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![Impurities
APIs
[mfg. & storage] Process & drug related organic impurities
Inorganic impurities
Residual solvents
Formulations
Those forming during formulation
Method related
Environment related
Dosage form factor related
Those forming on aging
Ingredient interactions
Functional group related degradations
Hydrolysis,
Oxidative
Photolytic
Decarboxylation](https://image.slidesharecdn.com/monographchanges-121012002541-phpapp01/75/Monograph-changes-18-2048.jpg)
Uploaded byBhaswat Chakraborty
Monograph changes
The document discusses changes in guidelines and monographs for analytical methods used in drug development and regulation. Specifically, it notes that pharmaceutical monographs now cover more drugs, assay and reference standards are better defined, and sources of impurities are better understood. Additionally, various FDA and international guidance documents provide harmonized recommendations for method validation and impurity profiling. While these changes have improved standards, they have also increased the complexity and volume of information required.
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Monograph changes
- 1. Evolution & Changesin Monograph/Guidelines: Issues in Analytical Development Dr. Bhaswat S. Chakraborty Senior Vice President, R&D, Cadila Pharmaceuticals Waters Technology Seminar, Hyderabad, Dec. 10, 2008
- 2. Clo Close se window wi nd ow Hood et al. Nature Biotechnology 22, 1215 - 1217 (2004)
- 4. Main Changes inGuidelines and Monographs From an analytical perspective, the main changes have been More and more drugs are now covered by pharmacopeial monographs Assay and RSs better defined Compendial methods exist Better understanding the sources of impurities FDA guidances on method validation, impurity profiling are in place and harmonized Q1, Q2, Q3, Q6A, FDA Analytical guidelines USP 31 Ch <1225>, <1226> Genotoxic impurities guidelines Association (Mfg., Medical, Scientific) guidelines Erudite papers Although, most of the changes have been an improvement, the volume and complexity have also increased tremendously
- 5. Guidelines and PharmacopeialMonographs Documents of excellence BUT…. Scientific (public or private standards) but treated as public “must do” regulations Regulatory guidelines USP, NF, IP, BP Often taken very seriously (rather rigidly) by reviewers and expert audit inspectors Open to interpretations Often encourage inclusion of “nice to know” in the same breadth as the “must know” information as long as it makes scientific sense Can be idealistic rather than pragmatic
- 6. Today For a moment, understand the development of guidelines and monographs and why they can be sometimes complex and over-demanding Current validation The thrust on keeping the target error in control Special stress on impurrities Unknown, toxic When do we Method transfer Method verification Full (de novo) method validation Examples Write to FDA and consult Experts? Discussion
- 7. Regulatory agencies appoint InternalGuideline Committees Guidelines Development or Working Groups or Expert Advisory Committees They deliberate and come up with draft guidelines Acceptance by the Ministry/Agency & the Stakeholders Draft guidelines are commented upon by (may be 1-4 rounds) Experts Industry Provincial Formularies, FDAs or Regulatory governments Impact Other stakeholders like professional Analysis associations
- 8. Monographing Process Source: R. Williams & Expert Project Team 4, J Pharm Biomed Anal (2006), 40, 3-15
- 9. ICH Method ValidationParameters LOD LOQ Precision Accuracy Specificity Linearity Assay range Robustness System suitability
- 10. Data Elements Requiredfor Validation Category II Analytical Performance Category I Quantitative Limit Tests Category III Category IV Characteristics Accuracy Yes Yes * * No Precision Yes Yes No Yes No Specificity Yes Yes Yes * Yes Detection Limit No No Yes * No Quantitation No Yes No * No Limit Linearity Yes Yes No * No Range Yes Yes * * No *May be required, depending on the nature of the specific test.
- 11. Data Elements Requiredfor Validation Category I – Analytical procedures for quantitation of major components of bulk drug substances or active ingredients(including preservatives) in finished pharmaceuticals products. Category II – Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceuticals products. These procedures include quantitative as says and limit tests. Category III – Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release). Category IV – Identification tests. For each category, different analytical information is needed. Listed in Table 2 are data elements that are normally required for each of these categories.
