Stability of Biological Products

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1 Stability of Biological Products Dr Jurgen Lindner Principal, BioPharma Consulting & Executive Secretary, APIMAA Biological Products Functional Proteins or Polypeptides (mab s, enzymes & inhibitors, growth factors / cytokines / hormones, etc) genetically engineered or purified from tissues, well characterised Vaccines (protein antigens, virus, bacteria) Combination Products (conjugated mab s, delivery vehicles) {tissues and cells}!"#$%&#!'"! ()*+,-.!

2 Key Challenges of Biologicals Large & complex molecules (3,000 to >1,000,000Da) Tertiary structure highly relevant Well Characterised molecules Not always possible to determine degradation pathways and identify decomposition products Degradation usually not amenable to kinetic analysis & extrapolation from accelerated studies there is no single stability-indicating assay or parameter that profiles the stability characteristics of a biotechnological/biological product (ICH Q5C) Required: Stability-indicating profile to identify changes in the identity, purity, and potency!"#$%&#!'"! ()*+,-. / Points to Consider Potency / functionality assay is critical Degraded Product may be active but may cause problems (immunogenicity / bioavailability) Absolute purity is extremely difficult to determine (heterogeneity) Shelf life must be supported by long term, real time, real condition stability studies Most biotech products must include genetic stability of production organism (MCB/WCB) Release Specifications vs Expiry Specifications Cumulative stability data from intermediate stages Shelf life extensions are not self-assessable!"#$%&#!'"! ()*+,-. 0

3 Stability Indicating Profile: Assays No single assay or parameter is sufficient Stability indicating assays must detect changes in IDENTITY, PURITY & POTENCY Stability for conjugated / combination products may need surrogate test (vs in vitro / in vivo potency / efficacy tests) Assays must be validated, and data must be available for review!"#$%&#!'"! ()*+,-. 1 Stability Indicating Profile: Potency Must be included if biological activity can be defined and measured Express results in relation to reference material If no international reference standard exists, report results vs (own) characterised reference material Monitor dissociation of conjugated products in real time / real temperature studies!"#$%&#!'"! ()*+,-. 2

4 Stability Indicating Profile: Purity Purity value derived is method dependent Typically assessed by multiple methods Focus on methods for determination of degradation products (quantitation) Individual and total amounts of degradation products must be reported and documented Limits of acceptable degradation should be derived from analytical profile of batches used in preclinical and clinical trials!"#$%&#!'"! ()*+,-. 3 Stability Indicating Profile: Purity Assays Should accurately detect degradation changes resulting from deamidation, oxidation, sulfoxidation, aggregation or fragmentation during storage Typical Assays electrophoresis (SDS & IEF-PAGE,Western Blots) immunoelectrophoresis chromatography (HPLC: SE, IEX, RP; Affinity) peptide mapping evaluation vs reference standard!"#$%&#!'"! ()*+,-. 4

5 Stability Indicating Profile: Purity Assays Reverse Phase: same for A & B Ion Exchange: Time point A Gel Permeation same for A & B Ion Exchange: Time point B!"#$%&#!'"! ()*+,-. 5 Stability Indicating Profile Other product characteristics Visual Appearance colour / opacity / texture / dissolution time visible particulates / precipitation ph Moisture content (freeze dried products) Sterility testing alternative: container / closure integrity testing Minimum: initial test and end of shelf life test In-Use stability Additives (stabilisers, preservatives) & Excipients - Monitor if preliminary studies indicate degradation / reaction with product!"#$%&#!'"! ()*+,-. "'

6 Trial Design - Storage Conditions May be confined to proposed storage temperature Humidity can usually be omitted (if humidity protecting containers are used - see below) Container & Closure liquid products: test upright & inverted (test for productpackaging material interactions) multidose vial: product stability must be maintained under maximum specified use conditions product in final container (Drug Product) or scaled down version (Drug Substance)!"#$%&#!'"! ()*+,-. "" Trial Design - Stress Studies Conduct studies with accelerated & stress conditions in addition to real time studies: provide useful support data help elucidate degradation profile indicate which specific test parameters may be best indicators of product stability indicate if accidental exposure to non-standard conditions (eg during shipping) is deleterious to product quality!"#$%&#!'"! ()*+,-. "!

7 Trial Design - Stress Studies Conditions which induce protein degradation: heat, light, agitation, freeze / thaw cycling oxidising conditions, extremes of ph various moisture levels (freeze dried product)!"#$%&#!'"! ()*+,-. "/ Trial Design - Test Frequency Shelf life less than 1 year 3x monthly, then 3 month intervals Shelf life greater than 1 year 4x 3monthly, 2x 6monthly, then annually!"#$%&#!'"! ()*+,-. "0

8 Trial Design - Selection of Batches (Drug Substance / API and Drug Product) Provide data for!3 batches Product manufacture and storage must be representative of the commercial scale of operation Data from pilot batches may be used for Drug Substance: requires commitment to perform long term stability tests on first 3 full scale batches Quality of batches must be representative of material used in preclinical & clinical studies!"#$%&#!'"! ()*+,-. "1 Trial Design - Selection of Batches (Drug Substance / API and Drug Product) Batches of drug product should be derived from different batches of drug substance Container / Closure system: containers of reduced size may be used for drug substance, but must be same material & type Intermediates should be defined and included in stability studies (also: set specifications) Demonstrate cumulative stability (use DP manufactured from intermediates / API held for maximum time)!"#$%&#!'"! ()*+,-. "2

9 Stability Specifications So far little guidance by authorities with respect to distinct release and product expiry specifications No recommendations yet for maximum acceptable loss of activity, limits for physicochemical changes, or degradation Products are considered on a case by case basis Product should meet specifications within established limits for safety, purity and potency throughout its proposed shelf life Use of different specifications for release and expiry should be supported by sufficient data to demonstrate clinical performance is not affected!"#$%&#!'"! ()*+,-. "3 Regulatory Requirements & Guidelines TGA ARGPM Appendix 14: Stability Testing (TGA, June 2004) ICH Guidelines Q1A-F Stability ICH Q5C Quality of biotechnological products : Stability Testing of Biotechnological/Biological Products ICH Q6B Specifications: Test procedures and acceptance criteria for biotechnological / biological products!"#$%&#!'"! ()*+,-. "4

10 SUMMARY Biologicals are complex structures Stability of production organism as well as API & product Potency / functionality assay(s) essential Purity is relative and method dependent - need to focus on methods for determining degradation products Inherent heterogeneity of biologicals Stability indicating profile - focus on changes Data requirements are similar to chemical entities Key regulatory requirements are defined in TGA s ARGPM appendix 14 and ICH Q5C!"#$%&#!'"! ()*+,-. "5