Agency for the Evaluation of Medicinal Products' to the 'European Medicines Agency‘. ❖ The acronym 'EMEA', however, remains unchanged. Contacting the EMEA by E-Mail ❖ General enquiries: [email protected] ❖ Press enquiries: [email protected] ❖ E-mail addresses for EMEA staff members are constructed as follows: [email protected] GMP Guidelines-EMEA Part I - Basic Requirements for Medicinal Products • Chapter 1 - Pharmaceutical Quality System • Chapter 2 - Personnel • Chapter 3 - Premise and Equipment • Chapter 4 - Documentation • Chapter 5 - Production • Chapter 6 - Quality Control • Chapter 7 - Outsourced activities • Chapter 8 - Complaints and Product Recall • Chapter 9 - Self Inspection Part II - Basic Requirements for Active Substances used as Starting Materials • Basic requirements for active substances used as starting materials
- 84. 58 Part III -GMP related documents • Site Master File • Q9 Quality Risk Management • Q10 Note for Guidance on Pharmaceutical Quality System • MRA Batch Certificate • Template for the "written confirmation" for active substances exported to the European Union for medicinal products for human use • Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities • Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use • Template for IMP batch release (applicable as from the date of entry into application of Regulation (EU) No 536/2014 on Clinical Trials) Part IV - GMP requirements for Advanced Therapy Medicinal Products • Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products Other documents related to GMP • Compilation of Community Procedures on Inspections and Exchange of Information updated to include new EU formats and procedures • A revised version of the "Guidelines on Good Distribution Practice of Medicinal Products for Human Use" • Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use
- 85. COMMITTEE FOR THEPURPOSE OF CONTROL AND SUPERVISION OF EXPERIMENTS ON ANIMALS (CPCSEA guidelines) Goals To promote the humane care of animals used in biomedical and behavioral research and testing. To provide quality in gaining advanced biological knowledge that is relevant to humans and animals To provide specifications that will enhance animal well being. 1. Veterinary care Adequate veterinary care must be provided and is the responsibility of a veterinarian. Daily observation. 2. Animal procurement All animals must be acquired lawfully as per the CPCSEA guidelines. A health surveillance program for incoming animals should be carried out to assess animal quality. Inspect for compliance with procurement specifications. 3. Quarantine An effective quarantine minimizes the chance for introduction of pathogens into an established colony. A minimum duration of quarantine Small lab animals - 1 week Larger animals - 6 weeks 4. Stabilization and separation Newly received animals should be given a period for physiological, psychological and nutritional stabilization before their use. Duration for stabilization will depend on the type of animal, transportation and intended use. Physical separation of animals by species is recommended. 5. Surveillance, diagnosis, treatment and control of disease Observe for signs of illness, injury, or abnormal behavior. Unexpected deaths and signs of illness should be reported. If animals are known to be exposed to an infectious agent the group should be kept intact and isolated during the process of diagnosis, treatment, and control. Diagnostic clinical laboratory may be made available.
- 86. 6. Animal careand technical personnel Employ people trained in laboratory animal science. They should be providing for both formal and on-the-job training. 7. Personal hygiene It is essential to maintain a high standard of personal cleanliness. Decontaminate clothing exposed to potentially hazardous microbial agents or toxic substances. Use disposable gear. No permission to eat, drink, smoke or apply cosmetics in animal rooms. 8. Animal experimentation involving hazardous agents Institutional Biosafety Committee. The procedures must be reviewed by both the Institutional Biosafety committee and Institutional Animal Ethics Committee (IAEC). Institutional Biosafety Committee (IBSC) Institutional Biosafety Committee (IBSC) is to be constituted in all centers engaged in genetic engineering research and production activities. 9. Multiple surgical procedures on single animal Multiple surgical procedures not to be practiced unless specified in a protocol only approved by the IAEC. 10. Duration of experiments No animal should be used for experimentation for more than 3 years unless adequate justification is provided. 11. Physical restraint Brief physical restraint can be accomplished manually or with devices. Prolonged restraint of any animal should be avoided unless essential to research objectives. Less restrictive systems, such as the tether system or the pole and collar system should be used when compatible with research objectives. The following are important guidelines for the use of restraint equipments Not be used simply as a convenience in handling or managing animals. Should be given training to adapt to the equipment. Observe the animal at appropriate intervals. Veterinary care should be provided if lesions or illness associated with restraint are observed.
- 87. 12. Physical plant The physical condition and design of animal facility should be well planned and properly maintained. Physical relationship of animal facilities to laboratory Isolated far away from human habitation. Place animal housing areas adjacent to or near laboratories but separated. 13. Functional areas Sufficient animal area required to: Ensure separation of species or isolation of individual projects when necessary; • Receive, quarantine, and isolate animals; • Provide for animal housing. 14. Physical facilites 1.Building material 2.Animal room doors 3.Floors 4.Drains 5.Storage areas 6.Experimental area 7.Corridor 8.Exterior windows Building materials Moisture-proof, fire-resistant, seamless materials are most desirable for interior surfaces including vermin and pest resistance. Corridor Wide enough to facilitate the movement of personnel as well as equipments and should be kept clean. Utilities Water lines, drain pipes and electrical connection Animal room doors Rust, vermin and dust proof it properly within their frames and provided with observation Floors Smooth, moisture proof, non-absorbent, skid-proof.
- 88. Drains Floor drains arenot essential in all rooms used exclusively for housing rodents. Walls and ceilings Free of cracks, unsealed utility penetrations, or imperfect junction with doors, ceilings, floors and corners. Storage areas Separate storage areas should be designed for feed, bedding, cages and materials not in use. Facilities for sanitizing equipment and supplies An area for sanitizing cages and ancillary equipment is essential with adequate water supply. Experimental area Should be carried out in a separate area from the place where animals are housed. 15. Environment air conditioning It is for laboratory animals. Temperature within the range of 180- 290oC. Relative humidity % throughout the year for large animal comfortable zone-18-37°˚c. Power and lighting The electrical system should be safe and provide appropriate lighting and a sufficient no. of power outlets. A time control light system should be used. Noise control Noise free environment. 16. Animal husbandry Caging and housing system Adequate ventilation Meet the biological need of animal Keep the animal dry and clean Cages made of steel or painted steel Feeding and watering devices should be easily accessible for filing, changing, cleaning and servicing.
- 89. 17. Food Shouldbe fed palatable, non-contaminated and nutritionally adequate food. Diet should be free from heavy metals. 18. Bedding Absorbent, free of toxic chemicals or other substances that could injure animals or personnel Should be removed and replaced with fresh materials as often as necessary to keep animal clean and dry. 19. Water Ordinarily animals should have continuous access to fresh, potable. Contaminated drinking water, according to their particular requirements. 20. Sanitation cleanlies Sanitation is essential in an animal facility. Animal rooms, corridors, storage spaces, and other areas should be cleaned with appropriate detergents and disinfectant. 21. Waste disposal Wastes should be removed regularly and frequently. All waste should be collected and disposed in a -safe and sanitary manner. The most preferred method of waste disposal is incineration. 22. Emergency, weekend and holding care Animal should be cared for by qualified personnel every day, including weekends and holidays, to safeguards their well- being including emergency veterinary care. Standard operating procedures (SOP’s) The Institute shall maintain SOPs describing procedures/methods of: • Animal Husbandry • Maintenance • Breeding • Animal house microbial analysis • Experimentation records. 23. Transport of laboratory animals The main considerations for transport of animals are: • Mode of transport • Containers • Animal density in cages • Food and water during transit • Protection from transit infections • Injuries and stress
- 90. 24. Anaesthesia Itmust also be ensured that the anesthesia is given for the full duration of experiment and at no stage the animal is conscious to perceive pain during the experiment. Sedatives, analgesics and anesthetics should be used to control pain or distress under experiment. 25. Euthanasia (Eu =good: Thanatos =death) Purpose End of experiment, to provide tissue for scientific purpose. Free the animal of pain. Diseased animal or animal in bad condition. a. Death, without causing anxiety, pain or distress with minimum time lag phase. b. Minimum physiological and psychological disturbances. c. Compatibility with the purpose of study and minimum emotional effect on the operator. d. Location should be separate from animal rooms and free from environmental contaminants.
- 91. 1 PURCHASE SPECIFICATIONS ANDMAINTENANCE OF STORES FOR RAW MATERIALS What are raw materials: All materials that are used in the manufacturing of the finished bulk and which are consumed by Person using it are called as raw materials. Raw materials can be either active drug or inactive substances. Example: Hard gelatin capsules. INTRODUCTION: Raw materials, including, processing aids, and packaging, are the foundation of finished food products. As such, they must meet not only specifications, but also regulatory requirements. As such, they must meet regulatory requirements (safe and legal for intended use) and specifications. PURCHASE SPECIFICATIONS: DEFINITION: Written guidelines that precisely define the operational, physical and/or chemical characteristics. As well as the quality and quality of a particular item to be acquired. Mode of purchasing: By inspection By sample By description of brand By grading Purchase specifications should be used whenever possible in purchasing. It is concise description of the quality, size and weight required for a particular item. Reasons for preparing specifications: It establishes a buying standard of a commodity It informs the supplier in writing precisely what is required It provides detail information of the goods to the receiving clerk and storekeeper Steps involved in purchase procedure: 1. Purchase requisition 2. Selection of supplies 3. Inviting quotation 4. Placing the order 5. Receiving the order 6. Checking of invoice or bill 7. Recording of bills in books 8. Releasing the payment to the supplier Raw material selection: R & D selects the appropriate raw materials based on functionality. Functionality can holds multiple areas, such as providing identified characteristics of the finished product (binders, thickeners, type of resin for plastic packaging, etc.), organoleptic characteristics (flavour,
- 92. 2 colour, aroma, texture),product safety characteristics (to lower the pH or water activity), and preservatives (extension of shelf life, colour, or flavour retention, etc.) Specifications for Raw materials and content of ingredients: This should contain the following information: 1. Name of the material 2. A description of the material, including biological, chemical, and physical characteristics. 3. Composition of the material, including additives and processing aids 4. Method of production 5. Packaging format/s or unit of measure 6. Delivery method/s 7. A description of labelling, lot ID 8. Storage conditions & shelf life 9. Preparation &/or handling before use 10. Acceptance & rejection criteria 11. Special requirements such as allergen information, organic status, GMO status, fair- trade & ethical sourcing policies 12. Information about compliance with statutory and regulatory requirements, where relevant 13. A requirement for suppliers to notify of any authenticity issues with the product 14. A requirement for suppliers to notify of any changes to the product 15. Formal agreement between the supplier and purchaser 16. Document control features, such as author, date & page numbers Food: grade, weight, quality, packaging, nutrition standards, delivery requirement etc. Supplies: size, quality, packaging etc. Equipment: utility and space requirements, quality and features required, installation requirements Services: certifications, licenses, etc. Specifications may be written with qualitative characteristics that are likely to be met by local products, i.e., specifying fresh foods (harvested within a 24 to 48 hours of delivery) MAINTENANCE OF STORES Location of stores: The stores should be located adjacent to the manufacturing area. The location depends upon the nature and value of items to be stored and the frequency with which items are received and issued Objectives of store location: 1. Minimum wastage of space 2. Maximum ease of operations 3. Minimum handling costs 4. Minimum other operating costs Storage area specifications: 1. Sufficient capacity 2. Clean, dry & maintained within acceptable temp, limit 3. Designed & equipped reception area
- 93. 3 4. Ensuring ofquarantine status 5. Separate sampling area 6. Segregation for storage of rejected, recalled or returned material 7. Safe and secure area for narcotics & highly active, dangerous & risky material 8. First in First out rule (FIFO) 9. First Expiring First Out (FEFO) Facilities: 1. Inspection centre 2. Space for storing retained samples for quality control 3. Centralised weighing room 4. Wash room quarantine room Storage conditions: 1. Room temp should be 300 C 2. Low temp storage 2-80 C 3. Light sensitive material in amber colour container Labelling of material in storage area: 1. Designated name of product and internal code reference 2. Batch no. given by supplier 3. Status of content expiry date or date beyond which retesting is necessary IN PROCESS QUALITY CONTROL (IPQC) AND FINISHED PRODUCTS QUALITY CONTROL (FPQC) FORMULATION IN PHARMA INDUSTRY ACCORDING TO IP, USP, BP IPQC: IPQC is concerned with providing accurate, specific, and definite description of procedures to be employed from the receipt of raw materials to the release of finished dosage forms IPQC procedures are generally quick, simple and rapid tests or inspection that carried out at ongoing manufacturing It is a planned system to identify the materials, equipment, process & operation Importance/need of IPQC tests: 1. To detect errors 2. To minimize the human errors 3. Provides accurate, specific, and definite description of procedures to be employed 4. Rigidly followed 5. Should detect any abnormality immediately & at the same time indicate the kind of action needed to correct the problem 6. To enforce the flow of manufacturing & packing operations according to established routes & practice TESTS FOR TABLETS OFFICIAL TESTS: 1. Uniformity of container contents 2. Content of active ingredients 3. Uniformity of content
- 94. 4 4. Uniformity ofweight 5. Dissolution 6. Disintegration NON-OFFICIAL TESTS: 7. Hardness 8. Friability 1. UNIFORMITY OF CONTAINER CONTENTS/ CONTENTS OF PACKAGED DOSAGE FORMS (IP) This test & specifications apply to oral dosage forms & preparations intended for topical use that are packaged in containers in which the labelled net qnty is NMT 100g or 300ml or 1000units Test method Select a sample of 10 containers & count the no. of tablets in each container The avg. no. of the contents in the 10 containers NLT the labelled amt & the no. in any single container is NLT 98% & NMT 102% of the labelled amt If the requirements are not met, count the no. of the contents in 10 additional containers The avg. no. of the contents in the 20 containers NLT the labelled amt & the no. in NMT 1 of the 20 containers is LT 98% or MT 102% of the labelled amt None of individual weights deviate by MT twice that of respective minimum & maximum %age limits 2. UNIFORMITY OF CONTENT I. This test is applicable to tablets that contain 10mg or LT 10mg or LT 10% w/w of active ingredient (as per IP) II. This test is applicable to tablets that contain LT 25mg or LT 25% w/w of active ingredient (as per BP/USP) III. For tablets containing MT one ingredient carry out the test for each active ingredient that corresponds to the above conditions IV. The test is also applicable to coated tablets other than film coated tablets, irrespective of their content of active substance/s V. The test for uniformity of content should be carried out only after the content of active ingredient/s in a pooled sample of the tablets has been shown to be within accepted limits of the stated content VI. The test for uniformity of content is not applicable to tablets containing multivitamins and trace elements VII. The test for uniformity of content of single dose preparations is based on the assay of the individual contents of active substance/s of a no. of single dose units to determine whether the individual contents are within limits set with reference to the avg. content of the sample Method: Determine the content of active ingredient/s in each of 10 dosage units taken at random using the method given in the monograph or by any other suitable analytical method of equivalent accuracy & precision
- 95. 5 Acceptance limits:The preparation complies with the test if each individual content is 85 to 115 percent of the avg. content. The preparation fails to comply with the test if MT one individual content is outside these limits or if one individual content is outside the limits of 75 to 125 percent of the avg. content. If one individual content is outside the limits of 85 to 115 percent of the avg. content but within the limits of 75 to 125 percent, repeat the determination using another 20 dosage units. The preparation complies with the test if NMT one of the individual contents of the total sample of 30 dosage units is outside 85 to 115 percent of the avg. content & none is outside the limits of 75 to 125 percent of the avg. content 3. UNIFORMITY OF WEIGHT OF SINGLE-DOSE PREPARATIONS (IP/BP/USP) Weigh individually 20 units selected at random or, for single dose preparations in individual containers, the contents of 20 units, and calculate the avg wt. NMT 2 of the individual wts deviate from the avg wt. by MT the %age shown in the table & none deviates by MT twice that %age Weight variation limits for uncoated tablets: As per USP: S. no Average wt. of tablets (mg) Maximum % difference allowed 1 130 or less 10% 2 130- 324 7.5% 3 More than 324 5% As per IP: S. no Average wt. of tablets (mg) Maximum % difference allowed 1 84 or less 10% 2 84- 250 7.5% 3 More than 250 5% 4. DISINTEGRATION TEST: For the purpose of this test, disintegration does not imply complete solution of the dosage unit or even of its active constituent Disintegration is defined as that state in which no residue of the unit under test remains on the screen of the apparatus or, if a residue remains, it consists of fragments of disintegrated parts of capsule component parts such as insoluble coating of the capsule shells, or of any melted fatty substance from the pessaries or suppository or is a soft mass with no palpable core If discs have been used with capsules, any residue remaining on the lower surface of the discs consists only of fragments of shells 28- 32 cycles (strokes) per minute – IP 29- 32 cycles (strokes) per minute – BP/USP
- 96. 6 Method: Unless otherwisestated in the individual monograph, introduce one tablet or capsule into each tube &, if directed in the appropriate general monograph, add a disc to each tube. Suspend the assembly in the beaker containing the specified liquid & operate the apparatus for the specified time Remove the assembly from the liquid. The tablets or capsules pass the test if all of them have disintegrated If 1 or 2 tablets or capsules fail to disintegrate, repeat the test on 12 additional tablets or capsules; NLT 16 of the total of 18 tablets or capsules tested disintegrate If the tablets or capsules adhere to the disc & the preparation under examination fails to comply, repeat the test omitting the disc. The preparation complies with the test if all the tablets or capsules in the repeat test disintegrate Disintegration testing condition and interpretation as per IP: S. No Type of tablets Medium Temperature Limit 1 Uncoated Water/buffer 37º ± 2ºC 15 min or as per individual monograph 2 Film coated Water 37º ± 2ºC 30 min or as per individual monograph 3 Sugar coated Water/0.1N HCl 37º ± 2ºC 60 min or as per individual monograph 4 Dispersible tablets Water 25º ± 1ºC 3 min or as per individual monograph 5 Effervescent tablets Water 25º ± 5ºC 5min or as per individual monograph 6 Enteric-coated tablets 0.1M HCl mixed phosphate buffer pH 6.8 37º ± 2ºC 2hrs in HCl: no disintegration 60min in buffer: disintegrate 7 Soluble tablets Water 20º ± 5ºC 3minutes Disintegration testing condition and interpretation as per BP: S. No Type of tablets Medium Temperature Limit 1 Uncoated Water/buffer 37º ± 2ºC 15 min or as per individual monograph 2 Film coated Water 37º ± 2ºC 30 min or as per individual monograph 3 Sugar coated Water/0.1N HCl 37º ± 2ºC 60 min or as per individual monograph
- 97. 7 4 Dispersible tabletsWater 20º ± 5ºC 3 min or as per individual monograph 5 Effervescent tablets Water 20º ± 5ºC 5min or as per individual monograph 6 Enteric-coated tablets 0.1M HCl mixed phosphate buffer pH 6.8 37º ± 2ºC 2hrs in HCl: no disintegration 60min in buffer: disintegrate 7 Soluble tablets Water 20º ± 5ºC 3minutes Disintegration testing condition and interpretation as per USP: S. No Type of tablets Medium Temperature Limit 1 Uncoated Water/as specified in monograph 37º ± 2ºC As per individual monograph 2 Coated Water/as specified in monograph 37º ± 2ºC As per individual monograph 3 Enteric-coated tablets Simulated gastric fluid TS Simulated intestinal fluid TS 37º ± 2ºC 1hr in Simulated gastric fluid TS: no disintegration 2hrs in Simulated gastric fluid TS: disintegration As per individual monograph: Simulated gastric fluid TS 4 Buccal tablets Water/as specified in monograph 37º ± 2ºC 4hrs 5 Sublingual tablets Water/as specified in monograph 37º ± 2ºC As per individual monograph 5. DISSOLUTION TEST: Use apparatus 1 unless otherwise directed Use the dissolution medium specified in the individual monograph. If the medium is a buffered solution, adjust the solutionso that its pH is within 0.05 units of the pH specified in the monograph
- 98. 8 Time: wherea single time specification is given in the monograph, the test may be concluded in a shorter period if the requirement for the minimum amt dissolved is met. If 2 or more times are specified, specimen are to be withdrawn only at the stated times, within a tolerance of ± 2 percent. Assemble the apparatus & warm the dissolution medium to 36.5º ± 37.5ºC unless otherwise stated Within the time interval specified, or at each of the times stated, withdrawn a specimen/ sample from a zone midway between the surface of the dissolution medium & the top of the rotating blade or basket, NLT 10 min from the wall of the vessel Except in the case of single sampling, add a volume of dissolution medium equal to the volume of the samples withdrawn Perform the analysis as directed in the individual monograph Acceptance criteria: Conventional- release dosage forms (IP) Unless otherwise specified, the requirements are met if the quantities of active substance dissolved from the dosage units conform to table below. If the results do not conform to the requirements at stage S1 given in the table, continue testing with additional dosage units through stages S2 and S3 unless the results conform at stage S2 Level Number tested Acceptance criteria S1 6 Each unit is NLT D* + 5 percent** S2 6 Avg. of 12 units (S1+ S2) is equal to or greater than D, & no unit is LT D- 15 percent** S3 12 Avg. of 24 units (S1+ S2+S3) is equal to or greater than D, not, MT 2 units are less than D- 15 percent** and no unit is less than D- 25 percent** D* is the amount of dissolved active ingredient specified in the individual monograph expressed as a percentage of the labelled content. ** percentage of the labelled content Conventional- release dosage forms (BP/USP) Unless otherwise specified, the requirements are met if the quantities of active substance dissolved from the dosage units conform to table below. continue testing though the 3 levels unless the results conform at either S1 or S2 The quantity Q, is the specified amt of dissolve active substance, expressed as a %age of the labelled content; the 5%, 15% and 25% values in the table are %ages of the labelled content so that these values and Q are in the same terms.
- 99. 9 Level Number tested Acceptance criteria S16 Each unit is NLT Q + 5 percent S2 6 Avg. of 12 units (S1+ S2) is equal to or greater than Q, & no unit is LT Q - 15 percent S3 12 Avg. of 24 units (S1+ S2+S3) is equal to or greater than Q, not, MT 2 units are less than Q - 15 percent, and no unit is less than Q- 25 percent Dissolution testing condition and interpretation (IP) S. No Type of tablets Medium Temperature Limit 1 Uncoated Water/buffer 37º ± 5ºC As per individual monograph or as per tablets shown before 2 Film coated Water 37º ± 5ºC As per individual monograph or as per tablets shown before 3 Sugar coated Water/0.1N HCl 37º ± 2ºC As per individual monograph or as per tablets shown before 4 Enteric-coated tablets 0.1M HCl mixed phosphate buffer pH 6.8 37º ± 2ºC 2hr in HCl & 60min in buffer As per individual monograph or as per tablets shown before 5 Prolonged-release tablets Water/buffer 37º ± 2ºC As per individual monograph or as per tablets shown before 6. FRIABILITY: Friability of a tablet can determine in laboratory by Roche friabilator. This consists of a plastic chamber that revolves at 25rpm, dropping the tablets through a distance of 6 inches in the friabilator, which is then operate for 100 revolutions. The tablets are reweighed. Compress tablet that lose LT 0.5 to 1% of the tablet weigh are consider acceptable. It is the tendency of the tablet to powder, chip or fragment and this can affect the elegance, appearance, consumer acceptance of the tablet, & also add to tablets wt. variation or content uniformity problems Friability is a property that is related to the hardness of the tablet
- 100. 10 An instrumentcalled Roche friabilator is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, shipping Procedure: Weigh 20 tablets together = W1 Put these tablets in the friabilator & adjust the instrument at 100rpm (i.e., 25rpm for 4min) Weigh the tablets (only the intact ones) =W2 Friability (%loss) = W1-W2/100 It must be LT or = 1% but if more we do not reject tablets as this test is non-official Perform this test using 20 tablets that were used first in the wt. variation test 7. HARDNESS: Tablet requires a certain amt of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging, and shipping. Hardness generally measures the tablet crushing strength Hardness is the load required to crush the tablet when placed on its edge Reasons to measure hardness because: To determine the need for pressure adjustments on the tableting machine Hardness can affect the disintegration So, if the tablet is too hard, it may not disintegrate in the required period of time & if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging In general, if the tablet hardness is too high, we first check its disintegration before rejecting the batch If the disintegration is within the limit, we accept the batch If hardness is high+ disintegration is within a time accept the batch Factors affecting the hardness: Compression of the tablet and compressive force Amt of binder (more binder, more hardness) Method of granulation in preparing the tablet (wet method gives more hardness than direct method, slugging method gives the best hardness) Limits: 5 kilograms minimum and 8 kilograms maximum or 80 N Make hardness test on 5 tablets and then the avg. hardness Normal tablet hardness ranges from 4 – 6 kgs however certain tablets like Lozenges, buccal tablets that are intended to dissolve slowly show deliberate higher hardness value. For floating tablets, the hard ness should be low. Different hardness testers are: Monsanto, Pfizer, Strong-cobb, Erweka, schleuniger OTHET TESTS: 8. General appearance: The general appearance of a tablet, its identity and general elegance is essential for consumer acceptance, for control of lot-to-lot uniformity and tablet-to-tablet uniformity. The control of general appearance involves the measurement of size, shape, colour, presence or absence of odour, taste etc.,
- 101. 11 9. Size andShape The size and shape of the tablet should be according to need of the dose requirement and can be dimensionally described monitored and controlled. It is determined by the tooling during the compression processes. 10. Colour and Odour For ease of identification many pharmaceutical tablets use colour and it also helpful for consumer acceptance. But it must be uniform with no mottling, within a single tablet, from tablet to tablet and from batch to batch. Stability problem may be indicated by odour in batches of tablets e.g. vitamins have a characteristic odour. For the chewable tablet taste is importance factor for consumer acceptance 11. Unique Identification Markings Pharmaceutical companies often use some type of unique markings on tablets in addition to colour, for rapid identification of their product these markings utilize some form of embossing, engraving or printing of the company name or symbol or a product code. 12. Thickness The thickness of a tablet is the only dimensional variable related to the process; Thickness of tablets measured by a micro-meter. Other techniques involve placing 5 or 10 tablets in a holding tray, where their total thickness may be measured by a sliding caliper scale or Vernier caliper/ screw gauge. Thickness of tablet should be controlled within a ± 5 % variation of a standard. Thickness must be controlled to facilitate packaging. It is expressed in mm or cm. 13. Moisture Content of Granules Granules should possess sufficient strength to withstand normal handling and mixing processes without breaking down and producing large amounts of fine powder. On the other hand, some size reduction during compaction into tablets is desirable to expose the areas of clean surface necessary for optimum bonding to take place so moisture content is the very important factor for producing good pharmaceutical product. TESTS FOR CAPSULES 1. Appearance: Appearance of capsule must be uniform. For detect of any flaws in the integrity and appearance of the capsule, visual or electronic inspection should be undertaken. Evidence of physical instability is demonstrated by gross changes in appearance, including hardening or softening, cracking, swelling, mottling, printing mistake or discoloration of the shell. Defective capsules should be rejected. 2. Size and Shape: Hard capsules are made in a range of sizes, the standard industrial range of size for capsule is from 000 (the largest, 1.40 ml) to 5 (the smallest, 0.13 ml) are commercially available. Soft gel capsules are available in variety of shapes such as spherical (0.05–5 ml), ovoid (0.05–7 ml), cylindrical (0.15– 25 ml), tubes (0.5–0 ml), pear (0.3–5 ml) etc.
