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

• Apply to chemically active substance previously approved in EU and product, except radio-pharmaceuticals 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 Accelerated 40°C ± 2°C 75% RH ± 5%

6-month data Long-term 25 °C ± 2°C 60% RH ± 5%

6-month data2. Three pilot-scale batches, same synthetic

route (6-month accelerated, 12-month long- term)

• For dosage form6-month accelerated6-month long-term

European Regulatory Agency (cont’d) Other Guidelines

• CPMP Guidelines: Dry Powder Inhaler

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:

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

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) 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/tpd-dpt/index_drugs_information_e.html): (stay tuned)

◦ FDA (www.fda.gov/cder/guidance/index.htm): 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 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 propertiesAssay of each API: ±10% of the label claim possible at the end of shelf-lifeAssay of degradation productsAssay of antioxidants and chemical preservatives, check also for their efficacyDissolution testing (limits should remain unchanged to release)Microbial contamination, sterility, bacterial endotoxins

In-use stability data (if applicable)

3.11. Stability testing 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

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.