PHA CEUTICAL

QUALITY ASSU NCE •

PERSONNEL

SAFETY BUILDINGS

SECURITY EQUIPMENT

COMPLAINTS MATERIALS

OUT
QUALITY
SOURCING

VALIDATION MFG

DOCUM ENTS

NIRALI PRAKASHAN
Copyn h xi c 1
PHARMACEUTICAL QUALITY ASSURNACE ISBN NO. 978-81-8S790-S9-6
Second Edition • December 2007
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 CO,NTEN'l'S I
CBAPTERl:PERSONNEL 1.] to 1.22
10 lntradnctian ll
1.1 Qualification, Experience and Training ll
1.2 Responsibilities and Key Personnel 1.4
1.3 Personal Hygiene and Clothing 1.1
1.4 Legal Aspects La
15 Consultants LlO
Documents and Formats LlO
CHAPTER 2 : SURROUNDING, BUILDINGS AND FACILITIES 2.1 to 2.15
2.0 •Introduction 2..1
2.1 Principal Areas 2.,_2
2.2 Plumbing and Drainage systems 2.6
2.3 Lighting 2.6
2.4 Sewage, Refuse and Disposal of Waste z.1
2.5 Washing and Toilet Facilities 2..8
2.6 Sanitation 2..8
2.7 Maintenance 2..a
Documents and Formats 2.10
CHAPTER 3 : EQUIPMENT 8.1 to 8.1'4
3.0 Introduction 3.1
3.1 Design, Size, Location and Construction of Equipment 3.1
3.2 Equipment Identification 3.3
3.3 Equipment log 3.3
3.4 Cleaning and Maintenance of Equipment 3.4
3.5 Automatic, Mechanical and Electronic Equipment 3.4
3.6 Planned Preventive Maintenance Programme 3.4
Documents and Formats 3.5
CHAPTER 4 : MATERIAIS MANAGEMENT 4.) to 4,18
40 Tntradnctian il
4.1 Purchasing 4.1
4.2 Raw Materials 4.2
4.3 Packaging Materials 4.4
4.4 Intermediate and Built Product's 4.5
4.5 Finished Products 4.5
4.6 Rejected and Recovered Materials 4.5
 4.7 Recalled Products 4.6
4.8 Retur ned goods 4.6
4.9 Reagents and Culture Media 4.7
4.10 Waste Materials 48
4. 11 Reference standards 48
4.12 Miscellaneous Materials 4.9
Docu1nents and Formats 49
CHAPTER 5 : QUALITY MANAGEMENT 5. 1 to 5.58
5.0 Introduction 6 .l
5.1 Quality Assurance 5.5
5.2 Components of Q.A. 5.8
5.3 Good Manufacturing Practice 5.10
5.4 Quality Control 5.12
Document,q and Formats 5.31
CHAPTER 6: MANJJFACTJJRING OPERATIONS AND CONTROT. 6 ,) to 6 ,34
6.0 Introduction 6.1
6.1 Sanitation of Manufacturing Premises• 6.2
6.2 Mix-ups and Cross Contamination 6.2
6.3 Processing of Intermediates and Bulk products 6.5
6.4 Packaging Operations 6.6
6.5 I.P.Q.C. 6.7
6 6 Release of Finished Product 68
6.7 Process Deviations 69
6.8 Charge-in of Components 6.9
6.9 Time Limitations on Production 6.10
6.10 Drug product Inspection 6.11
6.11 Expiration Dating 6.11
6.12 Calculation of Yields 6.11
6.13 Production Record Review 612
Documents and Formats 6.13
CHAPTER 7 : DOCUMENTATION AND RECORDS 7.1 to 7,36
7.0 Introduction 7.1
7.1 Specifications 7.5
7.2 Master Production and Control Record 7,7
7.3 Batch Production and Control Record 7.9
7.4 Important SOPs and Records 7.10
7.5 Change Control 7.11
76 Site Master File 7 12
Documents and Formats 7.14

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CHAPTER 8: PHARMACEUTICAL VAIJDATION 8.1 to 8.108
8.0 Introduction 8,1
8,1 Validation of Buildings and Facilities 8.9
8,2 Validation of Equipment 8.13 .
8.3 Process Validation 8.20
8.4 Cleaning Validation 8.22
8.5 Validation of Analytical Methods 8.28
8.6 Validation of Computer Systems 8.31
8.7 Validation of Specific Dosage Forms 8.36
8.8 Calibration Master Plan 8.38
8.9 Validation Master Plan 8.42
Documents and Formats 8.44
CHAPTER·9 : OUTSOURCING 9.1 to 9.4
9.0 Introduction 9.1
9.1 Manufacturing and Packaging Outsourcing 9.2
9.2 Analytical Outsourcing 9.4
9.3 Other Services Outsourcing 9.4
CHAPTER 10 : POST OPERATIONAL ACTIVITIES 10.1 to 10.8
10.0 lntroduction 10.1
10.1 Distribution 10.1
10.2 Recalled Products 10.2
10.3 Returned Products 10.3
10.4 Complaints and Adverse Effects 10.4
10.5 Drug Product Salvaging 10.6
Documents and Formats 10.6
CHAPTER 11 : SITE AND PLANT SECURITY 11.1 to 11.4
11.0 Introduction 11.1
11.1 Security Personnel 11.1
11.2 Entry to Site 11.2
11.3 Entry to Plant Buildings 11.2
11.4 lnternal Security 11.3
11.5 Current Issues 11.3
CHAPTER 12: SAFETY AND ENVIRONMENTAL PROTECTION 12.1 to 12.2
12.0 Introduction 12.1
12.1 Safety 12.1
12.2 Environmental Protection and Procedures 12.1
CHAPTER 13: STERILE PHARMACEUTICAL PRODUCTS 13.1 to 13.60
13.0 Introduction 13.l
13.1 Personnel 13,3

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 13.2 Building and Premises 13.9
13.3 HVAC system 13.10
13.4 Water and Steam System 13.11
13.6 Equipment 13.13
13,6 Processes 13.15
13.7 Sterilization 18.19
13.8 Quality Control 13.22
13 9 Sanit.atinn 13.23
13.10 Finishing of Sterile Products 13.24
13.11 Documentation 13.24
Documents and Formats 13.26
ABBREVIATIONS LIST A.1-A.2
GLOSSARY G.1 -G.8
REFERENCES R.1-R.8
INDEX 1.1 - 1.6

•••

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Chapter 1...

PERSONNEL
.. ,.. , .. ...
........... .,_..' , ,... --......
. . . . -·.- ,.

1.0 INTRODUCTION
Managements basic job is the effective utilization of people, which they have, to achieve
from the organisational objectives. It is through the co:mbined efforts of personnel that
technological, financial, physical and other resources are utilized. Without human efforts, no
organisation can achieve their objectives. Therefore, motivation of people is of utmost
importance everywhere.
Pharmaceutical manufacturers, manufacture quality medicines using various r esources,
in this, human resource is the most important. The quality of medicine depends upon the
quality of people who produce them.
The regulatory guidelines talks about many things, about people. Some of these are as
follows:
(i) People must be qualified, experienced and trained.
(ii) They must be sufficient in number.
(iii) Their job responsibilities must be well explained to them and monitored.
(iv) They must follo\v hygienic practices and finally,
(v) They must be highly motivated.
All the above points will be discussed in this chapter.
Document required
Nil
1.1 QUALIFICATION, EXPERIENCE AND TRAINING
Once I had an opportunity to speak to Dr. M. Venkashwaralu, the Dy. Drug controller of
India, Mumbai, about why organisations fail in regulatory inspections?
He laughed and said, "Potdar, people feel that good buildin_gs, costly equipment and a few
cleverly designed formats is the key to success in regulatory inspections, but they forget the
most important factor of success, and that is the people. The people behind every thing is the
only one important factor in any success story. And I can tell you, assuredly, that any
organisation who h as well qualified, experienced, trained and motivated people, will never fail
any regulatory inspections, I only wish that, organisations realise this thing and work on it".
I still remember his words. They were just engraved in my mind forever.
All regulatory requirements talk about the importance of right people, who are
appropriately qualified, experienced and trained. Let us go little more in this and see what it is.
The W.H.O. guidelines on G.M.P. opens the chapter on "Personnel", saying - The
establishment and maintenance of a satisfactory system of quality assurance and the correct
1. 1

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Pharmaceutical Quality Assurance 1.2 Personnel

manufacture and control of pharmaceutical products and active ingredients rely upon people.
For this reason there must be sufficient qualified personnel to carry out all the tasks for,
which the manufacturer is responsible. Individual responsibilities should be clearly
understood by the individual concerned and recorded as written descriptions. It further adds
that, all personnel should be aware of the principles ofGMP that affect them.
The M.C.C. South Africa further emphasises on following things, it states that, there
should be sufficient personnel at all levels with the ability, training, experience and where
necessary, the professional/ technical qualifications and managerial skills appropriate to the
tasks assigned to them.
If we distill the above comments of the W.H.O. and Il-1.C.C, we get the following points
coming out from the distillate.
(i) People must have appropriate techuical/professional qualifications.
(ii) They must be trained.
(iii) They must have sufficient relevant experience.
(iv) They must have ability to perform the given task at given level.
(v) They must have appropriate managerial skills.
Let us now try to look into the above five points :
(i) Appropriate Technical / Professional Qualifications :
W.H.O. guidelines on GMP give some guidelines on the qualifications e.g. it states that,
the education should include study of an appropriate combination of (a) Chemistry
(an.alytical and organic) or biochemistry, (b) Chemical engineering, (c) Microbiology,
(d) Pharmaceutical science and technology, (e) Pharmacology and toxicology, (f) Physiology,
(g) Other related sciences etc.
I personally think this guideline is quite elaborate, hence we can think of people with
following qualifications for relevant areas of operation viz.,
(a ) Pharma production B. Pharm, M. Pharm, Ph.D.
B. Sc. (Tech), M.Sc. (Tech), Ph. D. (Tech)
(b) Q. A.IQ. C. B. Phann, M. Pha.n n, Ph.D,
B. Sc. (Tech), l>-f. Sc. (Tech), Ph. D. (Tech)
B.Sc., M. Sc., Ph.D. (in analytical chemistry, organic chemistry,
biochemistry, pharmaceutical chemistry, microbiology etc.)
(c) Other areas P. G. Diploma in Packaging Technology.
Relevant area qualifications like B.E./M.E. in Mech. Electrical
electronics, chemical etc. for engineering work. Qualified people
in materials .m anagement for stores and purchase function etc.
(d) Managerial Appropriate technical qualifications must be backed with formal
managerial qualifications such as M.B.A./P.G.D.B.A 1n
appropriate specialisation.

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Pharmaceutical Quality Assurance 1.5 Personnel

Ideally a job description 1nust contain knowledge about :

(i) Organisational position giving reporting relationships i.e. clearly mentioning, who
reports to him and he will report to whom ?
(ii) Individual assignments.
(iii) J ob summary - what the job entails.
(iv) \Vorking conditions, hazards of the job.
(v) Duties, responsibilities and accountability.
The regulatory authorities expect all important positions must have written, authorised
and accepted job descriptions.
(2) Key Personnel :
Most regulatory guidelines define the key personnel and job descriptions of some of the
key personnel.
Key personnel can be defined as those positions in the organisation, which have a direct
impact on the working of the organisation and quality of the products produced. Different
regulatory guidelines have different positions mentioned as Key-personnel. Following is a
brief matrix on the same.

Sr. No. Positions India UK Aust. WHO SA USA

01 Head of Production - ✓ ✓ ✓ ✓ -
02 Head ofQ. C. - ✓ ✓ ✓ ✓ -
03 Head ofQ..A. - - - - ✓ -
04 Head of Sales and Dist ribution - - - ✓ - -
05 Authorised person - - - ✓ - -
06 Managing Director - - - - ✓ -
So totally there are six different.key-personnel identified in regulatory literature but only
two of these positions have been described in detail i.e. head of production anc l1P.i>d of Q. C.
However other regulatory literature randomly mention11 the importance of these positions
without calling them key personnel.
Now let us see the Job profiles of the two key-personnel described in the literature.
It is ex·pected that all the key personnel should have appropriate qualifications and
sufficient, suitable experience to carry out their responsibilities. The South African guide
lines specifically lay down a requirement that the Managing Director of the Pharmaceutical
Company should be a pharmacist residing in South Africa and registered with the Phannacy
Council.
{A) The llead of Quality Control
He generally h as the following responsibilities :
(a) To approve or reject starting 1naterials, packaging materials and inter1nediate, bulk
and finished products.

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Pharmaceutical Quality Assurance 1.6 Personnel

(b) To evaluate batch records.

(c) To ensure that all necessary testing is carried out.
(d) To approve sampling instructions, specifications, test methods, and other quality
control procedure.
(e) To approve and monitor analysis carried out under contract.
(0 To check the maintenance of the department, premises and equipments.
(g) To ensure that the appropriate validations, including those of analytical procedures
and calibrations of control equipment are done.
(h) To ensure that the required initial and continuing training of quality control
personnel is carried out and adopted according to need.
(i) To establish, verify and implement all quality control procedure.
(B) The Head of Production
He generally has the following responsibilities :
(a) To ensure that products are produced and stored according to the appropriate
documentation in order t-0 obtain the required quality.
(b) To approve the instructions relating to production operations, including in process
controls, and to ensure their strict implementations.
(c) To ensure that production records are evaluated and signed by a designated person
before they are made available to the quality control department.
(d) To check the maintenance oftbe department, premises and equipment.
• (e) To ensure that appropriate process validations and calibrations of control equipment
are performed and recorded and the reports are made available.
(0 To ensure that the initial and continuing training of production personnel is carried
out and adapted according to need.
(C) Joint Responsibilities of Q.C. and Production Heads
Following are some of the joint responsibilities of the heads of production and quality
control.
(a) To authorise written procedures and other documents including amendments.
(b) To monitor and control the manufacturing environment.
(c) Plant hygiene.
(d) Process validations and calibrations of analytical apparatus.
(e) Training, including the applications and principles of quality assurance.
(0 The approval and monitoring of supplies of materials.
(g) The approval and monitoring of contract manufacturers.
(h) The designing and monitoring storage conditions for materials and produ<.-ts.
{i) The retention of records
(j) The monitoring of compliances with GMP requirements
(k) The inspection, investigation and taking of samples, in order to monitor factors that
may affect product quality.

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 Pharmaceutical Quality Assurance 1.7 Personnel

In connection with key-personnel, following few re1narks in regulatory literature 111ust be

kept in mind. ;_ , .
(i) The firm must have an organisation chart.
(ii) People in key positions should have specific tasks recorded in vrritten job
descriptions and adequate authority to carry out their responsibilities.
(iii) The duties of key personnel may be delegated to designated deputies of a
satisfactory qualification level.
(iv) There should be no gaps or unexplained overlaps in the responsibilities of those
personnel concerned with application of GMP.
(v) The respon.sibilities placed on any one individual should not be so extensive as to
present any risk to quality.
(vi) The person responsible for production and the person responsible for quality
assurance should be different persons of equal level of authority, neither of whom.
should be responsible to other but both have a responsibility for achieving requisite
qu ality.
(vii) Key personnel show be provided with adequate supporting staff. •·
Documents Required
(i) Job descriptions of Key-personnel plus other positions.
e.g. Head of Q. C.
Head ofQ. A.
Head of Production.
Head of Sales and Distribution.
Authorised Person.
?.<1anaging Director.