- 102. 12 3. Unique IdentificationMarkings Capsule surfaces may bear symbols or other unique identification markings for better identification. 4. Assay In a capsule an active ingredient is present which is called API. So to prepare the capsule assay has to be done by using suitable analytical method to produce good finished product. 5. Content of Active Ingredients For this test a sample of the contents is assayed as described in individual monographs and calculates the amount of active ingredient in each capsule. According to IP the range for the content of active ingredient stated in the monograph is based on the requirement that 20 capsules, or such other number as may be indicated in the monograph, are used in the assay. In the circumstances where 20 capsules cannot be obtained, a smaller number, which must not be less than 5, may be used, but to allow for sampling errors the tolerances are widened in accordance with Table IP limits for content of active ingredients 6. UNIFORMITY OF CONTENT: Same procedure as in tablets up to method (except IV point- not necessary) Acceptance limits: The preparation complies with the test if NMT 1 individual content is outside the limits of 85 to 115% of avg. content & none is outside the limits of 75 to 125% of the avg. content The preparation fails to complies with the test if MT 3 individual contents are outside the limits of 85 to 115% of avg. content or if 1 or more individual contents are outside the limits of 75 to 125% of avg. content If 2 or 3 individual contents are outside the limits of 85 to 115% of avg. content but within the limits of 75 to 125%, repeat the determination using 20 dosage units Wt. of active ingredients in each capsule (g) Subtract from lower limit for sample of Add to upper limit for sample of 15 10 5 15 10 5 0.12 or less 0.2 0.7 1.5 1.5 0.8 1.8 More than 0.12 Bust less than 0.3 0.2 0.5 1.2 0.3 0.6 1.5 0.3 or more 0.1 0.2 0.8 0.2 0.4 1.0
- 103. 13 The preparationcomplieswith the test if NMT 3 individual contents of the total sample of 30 dosage units is outside the limits of 85 to 115 percent of the avg. content & none is outside the limits of 75 to 125 percent of the avg. content 7. DISINTEGRATION TEST: same as tablets till method Disintegration testing condition and interpretation as per IP: S. No Type of capsule Medium Temperature Limit 1 Hard gelatin Water/buffer 37º ± 2ºC 30 min or as per individual monograph 2 Soft gelatin Water 37º ± 2ºC 60 min or as per individual monograph 3 Enteric-coated 0.1M HCl mixed phosphate buffer pH 6.8 37º ± 2ºC 2hrs in HCl: no disintegration 60min in buffer: disintegrate Disintegration testing condition and interpretation as per BP: S. No Type of capsule Medium Temperature Limit 1 Hard gelatin Water/0.1M HCl/artificial gastric juice R 37º ± 2ºC 30 min or as per individual monograph 2 Soft gelatin Water/0.1M HCl/artificial gastric juice R 37º ± 2ºC 60 min or as per individual monograph 3 Enteric-coated 0.1M HCl mixed phosphate buffer pH 6.8 37º ± 2ºC 2hrs in HCl: no disintegration 60min in buffer: disintegrate 8. WT. VARIATION TEST: For hard gelatin capsules I. Weigh 20 capsules individually an determine the avg. wt. II. The individual weights should be within limit of 90-110% of avg. wt. III. If not all of the capsules fall within the limits, weigh 20 capsules individually IV. Remove the net content of each capsule with the aid of a small brush. V. Weigh the empty shells individually VI. Determine the avg. net content from the sum of individual net wt. VII. To determine the difference b/w each individual net content & avg. net content Net wt. of contents individually = The wt. of shell-gross wt. Limits: NMT 2 of the differences are GT 10% of the avg. net content No case is the difference GT 25% wt. range If MT 2, but NMT 6 capsules deviate from the avg. wt. b/w 10-25%
- 104. 14 WT. VARIATION TEST:For soft gelatin capsules Weigh capsules individually then cut & open the capsules Remove the contents by washing with the suitable solvent Allow the solvents to evaporate from the shells at room temp. Weigh the individual shells Calculate the net content Avg. wt. of capsule %age deviation LT 300mg 10 300mg or more 7.5 9. DISSOLUTION TEST: IP: Type II apparatus(basket), BP/USP: Type I apparatus (basket) The capsule is placed in a basket, & the basket is immersed in the dissolution medium & caused to rotate at a specified speed The dissolution medium is held in a covered 1000ml glass vessel & maintained at 37º ± 0.5ºC by means of a constant temp suitable water bath The stirrer speed & type of dissolution medium are specified in the individual monograph Dissolution tables: same as in tablets Comparison of specifications & parameters Tests IP BP USP Drug content uniformity 85-115% 85-115% 90-110% Content uniformity 85-115% 85-115% 85-115% Disintegration time: Hard gelatin Soft gelatin Enteric-coated LT 30 min LT 60 min 2hrs in HCl: no disintegration 60min in buffer: disintegrate LT 30 min LT 60 min 2hrs in HCl: no disintegration 60min in buffer: disintegrate LT 30 min LT 60 min NS Gastro resistant 60 60 60 Dissolution test GT 70% GT 70% GT 70%
- 105. 15 TESTS FORPARENTERALS 1. CONDUCTIVITY MEASUREMENT: Conductivity is measured by conductometer It measures the conductivity of vehicle used in sterile preparation Conductivity of pure water is 0.55 micro siemens/cm 2. PH MEASUREMENT: 2 methods are pH is measured by using a pH meter. pH meter is initially calibrated with respective buffer capsule then the pH of the preparation is measured. Dip a piece of pH paper into the sample 3. TEMPERATURE FOR HEAT STERILIZATION: It is imp to maintain the constant temp during heat sterilization of product The temp changes may cause some undesirable changes like change in potency, change in isotonicity The temp can be determined by normal thermometer 4. VOLUME FILLED: Volume in container An injection container is filled with a volume in slight excess of the labelled size Physical and chemical tests. Determination of filled volume: 10 mL or more: 1 container 3-10 mL: 3 containers Less than 3 mL: 5 containers 5. STERILITY TEST: Sterility can be defined as the freedom from the presence of viable microorganisms. It is done for detecting the presence of viable forms of bacteria, fungi and yeast in parenteral products. The test for Sterility must be carried out under strict aseptic conditions in order to avoid accidental contamination of the product during test. All glassware's required for the test must be Sterile. Sterility testing attempts to reveal the presence or absence of viable microorganisms in a sample number of containers taken from batch of product. Based on results obtained from testing the sample a decision is made as to the sterility of the batch.
- 106. 16 Major factors ofimportance in sterility testing: The environment in which the test is conducted The quality of the culture conditions provided The test method The sample size The sampling procedure Culture media used for sterility testing Strains of the microorganisms used for the test as per IP/BP/USP: Medium Test micro organism Incubation Temp (ºC) Duration (days) Type of micro organism Fluid thioglycolate (FTM) Bacillus subtilis 30-35 3 Aerobic Staphylococcus aureus 30-35 3 Aerobic Pseudomonas aeruginosa 30-35 3 Aerobic Alternate thioglycolate Bacteroides vulgates 30-35 3 Anaerobic Clostridium sporogenes 30-35 3 Anaerobic Soybean casein digest Aspergillus niger 20-25 5 Aerobic Candida albicans 20-25 5 Aerobic Composition of FTM: L-cysteine, trypticase peptone, dextrose, yeast extract, sodium chloride, sodium thioglycolate, resazurin, agar, purified water, final pH 7.1 Composition of Soybean casein digest: Trypticase soya broth, trypticase peptone, phytone peptone, sodium chloride, dipotassium phosphate, dextrose, purified water, final pH 7.3 Sterility test methods: 1. Direct inoculation method: Selection of filters for membrane filtration: Pore size of 0.45μ effectiveness established in the retention of microorganism’s appropriate composition the size of filter discs is about 50 mm in diameter The procedure of membrane filtration Sterilization of filtration system and membrane filtration of examined solution under aseptic conditions. Filtration of the sample through a membrane filter having the nominal size of 0.45μ and a diameter of 47mm. After filtration the membrane is removed aseptically from the metallic holder and divided into two halves.
- 107. 17 The firsthalf is transferred into 100 ml of culture media meant for fungi and incubated at 20˚ to 25 ˚c for not less than seven days. The other half is transferred into 100ml of fluid thioglycolate medium and incubated at 30 to 35 ˚c for not less than 7 days. Advantages of membrane filtration over direct inoculation method Greater sensitivity: The entire contents can be tested providing an advantage in the sterility testing of LVP and increasing the ability to detect contamination. The antimicrobial agent and antimicrobial solutes in the product sample can be eliminated by rinsing prior transferring the filter into test tubes of media Thereby minimizing the incidence of false-negative test results. Organisms present in an oleaginous product can be separated from the product during filtration and cultured in a more desirable aqueous medium. Disadvantages: This method cannot differentiate the extent of contamination between units if present because all product contents are combined and filtered through a single filter and cultured in single test tube. There exists a higher probability of inadvertent contamination in manual operations. Samples size to be taken: 2. Direct inoculation method Required quantities of liquid is removed from the test containers with a sterile pipette / sterile syringe. Aseptically transfer the specified volume of the material from each container to vessel of culture medium Mix the liquid with medium but not aerate excessively. Incubate the inoculated media for not less than 14 days, unless otherwise specified in the monograph at 300c - 350c in the case of fluid thioglycolate medium and 200c - 250 c for soybean casein digest medium. When materials examined renders the medium turbid so presence / absence of microbial growth cannot be determined readily by visual examination transfer suitable
- 108. 18 portions of mediumto fresh vessels of the same medium between 3 rd. and 7 th day after test is started. Continue incubation of the transfer vessel for not less than 7 additional days after transfer and total of NLT 14 days. Interpretation of results At the end of the incubation period the following observations are possible: No evidence of growth; hence the preparation being examined passes the test for sterility. If there is evidence of growth, retesting is performed using the same number of samples, volumes to be tested and the media as in the original test. If no evidence of microbial growth is then found, the preparation being examined passes the test for sterility. If there is again evidence of the microbial growth then isolate and identify the organisms. If they are not readily distinguishable from those growing in the containers of the first test then the preparation being examined fails the test for sterility. If they are distinguishable from the organisms of the first test then again do the test using twice the number of samples. The preparation being examined passes the test for sterility in case there is no evidence of microbial growth. In case there is evidence of growth of any microorganisms in second re –test, the preparation being examined fails the tests for sterility. Minimum quantity to be used for each medium Quantity in each container of injectable preparation (for liquids) Minimum quantity to be used for each culture medium LT 1ml Total contents of the container 1ml or more but LT 40ml Half the contents of the container 40ml or more but LT 100ml 20ml 100ml or more 10% of the contents of the container but NLT 20ml Antibiotic liquids 1ml 6. PYROGEN TEST (2 tests) Pyrogen: “Pyro” (Greek = Fire) + “gen” (Greek = beginning). Fever producing, metabolic by-products of microbial growth and death. Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi. Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates. Stable to at least 175ºC; steam sterilization ineffective. Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm) so endotoxins can easily pass through 0.22μm filters. Sources: Water (main), raw materials, equipment, process environment, people, and protein expression systems if using gram negative bacteria. Other Source: Equipment, Containers (Glass, plastic, metal), Solvent and Solute.
