Stability Bracketing and Matrixing


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Slide 1:

Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam, Tanzania Date: 10 to 14 September 2007 Evaluation of Quality and Interchangeability of Medicinal Products

Evaluation of Quality and Interchangeability of Medicinal Products:

Evaluation of Quality and Interchangeability of Medicinal Products Finished Pharmaceutical Products Stability/Shelf-life specification Matrixing and bracketing Presenter: Deus K. Mubangizi , pharmacist, MSc(Pharm.) , Chief Inspector of Drugs, National Drug Authority WHO expert

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.12. Container labelling 3.13. Product information for health professionals 3.14. Patient information and package leaflet 3.15. Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light and to establish a shelf-life for the FPP, to determine the storage conditions and the in-use stability. To know about length of the time and conditions where efficacy, safety and quality of the FPP are maintained

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing Lots included in the study: 1 production batch and 2 of pilot scale manufactured according to the process described in the dossier Pilot scale batch for solid dosage forms is 10% of production scale or 100 000 whichever is greater Parameters susceptible to change over storage should be followed: Organoleptic properties Assay of each API: ±10% of the label claim possible at the end of shelf-life Assay of degradation products Assay of antioxidants and chemical preservatives, check also for their efficacy Dissolution testing (limits should remain unchanged to release) Microbial contamination, sterility, bacterial endotoxins In-use stability data (if applicable)

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing Study should be performed in the claimed commercial packaging (container-closure) Storage conditions and frequency of testing according to ICH Q1A(R2) Minimum stability data to be submitted at time of submission: 12 months long term ICH 25°C/60% RH, 12 months intermediate ICH 30°C/65% RH and 6 months accelerated ICH 40°C/75% RH with exception according to Supplement 2 to the Main Generic guide Unless otherwise justified, 30°C / 65% RH is the recommended storage condition for Prequalification Definition of "significant change" is the same as ICH Q1A (R2) see later slide

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP):

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water loss in low relative humidity condition). The storage condition will be long term ICH 25°C / 40% RH and accelerated 40°C/25% RH Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments Supplement 2: tentative 2 year re-test period and /or shelf-life may be accorded to APIs and corresponding solid forms (tablets and capsules) listed in Supplement 2 based only on 6 months accelerated data and 6 months long term data Long term stability should anyhow be followed to cover the whole shelf-life accorded


SPECIFICATIONS Should include those attributes that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy Should cover as appropriate, the physical, chemical, biological and microbiological attributes, preservative content and functionality tests (e.g. for a dose delivery system) Analytical procedures should be fully validated and stability indicating Shelf life acceptance criteria should be derived from consideration of all available stability information


SPECIFICATION cont’ Justifiable differences between the shelf life and release acceptance criteria based on evaluation of stability data and changes observed on storage Any differences between release and shelf life acceptance criteria for antimicrobial preservative content to be supported by development data A single, primary stability batch should be tested for antimicrobial preservative effectiveness (in addition to preservative content) whether there is a difference between the release and shelf life acceptance criteria for preservative content or not


TESTING FREQUENCY Long-term conditions : every 3 months over the first year, every 6 months over the second year and annually thereafter Accelerated storage conditions: minimum of 3 points including the initial and final time points (e.g. 0, 3, & 6 months) from a 6-month study When testing at the intermediate storage condition is called for as a result of significant at the accelerated storage condition, a minimum of 4 time points, including the initial and final time points (e.g. 0, 6, 9 & 12 months) from a 12-month study is recommended. Reduced designs i.e. matrixing or bracketing can be applied, if justified


STORAGE CONDITIONS Thermal stability, and if applicable, sensitivity to moisture or potential for solvent loss The storage conditions and lengths of studies chosen to cover storage, shipment and subsequent use Stability testing of the finished product after constitution or dilution to labelling, storage condition and in-use period of the constituted or diluted product Long term studies : minimum of 6 months duration (1 st option) and 12 months (2 nd option) at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life


STORAGE CONDITIONS cont’ General Case STUDY STUDY CONDITION MIN TIME PERIOD Long term* 25 ±2 º C/60±5%RH or 6 months (option 1) 30±2 º C/65±5%RH 12 months (option 2) Intermediate 30±2 º C/65±5%RH 6 months Accelerated 40 ±2 º C/75±5%RH 6 months * It is up to applicant to decide whether long term stability studies are conducted at either of the conditions. If 30±2 º C/65±5%RH is chosen, then no additional data under intermediate conditions will be generated


STORAGE CONDITIONS cont’ If “significant change” occurs under accelerated studies, additional testing at the intermediate storage condition required A “significant change” can be defined as A 5% change in assay from its initial value Any degradation product exceeding its acceptance criterion Failure to meet acceptance criteria for appearance, physical attributes, or functionality tests (e.g. colour, phase separation, resuspendability, caking, hardness, dose delivery per actuation) Some changes in physical attributes (e.g. softening of suppositories, melting of creams, partial loss of adhesion for transdermal products) may be expected under accelerated conditions


IN-USE STABILITY TESTING The content of multi-dose containers, due to repeated opening and closing A minimum of 2 batches, at least pilot scale batches, should be subjected to the test. At least one should be chosen towards the end of its shelf-life Test design should simulate the use of the product in practice including fill volume, dilution/constitution before use The determined in-use shelf life should be stated on the label