1.3 PERSONAL HYGIENE AND CLOTHING

We have opened the chapter on personnel by emphasising the importance of people in the
manufacturing of pharmaceuticals. We said earlier that people engaged in the
manufacturing of drugs and pharmaceuticals should be qualified, experienced and trained,
we now add the fourth dimension i.e. the persons engaged in manufacturing of drugs and
pharmaceuticals must also be healthy and not only healthy; but they themselves have good
hygie·nic and sanitational habits and also propogate the same to others. Because
maintaining a high level of hygienic conditions in manufacturing environment is a must.
.
With these things.in Inind, the regulatory guidelines provide following guidance to the
manufacturer.
(i) High standardr of personal cleanliness should be observed by all those concerned
with production processes. Additional specific and stringent requirements must be
•
kept in mind for people employed in sterile - products manufacturing.
(ii) Habit of hand washing must be inculcated in all the employees.
(iii) Organisation should develop detailed hygiene programmes for their employees and
such programs must be implemented .
•

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Pharmaceutical Quality Assurance 1.8 Personnel

(iv) Eating, drinking, chewing and smoking or the storage of food, drink, smoking
materials and personal medication should not be permitted ,vithin manufacturing
areas or in any other area where they might adversely influence product quality.
(v) Direct contact should be avoided between the operators hands and starting
materials, intermediates and product.'! (other than when they are in closed
containers), as well as with any part of the equipment that comes in contact with
the product.
(vi) There should be pre-employment medical checks and at regular intervals thereafter,
the steps should be taken to see that no person with disease in a communicable form
or with open lesion on the exposed surface of the body, is engaged i.n the
manufacture of medicinal products.
(vii) Visual inspection staff should pass an annual eye examination, (or may be earlier if
required).
(viii) Staff should be required to report infections and skin lesion and defined procedure
followed when they are reported. Supervisory staff should look for the signs and
symptoms of these conditions.
(ix) A detailed Dress-code procedure should be implemented. This should also cover use
of other accessories used for human body protection.
(x) Hygiene programmes should be promoted by management and widely discussed
during training sessions.
(xi) Requirements regarding persona.I hygiene and protective clothing apply to all
persons (including visitors, maintenance personnel, senior management staff and
inspectors) entering production or other critical areas.
(xii) Only personnel authorised by supervisory personnel shall enter those areas of
buildings and facilities designated as limited access areas.
Documents Required
(i) SOP/R on Penicillin sensitivity tests carried out on employees working in ~-lactum
antibiotics area. This may also be extended to the other sensitive drugs being
manufactured in the plant.
(ii) SOP/R on pre and post employment medical check-ups and periodic recheck. This is
specifically important in case of eye check-ups and skin, and other infectious
disorders.
(iii) SOP/R on training of employees on personal hygiene.
(iv) SOP/Ron handling of illness of employees.
(v) SOP on dress-code.
(vi) SOP/Ron management of change rooms and their sanitation.
(vii) SOP on organisational policy on smoking, eating, drinking and chewing.
(viii) SOP on training of employee on Motivation.
(ix) SOP on prevention of entry of unauthorised persons in production or other critical
areas.
(x) SOP on working in clean rooms.

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Pharmaceutical Quality Assurance 1.9 Personnel

1.4 LEGAL ASPECTS

Personnel related Legal Aspects are covered in regulatory literature, only by M.C.C.
South Africa guidelines, W.H.O. and Schedule M ofD and C Act of India.
Let us see briefly what these guidelines say about this.
(1) Schedule M of D and C Act India says that :
(i) The manufacturing shall be conducted under the direct supervision of
Competent Technical Staff with prescribed qualifications and practical
experience in the relevant dosage form and/or active pharmaceutical products.
(ii) The testing shall be conducted under the direct supervision of Competent
Technical Staff, who shall be whole time employees of the licensee.
(2) W.H.O. guidelines say that:
(i) Key personnel responsible for supervising the manufacture and quality control
of pharmaceutical products should possess the qualifications of a scientific
education and practical experience required by national legislation. It
further states that, the scientific education and practical experience of experts
should be such as to enable them to exercise independent professional
judgment based on the application of scientific principles understanding to the
pract ical problems encountered in manufacture and quality control ·of
pharmaceutical product.
(3) M.C.C. South Mrica says that :
(i) The Company and the Managing Director (who must be a pharmacist residing
in the republic) must be registered with Pharmacy Council.
(ii) All directors must confirm that they will abide by the pharmacy councils ethical
rules.
(iii) Pharmaceutical operations must be conducted under the constant personal
supervision of pharmacists whose name is displayed over the main entrance.
(iv) Certain duties and responsibilities must be performed by pharmacists e.g.
manipulation, preparation or compounding of medicines, manufacturing,
furnishing of advice with regard to medicines, distribution and sale of
medicines.
(v) Other legal requirements cover:
• Labelling of medicines, including package inserts.
• Records and registers for scheduled medicines.
• Sale of medicines to only registered and approved customers.
• Registration of medicines with the M.C.C.
• Adherance to standards.
• Reporting of adverse reactions and technical errors.
• Advertising of medicines.
• Carrying and supply of professional samples.
(vi) Legislation aJso covers detailed procedures for handling of narcotics and
psychotropic drugs.

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Pharmaceutical Quallty Assurance 1. 10 Personnel

Documents Required
(i) Copies of drug licenses given by Drug Control Authorities along with list of
products permitted to be manufactured.
(ii) List of Competent Technical Staff along with their copy of Certificate of
Approval.

1.5 CONSULTANTS
Consultant is a person who provides expert advice professionally. Regulatory authorities
allow, pharmaceutical manufacturer to seek such advice from consultants if they need.
U.S.F.D.A. and M.C.C. South Africa has covered the requirements of such consultants.
Let us see what these guidelines say.
(1) As per U.S.F.D.A.
(i) U.S.F.D.A. has identified cei:tain areas for such advice e.g. manufacture, processing,
packaging and holding of drug products.
(ii) Such consultants must have sufficient education, training and experience or any
combination thereof to advice on the subjects for which they are retained.
(iii) :h{anufacturer should maintain records of such consultants giving the following
details:
Name
Address
Qualifications
Type of service provided
(2) M.C.C. South Africa
(i) Only in exceptional circumstances should person.s be engaged part time or in a
consultative capacity be appointed to key positions.
(ii) Other details remain same as given by U.S.F.D.A.

Documents Required
(i) Records of consultants, giving details of name, qualifications, address and type of
consultancy provided.

IDOCUMENTS AND FORMATS!

01 DOCUMENT TITLE: TRAINING MANUAL
Covering policy on employee training, areas of training evaluation of training and
training records.
Each organisation should have a training manual specifying the policy and procedures
related to training of employees. Employees can be divided mainly into three groups.
Viz.- Workers
Supervisors and
Managers and administrators.

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Phannaceutical Quality Assurance 1. 11 Personnel

The training is mainly divided into..three parts or areas e.g.

GMP/GLP/GVP related training
Job sp\lcific training and
Behavioural training.
The training can be provided in house or employees can be sent out side.
VarioUB methods can be used for training people in house e.g. lectures, group work, in
basket, management games, role playing etc. for supervisor and managerial training
International Labour Office Genera's supervisory development manuals are very useful. The
author has successfully used these manuals in companies like Ranbaxy, Wockhazdt, Intas,
Plethico and Alkem etc.
This training manual should have at least the following information :
(i) Classification of employees requiring training.
(ii) Procedure for identifying training needs. (This may be based on job descriptions of
various employees)
(iii) Proposed list of training programmes with contents.
(iv) Designing course of training based on needs of employees.
(v) Frequency of training and time required for each programme, specifying bow many
people can be effectively trained in one group. (Normally not less than 5 and not
more than 20, should be a reasonable number).
(vi) Qualification and experience ofin house and outside trainers. .
(vii) Training records to be maintained.
(viii)lmmediate and long term evaluation techniques and records of the same.
(ix) List of recommended books in the training library.
(x) List of training aids required e.g. O.H.P. Slide projector, T.VN.C.R.JD.V.D. Flip
charts models etc.
(xi) List of recommended outside institutions providing training to the employees.
(xii) Percentage of time, each employee should spend on training, each year. A 3 to 6%
time is normally recommended for training and new learning for each employee.
This amounts to about 10 to 16 days of training per employee per year. Which
includes, in house and out side training.
(xiii) Policy and procedure for developing selected in house trainers etc.
Minimum following records should be maintained.
(A) Attendance record of training
This record should have the following details :
(i) Subject of training.
(ii) Name, qualification, experience, designation of trainer.
(iii) Name, designation and department of trainee along with his/her signature on
attendance record.
(iv) Date and time of training.
(v) Venue/ location of training etc.

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(B) Training evaluation record

(i) Training evaluation should be done on immediate and long term basis.
(ii) Immediate training should be based on objective type tests, which is to be conducted
immediately after the training session is over. This test should not be more than
2 A4 size papers and containing 10 to 15 objective questions.
(iii) The top of the paper should cover minimum following information :
(a) Name of the trainee/designation/department to which he belongs.
(b) Details of the trainer and evaluator.
(c) Subject of training.
(d) Date and time of training.
(e) Venue/ Location.
(f) At the bottom, comments of the evaluator may be written. These comments
1nay be for departmental head and / or the trairiee himself.

02 DOCUMENT TITLE : JOB DESCRIPTION OF KEY PERSONNEL

The key personnel should be as follo\VS :
• .Head of Q.C. and Q.A.
• Head of Production.
• Head of Sales and Distribution.
• Authorised person and
• Managing Director of the company.
Each job should be described under the following headings.
(i) Name and Title or Designation of the person.
(ii) Department and location (Normal place of work i.e. name of city).
(iii) Reporting relationship (including dual reporting if any, e.g. a personnel manager at
factory may be reporting to factory manager, administratively and to the Vice-
President-Personnel, functionally.)
(iv) Job summary.
(v) Detailed job description.
(vi) Authorisation (signature of head of personnel or plant head or functional or
departmental head etc.)
(vii) Signature with date of employee for having received the job description and understood.
Note : These days, some companies are providing very detailed job description, including
listing of various reports he bas to make routinely and guide lines on bow he will be
evaluated on his job performance.

08 DOCUMENT TITLE: PENICILLIN SENSITMTY TESTS

'All employees working in Penicillin (and 1nay be other sensitive materials areas e.g.
other P-laci:ums) should under go the sensitivity tests for the materials they are handling.
This is conducted by an expert physician or a pbyi.-ician who is trained in allergy testing.

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The report should have the following details :

(i) Name of the employee.
(ii) Date of testing.
(iii). Substance for which the test was carried out.
(iv) Conclusion/ remarks of the test performed.
(iv) Certification of the employee for the sensitivity, by the testing physician etc.

04 DOCUMENT TITLE : PRE AND POST-EMPLOYMENT MEDICAL CHECK UP OF

EMPLOYEES
Compliance with the requirements that no production process should be carried out by
employees who are sick or have any open wound !ltc; starts from the pre-employment medical
check up and regularly at a predefined frequency (Normally 6 months to one year) there
after. This should include minimum following points :
(i) General physical checkup by a qualified physician.
(ii) Chest X-ray.
(iii) Wassermann Test.
(iv) Tuberculosis Test.
(v) Investigations of specific diseases like, hypertension, diabetes etc.
(vi) In specific cases a test for AIDS may be added.
(vii) Employee requiring to do visual inspection activities should be examined for eye
sight, every six months.
(viii) Company must maintain all records of such pre and post-employment medical
examination and advise the employees suitably, if required, by the company
physician.

05 DOCUMENT TITLE: SOP ON PERSONAL HYGIENE

Pharmaceutical manufacturing operations should always be carried out by the
employees who are healthy and practice good sanitation and hygiene practices.
This SOP should spell out how the employees should follow the sanitation and
healthy practices. This should normally cover the following points :
(i) Washing and drying of hands and feet to clean them, after the use of toilet facilities
and before entering the processing or packaging area.
(ii) Avoiding of drinking, chewing, smoking and eating in processing, packaging,
storage, Q. C. labs, animal houses, and other working area and change rooms.
(iii) Avoiding use ofjewellery, watches, face make-ups etc.
(iv) Reporting of sickness, injuries etc. to immediate supervisor and seek his advise.
(v) Wearing only clean uniforms.
(vi) Avoiding spitting.
(vii) Proper use of antiseptics and disinfectants etc.

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(viii) Proper maintenance of hair, beards, nails etc.

(be) \Vomen e1nployees should be specifically trained by suitable woman trainers about
healthy practices during the Ivl.C. periods.

06 DOCUltIENT TITLE : SOP ON HANDLING OF ILLNESS OF EMPLOYEES

This SOP should address the following points :
(i) Procedure for reporting on the job illness to the imn1ediate supervisor.
(ii) Action required to be taken by the supervisor and ill employee.
(iii) Isolating the ill e1nployee from the work place tiU such time he is declared fit to
work again by a suitable authorised person or a registered physician.
(iv) Records of all illnesses of employees to be maintained and should be available in
the company ,vith appropriate authorit ies e.g. personnel manager's office etc.

07 DOCUMEN'l' TITLE : SOP ON DRESS-CODE

This SOP should spell out type of uniforms worn by the various categories of employees
i.n the plant and the clothing management in general. This SOP should have the following
details :
• Clothing matrix i.e. what are the component of uniforn1s and who has to weai: it,
where and when etc.
• Laundering of the uniforms·and related other clothing.
• Special treatn1ent for sterile clothing, Lint free cloth, (sterilization of washed cloths
etc.).
• Method of wearing the uniforms.
• Disposal of torn and worn-out uniforms.
• Repairing of uniform which can be reused.
• The pharma uniforms may generally cover the following items :
• Caps / II air cover.
• Beard and moustache cover.
• Coats, coveralls, shirts, pants etc without top pockets.
• Gloves (Disposable or other suitable materials).
• Shoes/Sleepers.
• Shoes covers (if required in specific area).
• Masks.
• Safety glasses / Goggles/ Shields.
• Respiratory suits.
• Ear plugs (in high noise level working areas).
• Work clothing should not be \vorn outside the appropriate plant area, and changing
rooms should be available separately for gents and ladies.
• While designing the unifonn socio-cultural factor should also be taken into account.

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(Note : Half skirt / Top was an accepted uniform for ladies in multinational companies,
but these days it is changed to salwar-kamees. Once total white uniform was rejected by lady
employees on religious grounds, saying that total white dress is used only by widows)

08 DOCUME.NT TITLE: SOP ON MANAGEMENT OF CHANGE ROOMS

This SOP should cover the following points :
(i) Cleaning and sanitation procedures to be followed for the change rooms, including,
uri.n als, toilets, bathrooms, hand and feet wash places. Storage and distribution
areas for uniforms and dress change areas.
(ii) Regular cleaning and sanitation of uniform cupboards provided to employees.
(iii) Frequency of a laundering of employee uniforms.
(iv) Frequency and method of cleaning and sanitation or disinfection of shoes and
slippers used by employees.
(v) Procedure for air circulation in change rooms and also in the compartmented
uniform storage cupboards.
(vi) Records of U.V. light usage in the cupboards provided in change rooms of asepectic
operations area.
(vii) Records of all activities related to housekeeping of change rooms, laundering of
uniforms and cleaning and sanitations of foot wears must be maintained and
presented for inspection on demand by the inspecting authorities.

09 DOCUMENT TITLE : SOP ON ORGANISATION POLICY ON SMOKING,

EATING, CHEWING AND DRINKING
Currently, there is a trend in many pharmaceutical organisation to declare the entire-
site as No-smoking and No-chewing zone.

10 DOCUMENT TITLE: SOP ON TRAINING ON MOTIVATION OF EMPLOYEES

All employees working in pharmaceutical operations should be well trained and
motivated.
Trained employee means one who has appropriate knowledge, skill and attitude. Proper
or appropriate attitude can come only from highly motivated employees. The SOP on training
on motivation should cover the following points :
(i) What is motivation ?
(ii) Factors that motivate employees :
• Monitory factors.
• Working environment (Clean, hygienic).
• Respect for job they do.
• Importance of their job and its social contribution to the improvement of health of
people in society.
• Job satisfaction at work place.
• Good human relations at work place etc.

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11 DOCUMENT TITLE : SOP PREVENTION OF UNAUTHORISED PERSONS IN

PRODUCTION AND IN OTHER CRITICAL AREAS OF OPEARATION.
This SOP should address the following issues :
(i) Who is authorised and who is unauthorised person in a specific area?
(ii) Which areas are declared as critical operations area? for example, all processing
areas, packaging areas and area of storage where sterile raw materials are stored.
(iii) Some companies have now started giving electromagnetic entry cards to their
employees who work in most critical areas like aseptic filling operations. (e.g. Alkem
Laboratories Ltd.)
(iv) Records of entry in critical operation area is maintained.

12 DOCUMENT TITLE : RECORDS OF CONSULTANTS

Inclusion of this clause by U.S.F.D.A. regulation (C.F.R. 211.34) is to impress that only
capable people work as consultants for pharmaceutical industry. Particularly on technical
consultation work.
This record should have the following detail.s :
(i) Name of the consultant.
(ii) Educational qualifications.
(iii) Professional qualification and experience.
(iv) Address, Postal address and Phone / 1''ax / e-mail etc. of his office and residence.
(v) Area covered by the consultant for providing consultancy.