- 12. More & MoreReflection of ICH in USP During the 2000–2005 cycle, USP created a Guideline for Submitting Requests for Revision to USP–NF The Guideline provides instructions to Sponsors intending to submit Requests for Revision and harmonizes many elements of the USP monograph with the ICH Quality approaches USP expects to revise this document continuously For selected candidate reference materials, USP will add a section that provides a protocol with study design and analysis approaches This protocol will focus initially on small molecule ingredient and impurity candidate materials and can be expanded subsequently for other candidate materials as needed Source: R. Williams & Expert Project Team 4, J Pharm Biomed Anal (2006), 40, 3-15
- 13. Analytical Procedures &Validations Regulatory or Compendial Analytical procedures in Pharmacopeia/Formulary recognized legally Alternative Equal to or better than the regulatory analytical procedure. Provide a rationale for its inclusion and identify its use e.g., release, stability testing validation data, and comparative data to the regulatory analytical procedure Stability-indicating assay A validated procedure that can analyse changes with time in the pertinent properties of the drug substance and drug product Validations Full validation Revalidation Verification or Partial validation System suitability Method transfer
- 14. Full Validation andRevalidation ICH Method Validation Parameters LOD LOQ Precision Accuracy Specificity Linearity Assay range Robustness System suitability and Stability of samples over period of analysis Information from stress studies Impurities labeled with their names and location identifiers ….next slide
- 15. Full Validation (Prednisolone) Source: Gorog et al, J Pharm Biomed Anal (1998), 18, 511-525
- 16. System Suitability Tailing factor _ Relative retention _ Resolution _ Relative standard deviation (RSD) _ Capacity factor _ Number of theoretical plates
- 18. Impurities APIs [mfg. & storage] Process & drug related organic impurities Inorganic impurities Residual solvents Formulations Those forming during formulation Method related Environment related Dosage form factor related Those forming on aging Ingredient interactions Functional group related degradations Hydrolysis, Oxidative Photolytic Decarboxylation
- 19. Impurities Profiling Pharmacopeial impurities are controlled through the specifications of Related substances Chromatographic purity tests System suitability Response factors Does not consider differences in route of synthesis ICH overcomes this Stability (Q1) Analytical validation (Q2) Impurities (Q3) Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products (Q6A)
- 20. Ideal Control ofImpurities Identifies all impurities >0.1% Even <0.1% (sometimes in low ppm) if unusually potent or toxic In any case, Qualification threshold must well defined Official reference standards for all impurities are available Route of synthesis is public or known to regulatory agencies Both process-related and degradation impurities are identified and quantitated when required When changes in monograph impurities are published, clear instructions are given whether full, partial or system suitability validations are required Commitment by manufacturers, regulators, Pharmacopeias to stop counterfeits
- 21. ICH Thresholds forImpurity Identification & Quantification (Finished Products) Dose Identification (%) Quantification (%) <1 mg 1.0 1.0 1-10 mg 0.5 1.0 10-100 mg 0.2 0.5 100 mg – 2 g 0.1 0.2 >2 g 0.1 0.1
- 22. Yet there areMany issues And the common ones are: If the method is compendial, do I get a method transfer only with a DMF sourcing? or Validate partially? Validate fully? Should my method cover all known and unknown impurities? What should be range and LOQ? Should LOQ be a part of impurity specifications?
- 23. Process Impurities (Trimethoprim) Source: Rao & Nagaraju, J Pharm Biomed Anal (2003), 33, 335-377
- 24. Degradation Products (Ramipril) Source: Belal et al, J Pharm Biomed Anal (2003), 24, 335-342
- 25. Photodegradation (Trifluperazine) Source: Abdel-Moety, J Pharm Biomed Anal (1996), 14, 1639-1644
- 26. Source: J. Ermer,J Pharm Biomed Anal (1998), 18, 707-714
- 27. When do Youdo a Full Validation?