IMPERMEABLE CONTAINERS Sensitivity to moisture or potential for solvent loss is not of concern as there is a permanent barrier to passage of moisture or solvent Therefore stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity conditions


FFP IN SEMI-PERMEABLE CONTAINERS Aqueous based products packaged in semi-permeable containers should be evaluated for potential water loss Studies should be carried out at low relative humidity to demonstrate that container can withstand low relative humidity environments A 5% water loss is considered significant after an equivalent of 3months at 40±2 º C/ NMT 25%RH; however for small container i.e. 1ml or unit-dose products, this may be appropriate if justified


FFP INTENDED FOR REFRIDGERATOR STORAGE STUDY STUDY CONDITIONS MIN. TIME PERIOD Long term 5 ± 3 º C 6 months (option 1) 12 months (option 2) Accelerated 25±2 º C/60±5%RH 6 months Significant change after 3-6months under accelerated the proposed shelf life should be based on real-time data Discussion should be provided to address the effects of short term excursions e.g. during shipment supported by testing of a single batch for a period shorter than 3 months but with more frequent testing than usual


STABILITY COMMITMENT When available long-term stability data does not cover the proposed shelf life, a commitment should be made to continue stability studies in order to firmly establish the shelf life Such data should be submitted once available Where the data submitted is from fewer than 3 production batches, a commitment should be made to continue the long-term studies with additional production batches, to a total of at least 3 If the submission does not include data on production batches, a commitment should be made to place the first 3 production batches on long-term studies through the proposed shelf life and through 6months of accelerated study conditions


EVALUATION A systematic approach to presentation and evaluation of the data Degree of variability of individual batches to be evaluated Where the data show little degradation and variability that it is apparent from looking at the data that the requested shelf life can be granted, it is not necessary to go through formal statistical analysis Evaluation should not be limited to assay, but consideration of degradation products, appropriate attributes, adequacy of the mass balance and different stability and degradation performance

Extrapolation of data:

Extrapolation of data Limited extrapolation of the real-time data from long-term studies beyond the observed range to extend the shelf life may be applied on condition that: - mechanisms of degradation are known - results of accelerated stability testing are available - there is goodness of fit of any mathematical model to be used - supporting stability data exists The assumption is that the same degradation relationship will continue to apply beyond the observed data


SHELF LIFE The expiration period of a product should be calculated from the date of release of that batch The date of release should, under normal circumstances, not exceed 30days from the date of production If batches are released exceeding 30days from the production date, the date of production i.e. the date that the first step is performed involving combining the active with the other ingredients, should be taken as the start of the shelf life

Slide 23:



INTRODUCTION It is possible to reduce the scheduled test points where the stability of the samples tested represents the stability of all the products in the range being assessed This allows the saving of resources whilst providing acceptable proof of stability


DEFINITIONS BRACKETING The design of a stability schedule such that at any time point, only the samples on the extremes e.g. of container size and/or dosage strengths are tested. The design assumes that the stability of the intermediate condition samples is represented by the extremes MATRIXING The statistical design of a stability schedule so that only a fraction of the total number of samples are tested at any specified sampling point. At a subsequent sampling point, different sets of samples of the total number would be tested. The design assumes that the stability of the samples tested represents the stability of all the samples


PRECONDITIONS The concept of using a reduced testing plan is acceptable only for products which are closely related Where either bracketing or matrixing are used, the stability testing protocol should be justified by making use of stability data for both the API and the finished product To justify bracketing around batches, it should be shown that batch to batch variability is small It should be implied that not all the batches have to be started simultaneously i.e. the batches could be staggered compared to each other and the start of analysis


APPLICATION BRACKETING Can be used for the testing of a new drug product available in 3 different strengths, in 2 types of packaging material and for one of these types, three different pack sizes PACK TYPE DOSAGE STRENGTH 50MG 75MG 100MG A B C A B C A B C Blister x x x (x) (x) (x) x x x HDPE/15 x x x (x) (x) (x) x x x HDPE/100 (x) (x) (x) (x) (x) (x) (X) (x) (x) HDPE/500 x x x (x) (x) (x) x x x


APPLICATION MATRIXING It provides a systematic test protocol which ensures that ALL product strengths, types of packaging materials, pack size etc, are tested to THE SAME EXTENT. Unlike bracketing, none of the product strengths, pack sizes, or product variants are excluded from testing The applicant should demonstrate that the design is valid and will ensure that the testing of all variables is approximately evenly distributed (use of statistical programs)


ACCEPTANCE It will normally be acceptable to apply bracketing or matrixing in the following cases: Strength (small or no change in proportion of ingredients); strength (where these are applied simply changing/varying the amount of active and one or two major ingredients); container size (same contact materials); closure systems of demonstrated equivalence; different manufacturing sites (same company); batch size In the following cases applying matrixing will normally be acceptable Strength (significant change in proportion of ingredients or change in one or two minor components; orientation of container; fill volumes of containers; containers (different contact materials); closure systems (non-equivalent performance); manufacturing process; manufacturing site (different company)



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