Prequalification of Medicines Program Stability Testing Rutendo Kuwana Technical Officer Prequalification of Medicines Program WHO

PQ Assessors training, Jan 2011 Overview Scope of presentation – Generic/Multisource preparations API - Stress Testing Selection of Batches Container Closure System Methods to be validated Specifications: Stability indicating quality parameters Testing Frequency Storage Conditions Evaluation of data Bracketing/Matrixing Common deficiencies PQ Assessors training, Jan 2011

The Role of Stability in Drug Development Stability studies play a central role in drug development Permit understanding of the molecule Essential for developing analytical methods Essential for selecting packaging for drug substance and drug product Essential for choosing storage conditions for drug substance and drug product PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 API Stress Studies When available, it is acceptable to provide relevant data published in the scientific literature to support the identified degradation pathways and products. When no data are available, stress testing should be performed. PQ Assessors training, Jan 2011

The Role of Stress Testing Identification of degradation pathways Identification of degradants Determination of which type(s) of stress affect the molecule Photostability High Temperature Low Temperature Oxidation pH extremes Water PQ Assessors training, Jan 2011

API stability Stress testing Requirement: 1 API batch. Photostability testing: generally as per Q1B, however for PQP, literature data can support/replace experimental data: If “protect from light” is stated in one of the officially recognized pharmacopoeia for the API, it is sufficient to state “protect from light” on labeling, in lieu of photostability studies, when the container closure system is shown to be light protective. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Oxidation Typically done by placing the drug substance in aqueous solution with hydrogen peroxide Goal is significant degradation (typically 10-30% of API) Can identify degradants Determine whether protective packaging is required Determine if an antioxidant should be considered for the drug product formulation PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 pH Extremes Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10. Can be complicated by limited solubility of the drug substance under different pH conditions Again, the goal is significant degradation Determine degradants Decide if the molecule will survive passage through the stomach Is enteric coating necessary? Should the drug be given by injection? PQ Assessors training, Jan 2011

API stability Stress testing – Typical Stress conditions PQ Assessors training, Jan 2011

Identifying Degradants Predicting routes of degradation Acid/base hydrolysis of esters and amides Oxidation of thiols, alcohols and amines Loss of methyl groups Synthesizing possible degradants Prepare possible degradant Known Structure Test it in potential analytical method Detectability Separation from parent peak PQ Assessors training, Jan 2011

Stress studies: Approach Investigate impurities/degradants appearing at greater than (or approaching) the identification threshold, (the limit on individual unknowns) under long-term and accelerated conditions. Mass balance assessment if required to be based on the decrease in assay value and the increase in the amount of degradation products. Process related impurities to be monitored at release only with no need to monitor during long-term stability. However, if they increase during storage, or new impurities develop, they should be considered as “degradants” or “degradation products”, and analytical methods must be developed to monitor them. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Examples of physical stability stress testing conditions for drug substances - Industry Perspective (Source Handbook of stability testing and pharmaceutical development regulations, methodologies, and best practices) PQ Assessors training, Jan 2011

API - Selection of Batches Primary Batches : Batches used in stability studies to establish retest (API) or shelf-life (FPP). Generally at least 3 pilot batches. Even though TRS 953 Annex 2 says for existing API known to be stable data from at least 2 batches should be provided API - Pilot batches must be of the same synthesis route, and method of manufacture and procedure that simulate the final process for production batches. PQ Assessors training, Jan 2011

FPP Stability Selection of Batches Each strength and container type/size should be studied unless bracketing/matrixing is applied. FPP batches should use different lots of API where possible; NLT 2 batches of at least pilot scale For uncomplicated FPP (e.g. immediate-release solid FPPs (some exceptions), non-sterile solutions), NLT 1 batch at least pilot scale and a second batch which may be smaller (e.g. solid oral dosage forms, 25 000 or 50 000 tablets/capsules) Batches should be as proposed wrt: Formulation Container/closure system Manufacturing process simulating production process PQ Assessors training, Jan 2011

Container Closure System Should be the same or simulate the container proposed for storage/distribution unless justification provided (i.e. container used in studies is less than or equally protective compared to proposed container) a functionally similar container may be used to mimic the cardboard or plastic drum that is usually used to store raw material PQ Assessors training, Jan 2011

Importance of Analytical Methods in Development Stability Studies Without analytical methods it is not possible to know what has happened during stability Assay Impurities/Degradation Products Dissolution Chiral Purity Preservative Content PQ Assessors training, Jan 2011

