Description
The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Q1 Stability Testing of Drug Substances and Drug Products.” The draft guidance was prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The draft guidance outlines stability data expectations for drug substances and drug products to support drug product marketing, including marketing authorization applications and, where applicable, drug master files. This draft guidance is a consolidated revision of the ICH Q1A(R2), Q1B, Q1C, Q1D, Q1E, and Q5C series of stability guidances, published November 2003, March 1996, May 1997, January 2003, June 2004, and July 1996, respectively. The revision also provides stability related guidance for product categories such as advanced therapy medicinal products, vaccines, and other complex biological products including combination products that were not previously covered under the existing stability guidances. The draft guidance is intended to provide an internationally harmonized approach to conducting and presenting data on stability testing for drug substances and drug products, as well as providing alternative, scientifically justified approaches that may be encountered due to scientific considerations and characteristics of the data being evaluated.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
10Scope of the analytical procedures
ATMPs involving structural or functional tissue repair.
A category of ATMPs involving cell-based products.
A type of ATMP involving recombinant nucleic acids or viral vectors.
May obey humidity modified Arrhenius equation
Example 1 – Reduction from Primary Stability Study to the Commitment Study
Advanced Therapy Medicinal Products
Requires analytical comparability per ICH Q5E
Extrapolation rules for well characterised biologicals; Less amenable to modelling by humidity modified Arrhenius equation
Decision tree for data evaluation and shelf life estimation
Stakeholders
3Entity submitting development data and knowledge; Entity performing the work process for change
Early engagement recommended for novel model types
Regulatory body receiving proposed actions
Regulatory Context
Regulatory Activities
8Submission for product approval
Introduction of reduced protocols after original approval.
Changes to manufacturing or product after initial approval; risk-based reduced protocol is used to support a post-approval change
Studies conducted post-approval to confirm shelf life
The first filing of stability data for approval
Stability package provided to support re-test period or shelf life; Initial filing requiring stability data; Initial filing where photostability information is required; Stability data provided with the regulatory submission; Where stability models and risk management descriptions are provided
Stability studies required to support PACs.
FDA generally recommends that qualitative data are coded for these submissions
Document Types
5Protocol 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
Reduction from Primary Stability Study to the Commitment Study
Submission containing stability data
Applicable to regulatory submissions.
Where stability protocol summaries and data are provided; Document where stability data and justifications are provided
Attributes
10Determined 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
The measured changes of quality attributes over time
specifications for the purity, strength, and composition of dietary supplements
Lack of change to water activity
supporting data could be supplied showing relative moisture vapour transmission rates
Environmental condition determining storage statements
Intrinsic characteristic affecting the growth of L. monocytogenes; intrinsic characteristic used as a process control; parameter to monitor for control; Process control parameters such as pH; Used to define listeristatic formulations
Significant change defined as 5% change from initial value
Complex and decelerating profiles like biphasic degradation
Assumed for certain quantitative chemical attributes during storage
Technical Details
Substances
10Differences in excipients may affect product stability
Patient-specific cellular ATMPs
Used in gene therapy products to modify cells.; Used to modify cells ex vivo
Subject of WHO stability testing guidelines.
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
Failure to meet specification constitutes significant change
Example of biological drug substance where re-test period may apply
used in the analytical procedure and SST
Stability of the adjuvant should be assessed by formal stability studies
Testing Methods
10Plotting the results and using the slope to represent beta results in the following graphs.
Stability-indicating CQA for viral drug products
Used to evaluate potency for cell-based products.
Used to mitigate uncertainty in stability CQAs due to high assay variability.
Novel model types likely to emerge
Alternative to Frequentist statistics for evaluating prior knowledge
Used for thermo-kinetic reactions in stability data fit
chosen when five or more batches are available
chosen when limited batches are available
ANCOVA used to evaluate attribute stability profile
Processes
10Primary process described in the guideline; Core activity described in the guidance; General process for evaluating product quality over time; Formal stability studies to assess adjuvant stability; Evaluation of attributes at all storage conditions; The process of evaluating product quality over time under specified conditions.; Evaluation of product quality over time
Studies designed to increase the rate of chemical degradation or physical change using exaggerated storage conditions.
Characteristic evaluated for prior knowledge molecule grouping
Primary studies that models are not intended to replace
Studies undertaken to assess the effect of severe conditions on the drug substance or product
Stability studies under the recommended long-term storage condition
Testing conducted under conditions intended to increase the rate of physical, chemical and/or biochemical change
A change that may potentially impact the stability profile
Used to evaluate effects of excursions
Practice of using a known data set to infer information about future data; Enhanced techniques for extrapolation; Annex 2 Stability Modelling; scientific and regulatory considerations for enhanced stability model development; The use of mathematical models to predict stability profiles
Identified Hazards
Hazards
8Environmental factors affecting biological products
The description of degradation products observed during stability studies.
prior knowledge from product development, e.g., on leachables
Environmental stress impacting biological molecules
Degradants likely to arise from light exposure
Risk identified during photostability studies
Potential concern for aqueous-based products in semi-permeable containers
Important for developing suitable analytical procedures; Essential to establish via stress testing
Standards & References
Specifications
5limits for solid state form and particle size; Tightening acceptance criteria; Numerical limits or ranges for tests
Batches must meet these criteria for registration
May be more stringent than shelf life specification
Criteria to ensure quality through the end of shelf life
Critical Quality Attributes monitored during stability testing
ICH References (10)
Stability Testing of Drug Substances and Drug Products; Consolidated revision that supersedes ICH Q1A-F and Q5C guidelines.; Stability testing of drug substances and drug products; Stability studies for drug substances and drug products; Main guideline for stability studies of drug substances and drug products; Main guideline for stability studies of drug substances and products; Core guideline for stability studies of drug substances and drug products.; Stability Studies for Drug Substances and
Recommendations for cell bank stability
Quality Risk Management recommended for combination products
Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients; Reworking needs more evaluation and testing according to ICH Q7; Good manufacturing practice for API starting materials; Referenced regarding the definition of intermediates.
The CTD — Quality
Pharmaceutical Quality System
Referenced for continuous manufacturing and pilot batch definitions; Guideline for continuous manufacturing batch selection; Referenced for Continuous Manufacturing (CM); Continuous Manufacturing.
Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process
Extractables and leachables considerations
Elemental impurities and interaction with storage containers
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