01 FORMAT TITLE : LIST O.F TECHNICAL STAFF WITH QUALIFICATIONS,

EXPERIENCE AND F.D.A. APPROVALS IF ANY
MAP PIIARMACElITICAL LTD.
LIST OF TECHNICAL STAFF
DEPARTMENT:
Sr. Na_, D•teof Dtt.-i.pailon QuaUOc•tJona Experience 1.n Yean FDA
No. Joining A~n.rovala
Degree/ Ycu of lo Utio Ovtoi.dc Total Dept. Sta~ Year
Diploma pauinf company this end
compaay Ref.

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Pharmaceutical Quality Assurance 1. 17 Personnel

02 FORMAT TITLE : ORGANOGRAM AT OVERALL ORGANISATION CEVEL.

Organisational level organogram should start from the chairman / Managing Director
level in the organisation and end at the departmental head level e.g.

Chairman

'

Managing Director

President I V.President
(Technical Operations)

Head
l
Head
l
Head
* Head Head Any
Manufacturing Quality Engineering Personnel Finance and other
Management and H.R.D. Administration

03 FORMAT TITLE: PLANNED AND USED PLANT CAPACITY

A statement of plant capacity planned and at present used. (To prove that you have
sufficient number of people to carry out the various tasks.)
Planned Plant Capacity
(and capacity presently in use)
As on 1•1 April 2006
Sr. Department Planned Capacity %otplanned
No. One Day One Month One Year capacity
(1 Shift) (25 Shifts) (300 Shifts) presently used

01 Tablets 20 lacs 500 lacs 60.0 crores 70%

02 Capsules 5 lacs 12.5 lacs 15.0 crores 50%

03 Liq. Orals 50,000

.12.5 lacks 1.5 crores 60%

04 Ointments 20,000 5 lacks 0.6 crores 80%

05 •Liq. Inj. A1np. 100,000 25 lacks 3.0 crores 40%

06 Liq. lnj. Vial . 50,000 12.5 lacks 1.5 crores 65%

07 Others - - . -
Above is an arbitrary example, how the statement should look like.

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Chapter t ...

SURROUNDING, BUILDINGS &f ACILITIES

2.0 INTRODUCTION
2.0.1 Location and Surroundings
A pharmaceutical manufacturing facility should be located in such an environment,
which protects the manufacturing process, presents minimum risk of causing any
contamination to the materials or products. For this purpose it should have a good
surrounding environment, with sufficient protection from drains, sewage or other nearby
factories producing undesirable fumes, odours or other gaseous or liquid effluents which have
direct or potential danger of contamination of the materials and pr oducts being processed in
the factory premises.
M.H.R.A. (U.K.) and U.S.F.D.A. are now asking the organisations to provide the profile
or industry surrounding the pharmaceutical facility. They even ask the general profile of the
industries in the area of about 15 km radius to assess the potential danger of contamination
of the products being produced \Vith a sufficient length of time in future.
Other factors which should be · considered are direction of natural air flow, annual
rainfall, temperature and relative humidity of the area during the various seasons of the
year. The knowledge of the history of the natural calamities like, floods, earthquakes, storms
etc. may also be useful in deciding the location of the pharmaceutical plant.
Following are some of the major guidelines provided by the various regulatory
authorities.
(i) The building(s) used for the factory shall be so situated and sh all have such measures
as to avoid risk of contamination from external environment including open sewage,
drains, public lavatories or which produces disagreeable or obnoxious odours, fumes,
excessive soot, dust, smoke or chemical or biological emissions.
(ii) Premises should be situated in an environment that, when considered together with
measures to protect the manufacturing process, present minimum risk of causing any
contamination of materials or products.
2.0.2 General Re quirements of Buildings and Facilities
In the last section we have seen the general about the location of a pharmaceutical
facility. Now Jet us see what are the general requirements for the buildings used for the
pharmaceutical manufacturing. All the leading regulatory bodies are in agreement with the
general requirements. The requirements can briefly be stated as follows :
(i) Pharmaceutical premises should provide well sanitation system.

2.1

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(ii) Pharmaceutical premises should be carefully maintained and it shouJd be ensured

that repair and maintenance operations do not present any hazard to the quality of
the products. Premises should be cleaned and where applicable, disinfected
according to the written standard operating procedures.
(iii) Electric supply, lighting, temperature, humidity and ventilation should be
appropriate and such that they do not adversely affect directly or indirectly either
the pharmaceutical product during their manufacturing and storage or the accurate
functioning of the equipment.
(iv) Premises should be designed and equipped so as to allot maximum protection
against the entry of the insects, birds, vermins and other animals particularly
rodents etc.
Document Required
Site map of the location, giving detail.s about the immediately surrounding industries
or other activities.

2.1 PRINCIPAL AREAS OF A PHARMACEUTICAL MANUFACTURING FACILITJES

Once a decision is taken to create a facility for pharmaceutical manufacturing, the User
Requirement Specifications (URS} are made. For this purpose, few major issues are to be
addressed. They are :
(a} What formul ations are to be manufactured ?
(b) How much quantities are to be made (in what time frame planned capacity design)
(c) Based on (a) and (b) above a decision is taken as to which areas are required in what
capacity (area and volume).
The regulatory guidelines provide information on some common areas in the facility.
They are as follows :
(i) Ancillary areas,
(ii) Warehousing areas,
{iii) Production areas,
(iv) Quality control areas.
Let us briefly review the requirements.
(i) Ancillary areas: These areas cover,
• Rest and Refreshment rooms.
• Toilets and Wash areas.
• Clothes storage areas.
• Change rooms for employees.
• Engineering workshops.
• Animal house and similar areas.
Rest and Refreshment Rooms should be separate from other areas.
Facilities for Toilets should not communicate directly with production or storage areas.

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Areas for change rooms and storage of clothes and for washing, and toilet purposes
should be easily accessible and appropriate for the number of users. (Also ref. to Factories
Act and Rules of India).
Maintenance workshops should if possible be separated from production areas. Whenever
parts and tools are stored in the production area, they should be kept in rooms or lockers
reserved for that use.
Animal houses should be well isolated from other areas, \vith separate entrance (animal
access) and air handling facilities. - ~-·
(ii) Warehousing Areas :
(a) Storage areas should have sufficient capacity (calculated in tenns of pa!late space;
•
one pallate space is considered as one cubic metre) to allow orderly storage of the
various categories of materials ~d products like :
.
• Raw materials.
• Packaging Materials.
• Intermediates.
• Bulk and finished products.
• Products in quarantine.
• Released, returned, rejected and recaJled products.
(b) Storage areas should be designed to meet the required environmental conditions like :
• Temperature,
• Humidity.
Records of such environmental conditions monitoring should be maintained .
(c) Receiving and dispatch arefil! should have the following facilities,
• Weather protection while unloading·aiid Toading of materials.
• Cleaning of received materials, before taking into quarantine area.
• All received materials-should be kept s~gregated by physical partitioning either
fixed or flexible.
(d) Segregated sampling areas should be provided for active and inactive materials. Such
sampling cubicles _may be designed (or at present such booths are readily available)
with Reverse Laminar Flow Units of suitable size and also provided with cleaning,
drying and storage for sampling tools. This system avoids potential dangers of cross
contamination.
Sampling of liquid materials, solvents, flammable materials or toxic, poisons or
potent materials should be "&one in separate areas with taking all the necessary
precautions for safety of people and materials both.
(e) All returned, rejected and -r.ecalled materials_must be stored in lock and key and
necessary precaution should be taken to avoid mix-ups.
(f) Printed packaging materials are considered critical to the conformity of the
pham1aceutical product to its labelling and special attention should be paid to the
safe and secure storage of these materials.

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(g) Dispensing areas should be separate for active and inactive materials. They are
provided with Reverse Laminar Air flow units and provided with a separate and
suitable tools, provision for their washing, drying and storage should be made
appropriately.
(iii) Production Areas :
(a) General category products (e.g. other than antibiotics, beta-lactum, steroids, live
micro-organisms etc.) should be manufactured in separate manufacturing facilities.
(b) Highly potent, sensitive or live micro-organism etc. should be produced in well
segregated areas to avoid cross contamination.
(c) Products like technical poisons, herbicides etc. should not be normally produced
along with other pharmaceutical products to avoid risk of contamination.
In exceptional cases, this can be carried out, with product and process specific
precautions, on a campaign basis.
(d) Premises should be designed to have logical flow of materials, well organised layout
of plant and machinery and ease of cleaning, both equipment and facility.
(e) Depending upon the volumes of materials being handled, adequate space should be
provided to avoid congestion and possible danger of mix-ups.
(f/ All the areas, where pharmaceuticals, and primary packing materials are exposed,
should be hard, smooth, impervious and without open joints, to 111ake cleaning and
sanitization activity easy.
(g) Pipe work, light fittings, ventilation points and other services should be designed and
sited to avoid the creation of recesses that are difficult to clean. As far as possible
maintenance ,vork should be done from outside the production areas.
Technical (Maintenance) zones may be provided from behind the processing area
with separate lanes giving access to this technical zones.
(h) Drain of production areas should be of adequate size, sufficient in number and
suitably located and equipped to prevent backflow. Open channels should be avoided
wherever possible, but if they are necessary they should be shallow to facilitate
cleaning and disinfection
(i) Production areas should be effectively ventilated with suitable designed HVAC
system, appropriate to products being handled; to the operations undertaken and to
the external environment.
These areas should be regularly monitored during production and non-production
periods to ensure compliance with their design specifications.
(j) Premises for packaging of pharmaceutical, shou.ld be specifically designed and laid
out so as to avoid mix-up and cross contamination.
Primary packaging area where drug product is packed in the primary packaging
material, should meet the environm.ental conditions required by the products being
handled. This particularly refers to the temperature, hu1nidity and class of air
required.
(k) Production areas should be well lit, particularly where visual on-line checks are
carried out.

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(iv) Quality Control Areas :

(a) Q. C. laboratories should be separated from production areas.
Areas where biological, microbiological, or radio isotopes test methods are employed,
should be separate from each other.· • • •
(b) Q. C. laboratories should be designed to provide facilities for -
Wet chemical analysis.
Instrumental analysis.
Microbiological and biological analysis etc.
Storage for control samples, glasswares, chemicals, microbiological media
books, documents etc. and
Offices.
(c) Separate HVAC systems should be provided for various activities being carried out
in the lab to avoid cross-contamination.
(d) A separate room or area should be provided where highly sensitive instruments are
handled to protect them from electrical interference, vibration, contact with
excessive moisture, and other external factors.
Documents Required
(1) Site plan (showing main buildings block diagram plus surrounding area in brieO.
(2) Floorwise building plans showing the following details.
General layout of rooms with names and numbers of rooms and dimensions.
Equipment layout plan.
Men movement layout.
Material movement layout.
HVAC scopes with details of temperature, humidity, class of air and pressure
\ differentials designed.
(3) Area statement in the following fashion :
Plot area.
• Floonvise built up area.
Departmentwise area.
- Section I Subsectionwise area.
- Utilities / workshops.
Corridors I passages.
. Storage area RM/PM/FG/Others.
- Change rooms and wash places.
- Rest rooms / Offices.
Canteen/ Eating place.
- Other provisions in the plot or buildings.
(4) Plant capacity statement based on :
One shift
- Onemonth
- One year
(Define assumptions while giving details of capacity)

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(5) Utilities capacity planned.

- Electric power
Raw ,vater
- Purified ,vater
- Water for injection
Any other quality of water
Raw steam
Pure steam
Compressed air
- Total air-conditioning.
2.2 PLUMBING AND DRAINAGE SYSTEM
CFR 211.48 ofU.S.F.D.A. gives the following guide lines:
(a) Potable water shall be supplied u.nder continuous pressure in a plumbing system
free of defects that could contribute contamination to any drug product. Potable
water shall meet the standards in 'Environment Protection Agency'. Primary
Drinking Water Regulations set forth in 40CFR par 141. Water not meeting such
standards shall not be permitted in the potable water system (Alternatively a
suitable standa.rd of the country should be followed). .
(b) Drains shall be adequately sized, where connected directly to the sewer, shall be
provided with an air break or other mechanical devices to prevent back Siphonage.
Drainage system management in the phannaceutica! manufacturing facilities is very
critical from point of view of claaoiog and sanitation of ilie facilities and hence a detailed
SOP should be available dealing with the cleaning and sanitation of drains and their records
should be maintained.
Documents Required
(i) Plan of drainage system of the plant.
(ii) SOP/R of cleaning and sanitation of drain in the pharmaceutical plant.

2.3 UGBTING
CFR-211.44 gives only one line guideline and states that "Adequate lighting shall be
provided in all areas".
Regulatory guidelines do not make any comment on the intensity of light required in
various operational areas. But there are certain industry norms for specific critical areas in
the plant, they are as follows :
(i) Visual inspection areas for Ampoules / Vials or similar ➔ 100 foot candles.
sterile products.
(ii) Visual inspection areas for liquid oral bottles or ➔ 50 to 80 foot candles.
similar non-sterile products.
(iii) Packaging lines in the packaging departm«:nts. ➔ 50 foot candles.
(iv) Visual inspection of tablets / capsules on automatic / ➔ 50 to 80 foot candles.
semiautomatic inspection belts.
(v) Other operational areas in the plant. ➔ 50 foot candles.
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Light intensity should be checked at the operational height in the department.

Document required
Specifications and Records of light intensity at critical work areas as identified above.

2.4 SEWAGE, REFUSE AND DISPOSAL OF WASTE

CFR 211.50 states that "sewage, trash and other refuse in and from the building and
immediate premises shall be disposed ofin a safe and sanitary manner".
Schedule-M (1.4) of Drugs and Cosmetics Act.,.lndia also gives certain guidelines in this
regard. viz.,
(i) "The disposal of sewage and effiuents (solid, liquid, and gas) from the manufactory
shall be in conformity with the requirements of the Environment Pollution Control
Board".
(ii) All biomedical waste shall be destroyed as per the provisions of Bio.-Medical Waste
(Management and Handling) Rules, 1996.
(iii) Additional precautions shall be taken for the storage and disposal of rejected drugs.
Records shall be maintained for all disposal of waste.
(iv) Provisions shall be made for proper and safe storage of waste materials awaiting
disposal. Hazardous, toxic substances, and flammable materials shall be stored in
suitably designed and segregated enclosed areas in conformity with Central and
State Legislation".
Pharmaceutical manufacturing facilities produce different types of solid waste like,
• Paper
• Glass
• Plastic
• Aluminium
• Rubber .
• Containei:s / bottles of plastic, glass and metal.
This type of waste is collected from the point of generation and then segregated and
stored in scrapyards specially designed for this purposes.
This material is generally sold to the scrap dealers. Precautions should be taken befor)!
selling these materials to the scrap dealer e.g.
{i) Empty solvent containers should be freed from residual solvent lying at the bottom of
the drums. (The author has witnessed a fatal fire accident because of this).
(ii) Rejected printed packaging materials Oabels, cartons, foils etc.) should be defaced,,
destroyed before sending to scrap for storage and sale.
(iii) Labels on the empty containers should be removed or defaced to avoid intentional
misuse of the containers.
An authorised records of disposal of such materials must be kept and should be available
for inspection or audit if required.
Document required
SOP on handling (collection, storage and disposal) of scrap materials and its record.

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2.5 WASHING AND TOILET FACILITIES

CFR 211.52 states that "Adequate washing facilities shall be provided including bot and
cold water, soap or detergent, air dryers or single - service towels and clean toilet facilities
easily accessible to ,vo.r king areas".
The number of washrooms, urinals, latrines, and bathrooms (wherever required) should
be based on the number of people working in the facility. Factory Act and Rules of India
provide guidelines on this.
The general principle is that the number should be sufficient to avoid crowding of such
service at any time.
The minimum nun.1ber of water closets should be based on the following guidelines.
Number of users Minimum number of water closets
1 - 15 1
16-35 2
36-55 3
56 -80 4
81 - 110 5
111 - 150 6
Over 150 1 additional for every 40 users.
Document Required
SOP/Ron cleaning and sanitation of washing and toilet facilities.
2.6 SANITATION
CFR 211.56 gives guidelines of Sanitation. It states:
(a) "Any building used in the manufacture, processing, packing or holding of a, drug
product shall be maintained in a c.lean and sanitary condition, any such building shall be free
of infestation by rodents, birds, insects, and other vermins (other than laboratory animals).
Trash and organic matter shall be held and in a tilnely and sanitary manner.
(b) There shall be ,vritten ' procedures assigning responsibility for sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment and materials to
be used in the cleaning the buildings and facilities; such written procedures shall be followed.
(c) There shall be \vritten procedures for use of suitable rodenticides, insecticides,
fungicides, fumigating agents and cleaning and sanitising agents. Such written procedures
shall be designed to prevent the contamination of equipment, components; drug product
container and closures, packaging, labelling materials or drug products and shall be followed.
Rodenticides, insecticides, and fungicides shall not be used unless registered and used in
accordance with the Federal Insecticides, Fungicide and Rodenticide Act. (or any equivalent
act of the specific country)
(d) Sanitation procedures shall apply to work performed by contractors or temporary
employees as well as work performed by full time employees during the ordinary course of
operation. -

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Pharmaceutical Quality Assurance 2.9 Surrounding. Buildings & Facilities

Certain points to be noted in this regards :

(i) Disinfectants must be rotated during the sanitation programme to avoid resistance
development by the microbes.
(ii) l\1icrobial profiles of the critical areas in the manufacturing facility should be
studied and monitored.
(iii) SOPs on sanitation should clearly provide the frequency of sanitation, concentration
of specific detergent.<; and disinfectants used.
(iv) Procedures for preparation, filtration and storage of disinfectants. Diluted
disinfectants must be used on the same day and should not be stored for use in
future. No disinfectant should be added in diluted and stored disinfectant and
reused.
(v) Sanitary supervisor is an important person in the system of sanitation and he
should be trained enough in the requirement of sanitation in pharn1aceutical
manufacturing facilities.
(vi) SOPs should be available even for cleaning and sanitation of external areas of the
facilities like roads, lawns etc. Cutting and disposal of la,vns (grass) is an important
aspect of sanitation, since the cut grass has a potential of presence of small crawling
or other insects and they can pose a danger to the operating facilities.
Documents Required
(i) SOP/R on control of pests, rodents, birds and insects and vennins.
(ii) Job description of sanitary supervisor.

2.7 MAINTENANCE
CFR 211.58 states that "Any building used in the manufacture, processing, packing or
holding of a drug product shall be in a good state of repair".
Facility maintenance includes the following things :
• Spoilage of plaster.
• Peeling off of paints.
• Leakages fro1n ceiling or other surfaces.
• Leakages from pipe lines of waters, steam, gases etc.
• Plumbing problems.
• Loose or broken tiles.
• Improper closing of doors, windows.
• Improper electrical wiring.
• Improper electrical fittings/fixtures.
• ~Iissing tubelights etc.
A detailed check list may be prepared for the points to be looked into, during routine
inspection of the facilities and the identified deficiencies should be rectified immediately and
the facility must always be maintained in a state of good repair.
Document required
SOP/Ron facility maintenance.

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Pharmaceutical Quality Assurance 2.10 Surrounding, Buildings & Facilities

!DOCUMENTS AND FORMATS!

01 DOCUMENT TITLE: SITE MAP OF THE LOCATION

This document shows the location of the site in surrounding area. The site map shows
block diagrams of various buildings in the site. Following figure shows a sample site plan.

9 6
K1 5

4 R5

Re
..
u.

Main Road

Model Site Plan :

l. Security gate cum office.
2. Administrative and Q.C. block.
3. General products production block.
4. Cephalosporin production block.
5. Warehouse
6. Utilities block
7. Canteen.
8. Bore wells.
9. Parking place.
R1 to Rs - Internal road
JIJIJ/JIIIJJ : Site border.

02 DOCUMENT TITLE: FACILITY AREA STATEMENT

Facility area statement is a document giving details of area occupied by major activities/
functions in a factory and site.

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 Pharmaceutical Quality Assurance 2. 11 Surrounding, Buildings & Facilities

It can be sin1ply presented in the following way.

01 Total plot Area 20,000 M2•
02 Administration and Q.C. Block 1000 ~{2 on ground floor (Adm.).
1000 M2 on first floor (Q.C. Lab).
03 General Production Block 1500 M2 on ground floor (Tablets/ Liq.).
1500 M2 on first floor - Injectable.
04 Cephalosporin Block 1000 M2 on ground floor .
1000 M2 on first floor.
05 Ware House Block 2000 M2 on ground floor.
1500 M2 on first floor.
06 Utility Block 1000 M2.
•
07 Canteen 1200 M2 .
• On similar lines each of the above block can be provided with detailed area statements
for various departments, sections and work stations in each block.

03 DOCUMENT TITLE: SOP ON SANITATION OF THE DRAINS

This is a specific SOP on cleaning and sanitation of drains in the pharmaceutical
manufacturing facility. This should cover at least the following points.
(i) Layout plan showing positions of drains, marked with numbers and movement of
direction of flow of drain water through it.
(ii) . Validated cleaning procedures and frequency of deaning.
(iii) Validated sanitation procedures and frequency of sanitation.
(iv) Responsibilities for carrying out the job of cleaning and sanitation.
(v) Sampling and testing methods, for cleaning and sanitation procedures, routinely used.
(vi) Records of cleaning and sanitation carried out.
(vii) Reports of sanitation, monitoring done by Q.C. Lab.

04 DOCUMENT TITLE : SPECIFICATIONS AND RECORDS OF LIGHT INTENSITY

IN VARIOUS AREAS
This is a list indicating the following points :
(i) Room number and name.
(ii) Activity carried out in each room.
(iii) Recommended light intensity.
Routine records of light intensity verification should be maintained. A monthly or even
quarterly verification may be acceptable.

05 DOCUMENT TITLE : SOP ON HANDLING OF SCRAP MATERIALS AND ITS

RECORD
This SOP should address the following points :
(i) Definition of' scrap material.
(ii) Types of scrap materials.
(iii) Point and methods of collection of scrap.

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_P_h_a_,m
_a_c_e_u_tic_a_J_Q_u_a_
lity
-'-A_ss
_u_ra
_nc_e_______
2_
. 1_3_ _ _ _ _ _Surrounding, Buildinf!!_ & Facilities

(ii) Preparing SOPs for cleaning and sanitation of these areas.

(iii) Deciding cleaning schedules and preparing reports of cleaning and sanitation
performed.
(iv) Deciding on chemicals a.nd sanitation agents and their concentration.
(v) Deciding on equipments used.for sanitation.
(vi) Reporting any unusual happenings related to sanitation.
(vii) Maintaining a high level of overall sanitary condition in entire facility.

09 DOCUMENT TITLE: SOP ON BUILDING AND FACILITY MAINTENANCE

Tb.is SOP should cover the following points.
(i) Painting of facilities at regular intervals.
(ii) Avoiding water leakages and repairing them immediately if they occur.
(iii) Maintaining HVAC system in operation and good state of repair all the tin1e.
(iv) Replacing burnt tube lights or tnissing tube lights.
(v) Keeping all walls, ceilings crack free and free from peeled off paints etc.
(vi) Maintain building exterior, roads in the factory in good conditions.
(vii) Maintaining gardens and lawns in good conditions and free from insects, including
proper disposal of cut grass.
(viii) Clearly defining the responsibilities of the job for doing and supervising the work.
(ix) l'vlaintain records of repairs and maintenance work done.

FORMATS FOR BUILDINGS AND FACILITIES

FORMAT TITLE 1 : AREA CLEANING RECORD (DAILY) RM/PM/FG STORE
MAP PHARMACEUTICALS LTD.
AREA CLEANING RECORD (DAILY) RM/PM/FG STORE
Department : Mon th :
Area : Ref. SOP No. :
Room No.:

Date Floors Furnituni Office Containers Pal.lets Racks Bala.n ces Std. Cleaned Time of Initials
equipment wt. by cleaning of
From To officer

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Chapter! ...

EQUIPMENT
.·,-:· ,:~
.
,.
•• ....... '

3.0 INTRODUCTION
Equipment may be defined as any piece of plant, machinery, instrument etc. which is
used for carrying out a specific activity or operation e.g. mixer, granulator, dryer, HPLC etc.
Equipment can be a single piece or it may consists of a set of integrated pieces to perform
a common activity e.g. water demineralising plant.
Equipment is important because all the pharmaceutical manufacturing or con~rol
activities depends upon the good performance of the equipment. Hence, the regulatory
literature provides certain specific guidelines in this regard; Let us briefly look into these
specific guidelines now one by one.

3.1 DESIGN, SIZE, LOCATION AND CONSTRUCTION OF EQUIPMENT

While selecting a piece of equipment, we should consider the following points :
(a) Design : The design of the equipment should meet our requirements, for which we
are selecting the equipment. For this purpose we should prepare an User Requirement
Specification ( URS) : This spells out our requirements. It will vary from equipment to
equipn1ent but this should at least answer the following questions namely:
(i) What operations you want to perform with this equipment?
(ii) What capacity we should have in terms of holding and in terms of output?
(iii) Which materials we are going to use in this equipment and do they have any
interaction with the materials of construction ?
(iv) How this equipment will be cleaned ? Will we face any problem in validating the
cleaning operation!
(v) Do we have trained operators to operate this equipment ? or whether the
manufacturer will help us in training our existing operators ?
(vi) How our people will be required to operate this equipment?
(vii) What will be starting and stopping time for the equipment?
(viii) Will maintenance of this equipment cause any contamination to the product being
handled!
(ix) What is the level of technology used ?
(x) What is likely obsolescence time ?
Based on such information the user requirement specification is made and sent to the
supplier who prepares the design qualification or design specification and sends back to user.
3.1

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Pharmaceutical Quality Assurance 3.2 Equipment

In short this exercise will help in getting aU the design parameters incorporated into the
equipment, which mainly looks at the ease of operation, cleaning and maintenance of th.e
equipment.
\ (b) Size : Size of the equipment is decided based on the volumes of materials, which we
are going to handle. Batch sizes are also directly related to the size of the processing
equipment.
In case of size of equipment following three things should be considered.
(i) Physical dimensions of the machinery (length x height x ,vidth), size of the room in
which the machine is going to be installed and the path in the plant through, which it
will be transported, has to be taken into account. If it is to be installed in a new
facility which is under construction, then certain ,val]s or partition can be
constructed after the equipment is installed in place. This avoids lot of bassets of
carrying the equipment to its point of ini.-tallation.
(ii) I-lolding and output capacity is also directly related to the size of the equipment.
(iii) What .i s the minimum and maximum volu me of materials we are going to handle and
whether the equipment can process those minimum and maximum volumes should
be considered ,vhile deciding the size of the equipment.
{c) Location : Decision of locating the equipment in the plant depends upon the logical
process movement. In addition t.o this potential danger of contamination and mix-ups should
be taken into account.
Other factors which influence the location of the equipment are,
(i) Utility services required.
(ii) Material handling and movement.
(iii) Movement for processing and cleaning.
(iv) Men movement for repair and maintenance.
(v) If the equipment is discharging gases, fumes, powders etc, then this factor is also
important and should be considered ,vhile selecting the location of the equipment in
the plant.
(d) Construction : Four main factors are required to be considered. They are as follows :
(i) Ease of cleaning the equipment and surrounding area.
(ii) Ease of operation of the equipment.
(iii) Ease of maintenance of the equipment.
(iv) The material of construction (MOC), is the fourth point, in this connection we have to
see that the MOC of the equip1nent, which comes in contact \Vith the product should
not react with it, it should not leach any part of the .tvIOC to the product being
processed and MOC should not adsorb any materials or part of it from the products
being processed.
Documents Required
(i) .tvlachine/Equiptnent manuals.
(ii) Machine/Equipment layout drawing, showing the position of the equip1nent in the
rooms.

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Pharmaceutical Quality Assurance 3.9 Equipment

FORMAT TITLE 3: LIST OF EQUIPMENTS

--------------------- - - - -- -- - - - -- - -
MAP PHARMACEUTICALS LTD.
LIST OF EQUIPMENTS
Sr. No. Name of Capacity Holding/ Make Material of
equipment Output construction of contact
part made up of

·-

FORl\fAT TITLE 4: DIE PUNCH INSPECTION REPORT

MAP PHARMACEUTICALS LTD.
DIE PUNCH INSPECTION REPOltT
Department : Date:
Description : Supplier:
Quantity:
UPPER PUNCH INSPECTION REPORT
Sr. Tip Body Diamete r Head Overall Working Cup
•
No. size Reading l Reading2 Go No Go Length Length Depth

LOWER PUNCI-1 INSPECTION REPORT

Sr. Tip Body Diameter Head Overall Working Cup
No.
.
size Length Length Depth
Reading l Reading2 Go NoGo

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Pharmaceutical Quality Assurance 3.10 Equipment

DIE INSPECTION REPORT

Sr. Tip Body Diameter Head Overall Working Cup
No. size Reading 1 Reading2 Go NoGo Length Length Depth

NOTE : All the dimensions specified are in mm.

FORMAT TITLE 5 : EQUIPMENT CLEANING AND MAINTENANCE RECORD

MAP PHARMACEUTICALS LTD.
EQUIPMENT CLE.ANING AND MAINTENANCE RECORD
Department : Month:
Equipment: Make:
Equipment code No. : Working capacity:
Cleaning SOP No. : Maintenance SOP No.:

Cleaning Maintenance
Date Sign Remark Date Sign Remark

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Phannaceutical Quality Assurance 3.11 Equipment

FORMAT TITLE 6: EQUIPMENT/INSTRUMENT HISTORY CARD

MAP PHARMACEUTICALS LTD.
EQUIPMENT/ INSTRUMENT SERVICES HISTORY CARD
EQ / INS Name : Installed on :
Tag No.: Make and model :
Location: Tolerance:
-
Service contract given to : _ _ _ _ _ _ _ _ _ __
Service contract renewal period : _ _ _ _ _ _ __
Contract person: _ _ _ _ _ _ _ _ _ _ _ _ __
Tel. No. : _______ Address : _ _ _ _ _ __

Sr. Details of repairs Service Equipment Serviced Remark

No. servicing/calibration called on attended on by

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Pharmaceutical Quality Assurance 3. 14 Equipment

FORMAT TITLE 9: MACHJNE DETAIL'S CARD

MAP PHARMACEUTICALS LTD.
MACHINE DETAIL'S CARD
Name of Equipment : Room No. :
Identification No. : Floor:
Department :

1. Drive Details

2. Gear Box

3. Vacuum Pump

4. Afr Compression

6. Variator

6. Coupling

7. Chain a.nd sprockets

8. Pully and V-Belt

9. Bearing Details

10. Fasteners •

•••
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Cbapter4...

4.0 INTRODUCTION
The prime objective of the pharmaceutical manufacturing operations is to produce
finished pharmaceutical products from active, inactive raw materials and various packaging
materials. The quality of finished products produced solely depends upon the quality inputs
and hence materials management becomes a very important activity in pharmaceutical
manufacturing operations.
The total materials management activity starts right from selection of vendors for R.M.
and P.M. to dispatch of finished products to its destination.
All incoming materials should be quarantined immediately after receipt or prOCllSSing,
until they are released for use or distribution.
All materials and products should be stored under appropriate conditions, established by
the manufacturer, and/or user. These should be stored in an orderly fashion to permit batch
segregation and stock rotation by First In - First Out (FIFO) and First Expiry - First Out
(FEFO) rule.
There shall be written procedures for all activities carried out related to materials
handling e.g. receipts, identification, storage, handling, sampling, testing and approval or
rejection and RM/PM.
All these items should be handled all the time in such a fashion that no contamination or
mix-up can take place.
Bagged 01· boxed materials should be stored off the floor (on non-wooden pallets) and be
suitably placed to permit cleaning and inspection.
Each container or grouping of containers of RM/PM shall be clearly identified with
proper labelling for each lot in each shipment received. The labels should clearly define the
status e.g. quarantined, approved or rejected etc.