Methods Must be Stability-Indicating Analytical methods must effectively separate and permit quantification of degradants (including use of purity tests) Any significant changes in drug substance or drug product quality over time must be detectable Increase in degradants Change in dissolution behavior Change in stereochemistry cis to trans or vice-versa optical isomers interconverting PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Method Validation Types of Analytical Procedures to be Validated Identification tests; Quantitative tests for impurities' content; Limit tests for the control of impurities; Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product. Drug product assay This will also include quantifying dissolution results PQ Assessors training, Jan 2011

API Stability: Specifications Specifications: test attributes susceptible to change. Testing should cover physical, chemical, biological and microbiological attributes e.g. appearance, assay, degradation plus others susceptible to change. For impurities, a specification for individual and total impurities must be set. Numerical data for individual (known and unknown) and total impurities to be reported instead of conforms or complies. NB: The upper and lower acceptance criteria limits for innovator products are based on the potency and/or impurity levels of the clinical lots and safety and efficacy considerations. There is no justification, normally, for generic source to request for less stringent specifications. PQ Assessors training, Jan 2011

Other parameters to be monitored Commonly where the API is low solubility and micronized, and the FPP is low dose - PSD is critical Due to the potential for settling of material on storage, stability results for PSD should be provided to address this issue. Moisture is particularly important for solid orals in blisters and strips. Efficacy of additives and assay of preservatives Container/closure interactions, when applicable PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Testing Frequency Long term: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually Accelerated: Minimum three points including t0 and tfinal, e.g. 0, 3, 6. Intermediate: Four points including t0 and tfinal, e.g. 0, 6, 9, 12. PQ Assessors training, Jan 2011

Minimum Data Requirements at time of submission – API and FPP Storage Temp (◦C) RH (%) Min. Time period (months) Accelerated 40±2 75±5 6 Intermediate * * Long-term 30±2 65±5 or 75±5 (API only) 75±5 (FPP) *Where long-term conditions are 30ºC±2ºC/65%±5%RH or 30ºC±2ºC/75%±5%RH, there is no intermediate condition. For API when a valid CEP is provided or APIMF is referred to: no data is required if the proposed retest is as per retest on CEP/APIMF; if retest period longer than the CEP is proposed, submit data meeting above requirements PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Storage Conditions Conditions should test the API/Product's thermal stability and, if applicable, moisture sensitivity For PQ submissions long-term studies should be conducted at 30°C ± 2 °C/75 % RH ± 5% to account for all climatic zones, including IVa/b countries. (strict requirement as of September 2011) There is therefore no Intermediate Condition use of alternative long-term conditions to be justified and should be supported with appropriate evidence e.g. products unstable under these conditions PQ Assessors training, Jan 2011

Accelerated Stability Stability study run under more stressful conditions than expected for long term storage to account for excursions outside the label storage conditions e.g. during shipping or handling Acc Storage condition should be guided by intended climatic condition in which API/FPP will be stored Different from stress studies in that the goal is to get a quick understanding of what may be expected from a long term study Long-term conditions Accelerated Conditions Room temperature (25-30°C) 40°C ± 2°C/75% RH ± 5% Refrigerated (5°  3°C) 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% Freezer (-20°C 5°C) Can range from 5°C ± 3°C or 25°C ± 2°C or 30°C ± 2°C PQ Assessors training, Jan 2011

FPP Stability In-use studies In-use studies are for FPP intended to be diluted or reconstituted. (multi-use FPP) Two different batches (at least pilot), one near the end of its shelf-life should be used. NB: there is no in-use requirement (e.g. labelling “use within 30 days”) for dispersible tablets; a single dose is intended to be dispersed just prior to use. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 “Significant Change” For API - defined as failure to meet its specification For an FPP, significant change under accelerated and intermediate testing conditions is any of: More than 5% change in assay from initial; Degradant exceeding acceptance limit Failure to meet acceptance criteria for appearance, physical attributes and functionality (e.g. colour, phase separation) For tablets e.g. Failure to pass S2/L2 dissolution testing, i.e. n=12 (i.e. after failing S1/L1 as well) For FPP’s in semi-permeable containers, a 5% loss of water from initial (3 months at 40◦C/25%) PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 ICH Q1E Extrapolation Can extend expiration dating or retest date beyond available long-term stability data if Sufficient long-term data is available to assess any trends No significant change is observed within 6 months under accelerated conditions Little or no variability This process is spelled out in Q1E decision trees Shelf-lives/retest dates established based on extrapolation must be confirmed by long-term data when available PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Use of Statistics – Q1E to establish, with a high degree of confidence, whether a retest period or shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged, and stored under similar circumstances Not necessary if data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf-life will be granted Regression analysis is considered appropriate Examples of statistical approaches included in Appendix B PQ Assessors training, Jan 2011

