Regulatory Requirements Related to Stability Testing

Regulatory requirement related to Stability Testing

STABILITY: "The capacity of a drug product to remain within specifications established to ensure its identity, strength, quality and purity".

PURPOSE OF STABILITY STUDY: To provide evidence of how the quality of drug substances or products varies with time

under the influence of environmental factors. (temperature, humidity and light) To establish a re-test period for the drug substances or the shelf-life for the drug

products and recommended storage conditions. To ensure that drug products retain their full efficacy until the end of their expiration

date.

Most important guidelines are Food and Drug Administration (FDA) International Conference on Harmonization (ICH) European Union Guidelines (EU) Japanese Guidelines (MHW) World Health Organization (WHO) Guidelines

Currently ICH guidelines are most commonly accepted which provides information on stability testing within the areas of European Union (EU), Japan, and United States.

Overview of ICH guideline for stability testing...

Q1A (R2)

Stability Testing in New Drugs and Products (Revised guideline)

Q1B

Photo-Stability Testing

Q1C

Stability testing: New Dosage Forms

Stability

Q1D

Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products

Q1E

Evaluation of Stability Data

Q1F

Stability Data Package for Registration in Climatic Zones III and IV

Q2A Analytical validation

Q2B

Definitions and Terminology Methodology

Q3A

Impurity Testing in New Drug Substances

Impurities

Q3B

Impurities in Dosage Forms: Addendum to the Guideline on Impurities in New Drug Substances

Q3C

Impurities: Residual Solvents

Pharmacopeias

Q4

Biotechnology

Q5A

Quality Q5B

Q5C

Q5D

Specification

Q6A

Q6B

GMP

Q7A

Development

Q8

Management

Q9

Pharmacopeial harmonization Viral Safety Evaluation Genetic Stability Stability of Biotechnology Products Cell Substrates Specifications, Test Procedures, and Acceptance Criteria for New Drug Substances and Products Biotechnological substance GMP for active pharmaceutical ingredients

Pharmaceutical development Quality Risk Management

STABILITY GUIDELINE EFFICACY GUIDELINES

S1(A) S1(B) S1(C)

S2A

S2B S(3A) S(3B)

S4 S5

S6

S7

S8

E1 E2(A) E2(B) E2C

Guidelines on The Need For Carcinogenicity studies of pharmaceuticals

Testing for carcinogenicity of pharmaceuticals Dose selection for carcinogecity studies of pharmaceuticals Guidance on specific aspect of regulatory genotoxicity test for pharmaceuticals Standard for genotoxicity testing for pharmaceuticals Note for guidance on Toxicokinetics

Pharmacokinetic:- Guidance for repeated dose tissue distribution studies

Duration of Chronic Toxicity testing in Animals Detection of Toxicity To Reproduction for

Medicinal product and toxicity to male fertility Preclinical Safety Evaluation Of Biotechnology

derived Pharmaceuticals Safety Pharmacology studies for Human

Pharmaceuticals Immunotoxicity studies for Human

Pharmaceuticals

The Extent of Population Exposure to Assess clinical Safety

Clinical safety Data management Implementation working group Clinical safety Data management :- periodic safety

MULTIDISCIPLINEGUIDELINES

E2(D) E2(E) E2(F)

E3 E4

E5 E6 E7 E8 E9 E10

E11

E12

E13

M1

M2

M3

update reports & marketed drugs Post aproval safety data manegemant :Definations and Standards for expedited reporting

Pharmacovigillance Planning Development safety update report Structure and content of clinical study reports Dose response Information to support drug

regisitration Ethnic factors in the acceptability of foreign

clinical data Guideline for Good Clinical Practice Studies in support of Specific Population General Consideration For Clinical Trials Stastical Principles For Clinical Trials Clinical Investigation of medicinal products In The

Pediatric population Principles Of Clinical Evaluation of New Anti-

hypertensive drugs The Clinical Evaluation of proarrythmic potential

for Non-Antiarrythmic drugs Definations of genomic biomarkers, pharmacoecononomics, pharmacogenetics, Genomic DATA & sample coding categories Maintenance of The ICH Guideline on non-clinical safety studies for the conduct of human clinical

trials for pharmaceuticals Electronic Transmission of Individual Case Safety

Reports Message Specification Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human

