Stability testing of biotechnological/ biological products (Q5C )
- 2. Introduction Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications Labelling
- 3. OBJECTIVE Biotechnological/biological products have distinguishing characteristics to which consideration should be given in any well-defined testing program designed to confirm their stability during the intended storage period. Maintenance of biological activity dependent on non-covalent, covalent interactions. The products are particularly sensitive to environmental factors such as temperature changes, oxidation, light, ionic content, and shear. In order to ensure maintenance of biological activity and to avoid degradation, stringent conditions for their storage are usually necessary.
- 4. The evaluation of stability may necessitate complex analytical methodologies Physicochemical tests alone are insufficient to characterize the product sufficiently to permit prediction of the biological activity
- 5. SCOPE ICH Q5C applies to well characterized proteins and polypeptides isolated or manufactured by rDNA technology.
- 6. I.DRUG SUBSTANCE Batch selection for a Marketing authorization I. A) Stability data for Drug substance At least 3 batches representative of the manufacturing scale of production "Representative" data: Representative of the quality of batches used in pre-clinical and clinical studies Representative manufacturing process and storage conditions Representative containers
- 7. I. B) Stability data for Drug substance II If shelf life claimed: > 6 months: minimum 6 months data at the time of submission < 6 months: submission data discussed on a case-by-case basis. I. C) Stability data for Drug substance III At the time of Marketing Authorization application, data from pilot-plant scale batches may be submitted. Pilot scale batches should be produced and stored in conditions representative of commercial scale Pilot scale batches should use the same container/closure system A commitment to place the first 3 manufacturing scale commercial batches in a stability program after approval
- 8. Stability data for Intermediates May be critical to the production of finished product Hold time / storage step should be identified Generate in-house data and process limits should be defined Appropriate validation and/or stability study should be performed
- 9. III(A).Stability data for Drug Product (DP) At least 3 batches of the final container product, representative of manufacture scale DP batches should be derived from different batches of Drug substance If shelf life claimed: > 6 months: minimum 6 months data at the time of submission < 6 months: submission data discussed on a case-by- case basis
- 10. III(B).Stability data for Drug Product (II) Shelf life should be derived from representative real time / real conditions data. Data can be provided during the review and evaluation process. “Representative” data: Representative of the quality of batches used in pre- clinical and clinical studies Representative manufacturing process and storage conditions Use final containers
- 11. III(C).Stability data for Drug Product (III) Shelf life will be based upon real time / real storage conditions data submitted for review Pilot scale batches may be submitted, with a commitment to place the first 3 manufacturing scale batches in long term stability program
- 12. Full study design Samples for every combination, all factors included in the design of the stability programmed are tested at all time points Reduced study design* Samples for every combination of all design factors are NOT tested at all time points. Reduced design should be justified scientifically. Type and level of justification depends on available supporting data. Potential risk of establishing shorter shelf life due to more limited data. Matrixing and Bracketing* study designs can be applied to the testing of new drug substances and products.
- 13. Matrixing, i.e., the statistical design of a stability study in which different fractions of samples are tested at different sampling points, should only be applied when appropriate documentation is provided that confirms that the stability of the samples tested represents the stability of all samples. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same closure and possibly, in some cases, different container/closure systems.
- 14. Bracketing i.e., Where the same strength and exact container/closure system is used for 3 or more fill contents, the manufacturer may elect to place only the smallest and largest container size into the stability program. The design of a protocol that incorporates bracketing assumes that the stability of the intermediate condition samples are represented by those at the extremes. In certain cases, data may be needed to demonstrate that all samples are properly represented by data collected for the extremes.
- 15. There is no single stability indicating assay Should be product-specific Should allow the detection of any changes in purity, identity and potency Methods validated at the time of submission
- 16. A detailed protocol for stability of drug products and drug products to support the shelf life and storage conditions Necessary information to demonstrate the stability of the biotechnological / biological product through shelf life The design is critical for the successful establishment of shelf life.