Ongoing Stability Studies Purpose: to monitor and determine that API/FPP remains within specifications under the storage conditions, within the re-test period/shelf life in all future batches The programme should be described in a written protocol The programme should include at least one production batch per year, tested at least annually. An ongoing study should be conducted after any significant change to the synthetic route/manufacturing process or container which may impact stability. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Stability Commitment This is required when data did not cover the proposed re-test/shelf life (Primary Stability Study Commitment) and/or the primary stability batches studied did not consist of three production scale batches (Commitment Stability Studies) The applicant must commit to conducting long-term stability trials on the next production scale batches that are manufactured. The number of batches required depends on the number of production scale batches provided in the primary studies (to make at least 3 production batches) For all post-approval commitments: A signed and dated commitment is required. An authorised, dated and detailed protocol should be provided, including storage conditions, testing frequency, specifications, test methods… PQ Assessors training, Jan 2011

Q1D - Bracketing and Matrixing World Health Organization 25 April, 2017 Q1D - Bracketing and Matrixing Outlines recommendations, principles, and considerations for reduced designs. Rarely submitted in PQP dossiers Bracketing: testing samples on the extremes of certain design factors (e.g., strengths, container sizes and/or fills) Matrixing: testing a selected subset of the total number of possible samples for all factor combinations at a specified time point, while testing another subset of samples at a subsequent time point PQ Assessors training, Jan 2011 31

Q1D - Bracketing and Matrixing Bracketing - Strengths: Applicable: strengths of identical or closely related formulations Applicable with additional justification (e.g., supporting data): strengths where the relative amounts of the drug substance and excipients vary within the product line Not applicable: different excipients among strengths Bracketing – Container Size, Fill: Applicable: same container closure system where either the container size or fill varies while the other remains constant Applicable with additional justification (e.g., supporting data): same container closure system but both the container size and fill vary Not applicable: different container closure systems PQ Assessors training, Jan 2011

Q1D - Bracketing and Matrixing Bracketing - Considerations: If stability of extremes are shown to be different, the intermediates should be considered no more stable than the least stable extreme Selected extreme may be dropped from proposed market presentations PQ Assessors training, Jan 2011

Q1D - Bracketing and Matrixing applicable: strengths with identical or closely related formulations container sizes or fills of the same C/C system different batches made with the same equipment and process applicable with additional justification: where the relative amounts of excipients change or different excipients are used not applicable: different storage conditions different test attributes PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Common Deficiencies During assessment problem areas that warrant a closer look/more questions include: Data is provided in such a way that trends cannot be determined, e.g. range of dissolution values but no average, or limits cannot be assessed, OR average dissolution but no range of individual values. Data shows a lack of mass balance, or variability in results without trends - may indicate problems with analytical methods. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Common Deficiencies Expression of results as passes test or similar when a quantitative figure would be available. Failure to include quantitative or semiquantitative determinations of the content of degradation products, or to provide only total content rather than values for individual impurities. Use of an HPLC assay procedure to detect impurities without validation for the purpose. HPLC assay procedures as used for determination of the API are often unsuitable for separation and detection of impurities as they use too short a run time. Such a procedure would be acceptable if validated for impurity detection. Note, however, that long run times do not in themselves ensure good separation. PQ Assessors training, Jan 2011

PQ Assessors training, Jan 2011 Reference Documents Recommended documents that should be consulted for Stability requirements: Guideline on submission of documentation for multisource (generic) finished pharmaceutical product (FPP): Quality Part (In PQP supersedes any other guidance if there is conflict) The WHO stability guideline Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (WHO Technical Report Series, No. 953, Annex 2, 2009) Health Canada (www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_drugs_information_e.html): FDA (www.fda.gov/cder/guidance/index.htm): Stability Testing of Drug Substances and Drug Products (draft, 1998) Drug Substance - CMC Information (draft, 2004) Drug Product - CMC Information (draft, 2003) SUPAC series (IR, MR, SS) (and Q&A Document) Changes to an Approved NDA/ANDA (04/2004) (and Q&A Document) PQ Assessors training, Jan 2011 37

Other Reference Documents EU EMEA (www.emea.eu.int/Inspections/QWPhome.html): Manufacture of the Finished Dosage Form Annex - Start of Shelf -Life of the Finished Dosage Form (05/2001) Maximum Shelf-Life for Sterile Products after First Opening or Following Reconstitution (01/1998) Stability Testing Annex - Declaration of Storage Conditions for Medicinal Products Particulars and Active Substances (04/2003) Stability Testing Annex - In-Use Stability Testing of Human Medicinal Products (02/2001) Stability Testing for a Type II Variation to a Marketing Authorisation (04/1998) Stability Testing for Applications for Variations to a Marketing Authorisation (draft 04/2004) PQ Assessors training, Jan 2011 38