ICH Q5C Stability Testing Of Biotechnological / Biological .

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ICH Q5CStability testing of Biotechnological / Biological productsICGH CGC ASEAN training. Kuala Lumpur. 30-31 May 2011Presented by: A. Ganan Jimenez, B. BrakeEuropean Medicines Agency, Human Medicines Development and EvaluationAn agency of the European Union

ContentICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability1ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability2ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Stability guidelinesICH website: www.ich.org3ICH Q5C - Stability testing of Biotechnological / Biological products

ICH guidelines on stability Q1A - Stability testing for new drug substances andproducts (R2 - 2003) PARENT GUIDELINE.Defines the stability data package for registration of a newmolecular entity as drug substance/drug product. Q1B – Stability testing of new drug substances andproducts (1996) Recommendations on photostability testing Q1C – Stability testing for new dosage forms (1996) Recommendations on new dosage forms for authorised medicinalproducts4ICH Q5C - Stability testing of Biotechnological / Biological products

ICH guidelines on stability (II) Q1D – Bracketing and matrixing designs for Stabilitytesting for new drugs substance and products (2002) Specific principles for the bracketing and matrixing in the studydesigns. Q1E – Evaluation of Stability data (2003) Recommendations how to establish shelf life or retest periodbased on stability studies performed.5ICH Q5C - Stability testing of Biotechnological / Biological products

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 EMA guidance on stability CPMP/QWP/609/96: Declaration of storage conditions CPMP/QWP/2934/99: In-use stability testing CPMP/QWP/159/96: Maximum shelf-life for sterile products afterfirst opening or following reconstitution6ICH Q5C - Stability testing of Biotechnological / Biological products

EU definition of Biological substanceIn EU, a biological substance is a substance that is produced byor extracted from a biological source and that needs for itscharacterisation and the determination of its quality acombination of physico-chemical-biological testing, together withthe production process and its control. (Dir 2001/83/EC)7ICH Q5C - Stability testing of Biotechnological / Biological products

Why ICH specific guidance for biologicals? (I) Biological substances are complexmolecules Primary structure: amino acid sequence ofpolypeptide chain Secondary structure: a-helix, b-sheet - stabilised byhydrogen bonds Tertiary structure: 3D structure of a single moleculefoldedinto compact globule, stabilized by non-specifichydrophobicinteractions and specific interactions (salt bridges, Hbonds, -S-S- bonds)8 Quaternary: assembly of several polypeptide chains:ICH Q5C- Stabilitytesting ofinteractionsBiotechnological / Biologicalnoncovalent-S-S- productsbonds

Spectrum of complexitySpectrum of complexityAspirinMW: 0.2 kDaChemicals9IFN alfa165AA, MW: 19 kDaIgG 1300AA,MW: 150 kDaRecombinant DNAtechnologyFVIII 2330AA,MW: 330 kDaBlood-ICH Q5C - Stability testing of Biotechnologicalderived/ Biological productsVirus like particle MW: 20 000 kDaImmunologicalsAdvancedtherapySource: Dr Kowid Ho (Afssaps, France)

Protein instabilityMost common:Ig G 150 KDa 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 multimerscovalent or non covalent Glycoproteins – most common instability of glycosylationhydrolysis of sialic acid residues.10ICH Q5C - Stability testing of Biotechnological / Biological products

Monoclonal antibody11ICH Q5C - Stability testing of Biotechnological / Biological products

Why specific guidance for Biologicals? (II) 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 usuallynecessary12ICH Q5C - Stability testing of Biotechnological / Biological products

Why ICH specific guidance for Biologicals? (III) The evaluation of stability may necessitate complexanalytical methodologies Physicochemical tests alone are insufficient to characterize theproduct sufficiently to permit prediction of the biologicalactivity13 Physicochemical Biochemical Immunochemical assay for biological activitymethods analysis of molecular entity quantitative detection ofdegradation productsICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability14ICH Q5C - Stability testing of Biotechnological / Biological products

Scope of ICH Q5CICH Q5C was published as an Annex to the Tripartite ICH Guideline for Stability ofnew Drug substance and Products.ICH Q5C intends to give guidance to applicants regarding thetype of stability studies to be provided in support of marketingauthorisation applications for biological medicinal products.15ICH Q5C - Stability testing of Biotechnological / Biological products

Medicinal products covered by ICH Q5CICH Q5C applies to well characterised proteins andpolypeptides isolated or manufactured by rDNA technology.COVERS:16 cytokines (IFN, IL, CSF, TNF) EPO DOES NOT COVER: antibioticsplasminogen activators allergenic extracts blood products heparins growth hormones vitamins insulins monoclonal antibodies whole blood vaccines cellular/ blood componentsICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C - General PrinciplesThe applicant should: develop data to support the claimed shelf life consider any external condition affecting potency, purity andquality Primary data to support the requested shelf life should bebased on long–term, real time, real condition stabilitystudies. The design of the long-term stability program iscritical Retest period not appropriate for biotech/biologicals17ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability18ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability data for Drug substance At least 3 batches representative of the manufacturingscale of production "Representative" data: Representative of the quality of batches used in pre-clinical andclinical studies Representative manufacturing process and storage conditions Representative containers19ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability 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 basis20ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability data for Drug substance (III) At the time of Marketing Authorisation application, data frompilot-plant scale batches may be submitted Pilot scale batches should be produced and stored in conditionsrepresentative of commercial scale Pilot scale batches should use the same container/closure system A commitment to place the first 3 manufacturing scalecommercial batches in a stability program after approval21ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability 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– Usually documented in section: on process validation when hold time / short storage (CTD 3.2.S.2.5 or3.2.P.3.5) on stability when significant storage period (CTD 3.2.S.7 or 3.2.P.8)22ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability 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 Drugsubstance 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 basis23ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability data for Drug Product (II) Shelf life should be derived from representative real time /real conditions data. Data can be provided during the reviewand evaluation process. “Representative” data: Representative of the quality of batches used in pre-clinical andclinical studies Representative manufacturing process and storage conditions Use final containers24ICH Q5C - Stability testing of Biotechnological / Biological products

Batch selection for a Marketing authorisationStability data for Drug Product (III) Shelf life will be based upon real time / real storage conditionsdata submitted for review Pilot scale batches may be submitted, with a commitment toplace the first 3 manufacturing scale batches in long termstability program.25ICH Q5C - Stability testing of Biotechnological / Biological products

Sample selectionFull study designSamples for every combination, all factors included in the designof the stability programme are tested at all time pointsReduced study design*Samples for every combination of all design factors are NOTtested at all time points. Reduced design should be justified scientifically. Type and level ofjustification depends on available supporting data. Potential risk of establishing shorter shelf life due to more limiteddata.*Q1D Bracketing and matrixing designs for stability testing.26ICH Q5C - Stability testing of Biotechnological / Biological products

Matrixing and BracketingMatrixing and Bracketing* study designs can be applied to thetesting of new drug substances and products.Bracketing Only samples on the extremes of certain design factors aretested at all time points Stability of any intermediate levels is represented by thestability of the extremes Bracketing is generally not applicable for drug substance*Q1D Bracketing and matrixing designs for stability testing.27ICH Q5C - Stability testing of Biotechnological / Biological products

Bracketing (II) Can be applied to studies with multiple strengths of identicalor closely related formulations Only samples on the extremes of certain design factors (e.g.strength, container size, fill) are tested at all time points. In certain cases, needs to be demonstrated that the extremesare representative. Bracketing can be applied to studies with the same containerclosure system whether either the fill volume and/or thecontainer size change.28ICH Q5C - Stability testing of Biotechnological / Biological products

Bracketing (III)Strengths Applicable without justification with multiple strengths withidentical or closely related formulations. Applicable with justification to studies with multiple strengthswhere relative amounts of DS and excipients change in aformulation. Justification means that corresponding supportive data on thedrug product are available (e.g. stability profiles of differentstrengths in clinical or development batches) Not applicable if different excipients are used among strengths.29ICH Q5C - Stability testing of Biotechnological / Biological products

