Description
The guidance stated in the ICH harmonized tripartite guideline entitled “Stability Testing of New Drug Substances and Products” (issued by ICH on October 27, 1993) applies in general to biotechnological/biological products. However, 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. For such products in which the active components are typically proteins and/or polypeptides, maintenance of molecular conformation and, hence, of biological activity, is dependent on noncovalent as well as covalent forces. The products are particularly sensitive to environmental factors such as temperature changes, oxidation, light, ionic content, and shear. To ensure maintenance of biological activity and to avoid degradation, stringent conditions for their storage are usually necessary.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
7Example of a control strategy summary for biological drug substances
Requires analytical comparability per ICH Q5E
Covered by GFI #99
Products for which batch/lot information is particularly important
Circumstance where a mass balance study might not be recommended
General category of products covered by the stability testing guidance.
RTRT and CTD sections apply to drug products
Stakeholders
1Entity submitting development data and knowledge; Entity performing the work process for change
Regulatory Context
Regulatory Activities
1Submissions where clinical trial reports must meet ICH E3 standards.
Document Types
3Defines the standard of veterinary practice and limits for anesthetic regimens
approved design space described in the dossier
Protocol design for formal stability studies; Incorporates information to establish re-test period or shelf life; Design and execution of a stability protocol to support formal studies; Design for supporting drug substance or drug product shelf life; Design of the stability study including frequency and conditions; Written protocol for holding time studies; Design of in-use stability study protocols; Reduced Stability Protocol Design discussed in Annex 1; Including intermediate storage condition
Attributes
6Measurement of potency for biological products
Precisely defined storage temperatures are recommended
specifications for the purity, strength, and composition of dietary supplements
Specified in the product label based on stability studies
Determined based on stability data; Established through stability testing; also called dating period.; Established through formal stability studies; Establishing the period during which a drug product is expected to remain within specifications; Period for drug products; The period during which a drug product is expected to remain within specifications; Duration product remains within acceptance criteria; Period during which product remains within specifications; Established for intermediates pu
CMC changes after tentative approval; shelf-life period supported by stability data; proposing to extend the expiration dating period for the drug product
Technical Details
Substances
9Products composed of well-characterized proteins
A material produced during steps of the synthesis that undergoes further molecular change.
Any component of the drug substance or drug product which is not the active ingredient or excipient
Molecular variants or impurities resulting from chemical or biochemical changes; Shelf Life Estimation Based on a Degradation Product
Active ingredient bound covalently or noncovalently to a carrier
Products composed of well-characterized polypeptides
r-DNA technology used for production
Postapproval changes to drug substances; the active pharmaceutical ingredient being modified; Evaluation of physical properties for drug substance; Active ingredient intended to furnish pharmacological activity; The molecule or ion responsible for the physiological or pharmacological action.; The active pharmaceutical ingredient subject to postapproval changes
CQAs should be evaluated during vaccine stability studies
Testing Methods
9Should be part of pivotal stability studies
sponsors should propose statistical methods that properly account for missing data
Methods for analysis of the molecular entity
study designs generally inappropriate for recombinant protein products
study designs generally inappropriate for recombinant protein products
Analytical method specified in LOINC 2862-7
Includes reversed-phase, gel filtration, and ion exchange chromatography.
Complementary analytical technique
Product-specific sterile process validation question
Processes
7Production method requiring additional information in a notification; Manufacturing process using microorganisms like bacteria or yeast.; Changing conditions to alter the chemical or molecular composition.; ingredients produced using fermentation; information about the organism and fermentation process; relevant to safety and identity of microorganisms; NDI produced by fermentation using microorganisms
Production by a procedure fully representative of manufacturing scale
Manufacture at the scale typically encountered in a facility for marketing
Conducted monthly for the first 3 months
Preferable to rely on purification processes to remove impurities
Physical modification that does not result in chemical alteration.; A process that does not typically chemically alter an ingredient
Automated mixing of drug prior to injection.
Identified Hazards
Hazards
4Environmental factor causing degradation; A chemical degradation change that may occur during storage.
Environmental factor causing degradation
A chemical degradation change that may occur during storage.
Mechanism of product degradation
Standards & References
External Standards
1Standards used to calibrate potency assays across different laboratories.
Specifications
4Limits established for intermediates to assure stability
Distinct release and end of shelf life specifications
Criteria that must be met before product release
Limits derived from analytical profiles of batches used in clinical studies.
ICH References (1)
Quality of Biotechnological Products: Stability Testing
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter