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Q1F Stability Data Package for Registration Applications in Climatic Zones III & IV (withdrawn – June 2006)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
Drug Product
Drug Substance
Photostability testing
Stress testing
Selection of batches
Container closure system
Specification
Testing frequency
Storage conditions
Stability commitment
Evaluation
Statements/Labeling
January 18-21, 2012

6. Stress Testing/Photostability
Drug Product
Drug Substance
One primary batch
As in ICH Q1B:
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. Selection of Batches Drug Substance Drug Product
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. 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
January 18-21, 2012

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
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. 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. Storage Conditions General Case Drug Substance Drug Product Study
Minimum period covered by data at submission
Long term
25⁰C+2⁰C/ 60%+5%RH or
30⁰C+2⁰C /65% +5%RH
12 months
25⁰C+2⁰C /60%+5%RH or
Intermediate
6 months
Accelerated
40⁰C+2⁰C /75% +5%RH
General Case
June 2010
January 18-21, 2012

12. Storage Conditions Storage in refrigerator Drug Substance Drug Product
Study
Storage Conditions
Minimum period covered by data at submission
Long term
5⁰C + 3⁰C
12months
Accelerated
25⁰C + 2⁰C / 60% + 5% RH
6 months
June 2010
January 18-21, 2012

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
Long term
- 20⁰C + 5⁰C
12months
June 2010
January 18-21, 2012

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
June 2010
January 18-21, 2012

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
January 18-21, 2012

16. 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. 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. 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. 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)
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. Outcomes Data not amenable to statistical analysis:
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
Assay
Impurities
Quant limit ID
Validation characteristics + -
Accuracy
Precision
Repeatibility
Int.Precision
Specificity
LOD
LOQ
Linearity
Range
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
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
Concentration limit (ppm)
PDE (mg/day)
Solvent
410
360
4.1
3.6
Acetonitrile
Chlorobenzene
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 ppm mg
Excipient g ppm mg
Excipient g ppm mg
Drug Product g ppm 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. World Health Organization
Q6A Decision Trees
11 April, 2017
#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
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