4.1 PURCHASING
Regarding purchasing of pharmaceutical materials following points should be considered.
(i) All materials should be purchased against an approved and adequate specification
which defines not only the grade and quality of the materials, but also the nature of
the packaging and container to be used.
The quality material, should clearly specify the physical, chemical and
microbiological specifications as specified in pharamacopoeal specifications or
in-house specifications. The quality parameters should also specify characteristics

4.1

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Pharmaceutical_Quality Assurance 4.2 Materials Management

like, bulk density, particle size amorphous or crystalline nature of the material,
specificity of isomers etc.
(ii} Materials should be purchased and sourced only from approved suppliers and
manufacturers. Choice of vendor should be primarily based on quality considerations
and when these are met other commercial consideration should play their role, like,
price, delivery period. Consistency in quality, delivery and price should be given
importance.
(iii} R.M. and P.M. should only be purchased by buyers who arc trained and who possess
sufficient technical knowledge. Materials managers who has sufficient exposure on
R.l\f./P.M. for pharmaceuticals should be appropriate persons for this; alternatively
industrial pharmacists with training in materials management can do a much better
job.
Document Required
SOP/R vendor certification.
'
4..2 RAW MATERIALS
In case ofR.M. following points should be considered.
(i} Supplier/Manufacturer of the received material should have his name listed in
companies approved vendors list. Such list should be available ,vith the receiving
department.
(ii) All R.M. and other related materials should be checked for following things, after
receiving:
(a ) Name of the manufacturer/supplier.
(b} Name of the product.
(c) Batch numbers
(d) Date of manufacture and date of expiry.
(e) Quantity received and number of containers or packages.
(0 Condition of containers and materials.
All containers should be cleaned externally and damages if any, should be informed to
Q.C. department. The cleaned containers should be protected from contamination during storage.
The materials received should be taken into account only after •II the relevant
documents are available. (e.g. bills, invoice, customs or excise gate passes, certificate of
analysis etc.)
(iii) Sampling of these received materials should take place in specific sampling booths by
Q. C. persons only and containers should be labelled accordingly. These materials shall be
stored in sampled material quarantine.
(iv) All received materials must be properly identified ,vith their status (e.g. received,
sampled, approved, rejected, to be returned back etc.) labels and material identifications like,
product name, batch number, code number, sterility status etc.
{v) 1f one delivery of material is made up of different batches, each batch must be
considered as separate for sampling, testing and release. Conversely if a single batch is
delivered in different consignments may be at different times and by different delivery mode,
then even the different consignments of the same batch should also be considered as separate
batches for sampling, testing and release and assigned different A.R. nu.mber for
identification.

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Pharmaceutical Quality Assurance 4.3 Materials Management

(vi) Materials in the storage area should be appropriately labelled. Label.s should bear at
least the following information :
(a) The name and internal code number of the product.
(b) The batch number given by the supplier/manufacturer and given by the receiver
after analysis and release.
(c) Status of the material e.g. quarantine, on test, released, rejected, returned,
recalled etc.
(d) Retest and expiry date of the product.
(e) Appropriate special storage conditions e.g. store at low temperature, low
humidity away from direct light etc. or sterile material etc. should be clearly
mentioned.
In fully computerised storage system, all the above information may not be legible on the
container label, in such case a practice of referring to the computerised infonnation should be
followed.
(vii) Containers from which samples have been taken out should be identified.
Containers from ,vhich partial material is i.•1sued should also be identified by a label
indicating the various withdrawals from this and present quantity in the same at any moment
of tim.e. Generally, more than one container should not be with partially issued material.
(viii) Only 1naterials released by Q. C. department and within their shelf-life should be
used.
(ix) Materials should be dispensed only by designated persons, following a written
procedure, to ensure that the correct materials are accurately weighed or measured into
clean and properly labelled container.
The word correct 1naterial in above paragraph refers to the following points :
(a) Correct na1ne and category (I.P./B.P./U.S.P. etc.) of the material.
(b) Correct A. R. number.
(c) Correct weight/measure.
(d) For correct B.No. of the product.
(x) Each dispensed material and its weight or volume should. be independently checked
and the check recorded.
(xi) Materials dispensed for each batch of the final product should be kept together and
conspicuously labelled as or such.
(xii) All dispensed materials must be recorded in a register in chronological order of date
and time. This record should have at least the following information :
(a) Name of the product and B. No. for which the material is dispensed.
(b) Time and Date of &'tarting and completion of the dispensing activity.
(c) Name of the weigher and checker of the dispensed materials.
Normally a Q.C. person should check the weighings independently. The production
supervisor will check it at the time of processing the batch.
Documents Required
(i) List of approved vendors with materials,
(ii) List of materials classified according to storage conditions,
(iii) SOP on sampling, storage and dispensing of materials,
(iv) Register of sampling and dispensing activities.

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Pharmaceutical Quality Assurance 4.4 Materials Management

4.3 PACKAGING l\1ATERIALS

Packaging materials are divided into follo,ving categories :
(1) Primary Packaging Materials : Materials \vhich come in direct contact with the
medicinal product. e.g. bottles, ampoules, vials, foils etc.
(2) Secondary Packaging Materials : Materials which come in contact with the primary
packaging materials, e.g. labels, carton etc.
(3) Printed Packaging Materials : All packaging materials which have any thing printed
on it; even error medical literature sent along with finished product is also put in this
category. Such ,naterials include, labels, cartons, foils etc.
(4) Tertiary and other Packaging Materials : All other packaging materials other than
those covered in the above three catagories.
While handling all these materials follo,ving points should be kept in mind.
(i) The purchase, handling and control of primary and printed packaging materials
shall be as for raw materials.
(ii) Printed packaging materials should be stored securely in lock and key system to
avoid unauthorised access. Cut labels and other loose printed materials should be
stored and transported in separate closed containers so, as to avoid mix-ups.
A detailed SOP should be available for dispensing of packaging materials. Only
authorised persons should do dispensing and make records of all the activities.
(iii) Each delivery or batch of printed or primary packaging n1aterials should be given a
specific reference number or identification nu1rk.
(iv) Outdated and obsolete primary or printed packaging materials should be destroyed
by suitable and approved method of destruction and records maintained.
The destruction of printed packaging materials should be done under the direct
supervision of a responsible or Q. A. person.
(v) All products a.nd packaging rnaterials to be used should be checked on delivery to
the packaging department for quantity, identity, and conformity with the packaging
instruct ion.
Quantitative records of printed packaging materials should be maintained to the
last unit of counting. All audit and inspecting authorities are very much rigid and
strict on this issue; since unaccounted printed packaging materials have a potential
danger of its misuse.
(vi) Access to all storage areas should be limited to authorised personnel only.
(vii) A separate sampling room should be provided for sampling of prilnary packat,ring
,naterials, which should be a fairly clean area.
Documents Required
(i) A classified list of all packaging materials e.g. primary, secondary, printed and other
materials.
(ii) A list of approved vendors along with names of ,naterials.
(iii) Sampling and dispensing register in chronological order.
(iv) A list of materials based on their storage conditions.

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Pharmaceutical Quality Assurance 4.16 Materials M/Jflagement

FORMAT TITLE 07: RAW MATERIAL SAMPLING OBSERVATION SHEET

MAP PHARMACEUTICALS LTD.
RAW MATERIAL SAMPLING OBSERVATION SHEET
Ref. SOP No. :
Items name
Claimed Grade (IP/BP/USP etc.)
Import/ Mfg. Licence No.
Name and Address of the manufacturer
Name of packing trader
Inner lining of drums / bags
Checked against specification No.

Sr.
No.
Batch
No.
Quantity
··--:
Mfd. ~- No.of
pa.cks
Sample
qty.
Container
no.
Qty. per No.of Tota.I
pack packs qty. sampled sampled

Sr. No. Batch No. of packs Type of Remarks by QC

No. Damaged Damage Manager

Observations during sampling :

Form : Colour :
Odour : Foreign matter :
Spillage if any :

Sampled by : Name: Date :

Sample handed over to : A. Ref. No. :

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Pharmaceutical Quality Assurance 5.2 Quality Management
· -- -- - - - - - - - ~ - - - - - ' " - - -

5.0.3 Quality Management System

The improvement of cGMP by using l\1odern Quality Management System involves
follo,ving concepts.
(i ) Quality : Every pharmaceutical product must meet the following four attributes
namely, identity, strength, safety and purity to achieve the desired effectiveness of the
product. In short for our purpose "achieving quality" means achieving these attributes for the
product.
(ii) Quality by Design and Product Development : "Quality by Design" means
designing and developing the pharmaceutical products during product development stage to
achieve the desired characterisation in the product. This should not be left to chance but
must be by design. The quality system provides a robust framework to the technology
development and transfer to commercial manufacturing processes and for post development
changes and process optitnization.
(iii) Risk Management and Risk Assessment : Risk management guides us in
establisl1ing specification and process parameters.
Risk assessment is used in detern1ining the need for discrepancy investigation and
taking necessary corrective actions. •·
(iv) Corrective and Preventive Action (CAPA) : It is a well-known cGMP concept
which focuses on investigating i1J!d correcting discrepancies and attempting to prevent
recurrence. It has three aspects namely :
(a) Remedial corrections,
(b) Root cause analysis, with corrective action to prevent recurrence and
(c) Preventive action to prevent initial occurrence.
Change ·control : Change control is another well-known cGMP concept that focuses on
managing change and preventing unintended consequences.
(v) 'fhe Quality Unit : Modern pharmaceutical industry practice is to divide the
responsibility of Quality Unit into hvo parts namely Quality control and Quality
assurance.
• Quality Control consists of testing of selected in process mate1ials and finished
products to evaluate the performance of the manufacturing process, and to ensure
adherance to proper specifications and limits.
• Quality Assurance includes the revie\v and approval of all procedures related to
production, maintenance, and review of associated records and auditing and
performing trend analysis.
The cGlv1P regulations specifically assign the quality unit, the authority to create,
monitor and implement quality system.
Other cGMP assigned responsibilities of the quality unit are consistent with modeni
qual.ity systen1 approaches e.g.
• Ensuring that controls are implemented and completed satisfactorily during
1nanufacturing operation.
.•. • Ensuring that development procedures and specifications are appropriate a.nd
followed including those used by a firtn under contract to the manufacturer.
• Approving of rejecting in-process materials and drug products.
• Reviewing producti on records and investigating any unexpected discrepancies.

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Pharmaceutical Quality Assurance 5.6 Quality Management

(C) Ultimate user.

(D) Sum of total organised arrangement.
Now let us try to understand these issues related to management of Quality Assurance.
(A) Let us first try to understand the concept of Quality.
The regulatory authorities all over the world have unanimously accepted that a
pharmaceutical product which meets the following five characterisatics can be accepted
on a quality product, these five characteristics are :
(i) Identity
(ii) Strength
(iii) Safety
(iv) Purity and
(v) Efficacy.
Let us try to elaborate little more on these five characteristics.
Let us consider the First characteristic Identity. The regulatory authorities consider
'identity' as the product identity. i.e. the unique identity of a given product, which primarily
relates to the name and content of the product. So if you call the na.me of the product it will
refer to a specific product only containing the specific ingredients. Here we have certain
issues e.g. a product with same name but having different formulations may have different
compositions, a product with same name in the form of tablet and oral liquid have been seen,
having different active ingredient composition in terms of Active Pharmaceutical Ingredients
and even their contents in recom.mended unit dose. Hence, we 1nust consider identity with
respect to name of the product and its formulation.
Second issue is a product with same name and formulation will have different strengths
e.g. a tablet of same name and API will have 250 mg, 500 mg, 750 mg or even 1000 mg per
tablet . However this issue is taken care by the characteristics of "strength" ,vbich will be
soon of cou.r se be discussed separately at a latter stage. So in short a "product identity" may
be referred to as -
• Name of the Product ,
• Type of the Formulation, and
• Name and quantity of API in a unit dose.
This is so far as the identity of product is concerned which is the primary requirement.
If we are considering Q.A. to have control cover the totality of the manufacturing
operations (Not production alone), then we should extend the concept of identity to the entire
manufacturing operation. This means the batch manufacturing document of a
pharmaceutical product should identify all aspects of manufacturing e.g. it should answer all
questions like :
Who? ➔ Who carried out va.rious activities i.e. identify of the name and may be
positions of the persons who carried out all activities.
When? ➔ When a parti<;ular activity was carried out? e.g. when it was started, when
it was stopped. Give details of time/date for each activity performed.
Where? ➔ Where the various activities were carried out ? e.g. plant locations, room
name and room numbers.
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Pharmaceutical Quality Assurance 5. 10 Quality Management

5.3 GOOD MANUFACTURING PRACTICE

5.3.1 Definition of Gl.'tfi>
Two independent definition are found in the review of regulatory literature, they are
quite similar except 1'.1CC. South Africa uses the specific requirement of legal compliance,
which is silent but understood in WHO, MHRA or TGA guidelines. Let us however study the
definition ofGMP as specified in WHO and MCC South Africa guidelines.
(A) Definition of Good Manufacturing .P ractice as per \VHO
"GMP is that part of quality assurance, which ensure that products are consistently
produced and controlled to the quality standards appropriate to their intended use and as
required by the marketing a\lthorisation".
(B) Definition of Good Manufacturing Practice as per MCC South Africa
"Good lvlanufacturing Practice is that 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. GMP is thus concerned with both production
and quality control matters".
Comments : Follovving things are very clear from the above definitions.
(i) GMP is a part of Q.A.
(ii) Gl\1:P's main function is to produce quality products consistently.
(iii) GMP must meet legal requiren1ents of the country.
(iv) For meeting the expected requirements, GMP must deal \vith bot h production and
Q.C. related issues.
(v) WHO further comments that the main function of GMP is to diminish the risk of
niixups and contamination.
If we expect to produce quality product consistently then GMP should not be considered
as an destination to be reached but a nonstop journey to continue.
In other ,vords it should beco1ne a 'way of life'.
5.3.2 Components of GMP
The total activity of GMP can be summarised in the follo,ving points :
(a) "All manufacturing processes should be clearly defined".
All n1anufa.c turing processes should be systematically reviewed in the light of experience
and shown to be capable of consistently manufacturing pharmaceutical products of the
required quality that comply with their specifications".
This means you should have SOPs for all activities and Master Production and Control
records should be elaborate enough to clearly define the manufacturing and packaging
processes.
A document review system should be established to periodically review all documents to
keep them always updated and also to take care of changes to be incorporated in it, which
may have resulted because of newer experience gathered during this ti1ne.
(b) "Critical steps of manufacturing processes and any significant changes
made to the process validated".
In this case the GMP team should identify, which are the critical steps in the
manufacturing processes. This can be done by systematically reviewing each stage of

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Pharmaceutical Quality Assurance 5. 14 Quality Management
- - - -- - - - - - - - -- - - - - - - ---'-- --''--- -

(f) Records must be made of the resu.It of inspecting and testing of 1naterials;
interinediate, bulk and finished products against specifications, product assessment must
include a review and evalu.ation of the relevant production documentation and the
assess1nent of deviation from specific procedures.
The above statement is self explanatory hence does not require any additional
comments on it.
(g) No batch of a product to be released for sale or supply prior to certification by the
authorised person(s) that it is in accordance with the requirements of the marketing
authorisation. In certain countries, by law, the batch release is a task of the authorised
person from the production department together with the authorised person from the quality
control development.
As the batch starts getting packed, it may be transferred to F. G. store in parts and
await in F. G. till it is completed and released by the Q.A. departm.e nt.
If a batch is partly packed and required to be released for any co1nmercial purpose, it
must get completely analysed and then released, by specifically mentioning the quantity
released. The balance part may be released after giving a separate batch identity and again
after complete analysis of the second part.
In case of sterile products sterility of the finished product require 14 days. This increases
the load of storage of finished product in F.G. store, These goods may be transferred, after a
reasonable period of time after sterility test starts (say 5 to 7 days), to manufacturers
godown outside the manufacturing premises, provided, the manufacturers has complete
control over the activities of godown, and then after the results of sterility are acceptable,
then the same finished goods can be transferred further for supply or sale.
(h) Sufficient samples of starting materials and products n1ust be retained to permit
further examination of the product if necessary; the retained samples n.1ust be kept in its
final pack unless the pack is exceptiona.lly large.
Normally two full analysis equivalent materials should be kept as retained samples.
If the pack is exceptionally large, then a smaller pack of the same primary packaging
materials must be used to maintain the simulated condition.
5.4.3 Other Activities of Q.C.
(i) Establish, validate, and implement all the quality control procedures, maintain
sufficient standards and reagents.
(ii) Evaluate, maintain and store reference and working standards for substances.
(iii) Ensure the correct labelling of containers of materials and products.
(iv) Ensure that the stability of active pharmaceutical ingredient and product is
monitored.
(v) Participate in the invest igation of complaints related to quality of the product.
(vi) Participate in the environmental monitoring.
(vii) Assess the finished product after evaluation, all relevant factors, including the
production conditions, I.P.Q.C. results, manufacturing and packaging
documentation, compliance with the specification of the finished product and
examination of the finished pack.