Bracketing (IV)Container closure size and /or fills Applicable without justification with same container closuresystem where either size or fill varies. If both container and fill vary, largest or smaller container maynot represent the extremes of all packaging. Extremes should be selected comparing various characteristics(e.g. surface are to volume ratio, head space to volume ratio).30ICH Q5C - Stability testing of Biotechnological / Biological products

Example of a bracketing designA medicinal product containing: pancreatic lipaseStrengths: 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 excipientsproportions, manufacturing formula and batch size)Packaged in type II amber glass bottles containing desiccants closed with a polypropylene screw capcontaining 12, 50 and 150 capsulesStrenghtsBatchesBottlevolume3130 ml12 units100 ml50 units200 ml100 units3,000 U.5,000 U.10,000 U.15,000 ets)123xxx123123123xxxDesiccantamount1g2,5 gxxxICH Q5C - Stability testing of Biotechnological / Biological productsxxx5g

Matrixing Matrixing is the design of a stability study schedule such that: a selected subset of total number of possible samples for allfactor combinations is tested at a specific time point. at a subsequent time point, another subset of samples for allfactor combinations is tested. Each subset of samples represents the stability of all samplesat a given time point. Differences in the samples should beidentified as: covering different batches, different strengths different sizes of same container closure system.32ICH Q5C - Stability testing of Biotechnological / Biological products

Matrixing (II) A matrix design should be balanced such that eachcombination of factor is tested to the same extent over theduration of the studies Initial and final point values should be included in all samples All samples should be tested at the last time point beforesubmission of application. Should retain the ability to detect stability differences within /among factors.33ICH Q5C - Stability testing of Biotechnological / Biological products

Matrixing example - timepointsExamples of a matrixing in a long term stability study for one storage condition:-One half reduction eliminates one in every two time points-One third design eliminates one in very three time pointsThese examples reduce the number of tested time pointsin 32% and 18% respectively.Total time points34StrengthsContainer sizeBatchesExtended1/2 design2/3 design2164833 (68%)38 (82%)ICH Q5C - Stability testing of Biotechnological / Biological products

Matrixing example – timepoints factorsMedicinal product with:- 3 strengths- 3 containers- 8 timepointstested in one storage conditionFull programme: 216 testsMatrix on:- timepoints: 171 tests (79%)- factors timepoints: 114tests (53%)35ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability36ICH Q5C - Stability testing of Biotechnological / Biological products

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, identityand potency methods validated at the time of submission37ICH Q5C - Stability testing of Biotechnological / Biological products

5.1 Protocol a detailed protocol for stability of DS and DP to support theshelf life and storage conditions necessary information to demonstrate the stability of thebiotechnological / biological product through shelf life the design is critical for the successful establishment of shelflife38ICH Q5C - Stability testing of Biotechnological / Biological products

5.2 Potency is the specific ability or capacity of a product to achieve itsintended 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 aninternal, national or international reference material) potency assays should be part of the stability studies39ICH Q5C - Stability testing of Biotechnological / Biological products

Potency (II) should be presented as units of biological activity calibratedversus International reference standard (e.g. WHO) (if available), or Nationally recognised reference standard, or in-house reference standard40ICH Q5C - Stability testing of Biotechnological / Biological products

Potency assayWhat characteristics should a potency assay have? stability indicating specific – likely impurities should not interfere activity of an unknown sample is measured relative to that ofa reference standard of a similar material41ICH Q5C - Stability testing of Biotechnological / Biological products

Potency assay (II) Differences in the assay system should affect the test andreference preparations to the same extentresponseStdStdAassay (system) 1Alog doseassay (system) 2 Statistical analysis of results of biological assays and tests (Eur. Ph. General texts 5.3)42ICH Q5C - Stability testing of Biotechnological / Biological products

Potency assay - Functional similarity Functional similarity of the reference standard and sample is afundamental condition for assay validity Displacement between the cures along concentration axis isconstant and is a measure of the relative potency43ICH Q5C - Stability testing of Biotechnological / Biological products

Degradation productsDegradation products can interact with the performance of thebioassay If degradation products may not be functionally similar tooriginal, no relative potency can be calculated: change ofactivity can be noted If degradation product is functionally similar to original,measured relative potency may not reflect degree ofdegradation44ICH Q5C - Stability testing of Biotechnological / Biological products

Degradation products - ExampleBioassay alerts to degradation, then physicochemical analysis reveals nature of changeRehder et al Biochemistry 2008, 47, 2518-2530 Monoclonal antibody anti-EGFR, indication colorectal cancer When stored under certain conditions (increase Temp, decreased pH) decreased in vitropotency. Not due to aggregation or proteolysis, no change in molecular mass RP-HPLC: increased peak preceding light chain (LC) peak. Both LC & Pre-LC peak MW 23641 Peptide maps: additional early eluting peptide, same MW as control peptide Sequence analysis Asp-N enzymatic digestion: early eluting peptide has isomerization of Asp92 Potency decreases with increase in iso-Asp at position 9245ICH Q5C - Stability testing of Biotechnological / Biological products

Potency assays: Limitation in stability studies Potency measurement may be complex to interpret – nature ofchange and percentage of degradation products Formulation may interfere with bioassay Changes need to be identified by some form ofphysicochemical assay Change in potency may alert to degradation not detected byother techniques46ICH Q5C - Stability testing of Biotechnological / Biological products

5.3: Purity and molecular characterisation Purity is a relative term, difficult to determine and methoddependent Stability studies: Test for purity should focus on methods fordetermination of degradation products. More than one method, purity value is method dependent In stability, purity tests should focus on determination ofdegradation products Limits of acceptable degradation should be derived from theanalytical profiles of batches of the drug substance used inpreclinical and clinical studies.47ICH Q5C - Stability testing of Biotechnological / Biological products

Purity and molecular characterisation (II) The use of relevant physicochemical, biochemical andimmunochemical method to determine: comprehensive characterisation (e.g. molecular size, chargehidrophobicity) degradation changes (e.g. deamidation, oxidation, sulfoxidation,aggregation, fragmentation) during storage48ICH Q5C - Stability testing of Biotechnological / Biological products

Purity and molecular characterisation (III) when significative quantitative or qualitative changes indegradation products during long tem, accelerated or stressstudies: consider potential hazard need to characterize and quantify degradation products within thelong term studies Acceptable limits proposed and justified based on pre-clinicalclinical batch studies.49ICH Q5C - Stability testing of Biotechnological / Biological products

5.4 Other products characteristicsOther characteristics should also be monitored for the drugproduct 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/closure50ICH Q5C - Stability testing of Biotechnological / Biological products

Example of stability indicating profile of arecombinant proteinNon-glycosylated recombinant protein (150-180 aa)Formulated with acetate and polysorbate 8051ICH Q5C - Stability testing of Biotechnological / Biological products

Examples of stability indicating tests profile ofvaccineNon-adjuvanted flu vaccinesplit virion52Surface bacterial antigenvaccineICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability53ICH Q5C - Stability testing of Biotechnological / Biological products

Humidity Products are generally distributed in containers protectingagainst humidity. If demonstrated that container (& storageconditions) provide sufficient protection against high and lowhumidity, relative humidities can be omitted. if humidity protecting containers are not used,appropriate data should be provided.54ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Storage conditions - continuesTEMPERATURE most biologicals need precisely defined storage temperatures real time / real temperature studies are confined to theproposed storage temperature.LIGHT 55case by case basisICH Q5C - Stability testing of Biotechnological / Biological products

Accelerated and Stress conditions Shelf life established based on real time / real temperaturedataAccelerated 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 realstorage conditions56ICH Q5C - Stability testing of Biotechnological / Biological products

Accelerated and Stress conditions (II)Stress studies Representative accidental exposures to other conditions Determination of best product-stability indicators Can reveal patterns of degradation57ICH Q5C - Stability testing of Biotechnological / Biological products

Accelerated and Stress conditions (III) Conditions should be carefully selected on a case-by-case basis ICH Q1A recommends the following accelerated conditions related to the longterm studies. ICH Q1A addresses climatic zones I and II.58ICH Q5C - Stability testing of Biotechnological / Biological products