- 17. It is the specific ability or capacity of a product to achieve its intended effect (activity) Based on the quantitative measurement of an attribute The attribute is indicative of the clinical effect Compared to a reference material (calibrated versus an internal, national or international reference material) Potency assays should be part of the stability studies should be presented as units of biological activity calibrated versus International reference standard (e.g. WHO) (if available), or Nationally recognised reference standard, or in-house reference standard
- 18. Purity is a relative term, difficult to determine and method dependent Stability studies: Test for purity should focus on methods for determination of degradation products. More than one method, purity value is method dependent In stability, purity tests should focus on determination of degradation products Limits of acceptable degradation should be derived from the analytical profiles of batches of the drug substance used in preclinical and clinical studies.
- 19. Other characteristics should also be monitored for the drug product in the final container:
- 20. Humidity Products are generally distributed in containers protecting against humidity. If demonstrated that container (& storage conditions) provide sufficient protection against high and low humidity, relative humidities can be omitted. if humidity protecting containers are not used, appropriate data should be provided.
- 21. Temperature most biologicals need precisely defined storage temperatures real time / real temperature studies are confined to the proposed storage temperature. Light case by case basis Accelerated and Stress conditions Shelf life established based on real time / real temperature data
- 22. Accelerated studies supportive to establish shelf life can provide information on post development changes, validation of stability indicating tests generate help to elucidate the degradation profile testing conditions are normally one station higher than real storage conditions Stress studies Representative accidental exposures to other conditions Determination of best product-stability indicators Can reveal patterns of degradation
- 23. Container/closure interactions may occur between product and container/closure data to be supplied for all different container/closure combinations where lack of interactions cannot be excluded -> determine the effect of the closure to be determined (horizontal, upright studies) Additional stability studies In use stability for multidose presentations requirement to demonstrate that the protein retains its full potency, purity and quality taking into account the repeated insertions and withdrawals should be included in labelling Stability after reconstitution of freeze-dried analysis of maximum storage period after reconstitution inclusion in the labelling
- 24. Shelf life biological can vary ICH Guidance is based on a 0.5-5 years shelf life for most biological. The recommended intervals for long term studies in pre-licensing: Post approval, if adequate stability is demonstrated, the applicant can propose a protocol suppressing some time points
- 25. Should consider losses of activity, physicochemical changes, degradation during storage. No specific guidance on product classes. Includes stability indicating parameter Limits of acceptable degradation: justified taking into account levels observed in materials used in non-clinical / clinical studies Shelf-life specification acceptable, where appropriately justified (EU) All test parameters may not be required at all time points
- 26. For most biotechnological/biological drug substances and drug products, precisely defined storage temperatures are recommended. Specific recommendations should be stated, particularly for drug substances and drug products that cannot tolerate freezing. These conditions, and where appropriate, recommendations for protection against light and/or humidity, should appear on containers, packages, and/or package inserts. Such labelling should be in accordance with relevant national/regional requirements.
- 27. Conjugated Product: A conjugated product is made up of an active ingredient (for example, peptide, carbohydrate) bound covalently or non-covalently to a carrier (for example, protein, peptide, inorganic mineral) with the objective of improving the efficacy or stability of the product. Degradation Product: A molecule resulting from a change in the drug substance (bulk material) brought about over time. For the purpose of stability testing of the products described in this guideline, such changes could occur as a result of processing or storage (e.g., by de-amidation, oxidation, aggregation, proteolysis). For biotechnological/biological products some degradation products may be active. Impurity: Any component of the drug substance (bulk material) or drug product (final container product) which is not the chemical entity defined as the drug substance, an excipient, or other additives to the drug product.
- 28. Intermediate: For biotechnological/biological products, a material produced during a manufacturing process which is not the drug substance or the drug product but whose manufacture is critical to the successful production of the drug substance or the drug product. Manufacturing Scale Production: Manufacture at the scale typically encountered in a facility intended for product production for marketing. Pilot-Plant Scale: The production of the drug substance or drug product by a procedure fully representative of and simulating that to be applied at manufacturing scale. The methods of cell expansion, harvest, and product purification should be identical except for the scale of production.