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Regulatory requirements on
Medicine Stability Guidelines
relevant for Stability testing
 Sultan
Ghani
Regulatory Considerations
Guidelines relevant for stability testing
Highlights of new WHO Stability Guidelines
 Regulatory requirements in various
countries
 Pre- and post-marketing requirements
 Guidelines vs Regulations
European Regulatory Agency
 Adopted ICH guidelines, but practical
implementation may differ
 Wide range of other guidelines generated
by the CPMP included in the EU Directives
and Regulations (65/65 EEC, 75/318 EEC,
91/507 EEC)
European Regulatory Agency (cont’d)
 CPMP Guidelines – Stability testing of
existing active substances and related
finished product
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•
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Apply to chemically active substance previously
approved in EU and product, except radiopharmaceuticals or biological
Refer to ICH guidelines on stability testing of new
active substances and products
Consideration on pharmacopoeial monographs
with respect to stability data requirements of
active ingredients
European Regulatory Agency (cont’d)

CPMP Guidelines – Stability testing of existing active
substances and related finished product
•
Two options when data is required:
1.
Two industrial-scale batches
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2.
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Accelerated 40°C ± 2°C 75% RH ± 5%
6-month data
Long-term 25 °C ± 2°C 60% RH ± 5%
6-month data
Three pilot-scale batches, same synthetic route (6month accelerated, 12-month long- term)
For dosage form
6-month accelerated
6-month long-term
European Regulatory Agency
 Other Guidelines
•
CPMP Guidelines: Dry Powder Inhaler
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•
(cont’d)
Declaration of storage conditions for
medicinal products in product
particulars
European Union Requirements for Variations
(changes) related to stability
European Regulatory Agency

(cont’d)
Requirements for variations (changes) related to
stability
•
Three types of variation:
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•
Minor or type 1 (notification)
Major or type 2 (assessment and approval)
Significant changes requiring a new marketing
authorization
Data requirements depend on particular
circumstances. Normal extrapolation of data will
be allowed (e.g. up to two times of real time data
up to a limit of 3 years)
European Regulatory Agency (cont’d)

Requirements for variations (changes) related to stability
•
Specific Examples:

Modification to one or more steps of the same route of
synthesis

3 months of comparative accelerated and long-term
data

Change in synthetic route

3 batches of at least pilot manufacture for 6 months

Changes to the composition of the finished product

6 months data from two pilot-scale batches (LT and
accelerated)

Changes to the immediate packaging of the finished product

6 months data from three pilot-scale batches (LT and
accelerated)
FDA

Stability Testing for Abbreviated New Drug Application (21 CFR
31492 – 31499)
•
Consideration for a reduction in the amount of stability
required for an ANDA as compared to an NDA
•
Dosage forms are classified as simple or not simple
•
For “simple” dosage forms, the requirement is liberal
•
For “not simple” dosage forms, the requirements are less
liberal
FDA (cont’d)
•
Drug Substance (stability submission)

Appropriate referenced DMF

Stability data on pilot-scale batch (restriction on
design, equipment, process with exception of capacity)

For fermentation product, three production batches,
two of which should be generated from different
starter cultures

Stress-testing if not performed previously

Same composition and type of container, closure and
liner, but smaller in size
FDA (cont’d)
•
Drug Product

The ANDA data package is based on various factors,
such as complexity, existence of sufficient information,
etc.

ANDA data package recommendations are

For simple dosage form
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0, 1, 2, 3 months at controlled room temperature
25ºC
Accelerated stability 0, 1, 2 and 3 months
24-month expiry period granted based on
satisfactory accelerated data
A minimum of one batch pilot-scale
Additional stability studies (12 months at
intermediate or long-term data through proposed
expiry date) if significant change in 3-month
accelerated data, expiry date will be determined
based on the available data
FDA (cont’d)
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For complex dosage forms
Requires a modified ICH Q1A stability data package
3-month accelerated stability studies
Long-term stability studies
Expiry date will be determined on long-term
stability data
Minimum three batches according to ICH Q1A
batch size
Additional stability studies (12-month intermediate
or long-term stability) through proposed expiration
date (change in accelerated condition)
Other supportive data
Extension of expiration date is based on at least
three production batches according to the
approved protocol
Canadian Requirements for Generic Drugs
 The stability testing requirements for generic
drugs are the same as for innovator
products. All ICH guidelines are fully
endorsed by Health Canada.
Recommendation

Considering the differences in the regulatory
requirements, it is recommended to develop and
design stability studies according to ICH, so as to
meet all requirements.

In addition to the applicable Regulations and GMP documents,
following are some of the Quality documents that should be
consulted for Stability requirements:
◦ Health Canada (www.hc-sc.gc.ca/hpfb-dgpsa/tpddpt/index_drugs_information_e.html):
 (stay tuned)
◦ FDA (www.fda.gov/cder/guidance/index.htm):
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Stability Testing of Drug Substances and Drug Products (draft, 1998)
Drug Substance - CMC Information (draft, 2004)
Drug Product - CMC Information (draft, 2003)
SUPAC series (IR, MR, SS) (and Q&A Document)
Changes to an Approved NDA/ANDA (04/2004) (and Q&A Document)

In addition to the applicable Regulations and GMP documents, the
following are some of the Quality documents that should be
consulted for Stability requirements:
◦ EU EMEA (www.emea.eu.int/Inspections/QWPhome.html):
 Manufacture of the Finished Dosage Form
Annex - Start of Shelf -Life of the Finished
Dosage Form (05/2001)
 Maximum Shelf-Life for Sterile Products after
First Opening or Following Reconstitution
(01/1998)
 Stability Testing of Existing Active
Substances and Related Finished Products
(12/2003)
 Stability Testing Annex - Declaration of
Storage Conditions for Medicinal Products
Particulars and Active Substances (04/2003)
 Stability Testing Annex - In-Use Stability
Testing of Human Medicinal Products
(02/2001)
 Stability Testing for a Type II Variation to a
Marketing Authorisation (04/1998)
 Stability Testing for Active Substances and
Medicinal Products Manufactured in Climatic
Zones III and IV to be Marketed in the EU
(draft 02/2004)
 Stability Testing for Applications for
Variations to a Marketing Authorisation (draft
04/2004)
3.11. Stability testing
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Lots included in the study: 1 production batch and 2 of pilot scale
manufactured according to the process described in the dossier
Pilot scale batch for solid dosage forms is 10% of production scale
or
100 000 whichever is greater
Parameters susceptible to change over storage should be followed:
Organoleptic properties
Assay of each API: ±10% of the label claim possible at the end of
shelf-life
Assay of degradation products
Assay of antioxidants and chemical preservatives, check also for
their efficacy
Dissolution testing (limits should remain unchanged to release)
Microbial contamination, sterility, bacterial endotoxins
In-use stability data (if applicable)
3.11. Stability testing
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Study should be performed in the claimed commercial
packaging (container-closure)
Storage conditions and frequency of testing according to
ICH Q1A(R2)
Minimum stability data to be submitted at time of
submission: 12 months long term 30°C/65% RH and 6
months accelerated 40°C/75% RH with exception according
to Supplement 2 to the Main Generic guide
Unless otherwise justified, 30°C / 65% RH is the
recommended storage condition for Prequalification
Definition of "significant change" is the same as ICH Q1A
(R2)
see later slide
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Zone IVa: 30oC and 65% RH (hot & humid
condition).
Zone Ivb 300C and 75% RH (hot & very humid
conditions).
Store at temperature not 30oC in a dry place.
Protect from light.