ICH q5c ICH Q5C Stability testing of Biotechnological / Biological products
- 1. ICH Q5C Stability testing of Biotechnological / Biological products By SAIM IKHLAQUE SOLEJA (saim.7246@gmail.com) Mphil Student Humdard University
- 2. Content ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications Labelling
- 3. ICH guidelines on stability • Q1A - Stability testing for new drug substances and • products (R2 - 2003) • PARENT GUIDELINE. • Defines the stability data package for registration of a new molecular entity as drug substance/drug product. • Q1B – Stability testing of new drug substances and products (1996) • Recommendations on photostability testing • Q1C – Stability testing for new dosage forms (1996) • Recommendations on new dosage forms for authorised medicinal products
- 4. ICH guidelines on stability (II) Q1D – Bracketing and matrixing designs for Stability testing for new drugs substance and products (2002) • Specific principles for the bracketing and matrixing in the study designs. Q1E – Evaluation of Stability data (2003) • Recommendations how to establish shelf life or retest period based on stability studies performed.
- 5. ICH/EMA guidelines on stability • ICH guidance on biologicals • Q5C: Stability testing of biotechnological/ biological products • Main reference for biological medicinal substances/products • Q1: some principles defined in Q1 guidelines are also applicable
- 6. DEFINITION OF BIOLOGICAL SUBSTANCE • In EU, a biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physico-chemical- biological testing, together with the production process and its control. (Dir 2001/83/EC)
- 7. Why ICH specific guidance for biologicals? • Biological substances are complex molecules • Primary structure: amino acid sequence of polypeptide chain • Secondary structure: alpha -helix-sheet - stabilized by hydrogen bonds • Tertiary structure: 3D structure of a single molecule folded • into compact globule, stabilized by non-specific hydrophobic • interactions and specific interactions (salt bridges, H bonds, - S-S- bonds) • Quaternary: assembly of several polypeptide chains: non covalent bonds S-S chains
- 8. Spectrum of complexity 9 ICH Q5C - Stability testing of Biotechnological / Biological products Spectrum of complexity Chemicals Recombinant DNA technology Aspirin MW: 0.2 kDa IFN alfa 165AA, MW: 19 kDa IgG ~1300AA, MW: ~150kDa Blood- derived FVIII ~2330AA, MW: ~330kDa Advanced therapy Immunologicals Virus like particle MW: ~20 000 kDa … Source: Dr Kowid Ho (Afssaps, France)
- 9. Protein instability Most common: Deamidation – hydrolysis of Asn and Gln side chain amides Oxidation – of Met, His, Cys, Tyr amnd Trp residues Denaturation - loss of 3-D structure Aggregation –association of monomers or native multimers covalent or non covalent Glycoproteins – most common instability of glycosylation hydrolysis of sialic acid residues.
- 10. Why specific guidance for Biologicals? • Maintenance of biological activity dependent on non-covalent, covalent interactions, • Products particularly sensitive to environmental factors: temperature, oxidation, light, ionic content, shear, • STRINGENT CONDITIONS FOR STORAGE are usually • necessary
- 11. Why ICH specific guidance for Biologicals (III) • 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 • Physicochemical • Biochemical methods • Immunochemical • assay for biological activity • analysis of molecular entity • quantitative detection of degradation products
- 12. Scope of ICH Q5C • ICH Q5C was published as an Annex to the Tripartite ICH Guideline for Stability of new Drug substance and Products. • ICH Q5C intends to give guidance to applicants regarding the type of stability studies to be provided in support of marketing authorisation applications for biological medicinal products.
- 13. Medicinal products covered by ICH Q5C • ICH Q5C applies to well characterized proteins and polypeptides isolated or manufactured by rDNA technology. COVERS: • cytokines (IFN, IL, CSF, TNF) • EPO • plasminogen activators • blood products • growth hormones • insulins • monoclonal antibodies • vaccines DOES NOT COVER: • Antibiotics • Allergenic extracts • Heparins • Vitamins • Whole blood • Cellular/ blood components
- 14. ICH Q5C - General Principles The applicant should: • develop data to support the claimed shelf life • consider any external condition affecting potency, purity and quality • Primary data to support the requested shelf life should be based on long–term, real time, real condition stability studies. The design of the long-term stability program is critical • Retest period not appropriate for biotech/biologicals
- 15. Batch selection for a Marketing authorization • 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
- 16. Batch selection for a Marketing authorisation • 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
- 17. Batch selection for a Marketing authorization • 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
- 18. Batch selection for a Marketing authorisation • 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
- 19. Batch selection for a Marketing authorisation • 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
- 20. Batch selection for a Marketing authorisation • 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.