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Pharmaceutical Quality Assurance 5. 18 Quality Management ,

(iv) For an active ingredient in an OTC drug product that is exempted from bearing an
expiration date, the reserve sample shall be retained for 3 years after dii.'tribution of
the last lot of the drug product containing the active ingredient.
(v) For finished products the reserve sample shall be retain.e d for 1 year after the
expiration date of the drug product.
For radioactive drug products, except for non radioactive reagent kits, the reserve
sample shall be retained for :
(a) Three months after the expiration date of the drug product if the expiration
dating period of the drug product is 30 days or less or.
(b) Six months after the expiration date of the drug product if the expiration
dating period of the drug product is more than 30 days.
(c) For an OTC drug product that is exempted from bearing expiration date, the
reserve sample must be retained for 3 years after the lot or batch of drug
product is distributed.
(e) M.C.C. South Africa says samples of finished product should be kept for one
year after the expiry date of the product and it should be equal to one full
analysis. Such samples should be kept in their final packaging and stored
under the recommended conditions.
Samples of starting materials (other than solvents, gases and water) should be retained
until at least the expiry date of the batch in, which they are used.
If we review all the above guidelines, we can make following points for making our own
SOP on this:
(i) Active R. 1\-1. shall be retained for at least one year after the expiry of the finished
product in which it is used.
(ii) Finished products (other than radioactive substances) shall be retained for at least
one year after expiry of the finished product.
(iii) The quantity retained should at least be equal to two full analysis except test for
sterility and Bacterial Endotoxin Test.
(iv) Finished product samples shall be retained in their final packaging or simulated
conditions if the final pack is exceptionally large.
(v) Samples must be retained in the recommended conditions.
(vi) A separate SOP should be made for authorised, recorded destruction of the retained
sa1nples.
(v) Sampling of IPQC materials:
The USFDA gives specific guidance on IPQC Sampling and testing in CFR 211.110 (5).
Following are the points discussed in this guideline.
(a) Purpose : To assure batch uniformity and integTity of drug product. SOP should be
prepared for sampling of IPQC the materials and their testing. The results obtained from
such tests should be used for monitoring the progress of the manufacturing process.
(b) Selection of Parameters : Those parameters which are responsible for causing
variability in the characteristics of the in process materia1s and the drug product are selected.
VlZ.,

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Pharmaceutical Quality Assurance 5.22 Quality Management

(h) A clear statement of release or rejection (or other status decision) and the dated
signature of the designated responsible person.
(i) Quantity of product and code reference.
(j) Tests performed.
(k) Reference to the relevant specifications and test methods used and to any certificate
of analysis.
(Notes : In addition to above records, analyst's laboratory records should be retained,
with basic data and calculations from which test results were derived. (e.g. weighing,
readings, recorder charts etc.)
It is useful to record test results in a manner that will facilitate comparative reviews of
those results and the detection of trends.
(7) Release of Finished Product for Distribution
Every finished drug product shall have quality specifications. It should be tested to check
its compliance with those specifications and only products, which pass all the specifications
should be released to sale or distribution.
The authorised person designated by Q.A. should only have the authority to release the
product.
There should be a written SOP elaborating the release procedure. Following points must
be considered in this SOP.
(i) Every finished product must have a release specification and test method to test
these specification.
(ii) Every product must be tested according to the specifications by the approved and
validated test methods.
(iii) Complete batch documents must be reviewed by Q.A. along with the test report of
final finished product.
(iv) Only after full satisfaction of the reviewing authority the product should be released
specifying the exact quantity of product released.
(v) Products failing to meet the established specification or any other rel~vant quality
criteria should be rejected. Reprocessing may be performed, if feasible, but the
reprocessed product should meet all specifications and other quality criteria prior to
its acceptance and release.
Stability of such reprocessed products may be additionally monitored throughout their
shelf life.
(8) Legal Requirements :
The finished product must comply with all legal requirements, as specified by the
appropriate enforced laws in the country of manufacture and sale or distribution.
It must be packed in appropriate container and correctly labelled.
Documents Required
(1) SOP/Ron calibration and validation of all analytical instruments.
(2) List of all major analytical instruments.
(3) Lists of chemicals/ reagents/ media used.
(4) Lists of Glasswares.

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Pharmaceutical Quality Assurance 5.26 Quality Management

5.4.3.8 Batch Numbering

.
Pharmaceutical manufacturing is a batch operation. Any product history can be traced
by the reference of a batch number. Schedule-M of D.C. Act/Rule provides following
guidelines in this regard :
{a) There shall be standard operating procedures describing the details of the batch (lot)
numbering set up with the object ive of ensuring that each batch of intermediate,
bulk, or finished product is identified with specific batch number.
(b) Batch numbering SOP applied to a processing stage and to the respective packaging
stage shall be same or traceable to demonstrate that they belong to one
homogeneous mix.
(c) Batch number allocation shall be immediately recorded in a log book or by electronic
data processing system. The record shall include date of allocation, product identity
and size of the batch.
Comments : Normally batch number is a combination of alphabets, numbers and
symbols. It can be either or a suitable combination. The SOP on numbering should clearly
explain what each digit in the number stands for.
Documents Required
(i) SOP on batch numbering system.
(ii) Records of batch number allotted.
5.4.3.9 Stability Studies
Stability studies of the finished pharmaceuticals is an important activity under quality
system. Documents showing that the stability studies are carried out for each products being
manufactured, are required by regulatory authorities.
!.C.H. guidelines are now available, which 1,>ives full details about how to carry out these
studies
Pollowing is brief outline of regulatory guidance in this regard.
(i) Tests should be performed that are indicative of stability and if necessary additi.onal
tests monitoring possible. Degradation and deteriorations should be included..
(ii) Stability samples should be stored in their final, marketed containers and storage
conditions should be consistent with those approved for the product in question.
(iii) Reindts from the stability trials should be used to confirm or modify the prevailing
shelf-life and storage conditions.
(iv) The Q. C. department should establish expiry date and shelf life specification on the
basis of stability tests related to storage condition.a.
(v) Stability should be determined prior to marketing and following any significant
changes in processes, equipment, packaging material etc.
(vi) A written programme of on-going, follow-up, stability should be designed and
implemented so as to monitor the quality of the various marketed products through
out their intended shelf life. This programme should include following elements
such as:
(a) A complete description of the drug is involved in the study.

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Pharmaceutical Quality Assurance 5.30 Quality Management

The members may be pulled from some or all of the follo,ving functional areas. viz.
(i) Quality management.
(ii) Production and operations management.
(iii) Engineering.
(iv) Warehousing.
(v) Personnel etc.
(c) Frequency of self inspection:
The frequency of self inspection may depend on company requirements. However it may
be a quarterly or six monthly. In addition, if there is any regulatory inspection scheduled
then a self inspection may be advised before that.
(d) Self inspection report :
This report should consist of the following things namely :
(i) Observations made by the team members and conclusion drawn.
(ii) Recommendations for corrective actions.

(e) Follow-up action :

Company management should evaluate the report in terms of recommendation made and
corrective action taken by the concerned people.
(B) Quality Audits
A quality audit may be defined as an examination and assessment of all parts of a
quality &-ystem ,vith a specific purpose of improving it.
A quality audit is usually conducted by outside. or independent specialists or a team
designated by the management for this purpose. Such audits may also be extended to
suppliers and contractors.
The Q.C. department should have responsibility together with other relevant
departments for approving suppliers ,vho can reliably supply starting and packaging
materials that meet established specification.
The supplier evaluation should take into account a supplier history and nature of the
materials to be supplied.
Documents Required
(i) SOP/Ron Self inspection.
(ii) SOP/Ron Quality audit.
(iii) SOP/Ron Suppliers audit.
5.4.3.13 Q. C. Documentation
Laboratory documentation should follow the principles of documentation, discussed in
details, in chapter 7.
However, some important documents should readily be available in the Q.C. Department.
They are as follow :
(i) Specification ofR.M., P.M., Int., Finished products.
(ii) Sampling procedures ofR.M., P.M., Int and Finished products.

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Pharmaceutical Quality Assurance 5.34 Quality Management

(ii) Over printed batch details must be certified before the packaging operation starts.
(iii} Leak testing of strips, bottles, vials etc. must be carried out at specified frequency.
(iv) Number of units of strips, cortoo, bottles etc. must be checked.
(v} Packaging enclosures like literature, measuring cups / spoons / droppers etc. must
be checked for their inclusion.
(vi) Frequency of in process checks must be defined.
(vii) Co1nments on quantity of sampling and method of sampling 1nust be made with
clear directions.
(viii)Results must be recorded preferably in standard formats.
(ix} Directions should be given on providing feed back to operations people on any
critical observations. Records of such observation and any other untoward
incidences niust be made.

04 DOCUMENT TITLE : SOP ON CHANGE CON1'ROL SYS'fEM

Dr. David M. Stephon, an authority on G.M.P. con1pliance and training, of Etan

Pharmaceutical Technologies has said in his famous article on "Designing the perfect change
control system" that : "Change control system today are expected to be designed in a way
that provides a system not only document and approve changes but also anticipate change
,vithin the quality organisation".
The centralised change contt·ol syste1n should clearly describe the change, spell out
documentation requirements, talk on change classifications, itnpact assessment and quality
approval of any change that is encountered within the quality organisation.
Change control may be defined as a system of procedur es though which changes are
reviewed, justified, documented, approved and ilnplemented in confinnance \Vith regulatory
and corporate requirements. Change control is in fact a system that controls change by :
(i) Identifying ownership of the change.
(ii) Allowing for review and approval of change.
(iii) Preventing changes that could adversely affect product quality or conflict with
registration or regulatory requirements.
(iv) Providing an assessment of change and n1onitors the impact of change.
Therefore, the principal purpose of managing change within the quality system is for
evaluating the potential impaction :
• Validated conditions, processes or systems maintained in a state of control.
• Regulatory commitments.
• Product quality and safety.
A detailed n1odel of SOP on change control is given below, since this is one of the most
important SOP for quality management system in any pharmaceutical organisation. This
model is based on Dr. David M. Stephon's work.

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Pharmaceutical Quality Assurance 5.38 Quality Management

imposed by Regulatory Affairs assessment as outlined on the corresponding

approved CCE form.
7.13 The Quality Unit's approved and Regulatory Affairs evaluated change is
implemented by the designated change implementer followed by completion of
"Action Taken" in Exhibit C, Change Control Part 2 - Implementation Form.
7.14 Exhibit C is then forwarded to the Quality Unit for review and approval.
7.15 Quality Unit reviews the Action Taken section i.n Exhibit C and compares it to the
"Agreed Upon Act ion" in Exhibit A, and determines if the change made agrees-with
the approved change, and th at any change evaluation requirements (revalidation,
stability etc.) have been initiated or completed.
7.16 Regulatory Documentation updates the change control tracking system to record
any requirements listed on the approved CCE and Change Control Part 2 -
Implementation Form.
8. RECORDS
8. 1 Exhibit A : Change Control Part 1 - Approval Form. Change control form numbers
are assigned. Regulatory Documentation. The fonns are numbered sequentially as
CC-# beginning with CC- and continuing indefinitely.
8.2 Exhibit B : Change Control Evaluation Form. CCE form numbers are a~signed by
Regulatory Documentation. The forms are numbered sequentially as CCE-#
beginning with CCE-1 and continuing indefinitely.
8.3 Exhibit C : Change Control Part 2-Implementation Form. Change control
implementation forms are numbered to match the corresponding Change Control
Part 1 - Approval Form to which it refers (i.e. CC-#).
8.4 Change Control Tracking Syste1n.
9. RECORD DISTRIBUTION
9.1 Change Control Part 1 - Approval Form : original to be maintained by Regulatory
Documentation copy provided to change initiator and responsible manager.
9.2 Change Control Evaluation Form : original to be maintained by Regulatory
Documentation.
9.3 Change Control Part 2 - Implementation Form : original to be maintained by
Regulat.ory Documentation.
9.4 Change Control Tracking System : maintained by Regulatory Documentation.
10. REVISION LOG
Revision Date Section(s) Description
00 NIA Original Issue
11. APPROVALS
Written By : _ __ _ _ _ _ _ _ _ _ __ Date : _ _ _ _ __ _ _ _ _ __
Reviewed By: Date : _ _ __ _ _ _ _ _ _ __
Approved By: Date : _ _ __ ________ _
Quality Unit

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Pharmaceutical Qualitr Ass_u_ra_n_c_
e _ _ __ _ __5_
.4_4_ _ _ _ _ _ _ _ _ _o_u_a_li.,_
ty_M_a_n_a"-ge_m
_e_n_t

4.4 All written and oral complaints to be forwarded to I-lead, QA/QC/Regulatory or his
nominee for investigation.
4.5 All the Product Quality Complaints shall be investigated jointly with QA/F and D/
Manufacturing \vithin 5 days of the receipt of the complaint.
4.6 Medical complaint investigations shall be carried out jointly by Medical department,
QA, Production, F and D and Marketing departments within 3 days of receipt of
co1nplaint.
4.7 Packaging complaints and quality complaints shall be jointly investigated by QA, F
and D and Manufacturing department within 10 days of receipt of complaint.
4.8 The investigator shall investigate the complaint by referring to the Batch
h-1anufacturing Record, SOP, machine log tables, retain samples, reconciliation of
materials, i,-torage conditions used and prepare the Product. Complaint Report {PCR).
4.9 The PCR (Annexure-1) shall include the product details, details of the co1nplainant,
quantity involved, enclosed complaint sample (if any), details of investigation, actions
taken and recommended corrective actions to prevent such recurrences in future. Each
PCR shall bo approved by to Head, QA/QC/ Regulatory or his nominee.
4.10 In case the I-lead, QA/QC/Regulatory finds that investigation is not necessary, such
\vritten record shall be maintained including reason for not conducting the
investigation.
4.11 Each report shall be assigned a specific PCR number, which \Vil! be a 3 digit number
starting with "001" in continuous sequence prefixed \Vith "PCR" and suffixed with the
last t\vo digits of the year. For example, the first market co1nplaint for 2006 shall have
the number PCR/001/06.
4.12 If product defect is established or suspected in a batch, I'lead, QA/QC/Regulatory will
decide for checking other batches in order to determine whether they are also affected.
4.13 In case of medical complaints, if I-lead, QA/QC/Regulatory and 1Iedi.cal Advisor feels
that product will put the public at risk, he shall advise immediate recall of the batch.
The depth of recall is dependent on the seriousness of the complaint.
4.14 Complaint Record shall be maintained at least one year after expiration date of
medicine.
4.15 Complaint Record shall be reviewed and a monthly summary shall be prepared for the
1nanagement.
4.16 A Register is maintained having the complete details of complaint for future reference.
ABBREVIATIONS : Q.A/QC : Quality Assurance/Quality Control
PCR : Product Complaint Report
F and D : Forn1uJation and Development
REFERENCES : NIL
Prepared By Checked By Approved By Authorised By

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Pharmaceutical Qua/ffy Assurance 5.51 Quality Management

ANNEXURE-5
MAP PHARMACEUTICALS LIMITED
MEDICINE RECALL OR Wl1'W>RAWAL, PROCEDURES STATUS REPORT
DATE: PRODUCT: STRENGHT:
PACK SIZE :._ _ _ _ _ _ B.NO. : _ _ _ _ _ __ _ EXP. DATE:
NATURE OF DEFECT: _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ __ __
REASON FOR RECALL : _ _ _ __ __ _ _ _ _ _ _ _ _ _ _ _ _ __
INDICATION OF HEALTH RISK OR ANY OTHER REASONS: _ _ _ _ _ __ _
.
REPORTE.D CLINICAL PROBLEMS: _ _ _ _ _ _ _ __ _ _ _ _ _ _ __

METHOD OF COMMUNICATION TO USERS :

METHOD ACTION DATE TARGET GROUP Nt.Jl\,IB ER
Phone
Fax
Letter
Telex
T.. c1--,... ~m
•""'t.t• .A.

TV
Radio
Press

ANNEXURE-6
MAP PHARMACEUTICALS LIMITED
STANDARD RECALL LETTER
DEAR COLLEAGUE :
It has come to our notice (Product name) - - - - - - - - - - - - - - - - -~
having batch number _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ __ or
has shown _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ __
Please refrain from prescribing or dispensing any of this batch number and return all your
stock of this batch number to our office at :

All returned stock or this batch number \vill be replaced on free on change.
We apologies for any inconvenience caused to you and thank you for your co-operation.

Yours Faithfully,

G.M, QA.QC/Regulatory

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Pharmaceutical Quality Assurance 5.55 Quality Management

FORMAT TITLE 3: FAII.UltE INVESTIGATION REPORT

MAP PHARMACEUTICAL LTD.

. .
FAILURE
.
1NVESTIGATION REPORT
Department : _ - - ·· Date :
Description of failure : _

Production Manager (Signature/Date)

Investigation findings :

Material(s)/Batch(s) involved
Material/Product Batch noJAR no. Quantity Remarks

Cause of failure (Use additional sheet if required)

Sum1nary of test results/data (if Any)

Investigation done by
(Sign/Date) Production Manager QA Manager

:
Reviewed by :
General Manager (Sign/Date)
Decision by QA .r.fanager :

Sign/Date

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Pharmacevtical Quality Assurance 6.6 Manufacturing Operations and Control

6.4 PACKAGING OPERATIONS

Similar to manufacturing operations, packaging operations should also have to follow
certain precautions to get a good quality product at the end. Following are some of the
critical points, which should be remembered while carrying out the packaging operations.
(i) Avoid risk of cross-contamination and mix-ups.
(ii) All packaging equipment and lines must be cleaned before starting a fresh
packaging activity. "Line-clearance" SOP should be followed and records
maintained.
(iii) Each packaging equipment and line should be identified by a conspicuously fixed
board, indicating minimum following information e.g.
Name of product.
Batch numbers.
Pack size.
Date of packing.
(iv) Normally, filling and sealing should be followed as quickly as possible by labeling
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
packaging materials are available in full quantities. Otherwise at the same time you
are likely to have a situation in which, for a given batch of product you have
different stages of material in the packaging departments e.g.
Bulk Tablets (For want of Foils).
Strips or blisters (For W!Ult of cartons).
Filled cartons (For want of shippers) etc.
Such situations must be strictly avoided.
(v) Over printing on labels, cartons, coated tablet, etc. should be carefully planned and
activities clearly segregated to avoid mix-ups. If quantitative records and
reconciliation of packaging materials are strictly followed then such dangerous
situation can be avoided.
(vi) On line verification of all labels by automated electronic beam can be helpful in
preventing mix-ups, provided that such equipment are used correctly.
(vii) Empty packet detections system in tab/cap. should be used.
(viii)Printed and embossed information on packaging materials should be distinct and
resistant to fading or erasing. Laminated cartons or labels should have non-
laminated window space for over printing the batch details or suitable fast drying
inks should be used.
(x) On line packaging checks should be carried out at least for the following things :
(a) General appearance of the package.
(b) Completeness of package e.g. if a carton has to contain bottle, measuring cup,
literature etc. then all such components of the pack should be present.
(c) Correctness of pack and packaging materials.
(d) Correctness of over printed details.
(e) Correct version·ofprinted packaging material is being used.

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Pharmaceutical Quality Assurance
6. 10 Manufacturing Operations and Control
--'---------------------"'--'--- - - - --
(c) Weighing, measuring or subdividing operations for components shall be adequately
supervised. Each container of the component dispensed to manufacturing shall be ex.amined
by a second person (perferably a Q. A. person) to assure that,
(i) The component was released by the Q. C. unit.
(ii) The weight or measure is correct in the batch B.P.C.R.
(iii) The containers are properly identified.
(d) Each component shall be added to the batch by one person and verified by a second
person.
Generally, addition is done by an operator or ,vorker and verifi.e d by a production
pharmacist. It may be advisable that the addition of the active substance is done in the
presence of a I.P.Q.C. person, to enhance the level of confidence in manufacturing. The
I.P.Q.C. person should check following things during addition.
➔ Name of the product and B. No.
➔ Name of the active component and its Analytical Reference No. and quantity.
Document Required
B.P.C.R. (showing who has added and who has checked the addition of the active
component. Also the quantity added satisfies the condition of addition of 100% of the
active component in the batch)

6.9 TIME LIMITATIONS ON PRODUCTION

A pbarn1aceutical manufacturing process should be co.mpleted in a specified time period.
Normally, starting and finishing of a pharmaceutical process should be noted and it should
be as minimum as possible : If a process involves a number of stages then the maximum time
lapse between two consecutive stages must be defined and if deviations occur, such
deviat ions must be noted, justified and recorded and made known to the concerned
authorised persons.
The holding of a product at intermediate stage for abnormally long period have certain
potential danger e.g.
Chances of mix-ups.
Stability related problems (l\·1oisture pick up or loss).
Misuse of the material etc.
To avoid such problems all critical stages in the manufacturing process should be
identified for each formulation and time li.mit of hold at each such stage must be defined
based on the stability data and G.M.P. related issues. This should be done for each product
since the stability related issues of each product may be different. These data should be
available ,vith the manufacturing pharmacist or alternatively such data may be provided in
the M.P.C.R. or B.P.C.R. for each product.
Document Required
Product-wise time-limitation on production preferably at each critical stage of
manufacturing.

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Pharmaceutical Quality Assurance 6.14 Manufacturing Operations and Control

02 DOCUMENT TITLE : SOP ON INTERNAL LABELLING

Internal labelling means a system of unique identification of items like, processing
materials, equipments, rooms and processes being carried out.
This SOP should cover the following points :
(i) All rooms must be clearly identified by name and numbers and the same may be
recorded in the B.P.C.Rs.
(ii) All major equipment must be identified by distinctive identification number and the
same may be recorded in the B.P.C.R.
(iii) Status of all unprocessed semiprocessed or processed materials must be clearly
identified.
(iv) Some of the internal labels are as follows :
(a) Materials received label
(b) Materials sampled label.
(c) Materials Approved/Rejected label.
(d) Dispensed material labels.
(e) In process material labels like
• Granulated materials.
• Lubricated materials.
• Co1npressed tablet,a.
• Coated tablets.
• Ampoules/vials to be inspected.
• Ampoules/vials inspected.
• Ampoules/vials Good/Rejected.
• Unfiltered solution.
• Filtered solution.
• Sterile solution etc.
(v) Each of the label should generally have the following details:
• Name of the organi•iation.
• Product Name/B.No.
• Processing stage.
• Date of labelling.
• Signature of supervisory staff etc.

03 DOCUMENT TITLE : SOP ON TIME LIMITATION ON PRODUCTION

This SOP should cover the following points :
(i) Types of formulations.
(ii) Catagorisation of formulation e.g.-
• Sterile product.
• Liquid formulation.

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Pharmaceutical Quality Assurance 6.23 Manufacturing Operations and Control

FORMAT TITLE 14 : EQUIPMENT CLEANING AND USE LOG

MAP PHARMACEUTICALS LTD.
EQUIPMENT CLEANING AND USE LOG
Deptt. : l\-Ionth :
Area: Ref. SOP No. :
Equipment: Equipment Code No. :

Dt. Product B. Cleanliness Equipment Time of Checked Cleaned Time of Checked

No. (Just before used by use by by Cleaning by
use) (Operator) (After
Inspected by use)
From To From To

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Pharmaceutical Quality Assurance 6.29 Manufacturing Operations and Control

ACCEPTABLE QUALITY LEVEL WITH SAMPLE SIZE FOR INSPECTION

Pack Output per Sample size Sample size per Defectives
shift ru>r shift ins=ction
- Critical Maior l\tinor
BL/ S'r I l\1BI CCI 150000 200 40 00 03 10
CB
.BULK PACK 10000 80 16 00 01 05
ACCEPTABLE QUALITY LEVEL ➔ 0.0% 0.65% 2.5%
TIME
Shipper Label
Codin11
pad/ artition
-
No. of units packed
BOPP taping
Carton Coding
Availability of leaflets
Availability of oackers slip
NQ. of Units packed
Text and colour
Others
Label Codin2
Missin11
Crumoled/slanted/stained
--
Text and colour
Others
Primary Coding
Container Text and Colour
Emoty Pocket
Strips I .
Puncture
Blisters/ Sealing/ Knurling
Bottles Cuttin2 Ali ent
Others
Content ~/•
.
/Dented/
- .
Annearance
Printi ng/ E1nbossing
Others
Checked by QAO I PRO (Sim)
SUMMARY
Observations Actions Sirn.

Qty. Ins=cted No. of Defectives Remarks QAE I QAJ,I (Si )

Critical Maior l>1inor
--
Packaging inspection Record - Instructions : -
1. Cross Mark ( " ) if no defects observed. 2. Strike off the colun1u which is not in u.sed.
3. If defects ob,;erved. record No. ofdefective$ with prefix as 'C' fur criw:al. 'M' for • r w1d 'N' for minor defects.

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Pharmaceutical Quality Assurance 7.3 Documentation and Records

2.1 Define the manufacturers system of information and control.

2.2 To minimize the risk of misinterpretation and errors inherent in oral or casual written
communication.
2.3 To provide unambiguous procedures to be followed.
2.4 To provide confirmation of performance of a task.
2.5 To allow calculations to be checked .
2.6 And finally to allow tracing of the batch history of any product.
OS IMPORTANCE OF DOCUMENTATION:
3.1 Good documentation is an essential part of the quality assurance system and as such
should be related to all aspects of cG.M.P.
3.2 It defines the specification for all materials and methods of manufacture and control.
3.3 It ensures that all personnel concerned with manufacture know, what to do? how to do?
when to do ? and why to do ? etc.
3.4 It ensures that authorized persons have all the information necessary to decide,
whether or not to release a batch of a drug for sale or distribution
3.5 It provides an audit trail that will permit investigations of the history of any suspected
defective batch.
04 PREPERATION, ISSUE AND USE OF DOCUMENTS:
4.1 . Documents should be carefully and logically set out to encourage correct use and be easy
to check. Documents should contain all necessary, but no superfluous data. Any
headings items or spaces on a master document that ceases to be used should be
removed at the earliest opportunity.
4.2 Each document should indicate or include :
• The user's company or trading name.
• Purpose and title of document.
• Document identity number which uniquely identifies the document and indicate
revision if any.
• Date of authorization.
• Date of expiry or review (in case of SOP's etc.).
• Signature of authorizing persons and where different, the signature of the person
who prepared the document.
• The distribution list, where copies are distributed (at least on the master copy) and
• Page numbers (and number of total pages).
• The way in which the document is to be used, and by whom, should be clearly
apparent from the document itself.
• The reason for revision should be documented.
• Reference used for preparation of the document if any.
4.3 Issued documents should not be hand written. Reproduced of computer printed
document should be clear and legible, in the case of batch documents each must be
initialed to indicate a verified issue.

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Pharmaceutical Quality Assurance 7.7 Documentation and Records

(3) Specifications for Intermediate and Bulk Product

This document should have the following things in addition to the common contents
mentioned above :
(1) Specifications for intermediate and bulk products should be available if these are
purchased or dispatched or if data obtained from intermediate products are used in the
evaluation of the finished product. These specifications should be similar to starting material
or finished products as applicable.
(4) Specifications for Finished Products
This document should have the following things, in addition to the common contents,
mentioned above.
(i) Name of the product.
(ii) Code number reference.
(iii) Names of the active ingredients.
(iv) The formula or reference to the formula.
(v) A description of dosage forms and package details.
(vi) Direction for sampling and testing or reference to procedures.
(vii} The qualitative and quantitative requirements with acceptance limits.
(viii)Tho storage conditions and precautions, where applicable and
(ix) Shelf life.
Documents Required
(i) Specifications for ➔ Active and inactive starting materials.
➔ Packaging materials.
➔ Intermediate and bulk p;oducts.
➔ Finished products.

7.2 MASTER PRODUCTION AND CONTROL RECORD (M.P.C.R.)

The above term is borrowed from CFR 211.186. This document is also known in various
other regulatory literature as,
• Master Formula Record (Seh. ?YI. India).
• Master Formulae and Packaging instructions (W.H.O. Genera).
• l\1anufacturing Formula and Processing Instructions. (TGA) Australia.
• Master manufacturing instructions and Master Packaging instructions (M.C.C.
South Africa).
I personally preferred the term M.P.C.R. because it includes both the words 'Production'
and 'Control'. All the above documents l,>ive details about, what it should contain.
The purpose of this document is to assure uniformity from batch to batch.
This document should be prepared for each product, including each batch size thereof. It
should be d_ated and signed (Full, hand written signatures) by one person and independently
checked, dated and signed by a second person.
There should be a detailed S.O.P. for preparation of M.P.C.R.

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Pharmaceutical Quality Assurance 7. 11 Documentation and Reco~

(xiv) SOP and R related to product recalls and returns.

(xv) SOP and R related to finished product distribution.
(xvi) Log books for recording validation, calibration, repairs and maintenance, cleaning
and operation of the major equipments.
Log books should also record in chronological order the use of major or critical
equipment and the areas where the products have been processed.
(xvii) SOP and R for Retention and disposal of records.
(xviii) Site mru,-ter file.
(xix) Validation Master Plan.
(x.x) Planned Preventive Maintenance Programme.
(xxi) Records of_contract manufacture, analysis and services.
(xxii) Calibration Master Plan.
Documents Required
All those 22 documents described above will be required.

7.5 CHANGE CONTROL

Change control may be defined as a system of procedures through which changes are
reviewed, justified, documented, approved and implemented in conformances with regulatory
and corporate requirements.
Change control is in fact a system that controls change by,
(i) Identifying the ownership of the change.
(ii) Allowing for review and approval of the change.
(iii) Preventing changes that could adversely affect product quality or conflict with
registr ation or regulatory requirements.
(iv) Providing an assessment of change and monitor the impact of change.
This means in short, the purpose of managing change within the quality system is for
evaluating the potential impact on :
• Validated conditions, processes or systems maintained in a state of control.
• Regulatory commitments.
•· Product quality and safety.
Change control systems today are expected to be designed in a way that provides a
system to not only document and approve changes, but also to anticipate change within the
quality organization.
Follo\ving are some of the indicators, which help to anticipate changes in the quality
organisation e.g.
(i) An inordinate number of rejects means the process has shifted and the cause must be
found.
(ii) Product complaints are another indication that need changes to be implemented with
appropriate revie\v and approval.

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Pharmaceutical Quality Assurance 7.16 Documentation and Records

Item 7 •• SUBJECT: Mention the title of the SOP.

Item 8 •• PREPARED BY: Name and signature of the person who wrote the SOP.
ltem9 •• CHECKED BY: Name and signature of the department in-charge
Item 10 •• APPROVED BY: Name and signature of the Head of the department
Item 11 •• AUTHORISED BY : The authorisation of any SOP shall be done by the
Head (QA/QC/Regulatory).
4.6 PREPARATION, APPROVAL AND AUTHORISATION OF SOP
4.6.1 The SOP shall be written by a supervisor, who is supervising the actual performance,
who is actually involved with the activity in the respective department.
4.6.2 All SOPs must be written in the following format.
Section I : OBJECTIVE
Section II : RESPONSIBILITY
Section 111: ACCOUNTABILITY
Section IV : PROCEDURE
The following details must be included under of the above mentioned section
4.6.2.1 OBJECTIVE:
This section must mention the intended use and applicability of the SOP. It must be
a one sentence or maximum two sentences statement. It must start with a letter 'To'
4.6.2.2 RESPONSIBll.ITY :
This section must include the designation of the person / persons along with their
specific responsibility towards the implementation of the "objective" of the SOP.
4.6.2.3 ACCOUNTABILITY:
This section must include the designation of the person / persons who are the
immediate seniors to persons responsible for compliance .of any SOP.
4.6.2.4 PROCEDURE :
This section must include the operating procedure in short, unambiguous sentences.
All process checks, their frequency and recordings must be clearly defined. Any
special precautions need to be clearly described.
4.6.3 The draft SOP must be checked by the Section In-charge of originator department to
confirm the compliance of the SOP with the activity in consultation with the actual
user.
4.6.4 The Section - in -charge will circulate the draft SOP to Department Head, QA/QC/
Regulatory for review. Any comments on the draft SOP will be reviewed and
evaluated by the department head and incorporated (if necessary) in draft version.
4.6.5 The corrected final copy of the SOP incorporating all modification/ correction shall be
printed on the approved format.
4.6.6 After approval of SOP, the draft SOP must be destroyed.
4.6.7 All final SOPs shall have signatures of persons who prepared, checked, approved and
authorized the SOPs on every page.
4.6.8 The cycle time for all the above activities should not be more than 7 days.