Use

INTERNATIONAL CLIMATIC ZONES AND CLIMATIC CONDITIONS

Climatic Condition

Zone I Temperate

Zone II Mediterranean (sub-tropical)

Zone III Hot/dry or Hot/moderate

RH

Zone IV Very

hot/humid

Mean Annual < 20?C Temperature

20.5-24?C

>24?C

>24?C

Kinetic Mean 21?C

26?C

Temperature

(Virtual

temperature)

31?C

31?C

Mean Annual 45%

60%

Relative

Humidity

40%

70%

REQUIREMENT OF TEMPERATURE DEPENDED ON TYPE OF TESTING

TYPE OF STUDY

Long term Intermediate Accelerated

TEMPERATURE

25?C ? 2?C 30?C? 2?C 40?C? 2?C/

RELATIVE HUMIDITY /60% RH ? 5% RH /65% RH ? 5% RH 75% RH ? 5% RH

TIME DURATION

12 months 6 months 6 months

DIFFERENT TEMPERATURE REQUIREMENT DEPEND UPON TYPE OF DOSAGE FORMS

FOR DISTINCT PRODUCTS

Solid oral DF, solids for reconstitution, dry

&lyophilized powders in glass vials

Liquids in glass bottles ,vials, sealed glass

ampoules which provide an impermeable barrier to water loss

Drug products in semipermeable containers

AST

40?C ? 2?C 75 % ? 5%RH

40?C ? 2?C Ambient Humidity

40?C ? 2?C NMT 25 %

RH

TYPE OF STUDY

IST

40?C?2?C 75 % ? 5% RH

30?C?2?C Ambient humidity

30?C?2?C 65 % ? 5%

RH

LST

40?C?2?C 75 % ? 5% RH

25?C?2?C Ambient Humidity

25?C?2?C 40 % ? 5% RH Or 30?C?2?C 35 % ? 5% RH

SUPAC GUIDELINES

1) Stability Testing for New Drug Applications(NDA) A. Drug Substance B. Drug Product

2) Stability Testing for Abbreviated New Drug Applications(ANDA)

A. Drug Substance Stability Data Submission Supporting information may be provided directly to the drug product ANDA or by reference to an appropriately referenced drug master file (DMF). For ANDA bulk drug substances- on a minimum of one pilot-scale batch. ANDA bulk drug substances produced by fermentation- on three production batches, at least two of which should be generated from different starter cultures.

B. Drug Substance Testing

 A program for stability assessment may include storage at accelerated, long-term, and, if applicable, intermediate stability study storage conditions (refer to IV.G. of the ICH Q1A Guidance and Section II.A. of this guidance).

C. Drug Product As per ICH Q1 A [Section II.B.]

D. ANDA Data Package Recommendations Accelerated stability data at 0, 1, 2, and 3 months. A tentative expiration dating period of upto 24 months will be granted based on satisfactory accelerated stability data unless not supported by the available long-term stability data. Long-term stability data Additional stability studies accelerated stability study.

E. Stability Study Acceptance

3) Stability Testing For Investigational New Drug Applications

The amount of information needed to achieve that assurance will vary with o The phase of the investigation, o The proposed duration of the investigation, o The dosage form.

A. General Supportive stability data for changes to an approved drug application (i.e. post approval changes) required . If change does not alter the stability of the drug product, the previously approved expiration dating period can be used. But now SUPAC-IR, MR , SS guidance are followed for stability studies . Provides 5 stability data package types .

B. Change in Manufacturing Process of the Drug Substance Carried out at approved manufacturing site . Should be supported by the submission of sufficient data to show that such change does not compromise the quality , purity , or stability of the drug substance and the resulting drug product Special concerns are there for biological products.

C. Change in Manufacturing Site Site changes consists of change in location site of :

Manufacture Packaging operations Analytical testing laboratory both of company owned and contract

manufacturing. Sufficient data to show that such a change does not alter the characteristics or

compromise the quality, purity, or stability of the drug substance or drug product may be necessary. The data should include a side-by-side comparison of all attributes to demonstrate comparability and equivalency of the drug substance or drug product manufactured at the two facilities. New manufacturing locations should have a satisfactory cGMP inspection. D. Change in Formulation of the Drug Product Historically, all changes in drug product formulation were grouped together and required extensive stability documentation, usually submitted as a prior-approval supplement.

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