ICH.pdf
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This document provides an overview of several ICH quality guidelines related to stability testing, analytical validation, impurities, specifications, and other topics. It discusses the guidelines' focus on stability testing (Q1A, B, C, D, E, F), analytical validation (Q2), and impurities (Q3A, B, C). For each guideline covered, it provides a brief high-level summary of the key aspects and requirements.
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ICH.pdf
- 1. 2-4 ICH Quality Guidances: an overview
- 2. ICH Topics • Stability - Q1A – Q1F • Analytical Validation – Q2 • Impurities – Q3A - Q3C (Q3D – concept paper) • Pharmacopoeias – Q4A - Q4B (and annexes) • Quality of Biotechnological Products – Q5A – Q5E • Specifications – Q6A – Q6B • Good Manufacturing Practice – Q7 • Pharmaceutical Development – Q8 • Quality Risk Management - Q9 • Pharmaceutical Quality System – Q10 • Development and Manufacturing of Drug Substances – Q11
- 3. Focus • Stability - Q1A, B, C, D, E & F • Validation of Analytical Methods – Q2(R1) • Impurities – Q3A, B & C • Specifications – Q6A (Chemical Substances) & Q6B (Biotechnology/Biological Products)
- 4. Stability • Q1A(R2) Stability Testing of New Drug Substances and Products • Q1B Photostability Testing of New Drug Substances and Products • Q1C Stability Testing for New Dosage Forms • Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products • Q1E Evaluation of Stability Data • Q1F Stability Data Package for Registration Applications in Climatic Zones III & IV (withdrawn – June 2006)
- 5. Q1A(R2) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Drug Product Drug Substance Photostability testing Stress testing Selection of batches Selection of batches Container closure system Container closure system Specification Specification Testing frequency Testing frequency Storage conditions Storage conditions Stability commitment Stability commitment Evaluation Evaluation Statements/Labeling Statements/Labeling
- 6. Stress Testing/Photostability Drug Product Drug Substance One primary batch As in ICH Q1B: One primary batch Effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing) Effect of humidity (e.g., > 75%RH)
- 7. Selection of Batches Drug Product Drug Substance Data on at least three primary batches of the drug product – two pilot and third one can be smaller - same formulation and packaged in the same container closure system as proposed for marketing. The manufacturing process used for primary batches should simulate that to be applied to production batches Where possible, use different batches of the drug substance. Should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied. Data on at least three primary batches of minimum pilot scale manufactured by the same synthetic route as used for production batches.
- 8. Container Closure System Drug Product Drug Substance Studies to be carried out in container closure system identical to commercial packaging; studies carried out in other packaging materials can be used as supporting information Studies to be conducted on the API packaged in a container closure system that is identical to or simulates the proposed commercial packaging
- 9. Specification Drug Substance Drug Product Studies to include attributes susceptible to change during storage and which can influence quality, safety and efficacy: - Physical - Chemical - Microbiological Studies to include attributes susceptible to change during storage and which can influence quality, safety and efficacy: - Physical - chemical, - microbiological, - preservative content - functionality tests (e.g. with delivery systems) Validated analytical methods to be employed Validated analytical methods to be employed
- 10. Testing Frequency Drug Substance Drug Product For API with proposed re-test period/shelf-life of at least 12 months: Every 3 months over first year, every 6 months over next 12 months and annually thereafter. For FPP with proposed re-test period/shelf-life of at least 12 months: Every 3 months over first year, every 6 months over next 12 months and annually thereafter. Accelerated condition: Minimum of 3 time points, including initial and final time points (e.g. 0, 3 & 6 months) Accelerated condition: Minimum of 3 time points, including initial and final time points (e.g. 0, 3 & 6 months) Intermediate condition (due to significant change under accelerated condition): study design should include 4 time points (e.g. 0, 6, 9 and 12 months Intermediate condition (due to significant change under accelerated condition): study design should include 4 time points (e.g. 0, 6, 9 and 12 months) Matrixing or Bracketing may be applied
- 11. Storage Conditions • General Case Drug Substance Drug Product Study Storage Conditions Minimum period covered by data at submission Study Storage Conditions Minimum period covered by data at submission Long term 25⁰C+2⁰C/ 60%+5%RH or 30⁰C+2⁰C /65% +5%RH 12 months Long term 25⁰C+2⁰C /60%+5%RH or 30⁰C+2⁰C /65% +5%RH 12 months Intermediate 30⁰C+2⁰C /65% +5%RH 6 months Intermediate 30⁰C+2⁰C /65% +5%RH 6 months Accelerated 40⁰C+2⁰C /75% +5%RH 6 months Accelerated 40⁰C+2⁰C /75% +5%RH 6 months