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Pharmaceutical Quality Assurance 7.20 Documentation and Records

ANNEXURE - VI
SOP DISTRIBUTION LIST

SUBJECT:
SOP NO.:
EFFECTIVE DATE : .

DISTRIBUTION LIST
Sr. Dept.JSection No.of Retrieved No. of Copies Retrieved Status
No Copies By/Date Retrieved By/Date
Issued
1.
2.
3.
4.
5.
6.
7. .
8.

02 DOCUMENT TITI.E : SITE MASTER FILE

(Based on European regulatory Requirements)
Reference : European commission
Directorate General III
Industrial affairs III (Consumer Goods Industry)
Pharmaceutical products.
"Site Master File" is a very important and basic document. This provides detailed
information of a pharmaceutical manufacturing site. This is also an original document,
which inspecting/ auditing authorities use for the inspection or auditing of the organisation.
CHAPTER 1: GENERAL INFORMATION
1.1 General.
1.2 Pharmaceutical activities for, which license is granted.
1.3 Manufactured products, classified by active substances.
1.4 ?vledicines marketed within the European Union/ In manufacturing country.
1.5 List of formulations supplied solely to the export.
1.6 Non-pharmaceutical products manufactured on the site.
.
CHAPTER 2: PERSONNEL AND QUALITY MANAGEMENT
2.1 Staff on the site.

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Pharmaceutical Quality Assurance 7.24 Documentation and Records

1.3 Type of actual medicinal products manufactured, mentioned by active

substances.
Pharmacopoeia) and Dosage form Therapeutic class Batches per year
Brand Name (Last years actual
or proposed)

1.4 Medicinal products marketed within the European Union / EEA.

Brand Marketing Manufacturing Packaging Analysis, control Release
name authoJisation site /Filling site and reserve site
no. sample sites (S)

1.5 Medicinal product without marketing authorisation.

Brand Marke tin, Manufacturing Packaging Analysis, control Release
••
name authorisation site site and reserve site
number sample sites (S)

1.6 Non-pharmaceutical products manufactured on the site,

This has to be filled only if these products are manufactured in the same working areas/
buildings. •
Category Manufacturing Packaging Storage Remarks
Medical device
Cosmetics/
Health
Dietary
oroducts
Laboratory
reactants
Other products

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Pharmaceutical Quality Assurance 7.28 Documentation and Records

3.6 Water treatment systems (only for water used in the formulations)
Give a schematic drawing for each water treatment system, and fill in the following table :
Type Number of Capacity Period of Period of Remarks (e.g.
sampling analysis sanitation construction
points materials)
Drinkable
Purified
WFibulk
3.7 Manufacturing equipment
List of main items of equipment classified per plant with reference to the plan :
Location (reference Name of the Capacity Year of installation
to the plan) equipment

3.8 Control laboratory equipment

List of main laboratory control equipment with reference to the plan :
Location (reference to Name of the equipment Year of installation
the plan)

3.9 Maintenance and Calibration

Programmes Department Preventive / Department Recording of
for: in charge of curative in charge of maintenance /
maintenance Maintenance calibration calibration
operations
Premises
Production
equipment
QC equipment
CHAPTER 4: DOCUMENTATION
4.1 General
Brief description (not more than 200 words / half an A4 page) of arrangements for the
preparation, revision and distribution of necessary documentation for manufacture and
quality control, including specifications and master batch records (manufacturing /
packaging).

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Pharmaceutical Quality Assurance 7.36 Documentation and Records

FORMAT TITLE 5: GENERAL PROCEDURE

MAP PHARMACEUTICALS l,TD.
GENERAL PROCEDURE
(For Restricted circulation only)
Name: Pages:
Status: Effective Date :
GP No. : Review period :

Prepared by Checked by Approved by

Signature:
Date :

FORMAT TITLE 6: STANDARD TEST PROCEDURE

MAP PHARMACEUTICALS LTD.
STANDARD TEST PROCEDURE
(For Restricted circulation onlv)
Name : Pages:
Code No.: Shelf Life :
Status: Effective Date :
STP No.: . Review period :

'
Prepared by Checked by Approved !.ly
Signature :
Date:
-

♦♦♦

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Pharmaceutical Quality Assurance 8.4 Pharmaceutical Validation

6.0 Facilities :
Qualification of pharmaceutical facilities involve the following phases namely;
a. Defining user requirements in terms of user requirement specification.
b. Functional Requirement specification.
c. Deriving Design Qualification.
d. Construction of the facilities.
e. Certification of constructed facility and
f. Ongoing building main.tenance.
7 .O Manufacturing :
Pharmaceutical formulations are divided into various dosage forms. Each dosage form
has various processes involved in it. Eacb such process must be validated. Following is a
matrix of some common dosage forms and their processes.
Sr. Process Dosage forms
No. Tab Cap Liq. Amp. Vial. Oint.
1. Dispensing ◊ 0 0 0 0 0•
2. Sifting of Raw Materials 0 0 0
3. Milling (size r eduction) 0 0
4. Mixing (Dry/Wet) 0 0
5. Dying of materials 0 0
6. Compression of Tablets 0
7. Coating of Tablets 0
8. Filing of E.H.G. • Capsules 0
9. Sorting /Polishing /lnsp. 0 0
10. Bulk Preparation 0 0 0 0
11 Sterile filtration 0 0
12 Sterile filling/ filling 0 0 0
13 Sterilisation (DHS)• 0 0
14 Sterilisation (Autoclave) 0 0
15 Component Preparation 0 0
16 Particulate inspection 0 0
17 Leak testing 0 0 0 0 0 0
18 Tube filling/Jar filling 0
19 Strip sealing 0 0
20 Blister sealing 0 0 . 0 0
21 General packaging 0 0 0 0 0 0
22 Dispatching of F .G. * 0 0 0 0 0 0

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Phannsceutical Quality Assurance 8.24 Pharmaceutical Validation

cleaning method is directly related to the established evidence that the particular method
will give expected and reproducible results. The reproducibility of results is the heart of any
validation procedure.
8.4.5 Cleaning Continuum
Cleaning continuum is concept advocated by the lOenzaid G.M.P. academy and can be
defined as "an organisational model which helps to draft the operational details of a specific
cleaning validation programme".
The cleaning validation is a highly complex process and it refers to the following aspects
of cleaning activities viz.
* Establishing critical par_ameters.
• Developing grouping philosophies.
• Establishing the scientific rationale for a cleaning programme.
* Determining the processes, equipments and products that represent the greatest
concern.
• Establishing'the criticality of cleaning limits and methods.
The cleaning continuum comprises many coupled limits that represent the extreme
operating dilTerences found within the industry. These limits are also defined by cleaning
validation requirements that are either simple or compleL
8.4.6 Grouping Pb.ilosopby in Cleaning
Grouping philosophy in cleaning validation refers to a common denominator within the
cleaning context, whereby similar products, similar equipment, similar cleaning methods and
similar cleaning agents, etc. are grou~ together and a worst case is selected to demonstrate
the validity of a specific cleaning programme.
8.4.7 Factors In Cleaning Validation
I repeat here that cleaning validation is a complex, critical and vital activity. This
activity involves minimum following factors to be considered viz..
a. Product
b. Equipment
c. Facilities
d. Cleaning methods
e. Cleaning agents
f. Sampling
g. Testing, limits and acceptance criteria
Now Jet us briefly discuss each of the above aspects.
a. Products : The pri.me objective of the cleaning validation is to assure complete or
near to complet:e (i.e. the acceptable level of cleanliness) removal of the various materials
processed earlier in the equipme!}t or area. This is to avoid the contamination of the next
processed materials with the previously processed mat.erials. This includes following
categories of materials. e.g.

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Pharmaceutical Quality Assurance 8.30 Pharmaceutical Validation

The ICH documents state . that, when chromatographic procedures are used,
representative chromatogram should be represented to demonstrate the degree of specificity
(selectivity) and peaks should be appropriately labelled. Peak purity tests may be useful to
show that the analyte chromatographic peak is not attributable to more than one component.
8.5.5 Limit of Detection :
.
Definition : The limit of Detection may be defined as "The lowest amount of analyte
in a sample that can be detected, but not necessarily quantitated, under the stated
experimental conditions''.
The L.0.D. is generally expressed as the concentration of the analyte sample (e.g.
percentage or parts per million, etc.).
The I.C.H. documents describe a common approach, which is to compare measured
signals from samples with lµiown low concentrations of analytes with those of blank samples.
These detection limits should be subsequently validated by the analysis of a suitable
number of samples of known to be near or prepared at the detection limit.
8.5.6 Limit of Quantitation :
Definition: L.O.Q. May be defined as "A characteristic of quantitative assays for
low levels of compounds in sample matrices such as impurities in bulk substances
and degradation products in finished pharmaceuticals. It is the lowest amount of
analyte in a sample that can be determined with acceptable precision and
accuracy under the stated experimental conditions".
The L.O.Q. is generally expressed as the concentration of the analyte in the sample (e.g.
Percentage or parts per million, etc.).
The I.C.H. docu.ments describe a common approach, which is to compare measured
signals from samples with known low concentrations of analytes with those of blank samples.
These quantitation limits should be subsequently validated by the analysis of a suitable
number of samples known to be near or prepared at the quantitation limit.
8.5.7 Linearity:
Definition : The Linearity of an analytical method may be defined as "Its ability to
elicit tests th.at are directly or by a well def"med mathematical ti·..ni;formations
proportional to the concentration of analyte in samples within a given range•.
The Linearity should be established across the r ange of the analytical procedure. It
should be established initially by visual examination of a plot of signals as a function of
analyte concentration of contact. If this appears to be a linear relationship, test results
should be established by appropriate statistical methods like regression analysis, etc.
l.C.H. Recom.m ends that, for the establishment of Linearity, a minimum of 5
concentrations normally be used.
8.5.8 Range :
Definition : The range of an analytical method may be defined as "Interval between
the upper and lower levels of analyte (including these levels) that have been
demonstrated to be determined with a suitable level of precision, accuracy and
linearity using the method as written. The range is normally expressed in the same

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Pharmaceutical Quality Assurance 13.12 Sterile Pharmaceutical Products

The critical specification of purified \vater are as follows :

(i) Description - A clear, colorless, odourless and tasteless liquid.
(ii) pH - 5.0 to 7 .5.
(iii) Residue on Evaporation - Not more than 0.001 %.
(iv) Conductivity - Not more than 4.3 11s/cm2.
(v) Heavy met als - Not more than 0.1 ppm.
(vi) Nitrates - Not more than 0.2 ppm.
(vii) Microbiological count - Maximum 100 CFU/ml.
For other specification like acidity, alkalinity, ammonium, calciu1n and 1nagnesium,
chlorides, sulphates, oxidisable substances, see phannacopoeal n1anographs.
(ii) Water for injection : Water for injection is an excipient in the production of
injections and for use in pharmaceutical applications, such as cleaning of certain equipment ,
and in the preparation of some bulk pharmaceutical chemicals. The source or feed water for
this is drinking water which may have been preliminarily purified but \vbich is finally
subjected to distillation or reverse osmosis. It must meet all the chemical requirements for
"purified water" and in addition the requirements under bacterial endotoxins tests. It must
also be protected from microbial contamination. The system used to produce, store, and
distribute water for injection must be designed to prevent microbial contamination and
formation of microbial endotoxin, and it must be validated.
W.F.I. should be constantly circulated at<!: 80°C ors 4°C.
The critical specification of water for injection are as follows :
(i) Description : A clear, colourless, odourless and tasteless liquid.
(ii) pH : 5.0 to 7.5
(iii) Residue on evaporation: Not more than 0.001%.
(iv) Conductivity : Not more than 1.1 µs/cm 2 at 20°C.
(v) Total organic carbon: Not more than 500 ppb.
(vi) Microbial count :
(a)Bacteria : 10 CFU / 100 ml.
(b)Fungi : Nil
(vii) Bacterial endotoxins : Less than 0.26 I.U./ml.
For other specifications reader should refer to pham1acopoeal monograph.
(iii) Pure Steam : Pure steam condensate should be analysed against the specifications
of water for injection and it must pass, according to the sarne.
Presently pure steam generators are available where purified water is used as feed
water. These equipment must be validated before use.
Documents Required
(i) Specification, test methods and reports for purified water and water for injection.
(ii) Validation reports for purified water system, water for injection system and pure
steam generators.

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Pharmaceutical Quality Assurance R-7 References

Chapter 1O : Post
Operational
Activities
10.0 Introduction - 13 8 10.1 and
-
-
,_ 11 .1
•
/
10.1 Distribution - 13.23 to 13.24 - 211.196 -
and 14.45
10.2 Recalled products 27 13.29 8 211 .204 11 .4
10.3 Returned products 28 13.30 8.1 to 8.15 211.204 10.1 to 10.2
10.4 Complaints and 28 14.46 8. 1 to 8.15 211.198 11 .2
adverse effects
10.5 Drug product - 14.46 - 211 .208 -
salvaging
Chapter 11 : Site
and Plant Security
11 .0 Introduction - - . - 20.1
11 .1 Security Personnel - - , - . 20.1
11.2 Entry to site . - - . 20.2
11 .3 Entry to plant . - . . 20.3
buildings
11.4 Internal security . . . . 20.4
Chapter 12 : Safety
& Environmental
Protection
12..ll Introduction . . . . 21 .1
12.1 Safety - . . . 21.2
12.2 Environmental - - - . 21 .3
protection and
procedures
Chapter 13 : Sterile
Pharmaceutical
Products
13.0 Introduction 1A - 1 17.1 to 17.4 Anxt : 1 to 6 . 22.1
Personnel
- - 1A-5 17.61017.15 Anx1 : 13 . 22.6
13.1
to 21
13.2 Building and 1A2.1to 17.16 to 17.23 Anx1 : 22 . 22.3
Premises 2 .10 to 31
13.3 HVAC system 1A3.1 to . . . 22.4
310 and
4.1 to 4.3 .
···- -- ---
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 ABOUT THE AUTHOR •
Manohar A. Potdar
•
Prof. Manohar A. Potdar is highly experienced industrial pharmacist.
He has more than 85 years of industrial experience obtained from leading
Indian & multinational pharmaceutical organisations like, CIBA, Hoechst,
Boehriryer Knoll , Burronghs welcome, Laprin, Cadila, Ranbaxy,
Wockhardtt, Plethico &Alkem. His last assignment with industry was with
Alkem Laboratories Ltd. On Vice-President (Technical Operations),
responsible for Projects, Manufacturing & Quality Assurance. Presently he
is associated with Poona college of Pharmacy (Deemed University) as Professor & Head of
Department of Quality Assurance Techniques.
He obtained his B. Pharm. (1969) from Shivaji University Kolhapur. M. Pharm. (1973) from
B.I.T.S. Pilani & Ph.D (1987) in Production Management from T.I.V. Missouri (USA). He also has
to his credit D.B.M. from Mumbai & Dip. Trg. & Dev. (1.S.T.D)from Delhi.
He has helped many organisations to set WHO MHRA (UK) M.C.C. (South Africa), T.G.A.
(Australia), & U.S.F.D.A. Approach. He is approved on competent technical staff, by State Govts.
of Maharashtra & M.P. in Tablets, Capsules, lnjectables, Qintments, Opthalmics, & Cosmetics
Manufacturing. He is a qualified professional industrial trainer & has trained hundreds of people
in pharma industry.
He has published papers on phytochemistry, C.G.M.P, WHO, Certifications, Quality
assurance & similar subject in national & international journals. His book Pharmaceutical
Manufacturing Documentation is a recognized text-book in S.G.I.T.S. Indore.
His main interest & mission of life is to train young pharmacists for better industrial careers.

BOOKS AVAILABLE AT
PUNE
Pragatl Book Centre 157, Budhwar Peth, Opp. Ratan Talkies, Pune 411002.
Tel; (020) 2445 8887 16602 2707 Fax: (020) 2445 8887
Pragatl Book Centre 676/B, Budhwar Peth. Opp. Jogeshwari, Mandir, Pune 411002.
Tel: (020) 6601 7784 / 6602 0855
Pragatl Book Centre 152. Budhwar Peth, Pune 411002. Tel: (020) 2445 2254 / 6609 2463
Pragatl Book Centre 917/22, Sai Complex, F.C. Road, Opp. Hotel Roopall, Shivajinagar,
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MUMBAI
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Mumbai 400026. Tel: {022) 2422 3526 / 5622 5254
[email protected] www.pragstlonl1ne.com

Gopynqht • 1.;11