- 109. 19 Elimination of pyrogens: I.Dry heat sterilization: For glass wares, metal equipment’s, powders, waxes, oils, heat stable drugs. II. 650º C temp - 1 min III. 250º C temp - 30 min IV. 180º C temp - 240 min V. Ultra-filtration VI. Reverse osmosis: RO membrane is composed of cellulose acetate phthalate/ polyamide VII. Distillation VIII. Adsorption method A) Rabbit Test (in-vivo) 2 types: preliminary test (sham test) Main test This test basically involves the injection Sample solution which is to be tested into a Rabbits which are used as test animals through ear vein. The Temperature sensing probe (Clinical Thermometer, Thermosestor or similar probe) into a rectum cavity of Rabbit at the depth of 7.5 cm, the test solution must be warmed at 37º prior to injection. Then Rectal temperature is recorded at 1, 2, 3 hr subsequent to injection. This test is performed in separate area designed solely for this purpose under environmental conditions similar to animal house should be free from disturbances that likely to excite them. Initially this test is performed on 3 Rabbits but if required results are not obtained this test is repeated on 5 additional Rabbits with same sample solution administer to initial 3 rabbits. Prior to 1hr of injecting sample solutions the control temperatures of rabbits are determined. Use only those rabbits whose control temperature is no vary by more than 1ºc. Interpretation of Result (Rabbit Test)
- 110. 20 Results for pyrogentest according to IP, BP, USP Pharmacopoeia No. of rabbits in a grp Passes if temp is not more than Fails if temp is more than IP 3 8 1.4 3.7 Each rabbit temp raise should not be MT 0.6ºC BP 3 6 9 12 1.15 2.80 4.45 6.6 2.65 4.30 5.95 6.6 USP 3 8 _ 3.3 Each rabbit temp raise should not be MT 0.6ºC B. Bacterial endotoxin test(in-vitro) LAL (Limulus Amoebocyte Lysate) test is used to characterize the bacterial endotoxin that may be present. The USP reference standard contains 10,000 USP endotoxins per vial. The LAL reagent is used for gel-clot formation. The test is performed using stated amounts of volumes of products, standard, positive control, negative control of endotoxin. The tubes are incubated at 37±1ºC FOR 60 ±2 minutes. When the tubes are inverted at 180ºC angle, formation of firm gel confirms positive reaction. While formation of a viscous gel that doesn't maintain its integrity or absence of a firm gel confirms negative reaction. The test is invalid if the standard endotoxin or positive product control doesn't show end point within ± 1. Two-fold dilution from label claim sensitivity of LAL reagent or if the negative control shows gel-clot end point. The following methods can be used to monitor the endotoxin concentration: Method A - Gel- clot limit test method Method B -Semi quantitative gel clot method Method C - Kinetic turbidimetric method Method D - Kinetic chromogenic method Method E - End point chromogenic method 7. CLARITY TEST A. Visual inspection by naked eye: Clarity testing is carried out to check the particulate matter in the sample. In this test transparent particles or white particles observed against the black background and the black or dark particles observed against the white background. B. Coulter counter method The sample solution is added to an electrolyte solution which is drawn through a small orifice As particle passes through the orifice it displaces its own volume of electrolyte Particle detected by the increase in electrical resistance Voltage pulses are proportional to the particle size Particles below 0.2µm can also be detected
- 111. 21 8. PARTICULATE MATTERIN INJECTIONS The preparations intended for parenteral use should be free from particulate matter and should be clear when inspected visually. Two methods are described by USP according to the filled volume of the product to be tested. For large volume parenteral’s (LVP's), a filtration followed by microscopical examination procedure is used. For small volume parenteral’s (SVP's) a light obscuration-based sensor containing electronic liquid borne particle counter system is used. The USP standards are met if the LVP's under test contain NMT 50 particles per ml of 10μ m, and NMT 5 particles per ml of 25μm in an effective linear dimensional fashion. The USP standards are met if the SVP's under test contain NMT 10,000 particles per container of 10 μm, and NMT 1000 particles per container of 25μm in an effective spherical diameter. Limits of detection of subvisible particulate matter as prescribed in IP, BP, USP Particle size SVP LVP ≥10µm 3000/container 12/ml ≥25µm 300/container 2/ml 9. LEAKAGE TEST (visual inspection, bubble test, dye tests and vacuum ionization test) Leakage test is employed to test the package integrity. Package integrity reflects its ability to keep the product in and to keep potential contamination out”. It is because leakage occurs when a discontinuity exists in the wall of a package that can allow the passage of gas under pressure or concentration differential existing across the wall. Leakage test can be done by dye bath test. Dye Bath Test The test container is immersed in a dye bath. Vacuum and pressure is applied for some time. The container is removed from the dye bath and washed. The container is then inspected for the presence of dye either visually or by means of UV spectroscopy. The dye used may be of blue, green, yellowish-green colour. The dye test can be optimized by use of a surfactant and or a low viscosity fluid in the dye solution to increase the capillary migration through the pores. The dye test is widely accepted in industry and is approved in drug use. The test is inexpensive and is requires no special equipment required for visual dye detection. However, the test is qualitative, destructive and slow. The test is used for ampoules and vials. 10. CONTENT UNIFORMITY AND WEIGHT Determine the content of the active ingredient of each of 10 containers taken at random. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 percent of the average value. The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 percent of the average value or if any one individual value is outside the limits 75 to 125 percent of the average value. If one individual value is outside the limits 85 to 115 percent but within the limits 75 to 125 percent of the average value, repeat the determination using another 20 containers taken at random. The preparation under examination complies with the test if in the total sample of 30 containers not more than one individual value is outside the limits 85 to 115 percent and none is outside the limits 75 to 125 percent of the average value.
- 112. 22 Limits for Uniformityof Weight: Pharmaceutical Formulation Average Mass Percentage Deviation (%) Powders for parenteral use More than 40 mg 10 Powders for eye drops Less than 300 mg 10 Powders for eye lotions 300 mg or more 7.5 11. Extractable Volume a) Single Dose Containers Method I: Where the nominal volume does not exceed 5ml. Use 6 containers, 5 for the tests and 1 for rinsing the syringe used. Using a syringe with appropriate capacity, rinse the syringe and withdraw as much as possible the contents of one of the containers reserved for the test and transfer, without emptying the needle, to a dry graduated cylinder of such capacity that the total combined volume to be measured occupies not less than 40% of the nominal volume of the cylinder. Repeat the procedure until the contents of the 5 containers have been transferred and measure the volume. The average content of the 5 containers is not less than the nominal volume and not more than 115% of the nominal volume. Alternatively, the volume of contents in millilitre can be calculated as mass in grams divided by the density. Method II: Where the nominal volume is more than 5ml. Transfer the contents of not less than 3 containers separately to dry graduated cylinders such that the volume to be measured occupies not less than 40% of the nominal volume of the cylinder and measure the volume transferred. The contents of each container are not less than the nominal volume and not more than 110% of the nominal volume. Limits for extractable volume as per BP, USP Volume of solution No. of containers to be used for the test ≥ 10ml 1 3-10ml 3 ≤ 3ml 5 Other Quality Control Test Test Apparatus pH pH Meter Viscosity Ostwald viscometers Osmolality Osmometer (count of the number of particles in a fluid sample) Conductivity Conductometer (conductivity of vehicle used in sterile preparation) (Pure Water 0.55mS/cm) Temperature for Heat Sterilization Thermometer, Digital Thermometer (To maintain the constant temperature during heat sterilization of product)
- 113. 23 TESTS FOROINTMENTS 1. UNIFORMITY OF WEIGHT: Select a sample of 10 filled containers & remove any labelling that might be altered in wt. while removing the contents of the containers Clean & dry the outer surfaces of the containers & weigh each container Remove quantitatively the contents from each container If necessary, cut open the container & wash each empty container with suitable solvent, taking care to ensure that the closure & other parts of the container are retained Dry & again weigh each empty container together with its parts which may have been removed. The difference b/w the 2 weights is the net wt. of the contents of the container Limits: The avg. net wt. of the contents of the 10 containers is NLT the labelled amt & the net wt. of the contents of any single containers is NLT 91% & NMT 109% of the labelled amt where the labelled amt is 50g or less, or NLT 95.5% & NMT 104.5% of the labelled amt where the labelled amt is MT 50g but NMT 100g If this condition is not met, determine the net wt. of the contents of the 10 additional containers, the avg. net wt. of the contents of the 20 containers is NLT the labelled amt & the net wt. of the contents of NMT 1 of the 20 containers is LT 91% or MT 109% of the labelled amt where the labelled amt is 50g or less, or LT 95.5% or MT 104.5% of the labelled amt where the labelled amt is MT 50g but NMT 100g 2. STERILITY: No. of containers in the batch Minimum no. of containers recommended to be tested NMT 200 containers 5% or 2 containers, whichever is greater MT 200 containers 10 containers Fluid A: Dissolve 1g of peptic digest of animal tissue (eg: bacteriological peptone) or its equivalent in water to make 1litre, filter or centrifuge to clarify, adjust to pH 7.1± 0.2, dispense into flasks in 100ml quantities & sterilise at 121ºC for 20 mins Fluid B: If the sample contains lecithin or oil, use fluid A to each litre of which has been added 1ml of polysorbate 80, adjust to pH 7.1± 0.2, dispense into flasks & sterilise at 121ºC for 20 mins Method A (Membrane filtration): It is for the routine use of +ve & -ve controls +ve control: it is the small no. (NMT 100CFU) of microorganisms specified in separate portion of each medium. Dilute in a fatty base & emulsions of the w/o type to give a fluid concentration of 1% w/v, by heating, If necessary, to NMT 40ºC with a suitable sterile diluent such as isopropyl myristate previously rendered sterile by filtration through a 0.22µm membrane filter that has been shown not to have antimicrobial properties under the conditions of the test
- 114. 24 Filter asrapidly as possible & wash the membrane by filtering through it atleast 3 successive quantities, each of approximately 100ml, of sterile fluid B or any other suitable sterile diluent After filtration, aseptically remove the membrane or cut it aseptically into 2 equal parts. Transfer one half to each of 2 suitable media. Alternatively, transfer the medium on to the membrane in the apparatus Incubation & observation: Incubate the media for NLT 14 days & observe. If the specimen is +ve before 14days, further incubation is not necessary Interpretation: At intervals, media is examined under microscope If the material being tested is turbid, we cannot easily determine presence or absence of microbial growth After 14days transfer 1ml of the test medium to fresh medium & incubate for NLT 4days If there is no evidence of microbial growth, the preparation under examination complies with the test for sterility If the evidence of microbial growth is found, the preparation under examination does not comply with the test for sterility The test is considered to be invalid, only if 1 or more following conditions is fulfilled: a. Growth in -ve controls b. Sterility testing facility show a fault c. -If testing procedure is fault d. Material/technique is fault If the test is declared to be invalid, repeat the same no. of units as in the original test i. No microbial growth in repeat test, preparation complies with the test for sterility ii. If microbial growth is found & confirmed microscopically the preparation does not comply with the test for sterility 3. STORAGE: Store at a temp not exceeding 30 ºC unless otherwise directed. Do not freeze 4. LABELLING: The label states that: That the ointment is sterile, where necessary The name & concentration of any added antimicrobial preservative Storage conditions TESTS FOR CREAMS 1. UNIFORMITY OF CONTENT: same as ointments 2. STERITY: Method B (Direct inoculation): Prepare by diluting to about 1 in 10 by emulsifying with the chosen emulsifying agent in a suitable sterile diluent such as fluid A Transfer the diluted product to a medium not containing an emulsifying agent (before use, the emulsifying agent to ascertain that in the concentration used it has no significant antimicrobial effects during the time interval of all transfers)
- 115. 25 Mix 10mlof fluid mixture so obtained with 80ml of the medium Incubation & observation, interpretation- same as ointments 3. STORAGE: Store at a temp below 25 ºC unless otherwise directed. Do not freeze 4. LABELLING: same as ointments TESTS FOR SUPPOSITORIES 1. UNIFORMITY OF CONTAINER CONTENTS: same as in tablets (test method) 2. UNIFORMITY OF CONTENT: Same procedure as in tablets up to method (except IV, VI, VII points- not necessary) similar to capsules test for uniformity of content Acceptance limits: The suppositories comply with the test if NMT 1 of the individual values thus obtained is outside the limits 85 to 115% of the avg. value & none is outside the limits 75-125% If maximum of 3 individual values are obtained is outside the limits 85 to 115% of the avg. value repeat the determination using another 20 suppositories The suppositories comply with the test if in the total sample of 30 suppositories NMT 3 individual values are outside the limits 85 to 115% & none is outside the limits 75- 125% of the avg. value 3. UNIFORMITY OF WEIGHT: This test is applicable to suppositories that are required to comply with the test for uniformity of content for all active ingredients Weigh individually 20 suppositories, taken at random & determine the avg. wt. NMT 2 of the individual weights deviate from the avg. wt. by MT 5% & none deviates by MT 10% 4. DISINTEGRATION: This test is not necessarily applicable to suppositories intended for modified release or for prolonged local action For shell suppositories: disintegration occurs in NMT 30 mins For moulded suppositories: disintegration occurs in NMT 60 mins TESTS FOR OPHTHALMIC (Eye drops) 1. UNIFORMITY OF VOLUME: Pour completely the contents of each container into calibrated volume measures of the appropriate size & determine the volume of the contents of 10 containers The avg. net volume of the contents of 10 containers is NLT the labelled amt, & the net vol of the contents of any single container is NLT 91% & NMT 109% of the labelled amt where the labelled amt is 50ml or less, or NLT 95.5% & NMT 104.5% of the labelled amt where the labelled amt is MT 50ml but NMT 200ml or NLT 97% & NMT 103% of the labelled amt where the labelled amt is MT 200ml but NMT 300ml If the requirement is not met, determine the net vol of the contents of 10 additional containers. The avg. net vol of the contents of 20 containers is NLT the labelled amt, &
- 116. 26 the net volof the contents of NMT 1 of the 20 containers is LT 91% or NMT 109% of the labelled amt where the labelled amt is 50ml or less, or LT 95.5% & MT 104.5% of the labelled amt where the labelled amt is MT 50ml but NMT 200ml or LT 97% & MT 103% of the labelled amt where the labelled amt is MT 200ml but NMT 300ml None of individual weights deviates by MT twice that of the respective minimum & maximum %age limits 2. PARCTICLE SIZE: Applicable to eye drops that are suspensions Introduce a suitable vol of the eye drops into a counting cell or onto a microscope slide, as appropriate Scan under a microscope an area corresponding to 10µg of the solid phase Scan atleast 50 representative fields NMT 20 particles have a maximum dimension GT 25µm NMT 10 particles have a maximum dimension GT 50µm None has a maximum dimension GT 100µm 3. STERILITY: Same table as in ointments Quantities of sample to be used Ophthalmic solutions Quantity to be mixed Quantity to be used for each culture medium 10 to 100ml 5 to 10ml Method A -Membrane filtration is used Membrane with pore size NGT 0.45 µm & diameter of approximately 50mm Cellulose nitrate filters are used for aq., oily and weakly alcoholic solutions Cellulose acetate filters are used for strongly alcoholic solutions Droppers supplied separately also comply with these tests. Remove the dropper out of the package using aseptic precautions & transfer it to a tube containing suitable culture medium so that it is completely immersed. Incubate and carry out the test. 4. STORAGE: Store in sterile containers sealed so as to protect from microorganism 5. LABELLING: The label states that: The names & concentrations in %ages, or wt. or vol/ml of the active ingredients The names & concentrations of any added antimicrobial preservative That, for multiple application containers, the contents should not be used for MT 1month after opening of the container That, for multiple application containers, care should be taken to avoid contamination of the contents during use, That, the preparation is NOT FOR INJECTION The conditions under which the preparation should be stored
- 117. 27 TESTS FORSURGICAL PRODUCTS SURGICAL DRESSINGS (e.g. bandages) STERILITY TEST: Cotton wool, gauze, lint & adhesive plasters are examples of dressings thar may require sterile. Before sterilization cotton wool may be heavily contaminated with microorganisms. As an example, gauze may carry abut 15organisms/cm2 . Since surgical dressings are used in direct or close contact with wounds or, in the case gauze, within the operation field during surgery the method of confirming sterility must be reliable Sampling: Samples are about 1g or 10 cm2 are taken from woven of non-woven fabric respectively These are chosen from different places, including regions such as the centre (contamination is minimum) and the outside (where the probability of contamination is maximum) A test and if required (and possible) 2 or more repeat samples are taken Controls: To check the tester’s technique & the bacteriological condition of the atmosphere, a control is performed at the same time as the test Items that have been recently sterilised by a process known to ensure sterility are used for the purpose They should be equal in no. to the test items & preferably identical in structure No growth should occur in any container Elimination of inhibitory action: Some surgical dressings are impregnate with antimicrobial agents which may interfere with the growth of microorganisms in the culture medium The action of antimicrobial agents in medicated dressings is eliminated either by including a suitable inactivator in the culture medium or preferably by membrane filtration Procedure: The test is performed in an aseptic room or a screen provided with laminar flow of sterile air The dressings are generally wrapped in double wrapping. The area through which the outer wrapper is to be opened is first painted by weak iodine solution B.P. & left for 5 mins. The outer wrapper is cut along the painted sterile line with a sharp scalpel or blade. The dressing is pulled out of the inner wrap by a similar method If the dressing is a bigger one then 1g or 10 cm2 samples are cut by a pair of sharp scissors from different area of the fabric Each portion of the dressing are inoculated into separate wide mouthed container containing 50, 100, 150ml of a suitable culture medium (e.g. fluid thioglycolate medium U.S.P.). It is then incubated at 32º ± 2ºC for atleast 10days Interpretation: If there is no growth in any of container the batch passes If growth occurs in only 1 container the test is repeated &, if the same result is obtained again, a second repeat is allowed The product fails if there is growth in all 3 tests of the same organism is found in two
- 118. 28 SURGICAL SUTURES ANDLIGATURES Sterility tests: The tests for sterility are intended for detecting the presence of viable forms of microorganisms on the surgical suture materials Method-1: The suture materials are washed with a sterile fluid, the fluid is then passed through a filter membrane (for filtering bacteria), the filter membrane is then incubated in sterile medium and observed for minimum of 7days. If any forms of microorganisms were present in the suture material, they will grow Method-2: The suture materials are incubated in culture medium for NLT 14days. If microorganisms are present, they will render the medium turbid Gauge: This is measured by means of a dial reading micrometre at several points along the strand Tensile strength: This is done by means of a machine in which he load necessary to rupture the gut is measured, the tests being performed on straight and knotted samples
- 119. QUALITY CONTROL TESTFOR CONTAINERS, CLOSURES AND SECONDARY PACKAGING MATERIALS Packaging Packaging is the science, art and technology of enclosing or protecting products for distribution, storage, sale, and use. Role of Packaging: Protection against light against reactive gases against moisture against microbes against physical damage against adulteration Presentation Identification Information Convenience Packaging types Primary packaging Primary Packaging is the material that first envelops the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents. Secondary packaging Secondary Packaging is outside the primary packaging perhaps used to group primary packages together.
