2-4 ICH Quality Guidances:

an overview

PQP Assessment Training

January 18-21, 2012

Satish Mallya

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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
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2010 January20-22, 18-21, 2012 Satish Mallya January

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)

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Stability
Q1A(R2) Q1B Stability Testing of New Drug Substances and Products Photostability Testing of New Drug Substances and Products

Q1C
Q1D Q1E Q1F

Stability Testing for New Dosage Forms

Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Evaluation of Stability Data Stability Data Package for Registration Applications in Climatic Zones III & IV (withdrawn June 2006)

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Q1A(R2)
STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

Drug Substance
Stress testing Selection of batches Container closure system Specification Testing frequency Storage conditions

Drug Product
Photostability testing Selection of batches Container closure system Specification Testing frequency Storage conditions

Stability commitment
Evaluation Statements/Labeling

Stability commitment
Evaluation Statements/Labeling

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Stress Testing/Photostability
Drug Substance Drug Product

One primary batch Effect of temperatures (in 10C increments (e.g., 50C, 60C, etc.) above that for accelerated testing) Effect of humidity (e.g., > 75%RH)

One primary batch As in ICH Q1B:

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Selection of Batches
Drug Substance Drug Product

Data on at least three primary batches of minimum pilot scale manufactured by the same synthetic route as used for production batches.

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.

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Container Closure System

Drug Substance Drug Product

Studies to be conducted on the API packaged in a container closure system that is identical to or simulates the proposed commercial packaging

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Specification
Drug Substance
Studies to include attributes susceptible to change during storage and which can influence quality, safety and efficacy: - Physical - Chemical - Microbiological

Drug Product
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

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

Testing Frequency
Drug Substance
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. 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

Drug Product
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) Matrixing or Bracketing may be applied

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

Storage Conditions
General Case
Study

Drug Substance
Minimum period covered by data at submission 12 months Study

Drug Product
Storage Conditions Minimum period covered by data at submission 12 months

Storage Conditions

Long term

25C+2C/ 60%+5%RH or 30C+2C /65% +5%RH 30C+2C /65% +5%RH 40C+2C /75% +5%RH

Long term

25C+2C /60%+5%RH or 30C+2C /65% +5%RH 30C+2C /65% +5%RH 40C+2C /75% +5%RH

Intermediate

6 months

Intermediate

6 months

Accelerated

6 months

Accelerated

6 months

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

Storage Conditions
Storage in refrigerator
Drug Substance
Study Storage Conditions Minimum period covered by data at submission
12months

Drug Product
Study Storage Conditions Minimum period covered by data at submission
12months

Long term

5C + 3C

Long term

5C + 3C

Accelerated

25C + 2C / 60% 6 months + 5% RH

Accelerated

25C + 2C / 60% 6 months + 5% RH

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

Storage Conditions
Storage in freezer
Drug Substance
Study Storage Conditions Minimum period covered by data at submission 12months Study

Drug Product
Storage Conditions Minimum period covered by data at submission 12months

Long term

- 20C + 5C

Long term

- 20C + 5C

Storage below - 20C : Case by case basis

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

Storage Conditions Drug Product

Semi-permeable containers :
Study Storage Conditions Minimum period covered by data at submission
12 months

Long term

25C+2C/40%+5% RH or 30C+2C/35%+5% RH 30C+2C/65%+5% RH 40C+2C/NMT 25% RH

Intermediate

6 months

Accelerated

6 months

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

Significant Change
Drug Substance
Defined as failure to meet specifications

Drug Product
->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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Evaluation
Drug Substance
Statistical analysis not necessary if data exhibits little or no degradation and variability

Drug Product
Statistical analysis not necessary if data exhibits little or no degradation and variability

Limited extrapolation of real time data Limited extrapolation of real time data permitted with justification permitted with justification

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

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

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Q1C Annex to Q1A (R2)

Additional guidance on line extensions
Reduced requirements at time of filing: 6 months accelerated and 6 months long term

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Q1D - Bracketing

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Q1D - Matrixing

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Q1D - Matrixing

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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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

Outcomes
When there is no significant change under accelerated conditions (RT)
Long-term and accelerated data showing little or no change over time and little or no variability Long-term or accelerated data showing change over time and/or variability Retest period or shelf life can be up to twice, but NMT 12 months beyond the period covered by long-term data 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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

VALIDATION CHARACTERISTICS
Validation characteristics
Accuracy Precision Repeatibility Int.Precision Specificity LOD LOQ Linearity Range

ID

Impurities

Assay

Quant.
+ + + + + + + +

limit
+

+ + -

+ + + + +

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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)

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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Q3A(R2)

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Q3A(R2)

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Q3B(R2)

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Q3B(R2)

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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.
Solvent PDE (mg/day) Concentration limit (ppm)

Acetonitrile

4.1

410

Chlorobenzene

3.6

360

If TDI is more than 10 g use option 2

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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 exposure

Amount in formulation
0.3 g 0.9 g 3.8 g 5.0 g

Acetonitrile content
800 ppm 400 ppm 800 ppm 728 ppm

Daily
0.24 mg 0.36 mg 3.04 mg 3.64 mg

Drug substance Excipient 1 Excipient 2 Drug Product

The sum of the amounts of solvent per day should be less than that given by the PDE.

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21, 2012 Satish Mallya January

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

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20-22, 2010 January 18-21 2012 January 18-21, 2012 Satish Mallya January

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)

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