Container/closure interactions may occur between product and container/closure data to be supplied for all different container/closurecombinations where lack of interactions cannot be excluded - determinethe effect of the closure to be determined (horizontal, uprightstudies)59ICH Q5C - Stability testing of Biotechnological / Biological products

Additional stability studies In use stability for multidose presentations requirement to demonstrate that the protein retains its fullpotency, purity and quality taking into account the repeatedinsertions and withdrawals should be included in labelling Stability after reconstitution of freeze-dried analysis of maximum storage period after reconstitution inclusion in the labelling60ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability61ICH Q5C - Stability testing of Biotechnological / Biological products

Protocol testing frequency Shelf life biologicals can vary ICH Guidance is based on a 0.5-5 years shelf life for mostbiologicals. The recommended intervals for long term studies in prelicensing: Post approval, if adequate stability is demonstrated, theapplicant can propose a protocol suppressing some timepoints62ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability63ICH Q5C - Stability testing of Biotechnological / Biological products

Specifications 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 accountlevels observed in materials used in non-clinical / clinicalstudies Shelf-life specification acceptable, where appropriately justified(EU) All test parameters may not be required at all timepoints64ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability65ICH Q5C - Stability testing of Biotechnological / Biological products

Guidance ICH Q5C: Specific recommendations should be stated (e.g. do not freeze) Protection against light, humidity should appear on containers,packages and/or package inserts. EMA guidance on declaration of storage conditions in productinformation (CPMP/QWP/609/96/Rev 2) Storage conditions should be be included in Summary of productcharacteristics (SPC), Package leaflet (PL), and product labelling. Should be based on the demonstrated stability characteristics ofthe product Terms „room temperature‟ or „ambient conditions‟ unacceptable66ICH Q5C - Stability testing of Biotechnological / Biological products

ICH Q5C Introduction Scope Selection of Batches Stability indicating profile Storage conditions Testing frequency Specifications LabellingEMA guidance on Stability67ICH Q5C - Stability testing of Biotechnological / Biological products

Information on Stability guidelines-EMA website:www.ema.europa.euhome/regulatory/human medicines/scientific guidelines68ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Stability guidelines Guideline on Stability testing: Stability testing of Existingactive substances and related finished products(CPMP/QWP/122/02 rev 1 corr.) Stability Testing for Applications for Variations to a MarketingAuthorisation (CPMP/QWP/576/96/rev 1.) Guideline on declaration of storage conditions: a) in theproduct information of medicinal products b) for activesubstances (CPMP/QWP/609/96 rev 2) Note for guidance on in-use stability testing of humanmedicinal products (CPMP/QWP/2934/99)69ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Stability guidelines (II) Maximum Shelf-Life for Sterile Products for Human Use afterfirst opening or following Reconstitution (CPMP/QWP/159/96Corr.) Requirements for Quality documentation concerninginvestigational biological medicinal products in clinical Trials(EMA /CHMP/BWP/534898/2008) DRAFT70ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Guidance storage conditions / labelling EMA guidance on declaration of storage conditions in productinformation (CPMP/QWP/609/96/Rev 2) Storage conditions should be be included in Summary of productcharacteristics (SPC), Package leaflet (PL), and product labelling. Should be based on the demonstrated stability characteristics ofthe product Terms „room temperature‟ or „ambient conditions‟ unacceptable71ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Guidance storage conditions / labelling Storage conditions statements in product information72ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Guideline on in-use stability testing (I) Attempts to define a framework for batch selection, test design, test storageconditions, test parameters and test procedures,. to be undertaken to define anin-use shelf lifeBATCHES Minimum of two representative batches (at least pilot scale) should be tested. At lest one batch should be chosen at end of shelf life. If more than one container/strength, it should be tested in the at the final point.73ICH Q5C - Stability testing of Biotechnological / Biological products

EMA Guideline on in-use stability testing (II)TEST DESIGN Simulate the use in practice considering filling volume, dilution/reconstitution Sampling should be done under normal conditions of use The appro

4 ICH Q5C - Stability testing of Biotechnological / Biological products ICH guidelines on stability Q1A - Stability testing for new drug substances and products (R2 - 2003) PARENT GUIDELINE. Defines the stability dat

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