- 120. Tertiary Packaging Tertiary Packagingis used for bulk handling, warehouse storage and transport shipping. Different types of primary packaging Ampoules Vials Containers Dosing dropper Syringe Strip package Blister packaging Different types of primary packaging Paper and boards Cartons Box manufacture Types of glass 1. Type I (Neutral or Borosilicate Glass) 2. Type II (Treated Soda lime glass)
- 121. 3. Type III(Soda lime glass) 4. Type IV (General purpose soda lime glass) Quality control tests for glass 1. Chemical resistant of glass containers A. Powdered glass test It is done to estimate the amount of alkali leached from the powdered glass which usually happens at the elevated temperatures. When the glass is powdered, leaching of alkali is enhanced, which can be titrated with 0.02N sulphuric acid using methyl red as an indicator. Step-1: Preparation of glass specimen Few containers are rinsed thoroughly with purified water and dried with stream of clean air. Grind the containers in a mortar to a fine powder and pass through sieve no.20 and 50. Step-2: Washing the specimen 10gm of the above specimen is taken into 250 ml conical flask and wash it with 30 ml acetone. Repeat the washing, decant the acetone and dried after which it is used within 48hr. Procedure 10gm sample is added with 50ml of high purity water in a 250ml flask. Place it in an autoclave at 121⁰C±2⁰C for 30min.Cool it under running water. Decant the solution into another flask, wash again with 15ml high purity water and again decant. Titrate immediately with 0.02N sulphuric acid using methyl red as an indicator and record the volume.
- 122. B. Water attacktest This is only for treated soda lime glass containers under the controlled humidity conditions which neutralize the surface alkali and glass will become chemically more resistant. Principle involved is whether the alkali leached or not from the surface of the container. Procedure 1. Rinse thoroughly with high purity water. 2. Fill each container to 90% of its overflow capacity with water and is autoclaved at 121⁰C for 30min then it is cooled and the liquid is decanted which is titrated with 0.02N sulphuric acid using methyl red as an indicator. 3. The volume of sulfuric acid consumed is the measure of the amount of alkaline oxides present in the glass containers. Hydrolytic resistance of glass containers 1. Rinse each container at least 3times with distilled water and fill with the same to their filling volume. 2. Heat to 100⁰C for 10min and allow the steam to issue from the vent cork. Rise the temp from 100⁰C to 121⁰C over 20min. Maintain the temp at 121⁰C to 122⁰C for 60min. 3. Lower the temp from 121⁰C to 100C over 40min venting to prevent vacuum. 4. Remove the container from autoclave, cool and combine the liquids being examined. 5. Measure the volume of test solution into a conical flask and titrate with 0.01M HCl using methyl red as an indicator. Perform blank with water and the difference between the titration represents the volume of HCl consumed by the test solution.
- 123. Arsenic test 1. Thistest is for glass containers intended for aqueous parenterals. 2. The inner and outer surface of container is washed with fresh distilled water for 5 min. 3. Then similar steps are followed as performed in the hydrolytic test, previously described, till obtaining the final combined solution. 4. 10ml from the final combined volume is pipette out and to it 10 ml of HNO3 is added and dried in an oven at 130°C. 5. 10ml of hydrogen molybdate is added and refluxed for 25min. 6. It is cooled and absorbance is measured at 840nm. 7. The absorbance of the test solution should be less than the absorbance obtained using 0.1ml of arsenic standard solution (10ppm).
- 124. Thermal Shock Test Placethe samples in upright position in a tray. Immerse the tray into a hot water for a given time and transfers to cold water bath, temp of both are closely controlled. Examine cracks or breaks before and after the test. The amount of thermal shock a bottle can withstand depends on its size and design. Small bottles withstand a temp differential of 60 to 80⁰C and large bottle 30 to 40⁰C. A typical test uses 45C temp difference between hot and cold water. Leakage Test Fill 10 containers with water, fit with intended closures and keep them inverted at room temperature for 24hr.The test is said to be passed if there are no signs of leakage from any container. Internal bursting pressure test The most common instrument used is American glass research increment pressure tester. The test bottle is filled with water and placed inside the test chamber. A scaling head is applied and the internal pressure automatically raised by a series of increments each of which is held for a set of time. The bottle can be checked to a preselected pressure level and the test continues until the container finally bursts. Quality control tests for plastic containers for non-parenteral preparations 1. Leakage test 1. 10 containers are filled with water and fitted with intended closures. 2. They are kept inverted at room temperature for 24 hours. 3. The test is said to be passed if there is no sign of leakage from any container.
- 125. 2. Collapsibility test 1.This test is applicable to containers which are to be squeezed in order to remove the contents. 2. A container by collapsing inward during use, yield at least 90% of its normal contents at the required rate of flow at ambient temperature. 3. Clarity of aqueous extract 1. A suitable container is taken at random, and unlabeled, unmarked and non- laminated portions is selected. 2. These portions are cut into strips, none of which has a total surface area of 20cm2. 3. The strips are washed free from extraneous matter by shaking them with at least two separate portions of distilled water for about 30 secs. 4. The processed sample is taken in to the flask, previously cleaned with chromic acid and rinsed with distilled water. 5. 250ml of distilled water is added to the flask, covered and autoclaved at 121°C for 30min. 6. The extract is cooled and examined. It should be colorless and free from turbidity.
- 126. Quality control testsfor closures Preparation of sample 1. The closures are washed in 0.2% w/v of anionic surface-active agents for 5mins. 2. Rinsed five times with distilled water and 200ml water is added. 3. Subjected to autoclave at 119°C to 123°C for 20-30min covering with aluminum foil. 4. Cooled and solution is separated from closures (Solution A). 1. Residue on evaporation 1. 50ml of Solution A is evaporated to dryness on a water bath and dried at 105°C. 2. The residue weighs not more than 4 mg. 2. Sterilization test The closures used for the preparation of the sample solution shall not soften or become tacky and there shall be no visual change in the closure. 3. pH of aqueous extract: 1. To 20ml of solution A, 0.1ml of bromothymol blue solution is added. 2. NMT 0.3ml of 0.01M NaOH or 0.8ml of 0.01M HCl is required to change the color of the solution to blue or yellow ppt. 4. Self-stability test 1. Pierced ten times with hypodermic needle 2. Immersed in 0.1% methylene blue solution and subjected to a pressure of about 27 KPa 3. Restored to ATM pressure and made to stand for 30mins. 4. Traces of colored solution should not be found. Quality control tests for carton 1. Compression 1. Used to assess the strength of erected package there by estimating the degree of protection that it confers on the contents. 2. This is useful for products with no inherent strength in one plane or another.
- 127. 2. Carton openingforce 1. The carton should spring open in to its original shape without a need for unreasonable force. 2. If the carton does not spring open or buckles in on itself, it may cause problems on cartooning machine.
- 128. DOCUMENTATION IN PHARMACEUTICALINDUSTRY INTRODUCTION Documentation is the cornerstone of any company’s quality management system and is an essential GMP requirement. It is critical that anyone dealing with GMP documents and documentation systems understand the regulatory requirements and adopts best practice. It defines a system of information and control so that risks inherent in misinterpretation and/or error in oral communication are minimized. OBJECTIVES OF DOCUMENTS To define the specifications and procedures for all materials and method of manufacture and control. To ensure that all personal concern with manufacture know what to do and when to do it. To ensure that authorized persons have all the information necessary to decide whether or not to realize a batch of a drug for sale. To ensure the existence of documented evidence, trace ability, and to provide records and an audit trail thatwill permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. SCOPE Good documentation encompasses practically all the aspect of pharmaceutical production: Building and premises: installation, validation, cleaning and maintenance Personnel: Training, hygiene etc. Equipment: installation, calibration, validation, maintenance, cleaning Materials: specification, testing, ware-housing, use, rejection/disposal.
- 129. Processing: individual stepsin the process of manufacturing including controls thereof. Finished goods: specifications, testing, storage, distribution, and rejection/disposal. DOCUMENTATION LIFE TIERS OF DOCUMENTATION (ISO 9001:2008)
- 130. CHARACTERISTIC OF DOCUMENT Foreffective use of documents, they should be designed and prepared with utmost care. Each document shall: 1. Have a clear title. 2. Have an identification number. 3. Be approved by authorized person. 4. Have the date of issue 5. Have a due date of revision. 6. List to whom it has been issued. “Where the documents carry instructions” 1. The instructions shall be precise and not ambiguous. 2. They shall be for each individual step and not combined. E.g. Weigh the materials; charge the weighed materials into the blend. 3. Instructions shall be in imperative mood. “Where entry of any data is expected” 1. Sufficient space shall be provided for making the entry. 2. Heading shall clearly indicate what is to be entered, and who is responsible. 3. All entries shall be in ink. 4. All entries shall be clear and legible. 5. Person making the entries shall confirm the entry by initialling/signing the same. 6. An error in entry shall be so corrected that the original (wrong) entry is not lost. Such correction shall also be initialled and dated. Where
- 131. necessary, reason forcorrection shall also be recorded, initialled and dated. DOCUMENTATION REVIEW Documentation system should provide for a periodic review, and revision, if necessary, of any document, or part thereof. Such revised versions shall also be approved by the authorized persons. Updated/revised versions shall also be superseding the previous edition, and the document shall clearly indicate this. Outdate/superseded document shall be immediately removed from active use, and copy retained only for reference. ELECTRONIC DATA If documentation is through electronic data processing system (computerized system) there shall be adequate, reliable systems in place: 1. To check and ensure correctness of data. 2. To record changes (addition/deletion) 3. That meets other regulation requirement, if any “DOCUMENTS” MODEL D= Design, development, deviations, dossiers and Drug Master Files for regulated markets, distribution records O= Operational procedures/techniques/methods, Out of specifications (OOS), Out of trend (OOT) C= Cleaning, calibration, controls, complaints, containers and closures, contamination and change control U= User requirement specifications, utilities like water systems, HVAC, AHU etc. M= Man, materials, machines, methods, maintenance, manufacturing operations and controls, monitoring, master formula, manuals (quality, safety and environment), medical records E= Engineering control and practices, Environment control, Equipment qualification documents N= Non-routine activities, New products and substances T = Technology transfer, training, testing, Trend analysis, Technical dossiers S= SOPs, safety practices, sanitation, storage, self-inspection, standardization, supplier qualification, specifications and standard test procedures and site master file STANDARD OPERATING PROCEDURES A typical Pharmaceutical Industry has an average of 1200- 1300 SOPs. A Parenteral Drug Association (PDA) survey found that a typical pharmaceutical company must manage an average of 1250 SOPs.
