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2-4 ICH Quality Guidances : an overview

2-4 ICH Quality Guidances : an overview. PQP Assessment Training January 18-21, 2012 Satish Mallya. January 18-21, 2012. ICH Topics. Stability - Q1A – Q1F Analytical Validation – Q2 Impurities – Q3A - Q3C (Q3D – concept paper) Pharmacopoeias – Q4A - Q4B (and annexes)

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2-4 ICH Quality Guidances : an overview

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  1. 2-4 ICH Quality Guidances:an overview PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21, 2012

  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 January 18-21, 2012

  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) January 18-21, 2012

  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Q1E Evaluation of Stability Data • Q1F Stability Data Package for Registration Applications in Climatic Zones III & IV (withdrawn – June 2006) January 18-21, 2012

  5. Q1A(R2) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS January 18-21, 2012

  6. Stress Testing/Photostability January 18-21, 2012

  7. Selection of Batches January 18-21, 2012

  8. Container Closure System January 18-21, 2012

  9. Specification January 18-21, 2012 June 2010

  10. Testing Frequency January 18-21, 2012 June 2010

  11. Storage Conditions General Case January 18-21, 2012 June 2010

  12. Storage Conditions Storage in refrigerator January 18-21, 2012 June 2010

  13. Storage Conditions Storage in freezer Storage below - 20⁰C : Case by case basis January 18-21, 2012 June 2010

  14. Storage Conditions – Drug Product Semi-permeable containers : January 18-21, 2012 June 2010

  15. Significant Change January 18-21, 2012

  16. Evaluation January 18-21, 2012 June 2010

  17. Q1BPHOTOSTABILITY 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 January 18-21, 2012

  18. Q1CAnnex to Q1A (R2) • Additional guidance on line extensions • Reduced requirements at time of filing: 6 months accelerated and 6 months long term January 18-21, 2012

  19. Q1D - Bracketing January 18-21, 2012

  20. Q1D - Matrixing January 18-21, 2012

  21. Q1D - Matrixing January 18-21, 2012

  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 January 18-21, 2012

  23. Outcomes When there is no significant change under accelerated conditions (RT) January 18-21, 2012

  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 January 18-21, 2012

  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 January 18-21, 2012

  26. VALIDATION CHARACTERISTICS January 18-21, 2012

  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) January 18-21, 2012

  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 January 18-21, 2012

  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 January 18-21, 2012

  30. Q3A(R2) January 18-21, 2012

  31. Q3A(R2) January 18-21, 2012

  32. Q3B(R2) January 18-21, 2012

  33. Q3B(R2) January 18-21, 2012

  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 January 18-21, 2012

  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. January 18-21, 2012

  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 January 18-21, 2012

  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 January 18-21, 2012

  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 January 18-21, 2012

  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 January 18-21 2012 January 18-21, 2012

  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) January 18-21, 2012

  41. January 18-21, 2012

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