ICH GUIDELINE FOR BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS (Q5C)

1. ADVANCED PHARMACEUTICAL ANALYSIS
CHAPTER: 05
STABILITY ZONES
HOD: Dr. C. SREEDHAR
PRESENTED BY: KSHITIZ K. GAUND
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2.  INTRODUCTION
 STABILITY THEORITICAL CONSIDERATION
 FACTORS AFFECTING STABILITY
 OBJECTIVE
 TYPES OF STABILITY
 REGULATORY REQIREMENTS
 ICH GUIDELINES FOR BIOLOGICAL AND
BIOTECNOLOGICAL PRODUCTS
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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.
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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)/kο
Where, a = initial concentration
kο = 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.
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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.
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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.
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7.  Therapuetical stability
 Physical stability
 Chemical stability
 Microbiological stability
 Toxicological stability
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8.  Accelerated stability testing
 Long term testing
 Stress testing
 Photo stability study
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9.  Four climate zones can be distinguished for the
purpose of worldwide stability testing as follows :
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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 Drug Administration (FDA)
 European Medicine Agency
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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.
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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.
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13.  CONTENTS
 Preamble
 Scope of annex
 Terminology
 Selection of batches
 Stability indicating profile
 Storage conditions
 Testing frequency
 Specifications
 Labelling
 Glossary
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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.
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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.
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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.
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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.
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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.
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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 1st
three manufacturing scale batches into the long stability
program.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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34.  Precisely, definite temperture storage are
recommended.
 Specific recommendation should be stated, particularly
to those drug products and drug substances that cannot
tolerate freezing.
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35.  Degradation product
 Impurity
 Manufacturing scale production
 Pilot plant scale
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