- 132. A StandardOperating Procedure (SOP) is a set of written instructions that document a routine or repetitive activity which is followed by employees in an organization. The development and use of SOPs are an integral part of a successful quality system. It provides information to perform a job properly, and consistently in order to achieve pre-determined specification and quality end-result. BENEFITS OF SOP To provide people with all the safety, health, environmental and operational information necessary to perform a job properly. To ensure that production operations are performed consistently to maintain quality control of processes and products. To ensure that processes continue uninterrupted and are completed on a prescribed schedule. To ensure that no failures occur in manufacturing and other processes that would harm anyone in the surrounding community To ensure that approved procedures are followed in compliance with company and government regulations. To serve as a training document for teaching users about the process for which the SOP was written To serve as a checklist for co-workers who observe job performance to reinforce proper performance. To serve as a checklist for auditors. To serve as an historical record of the how, why and when of steps in an existing process so there is a factual basis for revising those steps when a process or equipment are changed. SOP PROCESS
- 133. How to write?” OBJECTIVE:To lay down procedure for the preparation of Standard Operating Procedures. SCOPE: This procedure is applicable to all the SOP’s throughout the organization. RESPONSIBILITY: Person Performing: Respective HOD’s of concerning departments Person Monitoring: QA officer/ HOD QA PROCEDURE: All SOP’s shall be computer typed using Times New Roman font. Format of SOP shall be as per Annexure SOP/QA/002/ Each SOP has 1. Header 2. Signature block and 3. Body Header: Present on all the pages of SOP and includes Company Logo, Name, address & Concerned Dept.: Company Logo, CHARAK Pharma Limited, Wagholi-Pune & Name of Concerned Department. Document Type: Standard Operating Procedure (In capital bold letters of font size 14) Ref. No.: It is like SOP/DC/YYY-Z Where DC depicts the department code as below: PE: Personnel Department PD: Production Department MT: Maintenance Department QA: Quality Assurance Department QC: Quality Control Department ST: Store Department PU: Purchase Department YYY is the sequential number starting from 001 for each department. And Z is the revision status, starting from 0 for the original version and 1 for the next version and so on. (In capital letters of font size Supersedes: It is the Ref. No. of the earlier version. (In capital letters of font size Effective Date: It is the date from which the SOP shall be put in use. The date format has to be DD/MM/YYYY, where DD indicates the date, MM indicates the month & YYYY indicates the year (e.g. 01/11/2007). Date shall be written with blue indelible ink pen. Review Date: It is the Month& Year during which the SOP shall be revised e.g. 21/2013, written with blue indelible ink pen. It shall be maximum 2 years from the effective date. Page No.: It is like X OF Y. Where X is the
- 134. individual page numberand Y is the total number of pages. (In capital letters of font size 12) Title: It shall be clear and descriptive. (In bold capital letters of font size 12). Signature Block: It shall be below the header and only on the first page of the SOP. (Titles in the rows & columns shall be in bold letters & other text in normal letters of font size 12. Name and designation shall be typed. And signature and date shall be put in blue indelible ink pen). Prepared by: Signature with date, name and designation of the person from user department who has drafted the SOP. Verified by: Signature with date, name and designation of the HOD or the person from user department who has verified the draft of the SOP. Authorized by: Signature with date, name and designation of the person authorizing SOP, DGM QA or HOD QA. Body: It shall contain the subject matter, which is written in the following Manner. (Subtitles in capital bold letters and text matter in normal letters of font size 12). OBJECTIVE: It shall define the purpose of the SOP. SCOPE: It shall define the area of application. RESPONSIBILITY: It shall specify the person responsible for carrying out and monitoring the activity as per the SOP. PROCEDURE: It shall give all steps required by the process in a proper sequence and instructions to be followed while carrying out the activity so as to achieve the desired goals. Procedure shall be: a. Logically lay out. b. Written in the imperative (authoritative) tense. c. User friendly. d. Simple to understand and in plain unambiguous English. e. To the point with no unnecessary information. f. In standardized terminology. ABBREVIATION: This shall include list of abbreviations used and their meaning. ANNEXURE: This shall include list of annexure attached. REFERENCE: This shall include list of reference documents. ABBREVIATION: HOD: Head of the Department SOP: Standard Operating Procedure.QA: Quality Assurance DGM: Deputy General Manager ANNEXURE: Annexure – SOP/QA/002/1 - ‘Standard Operating Procedure’ Form. REFERENCE: SOP issuance logbook Standard SOP format
- 135. MASTER FORMULA RECORD Master formula record (MFR) is a master document for any pharmaceutical product. It contains all information about the manufacturing process for the product. MFR is prepared by the research and development team of the company and all other documents like BMR and BPR are prepared using MFR by the manufacturing units. BATCH FORMULA RECORD A batch manufacturing record is a document designed to provide a complete record of the manufacturing history of a batch of product. The US Food and Drug administration defines a batch as “a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture”. PREPARATION OF BMR They normally contain information that relates to the following aspects of the manufacture of a batch of product: Dates of start and finish of manufacture. Lists all materials used and amounts of each used. Lists of packaging materials used. Details of the steps completed in the manufacturing process and times of completion. Initials of the person responsible at every stage. Details and results of all in-process checks. Reference to any equipment used. Batch yield and reconciliation. Any deviations. Quality Control information.
- 136. QUALITY AUDIT PLANAND REPORTS Conducting internal audits (self-inspections) and external audits of suppliers and outsourcing operations are key elements of a good quality system. One aspect of a quality system that is identified in the recently released International Conference on Harmonisation (ICH) Q10, “Pharmaceutical Quality System”, and in other quality system standards such as ISO 9001, is that of conducting audits as a means of evaluating compliance with the objectives of the quality system. Implementation of the quality management system model defined in ICH Q10 should result in achievement of the three main objectives stated in ICH Q10: Achieve product realization, establish and maintain a state of control, and facilitate continual improvement. Documentation and communication The audit results should be documented and communicated to management. The method of documentation and communication including the security and confidentiality of the audit reports should be defined in the procedure. It is important to remember that those responsible for the audited operation should always receive a copy of the report, including outsourcing management and supplier management. Such reports should clearly describe the audit team observations including specific examples when possible. If commitments have been made to implement corrective actions, such commitments should be included in the report. Security of audit reports should be strictly enforced and distribution of the report should be limited. When providing audit reports to external sources such as outsourcing companies or suppliers, a subset of the internal report may be provided as long as the observations are included SPECIFICATION AND TEST PROCEDURES A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. "Conformance to specifications" means that the drug substance and / or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
- 137. Specifications arecritical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval Periodic or skip testing Release vs. shelf-life acceptance criteria In- process tests Design and development considerations Limited data available at filing Parametric release Alternative procedures Pharmacopeial tests and acceptance criteria Evolving technologies Reference standard PROTOCOLS AND REPORTS A protocol is a written statement to conduct the process along with the procedure, test method, equipment handling, specifications, acceptance criteria, report and approval. The report summarizes all results, gives recommendations for fixing errors and/or improving the overall quality of the speech corpus and gives an executive summary. DISTRIBUTION RECORDS Distribution forms an important activity of the integrated supply chain management of pharmaceutical products. Various persons and entities are often responsible for the handling storage and distribution of such products. The guidelines are intended to apply to all steps in the entire distribution/supply chain Permanent information, written or electronic, should exist for each stored product indicating recommended storage conditions, any precautions to be observed and retest dates. Pharmacopeial requirements and current national regulations concerning labels and containers should be respected at all times. Procedures should be in place for temperature mapping, security services at the warehouse, destruction of unsaleable stocks and on retention of the records. ELECTRONIC DATA Electronic data can stand for data in general that is exchanged via electronic communication lines digital data in particular Data (computing), i.e. computer - processable data as opposed to executable code The Pharmaceutical industries are in a highly regulated environment, hence it requires effective document management processes. Having timely accurate data is critical for the success of any company. Data has never been easy to manage, and is especially true in pharmaceutical industry. Note that electronic information includes everything such as emails, adverse event reports, complaints, batch records, quality control records - everything that is stored electronically.Several technologies are being used currently in
- 138. pharmaceutical industry tomanage their huge volumes of data generated on daily basis. CONCLUSION Just as with GMPs, the goal of implementing strict compliance with GDPs will help pharmaceutical companies establish consistent practices that will minimize risk of misinterpretation, errors in communication and ensure product quality. Setting and following good document practices is not only an essential aspect of compliance with federal regulations, but also critical to consumer health.
- 145. 1 MANUFACTURING OPERATIONS ANDCONTROLS (PART-1) INTRODUCTION: All manufacturing operations shall be carried out under the supervision of technical staff approved by the licensing authority. Precautions against mix-up and cross contamination: 1. By proper air handling system, pressure differential, segregation, status labelling and cleaning. Proper records and SOP there of shall be maintained. 2. Processing of sensitive drugs and cytotoxic substances in segregated areas 3. Proper labelling of materials and equipment’s 4. Packaging lines shall be independent and adequately segregated 5. All printing and overprinting shall be authorized in writing 6. The manufacturing environment maintained at the required levels of temperature, humidity and cleanliness SIGNIFICANCE: Manufacturing: To produce goods and service of quality accepted by customers in desired quantities according to time schedules and at minimum cost. Control: Producing right kind of goods and services that satisfy customers need. Minimizing cost of producing goods or services Good manufacturing practices which are currently acceptable should be followed during carrying out all manufacturing operations and their control. Four key words should always be kept in mind during this, they are: 1. Identity- Refers to correct identification of product, people, materials, machines, equipment & locations where manufacturing activities are carried out. 2. Strength- Refers to concentration of active substance in desired quantity in each unit of the finished pharmaceutical product. 3. Safety- Person who is going to consume the product, safety of people should be also considered. Manufacturing operations should be safe while products are being manufacturing. 4. Purity- Freedom from cross contamination and staff To achieve these things the manufacturing operations must be carried out under the direct supervision of the qualified technical staff (Industrial pharmacists, chemists, microbiologists etc), who are approved as "Expert Technical Staff" by state FDA. Authorities. SANITATION OF MANUFACTURING PREMISES 1. The manufacturing premises shall be cleaned and in an orderly manner 2. The manufacturing areas shall not be used for other operations 3. A routine sanitation program shall be drawn up which shall be properly recorded and which indicate: a. specific areas to be cleaned and cleaning intervals b. cleaning procedure to be followed c. personnel assigned to and responsible for the cleaning operation 4. Sanitization maintain the manufacturing area, free from dust, insect, dust, debris, waste or trash material
- 146. 2 5. There maybe containers of suitable size and shape {containers may be made from either Plastic or any other material} 6. Cleaning all these premises with detergent 7. Premises again wash with disinfectant Measures to ensure good sanitation in: - Premises & personnel Equipment & apparatus Processes, materials & containers Premises: The manufacturing premises shall be cleaned and maintained in an orderly manner. Cleaning all these premises with detergent. Premises again wash with disinfectant. Premises shall be suitably designed and constructed to facilitate good sanitation. A validated cleaning procedure shall be maintained. Sanitization maintain the manufacturing area free from Dust, Insect, Debris. Examples: IN TABLET MANUFACTURING: 1. Powder clean with best napkins 2. After completion clean with disinfectant solution i.e. 1% glycol solution Glass material: 1. Glass material and residue collected in wastage 2. All glasses are clean by 70% isopropyl alcohol Manufacturing area: The manufacturing area shall not be used for storage of materials except for the materials being processed. It shall not be used as a general thorough fare. Certain locations in each area should be marked in each processing area for collection of dust, debris and waste materials. All areas must be cleaned using suitable detergents and methods of cleaning at pre- decided time intervals. The concentration of detergent used, cleaning method and frequency of cleaning must be monitored. After cleaning activity is over the area should be disinfected by suitable method. A detailed SOP must be followed. Equipment and apparatus: Equipment should be cleaned both inside and outside after use according to established procedure and should be kept or stored in a clean condition. Vacuum or wet cleaning methods are to be preferred. Cleaning and storing of mobile equipment and storing of cleaning materials in rooms separated from processing area. Written procedure in sufficient details should be established, validated and followed.
- 147. 3 Records ofcleaning, sanitizing, sterilization and inspection prior to use should be kept properly. Personnel: Every person entering the manufacturing area should wear protective garments. Detailed hygiene programmes should be established and adapted. The personnel assigned to and responsible for cleaning operations must have proper attitude and knowledge towards sanitation and hygiene. Direct contact should be avoided between the operator’s hands and the exposed starting materials, intermediate and bulk products. Their working should be well monitored. Validation of cleaning and sanitation procedures: Validation studies should reinforce GMP and be conducted in accordance with defined procedures. The reproducibility of the process should be validated Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended result. Documents Required: 1. SOP on housekeeping, covering, cleaning and disinfection of the various areas. 2. Reports of cleaning and disinfection activities that have been actually carried out. MIX-UPS AND CROSS CONTAMINATION MIX-UPS: It is defined as presence of undesired materials into desired materials which can be visibly seen. Ex: - Paracetamol mix with Diclofenac. Tablets of one product with another product which have different size, shape, colour, etc. Sources of mix-ups: 1.The close proximity or location of similar items. 2.Items having same colour or combination of colours kept nearby. 3.Improper storage of sterile and non-sterile products. 4.Multiple products handled at the same time. 5.Manual packaging and repackaging. 6.Failure of processing equipment. 7.Lack of proper validation. CONTAMINATION: Contamination may be defined as the presence of the undesired material; it should be not visible. The undesired introduction of impurities of chemical or microbiological nature or foreign matter in to starting material or intermediate during production, sampling, repackaging, storage or transport.
- 148. 4 CROSS CONTAMINATION: Contamination ofstarting material or intermediates or finished product by another material or product during the production is called as cross-contamination. Ex: - Fine dust of one product into another product SOURCES: Contaminated clothing and/or equipment. Contaminated or faulty HVAC system. Contaminated premises. People in the working area. Processing operations. Sources of mix ups and contamination: Contamination and mix ups are presence of undesired things in desirable things. These contaminations can be from various source 1. Materials 2. Area 3. Machine and operations 4. People 1. Materials Improper handling of material lead to spillage on ground & cause contamination Broken containers Dusty uncontrolled activities 2. Area: Manufacturing areas-Aseptic filling area Other sterile area Non-sterile processing area Corridors, cleaning rooms, outside areas of the plant 3. Machine and operations: Must be clean Covered when not in use Should be checked before use to avoid contamination Ex: -Discharge of exhausted dust, smoke, fumes, gases should be monitored. Sensitive Material-Beta lactam antibiotics, toxic drugs SOPs, records should be kept 4. People: Undisciplined activities Infectious nature of skin/body parts Trained people By keeping movements restricted Using hand gloves Mask Proper uniform Medically strictly examined Infectious disease/open wound treated by qualified doctor.
