2-4 ich overview

Satish Mallya January 20-22, 2010

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2-4 ICH Quality Guidances:an overview

PQP Assessment Training

January 18-21, 2012

Satish Mallya

January 18-21, 2012

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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


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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) & Q6B (Biotechnology/Biological Products)

January 18-21, 2012


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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Applications in Climatic Zones III & IV (withdrawn – June 2006)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


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Q1A(R2) STABILITY TESTING OF

NEW DRUG SUBSTANCES AND PRODUCTS

Drug SubstanceDrug ProductStress testingPhotostability testing

Selection of batchesSelection of batches

Container closure systemContainer closure system

SpecificationSpecification

Testing frequencyTesting frequency

Storage conditionsStorage conditions

Stability commitmentStability commitment

EvaluationEvaluation

Statements/LabelingStatements/Labeling

January 18-21, 2012


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Stress Testing/Photostability

Drug Substance Drug Product

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)

One primary batch

As in ICH Q1B:

January 18-21, 2012


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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.

January 18-21, 2012


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Container Closure System

Drug SubstanceDrug 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

January 18-21, 2012


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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

June 2010January 18-21, 2012


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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

June 2010January 18-21, 2012


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Storage Conditions

General Case Drug Substance

Drug Product

StudyStorage Conditions

Minimum period covered by data at submission



Long term25⁰C+2⁰C/ 60%+5%RH or30⁰C+2⁰C /65% +5%RH

12 monthsLong term25⁰C+2⁰C /60%+5%RH or30⁰C+2⁰C /65% +5%RH

12 months

Intermediate

30⁰C+2⁰C /65% +5%RH

6 monthsIntermediate

30⁰C+2⁰C /65% +5%RH

6 months

Accelerated

40⁰C+2⁰C /75% +5%RH

6 monthsAccelerated

40⁰C+2⁰C /75% +5%RH

6 months

June 2010January 18-21, 2012


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Storage Conditions

Storage in refrigerator Drug Substance

Drug Product





Long term5⁰C + 3⁰C12monthsLong term5⁰C + 3⁰C12months

Accelerated

25⁰C + 2⁰C / 60% + 5% RH

6 months Accelerated

25⁰C + 2⁰C / 60% + 5% RH

6 months

June 2010January 18-21, 2012


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Storage Conditions

Storage in freezer

Storage below - 20⁰C : Case by case basis

Drug Substance

Drug Product





Long term

- 20⁰C + 5⁰C

12monthsLong term

- 20⁰C + 5⁰C

12months

June 2010January 18-21, 2012


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Storage Conditions – Drug Product

Semi-permeable containers :StudyStorage

ConditionsMinimum period covered by data at submission

Long term25⁰C+2⁰C/40%+5% RH or30⁰C+2⁰C/35%+5% RH

12 months

Intermediate30⁰C+2⁰C/65%+5% RH6 months

Accelerated40⁰C+2⁰C/NMT 25% RH6 months

June 2010January 18-21, 2012


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Significant ChangeDrug SubstanceDrug Product Defined as failure to meet specifications

->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 unitsJanuary 18-21,

2012


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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

June 2010January 18-21, 2012


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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


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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

January 18-21, 2012


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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

January 18-21, 2012


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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

Retest period or shelf life can be up to twice, but NMT 12 months beyond the period covered by long-term data

Long-term or accelerated data showing change over time and/or 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

January 18-21, 2012


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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


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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


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VALIDATION CHARACTERISTICS

Validation characteristics

ID Impurities

Quant. limit

Assay

Accuracy

Precision

Repeatibility

Int.Precision

Specificity

LOD

LOQ

Linearity

Range

-

-

-

+

-

-

-

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+ -

+ -

+ -

+ +

- +

+ -

+ -

+ -

+

+

+

+

-

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+

+

January 18-21, 2012


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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


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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


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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


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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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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

SolventPDE (mg/day)Concentration limit (ppm)

Acetonitrile

Chlorobenzene

4.1

3.6

410

360

January 18-21, 2012


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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 productExample: PDE of acetonitrile is 4.1mg/dayComponent 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


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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


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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


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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


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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 2012January 18-21, 2012


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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


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January 18-21, 2012

2-4 ich overview

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