Stability zones and ich guideline q5c

ICH GUIDELINE FOR BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS (Q5C)

1. KARNATAKA COLLEGE OF PHARMACY ADVANCED PHARMACEUTICAL ANALYSIS CHAPTER: 05 STABILITY ZONES HOD: Dr. C. SREEDHAR PRESENTED BY: KSHITIZ K. GAUND 1 1

2. INTRODUCTION STABILITY THEORITICAL CONSIDERATION FACTORS AFFECTING STABILITY OBJECTIVE TYPES OF STABILITY REGULATORY REQIREMENTS ICH GUIDELINES FOR BIOLOGICAL AND BIOTECNOLOGICAL PRODUCTS 1 2 CONTENTS

3. Drug stability refers to the capacity of a drug substance or product to remain within established specification of identity, strength, quality and purity in specified period of time. Stability is officially defined as the time lapse during which the drug product retains the same properties and characteristics that it possessed at the time of manufacture. The stability of a product is expressed as the expiry period or technically as shelf life. 1 3 INTRODUCTION

4. It is defined as the time required for the concentration of the reactant to reduce to 90% of its initial concentration . It is represented as t90 and the units of time/sec. t90 = (a-0.9a)/k ο Where, a = initial concentration k ο = specific rate constant for zero order reaction. The time from the date of manufacture and packaging of the formulation until its chemical or therapeutic activity is maintained to a predetermined level of labelled potency and, its physical characteristic have not changed appreciably or deleteriously. 1 4 SHELF LIFE

5. The primary factors effecting stability: pH, temperature, moisture, humidity, light, storage, closure, containers and oxygen. The major factors affecting drug stability are; particle size (suspension and emulsion), pH, additives, and molecular binding, and diffusion of drugs and excipients . 1 5 Factors affecting drug stability

6. To determine maximum expiration date/ shelf life To provide better storage condition. To determine the packaging components To gather information during pre formulation stage to produce a stable product. 1 6 OBJECTIVES

7. Therapuetical stability Physical stability Chemical stability Microbiological stability Toxicological stability 1 7 TYPES OF STABILITY

8. Accelerated stability testing Long term testing Stress testing Photo stability study 1 8 TYPES OF STABILITY STUDY

9. Four climate zones can be distinguished for the purpose of worldwide stability testing as follows : 1 9 CLIMATE ZONE ZONE TYPE OF CLIMATE ZONE I Temperate zone ZONE II Subtropical zone ZONE III Hot and dry zone ZONE IV Hot humid tropical zone

10. International conference harmonization (ICH) World Health Organisation (WHO) US Food and D rug Administration (FDA) European Medicine Agency 1 10 REGULATORY BODIES

11. Q1A(R2) – Stability testing of new drug substances and products. Q1B – Photo stability Testing of new drug substance and products. Q1C – Stability testing for new dosage forms. Q1D – Bracketing and matrixing design for stability of new drug substance and products. 1 11 ICH GUIDELINE FOR STABILITY STUDIES

12. Q1E – Evaluation of stability data Q1F – Stability data package for registration. Application in climatic zones III and IV. Q5C- Stability testing of biotechnological /biological products. 1 12 CONTINUE

13. CONTENTS Preamble Scope of annex Terminology Selection of batches Stability indicating profile Storage conditions Testing frequency Specifications Labelling Glossary 1 13 ICH GIDELINES FOR BIOLOGICAL PRODUCTS (Q5C)

14. In ICH guideline, stability testing of new drugs and products applies in general to biotechnological and biological products. Despite, an extra consideration has to be taken since these products have distinguishing properties over the storage period of time. The products includes bio-molecules, proteins, polypeptides which needs specific testing for the stability consideration. 1 14 1. PREAMBLE

15. The guidance in the annex applies to well characteristics proteins, polypeptides, their derivatives and products of which they are the components and which are isolated from tissues, body fluids, cell culture or produced using rDNA technology. 1 15 2. SCOPE OF THE ANNEX

16. Thus, the documents covers the generation and submission of stability data for products such as cytokines (interferon, interleukins, colony stimulating factor, tumor necrosis factors), erythropoietin, plasminogen activators, blood plasma factors, growth hormone and growth factors, insulin, monoclonal antibodies, vaccines consisting of well characterized proteins and polypeptides. 1 16 CONTINUE…

17. The reader are referred to the glossary in the ICH harmonized tripartite guideline for stability testing of new drugs and products. However, manufacturer sometimes use traditional terminology, terms as specified in the parenthesis to assist the reader. A supplement glossary is also included that explains certain terms used in the production of biotechnological /biological products. 1 17 3. TERMINOLOGY

18. 4.1. DRUG SUBSTANCE(BULK MATERIAL) A bulk material after the manufacture has to be stored however prior to formulation and manufacture. Stability data should be provided on at least 3 batches for which manufacture and storage are representative of the manufacturing scale of production. A minimum of six months stability data at the time of submission should be submitted in cases where storage periods are greater than 6 months are requested. 1 18 4. SELECTION OF BATCHES

19. For a drug substance with storage periods of less than 6 months minimum amount of stability data in the initial submission should be determined on case by case basis. Data from pilot plant scale batches of drug substance produced at a reduced scale of fermentation and purification may be provided at the time the dossier is submitted to regulatory agencies with the commitment to place the 1 st three manufacturing scale batches into the long stability program. 1 19 Continue….

20. During manufacture of biotechnological/ bioligical products, the quality and control of intermediates may be critical to the production of the final product. In general, manufacturer should identify intermediates and generate in house data and process limits that assures their stability within the bounds of the developed process. While the pilot plant scale data is permissible, the manufacturer establish the suitability of such data using manufacturing scale process. 1 20 4.2 INTERMEDIATES

21. Stability information should be provided on at least 3 batches of final container product representative of that which will be used in manufacturing scale. A minimum of six months data at the time of submission should be submitted in cases when storage periods greater than six months are requested. 1 21 4.3 STABILITY PRODUCT (FINAL CONTAINER PRODUCT)

22. For drug products with storage periods less than 6 months, the minimum amount of stability data in the initial should be determined in a case by case studies. Product expiration dating will be based upon the actual data the actual data submitted in support of the application. The quality of the final container product placed on stability studies should be representative of the quality of material used in preclinical and clinical studies. 1 22 CONTINUE…

23. Where one product is distributed in batches differing in fill volumes ( eg ; 1 ml, 2 ml, 10 ml), unitage 10 units, 20 units, or 50 units) or mass ( eg ; 1 mg, 2 mg, 5 mg) samples to be entered into the suitability program may be selected on the basis of a matrix system and /or by bracketing. 1 23 4.4 SAMPLE SELECTION

24. On the whole, there is no single stability – indicating assay or parameter that profiles the stability characteristics of a biotechnological/biological products. Consequently, the manufacturer should propose a stability indicating profile that provides assurance that changes in the identity, purity, and potency of the product will be detected. At the time of submission applicants should have validated the method that comprise the stability indicating profile and the data should be available for the review. 1 24 5. STABILITY INDICATING PROFILE

25. The dossier accompanying the application for marketing authorization should include a detailed protocol for the assessment for the stability of both drug substance and drug product. 1 25 5.1 PROTOCOL

26. Potency studies are to be performed at appropriate intervals as defined in the stability protocol and the results should be represented in units of biological activity calibrated, whenever possible, against nationally and internationally standards. 1 26 5.2 POTENCY

27. For the purpose of stability testing of the products described in the guideline, purity is a relative term. Due to the effect of glycosylation, deamination or other heterogeneities, the absolute purity of a biotechnological/biological product should be typically assessed by more than one method and the purity value desired is method dependent. For the purpose of stability testing, tests for purity should focus on methods for determination of degradation products. 1 27 5.3 PURITY AND MOLECULAR CHARACTERISATION

28. 6.1 TEMPERATURE Since most finished biotechnological/biological products need precisely defined storage temperatures, the storage conditions for the real time/real-temperature stability studies may be confined to the proposed storage temperature. 1 28 6 . Storage conditions

29. Biotechnological/biological products are generally distributed in containers protecting them against humidity. Therefore, where it can be demonstrated that the proposed containers (and conditions of storage) afford sufficient protection against high and low humidity, stability tests at different relative humidities can usually be omitted. Where humidity protecting containers arw not used, appropriate stability data should be provided. 1 29 6.2 HUMIDITY

30. Studies under accelerated and stress conditions may provide useful support data for establishing the expiration date, provide product stability information for future product development. 1 30 6.3 ACCELERATED AND STRESS CONDITION

31. Applicants should consult the appropriate regulatory authorities on a case by case basis to determine guidance for testing. 6.5 CONTAINER CLOSURE The interaction of the product and container should not result into degradation of product. Hence, a proper consideration has to be undertaken to maintain the stability of the product. 1 31 6.4 LIGHT

32. The shelf lives of biotechnological/biological may vary days to several years. Thus, it is difficult to draft uniform guideline regarding the stability study duration and testing frequency that would be applicable to all biotechnogical and biological products. However with few exceptions it is considered 0 tp 5 years. When self lives of 1 year or less is proposed, the real time stability studies should be conducted monthly for the first 3 months and at at 3 months intervsn thereafter. 1 32 7. Testing frequency

33. For the product with proposed shelves life more than 1 year, the studies should be conducted every three months during the first year of storage, every six months during the second year and thereafter. 1 33 CONTINUE…

34. Precisely, definite temperture storage are recommended. Specific recommendation should be stated, particularly to those drug products and drug substances that cannot tolerate freezing. 1 34 LABELLING

35. Degradation product Impurity Manufacturing scale production Pilot plant scale 1 35 Other factors

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