- 149. 5 Precautions against mix-upand cross contamination: 1. The drug material and drug product (from environmental dust) by proper air handling system. 2. The processing of sensitive drugs like Beta-Lactam antibiotics, sex hormones and cytotoxic substances is isolated production areas. 3. To prevent mix-up during production stages, material under process shall he conspicuously labelled to demonstrate their status. 4. The packaging lines, printing machines, and other equipment is clean and free from any products, materials and spillages. 5. The manufacturing environment shall be maintained at the required levels of temperature, humidity and cleanliness. 6. Authorised persons shall ensure change-over into specific uniforms before undertaking and manufacturing operations including packaging. Controlling of mix-ups and cross-contamination: 1. Where dry materials and products are used in production, special precaution should be taken to prevent the generation and dissemination of dust. 2. All the procedure regarding materials and products, regarding their sampling, storage, cleaning, labelling, quarantine and dispensing should be in accordance with written procedure. 3. Production in segregated areas should be conducted or at different timings followed by appropriate cleaning. 4. Wearing protective clothing in areas where products with special risk of cross- contamination are processed. 5. At each step in processing the materials should be labelled with their indication, batch number and strength. 6. Appropriate written procedure shall be established and followed. 7. Production area should undergo periodic microbiological monitoring. 8. Non-medical products should not be produced in places where the pharmaceutical products are produced. 9. Using “closed systems” of production. 10. EXHAUST SYSTEM: Certain procedure should be used to control mix ups and contamination Exhaust system with proper air filtration and dust collection There should be separate air handling unit There should be air pressure control maintained Packaging unit should be well separated i.e. 1.2-1.5 m in two adjacent packaging line 11. TRAINED PEOPLE: In pharma processing the people should be trained in their job and also in their principle of CGMP It should have discipline procedure of correct procedure, products training and equipment handling 12. TEACHNICAL MEASURE: Production in segregated area
- 150. 6 Provide appropriateair loss and system Always use the cleaning equipment Using a close system for material handling and production Documents required: SOPs on: - 1. Handling materials in processing area. 2. Line clearance and its record thereof. 3. Machine and equipment cleaning. 4. Collection and disposal of waste. 5. Internal labelling of material. PROCESSSING OF INTERMEDIATES AND BULK PRODUCTS Intermediate Product: A partly processed material that must undergo the further manufacturing steps before a bulk product. Bulk Product: Any product that has completed all processing steps up to but not including final packaging. Starting from the receipt of raw material till these materials are converted into bulk goods ready for packaging into their primary and then finished packs Certain points are required to be kept in mind so That the identify, strength, safety, and purity of the product is maintained 1. Before starting any processing, the material received from the store should be checked for the identity and quality. This verification can be done against labels on their containers 2. Process area and equipment must be clean and no trace of previous product should not be present 3. Environmental condition must meet the processing requirement E.g. Temperature, pressure, relative humidity, class of air, lighting etc 4. All primary containers used for filling finished product should be clean to be acceptable level of cleanliness 5. Yield of material at all critical stage of operation should be checked and compared against theoretical yield expected E.g. Granulation, compression, filling operation of capsule, liquid bottle etc 6. Any abnormal deviation must be investigated and corrective action taken 7. Check should be carried out to ensure pipeline and other equipment used for transportation of product from one area to another connected in correct manner 8. Such pipe line thoroughly cleaned and sanitized to get desired level of limit of microbial presence 9. All measuring, weighing, recording, and controlling equipment and instrument should be calibrated regularly. 10. Record of such calibration should be maintained 11. Repairs and maintenance of operations should not present any hazard to the quality of product 12. All IPQC checks should be carried out at pre - determined stages and deviation should Be recorded and investigated
- 151. 7 13. Access toproduction area should be restricted only to authorized person Documents required 1. B.P.C.R(batch production and control records) for each batch produced 2. calibration records PACKAGING OPERATIONS As for manufacturing operations, packaging operations also follow precautions to get a good quality product at end. Following points should be considered. 1.Avoid risk of contamination and mix-ups 2.All packaging equipment & lines must be cleaned before staring a fresh packaging activity. Line clearance record should be maintained. 3.Each packaging equipment and line identified by fixed board indicating following information-Name of product, batch no., Pack size, date of packing. 4. Normally filling & sealing should be followed by labelling and final packing. If labelling is delayed appropriate steps should be taken to prevent mix-ups. To avoid this no batch should be taken for packing unless all the packing materials are available in full quantities. -Bulk tablets (for want of foils) -Strips or blisters (for want of cartons) -Filled cartons (for want of shippers) such situation must be avoided. 5.Over printing on labels, cartons, coated tablets etc. Should be carefully planned 6.On line verification of all labels by automated electronic beam helpful in preventing mix-ups 7.Empty packet detection in tab/cap. should be used. 8. Online packaging checks should be carried out for following a. General appearance of the package b. Completeness of package c. Correctness of pack & packaging materials d. Correctness of over printed details e. Correct version of printed packaging material is used. f. Weight check of carton & shipper may be useful. 9. Products which are involved in an unusual event during packaging operations should be fully investigated-record made-packed after approval of authorized person additional Q. A. dept. 10. Any significant or unusual discrepancy observed then it should be investigated & satisfactorily accounted before release. 11. After completion any unused batch coded packaging materials should be destroyed and the destruction recorded. Documents Required 1.BPCR 2.SOP & record of IPQC 3.Deviation records if any 4.Incident reports if any
- 152. 8 IPQC For manufacturing operations: 1.Assay, moisture, angle of repose at end of granulation 2. Physical parameters of compression of tablets Weight Thickness Hardness Friability Disintegration test Dissolution test 3. Fill weight/vol. in ampoules/liq. Orals etc. 4. pH of solution before filling 5. Bulk volumes of liquids etc. 6. Environmental conditions verification E.g. temp. etc. For Packaging Operations a. Packaging operations/lines continually monitored to sure the integrity of finished products not compromised. SOP & check list should be regularly signed by trained people. b. Automated controls & monitors should be checked regularly during production c. Online control of the product: 1. General appearance of the package & physical defects if any 2. Fill weights, volumes, unit quantities etc. 3. Completeness of package-all components of the pack without fail 4. Correctness of all materials used. 5. Correctness of over printed details 6. Correct functioning of all on line monitors. 7. Environmental conditions records- temp., humidity etc 8. Collection of samples for testing & retention should be recorded. Tested/Inspected samples should not be returned back RELEASE OF FINISHED PRODUCT 1. Releasing of finishing product is the last activity in the manufacturing and packaging operations at the factory. Done with great care. 2. Finished products must be placed in quarantine in such a way that these cannot be removed for use until such time these are released. 3. Samples of the product taken at intervals during the packaging process must be retained for examination by the Q.C. laboratory. 4. Documentation should be re-checked, completed and sent for a complete documentation audit 5. by Q.A. 6. When all required parameters are satisfied, including the document audit, Q. C. may 7. recommend release of the product from its quarantine status. 8. The finished product should be released for sale by authorised person from Q.A. department. Documents required: Batch release SOP & reports
- 153. 9 PROCESS DEVIATIONS 1. Processdeviation can be defined as variation, in the production or any other process from the predefined procedure. 2. Such deviations may adversely affect the desired quality of the pharmaceutical product and hence such deviations should be generally avoided and if exceptionally required then such deviations must be justified and properly authorizing and recorded. 3. The main purpose of written manufacturing procedures is to build the desired quality into the product. Example of deviation: Ex. 1 Deviation in weight uniformity in tablet: Tablet Weight % deviation 1. 684.2 0.04% 2. 671.2 -1.86% Ex. 2 Process variation: In relation to the deviation with Batch X of Product Y 120mg Tablets, which involved a problem with powder flow ability during blending: In relation to the flow ability issue, no potential causes were investigated or identified. 10
- 154. 1 MANUFACTURING OPERATIONS ANDCONTROLS Charge-in of components: Written production and control procedures shall include the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess: (a) The batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient. (b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information: (1) Component name or item code, (2) Receiving or control number, (3) Weight or measure in new container, and (4) Batch for which component was dispensed, including its product name, strength, and lot number. (c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that: (1) The component was released by the quality control unit, (2) The weight or measure is correct as stated in the batch production records, (3) The containers are properly identified. If the weighing, measuring, or subdividing operations are performed by automated equipment under 211.68,only one person is needed to assure of this section. (d) Each component shall either be added to the batch by one person and verified by a second person or, if the components are added by automated equipment under 211.68, only verified by one person. Automatic, mechanical, and electronic equipment(211.68) (a) Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program
- 155. 2 designed to assureproper performance. Written records of those calibration checks and inspections shall be maintained. (b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system. A backup file of data entered into the computer or related system shall be maintained except where certain data, such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes. In such instances a written record of the program shall be maintained along with appropriate validation data. Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained. Time limitations on production: When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. Time limits should include, for example, the period between the start of bulk product compounding and its sterilization, filtration processes, product exposure while on the processing line, and storage of sterilized equipment, containers and closures. The total time for product filtration should be limited to an established maximum to prevent microorganisms from penetrating the filter. Such a time limit should also prevent a significant increase in upstream bioburden and endotoxin load Deviations:- (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. (b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be
- 156. 3 documented at thetime of performance. Any deviation from the written procedures shall be recorded and justified. Drug product inspection: (a) Packaged and labeled products shall be examined during finishing operations to provide assurance that containers and packages in the lot have the correct label. (b) A representative sample of units shall be collected at the completion of finishing operations and shall be visually examined for correct labeling. (c) Results of these examinations shall be recorded in the batch production or control records. Expiry date calculation: (a)To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing. (b) Expiration dates shall be related to any storage conditions stated on the labeling, as determined by stability studies. (c) If the drug product is to be reconstituted at the time of dispensing, its labeling shall bear expiration information for both the reconstituted and unreconstituted drug products. (d) Expiration dates shall appear on labeling in accordance with the requirement of location of expiration date i.e as follows:- When an expiration date of a drug is required it shall appear on the immediate container and also the outer package, if any, unless it is easily legible through such outer package. However, when single-dose containers are packed in individual cartons, the expiration date may properly appear on the individual carton instead of the immediate product container. (e) Homeopathic drug products shall be exempt from the requirements of this section. (f) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt from the requirements of this section. (g) New drug products for investigational use are exempt from the requirements of this section, provided that they meet appropriate standards or specifications as demonstrated by stability studies during their use in clinical investigations. Where new drug products for investigational use are to be reconstituted at the time of dispensing, their labeling shall bear expiration information for the reconstituted drug product. (h) Pending consideration of a proposed exemption, published in the FEDERAL REGISTER of September 29, 1978, the requirements in this section shall not be
- 157. 4 enforced for humanOTC drug products if their labeling does not bear dosage limitations and they are stable for at least 3 years as supported by appropriate stability data. Stability testing:- (a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include: (1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability, (2) Storage conditions for samples retained for testing, (3) Reliable, meaningful, and specific test methods, (4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed, and (5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted. (b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined. (c) For homeopathic drug products, the requirements of this section are as follows: (1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use. (2) Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed. (d) Allergenic extracts that are labeled “No U.S. Standard of Potency” are exempt from the requirements of this section.
- 158. 5 Calculation of yield: Actualyields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall either be performed by one person and independently verified by a second person, or, if the yield is calculated by automated equipment under 211.68, be independently verified by one person. Production record review: All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up. Master production and control records:- (a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed. (b) Master production and control records shall include: (1) The name and strength of the product and a description of the dosage form, (2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit, (3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic, (4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they
- 159. 6 are justified inthe master production and control records, (5) A statement concerning any calculated excess of component, (6) A statement of theoretical weight or measure at appropriate phases of processing, (7) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to production records. (8) A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling, and (9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed. Batch production and control records:- Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include: (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed, (b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including: (1) Dates, (2) Identity of individual major equipment and lines used, (3) Specific identification of each batch of component or in-process material used, (4) Weights and measures of components used in the course of processing, (5) In-process and laboratory control results, (6) Inspection of the packaging and labeling area before and after use, (7) A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing, (8) Complete labeling control records, including specimens or copies of all labeling used, (9) Description of drug product containers and closures, (10) Any sampling performed; (11) Identification of the persons performing and directly supervising or checking each significant step in the operation, or if a significant step in the operation is performed by automated equipment under §211.68, the identification of the person checking the significant step performed by the automated equipment,
- 160. 7 (12) Any investigationmade according toproduction record review, (13) Results of examinations made in accordance with drug product inspection. Packaging and labeling operations. There shall be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products; such written procedures shall be followed. These procedures shall incorporate the following features: (a) Prevention of mixups and cross-contamination by physical or spatial separation from operations on other drug products. (b) Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. Identification need not be applied to each individual container but shall be sufficient to determine name, strength, quantity of contents, and lot or control number of each container. (c) Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch. (d) Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record. (e) Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection shall be documented in the batch production records. Change Control Procedure:- Change control is a CGMP concept that focuses on managing change to prevent unintended consequences sometimes encountered when making a change to a product or system. • Change control is not department-specific, rather the task of the whole company. Manufacturers certified to ISO 9000:2000 and ISO 13485 standards are required to ensure that any changes. Certain manufacturing changes (i.e changes that alter specifications, a critical product attribute or bioavailability) require regulatory filings and prior regulatory approval. Change is an inherent part of the life cycle of a pharmaceutical product. A change can be an addition to, deletion of, or modification to manufacturing facility, utilities, process, material,
- 161. 8 product, procedures orequipment.(including software) which impacts quality or regulatory requirements. Change control is a procedure that ensures changes are implemented in a controlled and coordinated manner. The change control program evaluate all changes that could affect the production and control of the drug product, intermediate or API. It is the most critical element in the overall quality management of pharmaceutical industry. A change control system provides checks and balances in the quality system by tracking, reviewing and approving the changes. In adequate change control procedures ends up in regulatory non compliance. Benefits of change control system: Structured and systematic approach for change management with proper change evaluation Documenting & tracking the details of change Routing of change requests to appropriate individuals/team for approvals Demonstrate compliance to regulatory agencies Change control Process flow: Changes can happen anytime during a product’s life cycle. Steps as follows 1. Change proposal 2. Change Evaluation/review 3. Change Classification 4. Identification of impacted systems/documents & risk assessment 5. Change Approval 6. Change implementation 7. Verification of change implementation 8. Change control close out Change control Procedure: A formal change control procedure always begins with a change proposal, which is initiated by user department personnel with proper justification. Initiator Change is typically introduced by a initiator or originator. Initiating a changes involves filling out a change request form which them moves through a process or system of review and approval.