- 28. System Suitability Tests(Fenofibrate) System Suitability. Six 5 ml aliquots of the system suitability solution were injected into the system. The system was deemed to be suitable if the efficiency of the column, calculated using the fenofibrate peak, was not less than 7000 plates, the resolution between compound V and fenofibrate was not less than 20, the retention time of fenofibrate was about 7.3 min, the relative retention time of compound V about 0.26, and the R.S.D. of the peak response from fenofibrate was not more than 5.0%. Source: Lacroix et al, J Pharm Biomed Anal (1998), 18, 383-402
- 29. Source: Lacroix etal, J Pharm Biomed Anal (1998), 18, 383-402
- 30. Validation vs. Qualificationvs. Method Transfer Method Validation (Full Validation) Assess all appropriate validation characteristics Pre-defined acceptance criteria Follows formal validation protocol/sign off by the QU ICH Guideline: Q2 (R1): Validation of Analytical Procedures: Text and Methodology Method Qualification (Partial validation, suitable for it’s intended purpose) Assesses a critical subset of validation characteristics No pre-defined acceptance criteria No official guidelines Suitable for early IND studies, characterization assays
- 31. Validation vs. Qualificationvs. Method Transfer Method Validation (Full Validation) Assess all appropriate validation characteristics Pre-defined acceptance criteria Follows formal validation protocol/sign off by the QU ICH Guideline: Q2 (R1): Validation of Analytical Procedures: Text and Methodology Method Qualification (Partial validation, suitable for it’s intended purpose) Assesses a critical subset of validation characteristics No pre-defined acceptance criteria No official guidelines Suitable for early IND studies, characterization assays
- 32. Validation vs. Qualificationvs. Method Transfer Method Transfer Transfer of validated analytical procedures to a new laboratory Assesses a subset of validation characteristics Pre-defined acceptance criteria No official guidelines
- 33. Method Transfer Transfer of validated analytical methods from originating laboratory to secondary laboratory To ensure comparability in the validation characteristics between laboratories To prevent and/or detect changes in data trend Assess a subset of validation parameters Using Equivalence Testing Precision and Accuracy Using Key attributes Precision LOD/LOQ Accuracy Identity Linearity It may be useful to analyze historical data from the originating site to identify the greatest causes of variance in an assay to improve transfer success
- 34. Method Transfer A recommended approach is to use equivalence testing as the statistical approach Assumes not equivalent as the default hypothesis Concludes equivalent with enough evidence Does not penalize large sample size Need a predefined meaningful allowable difference Traditional hypothesis testing assumes equivalence as default Rewards assays with high variability Penalize large sample sizes, tiny differences will be significant if sample size is large enough Not a reasonable approach
- 35. Prior to FormalMethod Transfer Receiving laboratory should perform the method Helps to determine where there are differences and gaps in documentation Lack of detailed test method instructions Assay Conditions Calculations System Suitability Differences with instrumentation or reagents
- 36. Prior to FormalMethod Transfer Training of Personnel Review of relevant SOPs Observation of test procedure Performing test procedure Helpful to include development, qualification and validation reports to recipient laboratory
- 37. Method Transfer Typical Transfer should include: More than one lot of material Reference Standards Samples at extremes of the established acceptable limits Stress samples One laboratory, typically the originating laboratory, will prepare initial samples to be tested at both laboratories. One analyst at the originating laboratory and multiple analysts in the receiving laboratory
- 38. Method Transfer Protocol Test Method Parameters being assessed Precision, specificity, etc. Sample Preparation/Reagent Performance Parameters Different analyst on different days Pre-defined Acceptance Criteria Statistical Analysis Sign-off by Quality Assurance Unit
- 39. Successful Method Transfers Pre-defined acceptance criteria using an appropriate statistical approach. Prior to transfer, perform assay, train personnel and determine if differences in equipment and reagents effect the assay results. Test more than one lot of material.
- 40. Successful Method Transfers Include in the Regulatory Submission: Transfer Protocol Final Transfer Study Report Include representative and/or full data sets Deviations Statistical analysis Conclusions
- 41.
Editor's Notes
- #31 Validation is defined by the FDA as suitable for its intended purpose we should be careful to be consistant with this definition. By these definitions almost all IND studies are out of compliance with GMP in that they require validation and not qualification. Qualification is a term that has no meaning for compliance so we should be careful when using this term.
- #32 Validation is defined by the FDA as suitable for its intended purpose we should be careful to be consistant with this definition. By these definitions almost all IND studies are out of compliance with GMP in that they require validation and not qualification. Qualification is a term that has no meaning for compliance so we should be careful when using this term.
- #33 Either off site or on site too
- #34 Critical equipment/reagents- these are not validation characteristics? Most manufacturer will not test all these characteristic but rather do equivalence testing which may only monitor precision and accuracy and not other validation characteristics
- #38 what about at the extremes of the established acceptable limits or out of specification samples when relevant What about the RS?