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Satish Mallya January 20-22, 2010 1 |1 | 2-4 ICH Quality Guidances: an overview PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21,

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Presentation on theme: "Satish Mallya January 20-22, 2010 1 |1 | 2-4 ICH Quality Guidances: an overview PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21,"— Presentation transcript:

1 Satish Mallya January 20-22, |1 | 2-4 ICH Quality Guidances: an overview PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21, 2012

2 Satish Mallya January 20-22, |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 Satish Mallya January 20-22, |3 | Focus Stability - Q1A, B, C, D, E & F Validation of Analytical Methods – Q2(R1) Impurities – Q3A, B & C & Q6B (Biotechnology/Biological Products) Specifications – Q6A (Chemical Substances) & Q6B (Biotechnology/Biological Products) January 18-21, 2012

4 Satish Mallya January 20-22, |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 Q1DBracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1FStability Data Package for Registration Applications in Climatic Zones III & IV ( withdrawn – June 2006) January 18-21, 2012

5 Satish Mallya January 20-22, |5 | Q1A(R2) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Drug ProductDrug Substance Photostability testingStress testing Selection of batches Container closure system Specification Testing frequency Storage conditions Stability commitment Evaluation Statements/Labeling January 18-21, 2012

6 Satish Mallya January 20-22, |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) January 18-21, 2012

7 Satish Mallya January 20-22, |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. January 18-21, 2012

8 Satish Mallya January 20-22, |8 | Container Closure System Drug ProductDrug 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 January 18-21, 2012

9 Satish Mallya January 20-22, |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 June 2010 January 18-21, 2012

10 Satish Mallya January 20-22, | 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) 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 June 2010 January 18-21, 2012

11 Satish Mallya January 20-22, | 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 25 ⁰ C+2 ⁰ C/ 60%+5%RH or 30 ⁰ C+2 ⁰ C /65% +5%RH 12 monthsLong term 25 ⁰ C+2 ⁰ C /60%+5%RH or 30 ⁰ C+2 ⁰ C /65% +5%RH 12 months Intermediate 30 ⁰ C+2 ⁰ C /65% +5%RH 6 monthsIntermediate 30 ⁰ C+2 ⁰ C /65% +5%RH 6 months Accelerated40 ⁰ C+2 ⁰ C /75% +5%RH 6 monthsAccelerated40 ⁰ C+2 ⁰ C /75% +5%RH 6 months June 2010 January 18-21, 2012

12 Satish Mallya January 20-22, | 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 term5 ⁰ C + 3 ⁰ C12monthsLong term5 ⁰ C + 3 ⁰ C12months Accelerated25 ⁰ C + 2 ⁰ C / 60% + 5% RH 6 monthsAccelerated25 ⁰ C + 2 ⁰ C / 60% + 5% RH 6 months June 2010 January 18-21, 2012

13 Satish Mallya January 20-22, | Storage Conditions Storage in freezer Storage below - 20 ⁰ C : 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 - 20 ⁰ C + 5 ⁰ C12monthsLong term - 20 ⁰ C + 5 ⁰ C12months June 2010 January 18-21, 2012

14 Satish Mallya January 20-22, | Storage Conditions – Drug Product Semi-permeable containers : StudyStorage Conditions Minimum period covered by data at submission Long term 25 ⁰ C+2 ⁰ C/40%+5% RH or 30 ⁰ C+2 ⁰ C/35%+5% RH 12 months Intermediate30 ⁰ C+2 ⁰ C/65%+5% RH6 months Accelerated40 ⁰ C+2 ⁰ C/NMT 25% RH6 months June 2010 January 18-21, 2012

15 Satish Mallya January 20-22, | Significant Change Drug ProductDrug 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 January 18-21, 2012

16 Satish Mallya January 20-22, | Evaluation Drug Substance Drug Product Statistical analysis not necessary if data exhibits little or no degradation and variability Limited extrapolation of real time data permitted with justification June 2010 January 18-21, 2012

17 Satish Mallya January 20-22, | 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 January 18-21, 2012

18 Satish Mallya January 20-22, | Q1C Annex 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 Satish Mallya January 20-22, | Q1D - Bracketing January 18-21, 2012

20 Satish Mallya January 20-22, | Q1D - Matrixing January 18-21, 2012

21 Satish Mallya January 20-22, | Q1D - Matrixing January 18-21, 2012

22 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 January 18-21, 2012

24 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | VALIDATION CHARACTERISTICS Assay Impurities Quant. limit IDValidation characteristics Accuracy Precision Repeatibility Int.Precision Specificity LOD LOQ Linearity Range January 18-21, 2012

27 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | Q3A(R2) January 18-21, 2012

31 Satish Mallya January 20-22, | Q3A(R2) January 18-21, 2012

32 Satish Mallya January 20-22, | Q3B(R2) January 18-21, 2012

33 Satish Mallya January 20-22, | Q3B(R2) January 18-21, 2012

34 Satish Mallya January 20-22, | 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 Acetonitrile Chlorobenzene January 18-21, 2012

35 Satish Mallya January 20-22, | 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 g 400 ppm 0.36 mg Excipient 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | 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 January 18-21, 2012

40 Satish Mallya January 20-22, | 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 Satish Mallya January 20-22, | January 18-21, 2012


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