- 12. Storage Conditions • Storage in refrigerator Drug Substance Drug Product Study Storage Conditions Minimum period covered by data at submission Study Storage Conditions Minimum period covered by data at submission Long term 5⁰C + 3⁰C 12months Long term 5⁰C + 3⁰C 12months Accelerated 25⁰C + 2⁰C / 60% + 5% RH 6 months Accelerated 25⁰C + 2⁰C / 60% + 5% RH 6 months
- 13. Storage Conditions • Storage in freezer • Storage below - 20⁰C : Case by case basis Drug Substance Drug Product Study Storage Conditions Minimum period covered by data at submission Study Storage Conditions Minimum period covered by data at submission Long term - 20⁰C + 5⁰C 12months Long term - 20⁰C + 5⁰C 12months
- 14. Storage Conditions – Drug Product • Semi-permeable containers : Study Storage Conditions Minimum period covered by data at submission Long term 25⁰C+2⁰C/40%+5% RH or 30⁰C+2⁰C/35%+5% RH 12 months Intermediate 30⁰C+2⁰C/65%+5% RH 6 months Accelerated 40⁰C+2⁰C/NMT 25% RH 6 months
- 15. Significant Change Drug Product Drug Substance ->5% change in assay from the initial results -Any degradation product exceeding its acceptance criterion -Failure to meet acceptance criteria for appearance, physical attributes and functionality tests -Failure to meet acceptance criteria for pH -Failure to meet acceptance criteria for dissolution of 12 dosage units Defined as failure to meet specifications
- 16. Evaluation Drug Substance Drug Product Statistical analysis not necessary if data exhibits little or no degradation and variability Statistical analysis not necessary if data exhibits little or no degradation and variability Limited extrapolation of real time data permitted with justification Limited extrapolation of real time data permitted with justification
- 17. Q1B PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS • Provides 2 options for sources of light: – artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp – sample should be exposed to both the cool white fluorescent and near ultraviolet lamp • Test on API first – if not photosensitive then no further testing is required • If API is photosensitive then testing to be continued on (as appropriate): – Tests on the exposed drug product outside of the immediate pack – Tests on the drug product in the immediate pack – Tests on the drug product in the marketing pack • Where appropriate, impact of light during manufacturing
- 18. Q1C Annex to Q1A (R2) • Additional guidance on line extensions • Reduced requirements at time of filing: 6 months accelerated and 6 months long term
- 19. Q1D - Bracketing
- 20. Q1D - Matrixing
- 21. Q1D - Matrixing
- 22. Q1E EVALUATION OF STABILITY DATA • Provides recommendations for: (at RT, Refrigerated and Freezer storages) – treating stability data – Extending re-test period or shelf-life beyond period covered by long-term data – Statistical approaches to analysis of stability data • Progression: – Start with data under accelerated condition – Then assess data under intermediate condition, if appropriate – Finally evaluate trends and variability of the long-term data
- 23. Outcomes When there is no significant change under accelerated conditions (RT) Retest period or shelf life can be up to twice, but NMT 12 months beyond the period covered by long-term data Long-term and accelerated data showing little or no change over time and little or no variability Data not amenable to statistical analysis, but relevant supporting data provided: Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond the period covered by long-term data If a statistical analysis is performed: Retest period or shelf life of up to twice, but not more than 12 months beyond the period covered by long-term data Long-term or accelerated data showing change over time and/or variability
- 24. Outcomes When there is significant change under accelerated conditions (RT) but no significant change at intermediate condition: Data not amenable to statistical analysis: Retest period or shelf life can be up to 3 months beyond the period covered by long- term data if backed by relevant documentation If statistical analysis is performed: Retest period or shelf life can be up to 1.5 times, but NMT 6 months beyond the period covered by long-term data when backed by statistical analysis and relevant supporting data
- 25. Q2(R1) VALIDATION OF ANALYTICAL PROCEDURES • Defines validation characteristics: – Accuracy – Precision • Repeatability • Intermediate Precision – Specificity – Detection Limit – Quantitation Limit – Linearity – Range • Robustness to be considered at appropriate stage of development of the analytical method • System suitability test parameters to be established for a particular procedure depending on the type of procedure being validated - Pharmacopoeias to be consulted for additional information
- 26. VALIDATION CHARACTERISTICS Assay Impurities Quant. limit ID Validation characteristics + + + + - - + + + - + - + - + + - + + - + - + - - - - + - - - - Accuracy Precision Repeatibility Int.Precision Specificity LOD LOQ Linearity Range
- 27. Q3 Impurities • Impurities in New Drug Substances Q3A(R2): Defines thresholds for reporting, identification and qualification of impurities in DS • Impurities in New Drug Products Q3B(R2): Defines thresholds for reporting, identification and qualification of impurities in DP • Guideline for Residual Solvents Q3C (R5): Classifies residual solvents by risk assessment: – Class 1 solvents: solvents to be avoided – Class 2 solvents: solvents to be limited – Class 3 solvents: solvents with low toxic potential • Guideline for Metal Impurities Q3D (Concept paper – July 2009)
- 28. Q3A(R2) CLASSIFICATION OF IMPURITIES • Organic Impurities – Starting materials – By-products – Intermediates – Degradation products – Reagents, ligands, catalysts • Inorganic Impurities – Reagents, ligands, catalysts – Heavy metals or other residual metals – Inorganic salts – Other materials (e.g., filter aids, charcoal) • Residual Solvents
- 29. Q3A(R2) Definitions • Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. • Reporting Threshold: A limit above (>) which an impurity should be reported. • Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified. • Unidentified Impurity: An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time) • Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification
- 30. Q3A(R2)
- 31. Q3A(R2)
- 32. Q3B(R2)
- 33. Q3B(R2)
- 34. Q3C(R5) • Provides 2 options for describing limits of Class 2 Solvents • Option 1: As per the table provided - calculated using TDI of 10 g and the calculation - – Concentration (ppm) = 1000 x Permitted Daily Exposure (PDE)/ Dose – PDE is given in terms of mg/day and dose is given in g/day. • If TDI is more than 10 g use option 2 Concentration limit (ppm) PDE (mg/day) Solvent 410 360 4.1 3.6 Acetonitrile Chlorobenzene
- 35. Example for Option 2 • Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. The PDE in terms of mg/day can be used with the known maximum daily dose and equation (Concentration (ppm) = 1000 x PDE/ Dose) to determine the concentration of residual solvent allowed in drug product Example: PDE of acetonitrile is 4.1mg/day Component Amount in formulation Acetonitrile content Daily exposure Drug substance 0.3 g 800 ppm 0.24 mg Excipient 1 0.9 g 400 ppm 0.36 mg Excipient 2 3.8 g 800 ppm 3.04 mg Drug Product 5.0 g 728 ppm 3.64 mg • The sum of the amounts of solvent per day should be less than that given by the PDE.
- 36. Q6A • Addresses aspects such as: – Periodic or skip testing – Release vs shelf-life criteria – In-process tests – Design and development considerations – Limited data available at filing – Parametric release – Alternative procedures – Pharmacopoeial tests and acceptance criteria – Evolving technologies – Impact of drug substance on drug product specifications – Reference standard
- 37. Q6A Decision Trees • #1 – Establishing acceptance criteria for specified impurity In DS • #2 – Establishing acceptance criteria for degradation product in DP • #3 – Establishing acceptance criteria for PSD in DS • #4 – Investigating need to set acceptance criteria for polymorphism in DS and DP • #5 – Establishing ID, Assay and enantiomeric impurity procedures for chiral DS and chiral DS in DP • #6 – Microbiological Quality Attributes of DS and Excipients • #7 – Setting acceptance criteria for DP dissolution • #8 – Microbiological Quality Attributes of non sterile DP
- 38. Periodic or Skip Testing • Should be justified. • May be applied to certain tests only (e.g. residual solvents and microbiological test for solid oral products) • Recommend that it should be applied post approval • Batch to batch retesting to be restored in the event of failure
- 39. Design and Development Considerations • It may be possible to propose excluding or replacing certain tests based on experience and data accumulated: – microbiological testing for drug substances and solid dosage forms which have been shown during development not to support microbial viability or growth (Decision Trees #6 and #8) – extractables from product containers where it has been reproducibly shown that either no extractables are found in the drug product or the levels meet accepted standards for safety
- 40. Design and Development Considerations – particle size testing may be performed as an in- process test, or may be performed as a release test, depending on its relevance to product performance – dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing, if these products have been demonstrated during development to have consistently rapid drug release characteristics (Decision Tree #7) (only accepted in exceptional circumstances and all conditions must be met including substantial development data)