- 162. 9 The changeproposal then, evaluated by an expert team (change control committee) contributing the appropriate expertise and knowledge from relevant areas. After change evaluation, quality unit will classify the change (i.e minor/major/critical).Benefits of change classification includes Classification can help in assessing the impact of change in a reliable way. Change classification can be used to identify risk associated with each change request. Change classification can help to determine the change acceptability (i.e reject or approve changes). • A classification procedure may help in determining the level of testing, validation and documentation needed to justify the changes of validated process. • They can also be categorized as specification changes, raw material changes, equipment changes. Change classification triggers impact analysis of the proposed change for identification of impacted systems and documents. There are several risk associated with each change proposal, including reduced product quality. Risk assessment in changing requirements of existing systems is an important aspect of producing the desired result of a change. EXAMPLES: • Changes of manufacturers, other synthesis route of a starting material (other impurities) • Removal of processes to other site • Change in the product composition • Change to the process parameters. • Replacement of apparatus part of the same design • Change of cleaning agent for floors • Change of laundry for work clothes (non-sterile or antibiotics area) • Change to working times • Installation of air conditioner in administrative area • Change in purchase procedure After impact analysis and risk reduction, quality unit will approve or reject the change proposal based on the criticality of the proposed change. The change can be implemented after change approval by quality unit. After implementation, quality unit verify the effectiveness of implemented changes, to confirm the change objectives were achieved and that there was no deleterious impact on product quality. After verification of change implementation, the change control can be closed. Three primary tasks at this end phase include determining that the project is actually complete, evaluating "the project plan in the context of project completion," and providing tangible proof of project success. Change control procedure should ensure that the level of documentation and effort is matched to the risk associated with the change. It should be ensured that Includes criteria to evaluate whether changes affects regulatory filings. Includes evaluation criteria for determining if changes are technically justified.
- 163. 10 GMP deficiencies relatedto change control: Inadequate review & approval of the change by quality control unit. Failure to file the changes with regulatory. Failure to evaluate/justify the changes. Excluding "like-for-like" changes from change control program. Sterile products and aseptic process control:- "Sterile products" refers to products that are going to be administered using an enteral route of administration. The "products" are going to be infused directly into the bloodstream or body tissue, it is extremely important they be "sterile".
- 164. 11 Aseptic process control: AsepticProcessing is the production of sterile drug products by bringing together the product, container, and closure that have been subjected to different sterilization methods separately, and assembled them in an extremely high quality environment by skilled personnel using the right tools. There are basic differences between the production of sterile drug products using aseptic processing and production using terminal sterilization. Terminal sterilization: Usually involves filling and sealing product containers under high-quality environmental conditions. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in- process product and to help ensure that the subsequent sterilization process is successful. In most cases, the product, container, and closure have low bioburden, but they are not sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation. Aseptic process: The drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. For example:- Glass containers are subjected to dry heat; Rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. A terminally sterilized drug product, on the other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of error. Regulations: Aseptic processing, which includes as appropriate: (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable,
- 165. 12 (ii) Temperature andhumidity controls, (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar, (iv) A system for monitoring environmental conditions, (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions, and (vi) A system for maintaining any equipment used to control the aseptic conditions. (vii) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product. 21 CFR 211.46(c) states, that Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. 21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.” 21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.” 1.Clean area: Clean area control parameters should be supported by microbiological and particle data obtained during qualification studies. Initial clean room qualification includes, in part, an assessment of air quality under as-built, static conditions. It is important for area qualification and classification to place most emphasis on data generated under dynamic conditions (i.e., with personnel present, equipment in place, and operations ongoing). An adequate aseptic processing facility monitoring program also will assess conformance with specified clean area classifications under dynamic conditions on a routine basis.
- 166. 13 Clean Area Classification (0.5 um particles/ft3) >0.5 μm particles/m3 Microbiological Active Air Action Levelsc (cfu/m3 ) Microbiological Settling Plates Action Levelsc,d (diam. 90mm; cfu/4 hours) 100 3520 1 1 1000 35200 7 3 10000 352000 10 5 100000 3520000 100 50 Critical Area – Class 100 A critical area is one in which the sterilized drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility. Activities conducted in such areas include manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile materials prior to and during filling and closing operations. This area is critical because an exposed product is vulnerable to contamination and will not be subsequently sterilized in its immediate container. To maintain product sterility, it is essential that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be controlled and maintained at an appropriate quality. One aspect of environmental quality is the particle content of the air. HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. Supporting Clean Areas class (1000-100000) Supporting clean areas can have various classifications and functions. Many support areas function as zones in which non sterile components, formulated products, in-process materials, equipment, and container/closures are prepared, held, or transferred. These environments are soundly designed when they minimize the level of particle contaminants in the final product and control the microbiological content (bio burden) of articles and components that are subsequently sterilized. The nature of the activities conducted in a supporting clean area determines its classification:- FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards under dynamic conditions.
- 167. 14 Manufacturers canalso classify this area as Class 1,000 (ISO 6) or maintain the entire aseptic filling room at Class 100 (ISO 5). An area classified at a Class 100,000 (ISO 8) air cleanliness level is appropriate for less critical activities (e.g., equipment cleaning). Clean Area Separation To maintain air quality, it is important to achieve a proper airflow from areas of higher cleanliness to adjacent less clean areas. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. The Agency recommends that pressure differentials between clean rooms be monitored continuously throughout each shift and frequently recorded. All alarms should be documented and deviations from established limits should be investigated. Air change rate is another important clean room design parameter. For Class 100,000 (ISO 8) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable. Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas. 2. Air Filtration i. Membrane A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological and particle quality after filtration should be equal to or better than that of the air in the environment into which the gas is introduced. Compressed gases such as air, nitrogen, and carbon dioxide are often used in cleanrooms and are frequently employed in purging or overlaying. Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality standard. These filters are often used to produce a sterile compressed gas to conduct operations involving sterile materials, such as components and equipment. For example, we recommend that sterile membrane filters be used for autoclave air lines, lyophilizer vacuum breaks, and tanks containing sterilized materials. Gas filters (including vent filters) should be dry. Condensate on a gas filter can cause blockage during use or allow for the growth of microorganisms. Use of hydrophobic filters, as well as application of heat to these filters where appropriate, prevents problematic moisture residues. ii. High-Efficiency Particulate Air (HEPA) HEPA filter integrity should be maintained to ensure aseptic conditions. Leak testing should be performed at installation to detect integrity
- 168. 15 breaches around thesealing gaskets, through the frames, or through various points on the filter media. Thereafter, leak tests should be performed at suitable time intervals for HEPA filters in the aseptic processing facility. For example, such testing should be performed twice a year for the aseptic processing room. Additional testing may be appropriate when air quality is found to be unacceptable, facility renovations might be the cause of disturbances to ceiling or wall structures, or as part of an investigation into a media fill or drug product sterility failure. Among the filters that should be leak tested are those installed in dry heat de-pyrogenation tunnels and ovens commonly used to depyrogenate glass vials. Where justified, alternate methods can be used to test HEPA filters in the hot zones of these tunnels and ovens. There is a major difference between filter leak testing and efficiency testing. An efficiency test is a general test used to determine the rating of the filter.8 An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 μm in diameter. 3.Design Other appropriate technologies that achieve increased sterility assurance are also encouraged. Aseptic processes are designed to minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation. Limiting the duration of exposure of sterile product elements, providing the highest possible environmental control, optimizing process flow, and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility. Both personnel and material flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment. Any intervention or stoppage during an aseptic process can increase the risk of contamination. The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. Products should be transferred under appropriate cleanroom conditions. For example, lyophilization processes include transfer of aseptically filled product in partially sealed containers. The sterile drug product and its container-closures should be protected by equipment of suitable design.
- 169. 16 Carefully designedcurtains and rigid plastic shields are among the barriers that can beused in appropriate locations to achieve segregation of the aseptic processing line. Use of an isolator system further enhances product protection If stoppered vials exit an aseptic processing zone or room prior to capping, appropriate assurances should be in place to safeguard the product, such as local protection until completion of the crimping step. Use of devices for on-line detection of improperly seated stoppers can provide additional assurance. 4.Personal, Training, Qualification, & Monitoring: A. Personnel A well-designed, maintained, and operated aseptic process minimizes personnel intervention. As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times. Appropriate training should be conducted before an individual is permitted to enter the aseptic manufacturing area. Some of the techniques aimed at maintaining sterility of sterile items and surfaces include: Contact sterile materials only with sterile instruments Sterile instruments should always be used in the handling of sterilized materials Sterile instruments should always be used in the handling of sterilized materials. Between uses, sterile instruments should be held under Class 100 (ISO 5) conditions and maintained in a manner that prevents contamination (e.g., placed in sterilized containers). After initial gowning, sterile gloves should be regularly sanitized or changed, as appropriate, to minimize the risk of contamination. Personnel should not directly contact sterile products, containers, closures, or critical surfaces with any part of their gown or gloves. Move slowly and deliberately Rapid movements can create unacceptable turbulence in a critical area. Keep the entire body out of the path of unidirectional airflow Unidirectional airflow design is used to protect sterile equipment surfaces, container-closures, and product.
- 170. 17 5. Components andContainer/Closures: Components A drug product produced by aseptic processing can become contaminated through the use of one or more components that are contaminated with microorganisms or endotoxins. Examples of components include active ingredients, Water for Injection (WFI), and other excipients. It is important to characterize the microbial content (e.g., bioburden, endotoxin) of each component that could be contaminated and establish appropriate acceptance limits. Endotoxin load data are significant because parenteral products are intended to be nonpyrogenic. There should be written procedures and appropriate specifications for acceptance or rejection of each lot of components that might contain endotoxins. Any components failing to meet defined endotoxin limits should be rejected. Dry heat sterilization is a suitable method for components that are heat stable and insoluble. However, conducting carefully designed heat penetration and distribution studies is of particular significance for powder sterilization because of the insulating effects of the powder. Irradiation can be used to sterilize some components. Containers/Closures : 1. Preparation : Containers and closures should be rendered sterile and, for parenteral drug products, nonpyrogenic. The process used will depend primarily on the nature of the container and/or closure materials. The validation study for such a process should be adequate to demonstrate its ability to render materials sterile and non-pyrogenic. Written procedures should specify the frequency of revalidation of these processes as well as time limits for holding sterile, depyrogenated containers and closures. Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles The adequacy of the depyrogenation process can be assessed by spiking containers and closures with known quantities of endotoxin, followed by measuring endotoxin content after depyrogenation. Plastic containers can be sterilized with an appropriate gas, irradiation, or other suitable means. For gases such as Ethylene Oxide (EtO), certain issues should receive attention. For example, the parameters and limits of the EtO sterilization cycle (e.g., temperature, pressure, humidity, gas concentration, exposure time, degassing, aeration, and determination of residuals) should be specified and monitored closely.
- 171. 18 Rubber closures(e.g., stoppers and syringe plungers) can be cleaned by multiple cycles of washing and rinsing prior to final steam or irradiation sterilization. At minimum, the initial rinses for the washing process should employ at least Purified Water, USP, of minimal endotoxin content, followed by final rinse(s) with WFI for parenteral products. Normally, depyrogenation can be achieved by multiple rinses of hot WFI. Potential source of contamination is the siliconization of rubber stoppers. 2. Inspection of Container Closure System A container closure system that permits penetration of microorganisms is unsuitable for a sterile product. Any damaged or defective units should be detected, and removed, during inspection of the final sealed product. Safeguards should be implemented to strictly preclude shipment of product that may lack container closure integrity and lead to nonsterility. Microbiological Testing Objectives:- To review microbiological environmental and quality control testing Microbiological Environmental Monitoring Container integrity testing Pre-sterilization testing. Media fill medium growth promotion testing Sterility Testing Other microbiological laboratory issue Microbiological testing of water:- Water should also be tested for presence of coli forms and/or pseudomonas if appropriate (may cause bio film) Water used for parenterals should be tested for pyrogens – limit is not more than 0.25 EU/ml. Water should be tested using R2A agar (low nutrient for the recovery of water borne organisms) incubated for at least 5 days at 30-35°C Sampling procedures should follow those used in production. Microbiological testing of Air Sampling Locations:- Should be based on risk of microbiological contamination , Should be clustered around areas where product or components are exposed e.g. at filling heads on filling lines , loading of product into lyophilizers , stopper bowls ,where aseptic connections are made ,where there are high levels of operator activity (but without impacting on production) Control of microbiological contamination. (a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.
- 172. 19 (b) Appropriate writtenprocedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes. (c) Following stability testing