- 21. Sample selection • 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. *Q1D Bracketing and matrixing designs for stability testing.
- 22. Matrixing and Bracketing • Matrixing and Bracketing* study designs can be applied to the testing of new drug substances and products. • Bracketing • Only samples on the extremes of certain design factors are tested at all time points • Stability of any intermediate levels is represented by the stability of the extremes • Bracketing is generally not applicable for drug substance *Q1D Bracketing and matrixing designs for stability testing.
- 23. Example of a bracketing design • A medicinal product containing pancreatic lipase • Strengths: 3,000, 5,000, 10,000, 15,000 Eur. Ph Units of lipase enzymatic activity. • Pharmaceutical form: HPMC Capsule shell containing enteric coated minitablets (same excipients proportions, manufacturing formula and batch size) • Packaged in type II amber glass bottles containing desiccants closed with a polypropylene screw cap containing 12, 50 and 150 capsules Strenghts 3,000 U. (minitablets) 5,000 U. (minitablets) 10,000 U. (minitablets) 15,000 U. (minitablets) Desiccant amount Batches 1 2 3 1 2 3 1 2 3 1 2 3 Bottle volume 30 ml 12 units x x x x x x 1 g 100 ml 50 units 2,5 g 200 ml 100 units x x x x x x 5 g
- 24. Strenghts 3,000 U. (minitablets) 5,000 U. (minitablets) 10,000 U. (minitablets) 15,000 U. (minitablets) Desiccant amount Batches 1 2 3 1 2 3 1 2 3 1 2 3 Bottle volume 30 ml 12 units x x x x x x 1 g 100 ml 50 units 2,5 g 200 ml 100 units x x x x x x 5 g
- 25. Matrixing • Matrixing is the design of a stability study schedule such that: • a selected subset of total number of possible samples for all • factor combinations is tested at a specific time point. • at a subsequent time point, another subset of samples for all factor combinations is tested. • Each subset of samples represents the stability of all samples at a given time point. Differences in the samples should be identified as: • covering different batches, • different strengths • different sizes of same container closure system.
- 26. Matrixing example – timepoints + factors ICH Q5C - Stability testing of Biotechnological / Biological products Medicinal product with: - 3 strengths - 3 containers - 8 timepoints tested in one storage condition Full programme: 216 tests Matrix on: - timepoints: 171 tests (79%) -factors + timepoints: 114 tests (53%)
- 27. ICH Q5C – Stability indicating profile • 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
- 28. 5.1 Protocol • a detailed protocol for stability of DS and DP 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
- 29. 5.2 Potency • 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
- 30. Potency (II) • 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
- 31. Potency assay What characteristics should a potency assay have? • stability indicating • specific – likely impurities should not interfere • activity of an unknown sample is measured relative to that of a reference standard of a similar material
- 32. Degradation products • Degradation products can interact with the performance of the bioassay • If degradation products may not be functionally similar to original, no relative potency can be calculated: change of activity can be noted • If degradation product is functionally similar to original, measured relative potency may not reflect degree of degradation
- 33. Potency assays: Limitation in stability studies • Potency measurement may be complex to interpret – nature of change and percentage of degradation products • Formulation may interfere with bioassay • Changes need to be identified by some form of physicochemical assay • Change in potency may alert to degradation not detected by other techniques
- 34. 5.3: Purity and molecular characterization • 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.
- 35. 5.4 Other products characteristics • Other characteristics should also be monitored for the drug product in the final container: • - visual appearance (e.g. colour/opacity of solutions/suspensions) -visible /subvisible particulates in solution / after reconstitution -pH -moisture levels (powders or lyophilised pdts.) -sterility or alternative tests (at least initially or end of shelf life) -additives (e. g. preservatives) that may degrade during storage -container/closure
- 36. 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.
- 37. ICH Q5C Storage conditions - continues 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
- 38. Accelerated and Stress conditions • Shelf life established based on real time / real temperature data • 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
- 39. 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)
- 40. 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
- 41. Protocol testing frequency • Shelf life biologicals can vary • ICH Guidance is based on a 0.5-5 years shelf life for most biologicals. • 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 timepoints
- 42. THANKYOU If you have any other questions or need further clarification, simply email me at saim.7246@gamil.com “The science of today is the technology of tomorrow.” Edward Teller