1. Regulatory requirements on Medicine Stability Guidelines relevant for Stability testing
Sultan Ghani

2. Focus of The Presentation
Regulatory Considerations
Guidelines relevant for stability testing
Highlights of new WHO Stability Guidelines

3. Regulatory Considerations
Regulatory requirements in various countries
Pre- and post-marketing requirements
Guidelines vs Regulations

4. Regulatory Considerations (cont’d)
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)

5. Regulatory Considerations (cont’d)
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

6. Regulatory Considerations (cont’d)
European Regulatory Agency (cont’d)
CPMP Guidelines – Stability testing of existing active substances and related finished product
Two options when data is required:
Two industrial-scale batches
Accelerated 40°C ± 2°C 75% RH ± 5%
6-month data
Long-term 25 °C ± 2°C 60% RH ± 5%
Three pilot-scale batches, same synthetic route (6-month accelerated, 12-month long- term)
For dosage form
6-month accelerated
6-month long-term

7. Regulatory Considerations (cont’d)
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

8. Regulatory Considerations (cont’d)
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)

9. Regulatory Considerations (cont’d)
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)

10. Regulatory Considerations (cont’d)
FDA
Stability Testing for Abbreviated New Drug Application (21 CFR – 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

11. Regulatory Considerations (cont’d)
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

12. Regulatory Considerations (cont’d)
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

13. Regulatory Considerations (cont’d)
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

14. Regulatory Considerations (cont’d)
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.

15. Regulatory Considerations (cont’d)
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.

16. GUIDELINES RELEVANT FOR STABILITY TESTING

17. Other Reference Documents
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 ( dpt/index_drugs_information_e.html):
(stay tuned)
FDA (
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)

18. Other Reference Documents
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 (
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)

19. Highlights of new WHO Stability Guidelines

20. Quality dossier / Section 3: Finished Pharmaceutical Product (FPP)
World Health Organization
19 April, 2017
Quality dossier / Section 3: Finished Pharmaceutical Product (FPP)
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 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)
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

21. Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)
World Health Organization
19 April, 2017
Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

22. Climatic Zone IV 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.

23. Thank you Sultan Ghani Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate (TPD), Health Canada Phone: Fax: