GL3 (R) – Stability Testing of New Veterinary Drug Substances and Medicinal Products (+ Annex GL 4 - Requirements for New Dosage Forms)

Presentation Plan General objective / scope of guideline GL 3 Terminology used for stability testing General principles for designing stability studies and evaluating data: Stress testing / Forced degradation Design of formal stability studies Stability commitment Evaluation of data Statements/Labeling Additional guidance for new dosage forms (GL 4)

General objective / scope of the guideline Objective of the guideline: It defines recommended stability data to establish re-test periods for new drug substances, shelf lives for new drug products and recommended storage conditions for registration in climatic zones I and II. Alternative approaches can be used when scientifically justified.

General objective / scope of the guideline What is not covered by the guideline: information to be submitted for abbreviated / abridged applications or variations. specific details on sampling procedures specific requirements for particular dosage forms. specific requirements for climatic zones III or IV Stability testing following first use (e.g. first broaching of a vial) formal labeling requirements label requirements are established by national/regional requirements

General objective / scope of the guideline Link with other VICH stability guidelines: VICH GL3 is the parent VICH stability guideline. It presents the general principles applicable to all new drug substances and new medicinal products. More details on some specific dosage forms or on some aspects of the methodology are provided in annex guidelines: Further guidance on new dosage forms, medicated premixes and biotechnological/ biological products can be found in VICH guidelines GL4, GL8 and GL17 respectively. Further guidance on bracketing/matrixing (i.e. reduced design studies) and on statistical evaluation of data can be found in VICH guidelines GL45 and GL51 respectively.

Terminology to be used in registration applications Definitions pertaining to label claims: Re-test period (only applicable to drug substances): period of time during which the drug substance is expected to remain within its specification and can be used during the manufacture of a given medicinal product without re-testing before use (provided it has been stored under the defined conditions). Shelf life (for medicinal products and some drug substances: biotechnological/biological substances, certain antibiotics): time period during which the product/substance is expected to remain within shelf life specification (provided it is stored under recommended conditions).

Terminology to be used in registration applications Definitions pertaining to the type of stability studies presented in the registration package: Formal stability studies: all long-term, accelerated and intermediate conditions studies undertaken on primary and/or commitment batches to establish a re-test period or a shelf life. Long term testing: stability studies conducted under the recommended storage condition for labelling. Accelerated testing: stability studies designed to increase the rate of degradation/physical change by using exaggerated storage conditions. Study results can used to evaluate the effect of short term excursions outside the label storage conditions (such as might occur during shipping). Intermediate testing: studies conducted at 30°C/65%RH and designed to moderately increase the rate of chemical/physical degradation for a drug substance or medicinal product intended to be stored at 25°C.

Terminology to be used in registration applications Definitions pertaining to the type of batches placed in formal stability studies: Primary batch: batch used in a formal stability study from which data are submitted in a registration application for the purpose of establishing a re-test period or a shelf life. Commitment batch: production batches of a drug substance or a medicinal product for which stability are initiated or completed post approval through a commitment made in the registration application. Production batch: batch manufactured at production scale by using the production equipment in a production facility as specified in the application. Pilot batch: batch manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. For solid dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale.

General principles for designing stability studies and evaluating data for drug substances and medicinal products For both drug substances and medicinal products, the guideline addresses recommendations for: Stress testing Design of formal stability studies: Selection of batches Container closure system Specification Storage conditions Testing frequency Products to be constituted/diluted before use Stability commitment to authorities Evaluation of stability data Statements/Labeling

Stress testing to carry out before the formal stability studies

Stress testing: WHY? Forced degradation studies are necessary to: Identify the likely degradation products and help establish the degradation pathways and the intrinsic stability of drug substances. Assess the risk of degradation of the active substance as raw material & as component of the drug product, and assess the need for precautionary measures (e.g. for protection from oxidation, humidity, light exposure). Develop suitable stability indicating analytical procedures for both drug substances and medicinal products.

Stress/Forced degradation testing: WHAT? HOW? Studies to perform Section Drug Substances Stress testing is likely to be carried out on a single batch. It should include the effect of temperature (in 10°C increments above that of accelerated testing), humidity where appropriate (75%²RH or higher), oxidation and photolysis (as per VICH GL 5), hydrolysis across a wide range of pH when in solution or suspension. Results of these studies form an integral part of the information provided to regulatory authorities. 2.1.2 Medicinal products Photostability testing should be conducted on at least one primary batch of medicinal product if appropriate The systematic stepwise approach to assess photostability of medicinal products and the recommended procedure for light exposure are described in VICH guideline GL 5. NB: it is not always necessary to perform photostability studies of the medicinal product in its container closure system. Refer to VICH GL 5 for more details. 2.2.2

Design of formal stability studies: Selection of batches Container closure system Specification Testing frequency Storage conditions

Design of formal stability studies: Selection of batches

Selection of batches for formal stability studies: WHY? In order to provide reliable information on the stability of drug substances and medicinal products at the time of regulatory submission and confirm stability on batches fully representative of commercial batches, it is required to: Launch all formal stability studies on batches whose overall quality is representative of the quality to be made on a production scale. Have the retest period/shelf life of drug substances/ medicinal products ultimately confirmed by at least three production batches (may be achieved post-approval, through regulatory commitments).

Selection of batches for formal stability studies: WHAT? HOW? Characteristics of batches presented in the stability registration package Section Drug Substances Data from formal stability studies should be provided on at least three primary batches (batches manufactured to a minimum of pilot scale by the same synthetic route as, and using the same method of manufacture and procedure that simulates the final process to be used for, production batches. The overall quality of the batches placed on formal stability studies should be representative of the quality of the material to be made on a production scale. Other supporting data can be provided (*). 2.1.3 *Supporting data (definition): data, other than those from formal stability studies, that support the analytical procedures, the proposed re-test period or shelf life, and the label storage statements. Such data include: stability data on early synthetic route batches of drug substance, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing; information regarding test results on containers; other scientific rationales.

Selection of batches for formal stability studies: WHAT? HOW? Characteristics of batches presented in the stability registration package Section Medicinal products Data from formal stability studies should be provided on at least three primary batches (batches of the same formulation and packaged in the same container closure system as proposed for marketing, manufacturing simulating that to be applied to production batches. Two of the three batches should be at least pilot scale batches, and the third one can be smaller if justified. Where possible, batches of the medicinal product should be manufactured by using different batches of the drug substance. Stability studies should be performed on each individual strength and container size of the medicinal product unless bracketing is applied (see VICH GL 51 for more guidance on matrixing/bracketing approaches).  Other supporting data can be provided (*). 2.2.3 *Same comment as for drug substances

Design of formal stability studies: Container closure system

Container closure system for formal stability studies: WHY? The stability of the drug substance is dependent on the packaging where it is stored. The stability of the medicinal product is dependent on the container closure system. Definition of a container closure system (glossary of VICH GL 3): “The sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components if the latter are intended to provide additional protection to the medicinal product.”

Container closure system of formal stability studies Container closure system for formal stability studies: WHAT? HOW? Container closure system of formal stability studies Section Drug Substances The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. 2.1.4 Medicinal products Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary packaging and container label). In some cases, a smaller container closure system simulating the actual container closure system for marketing may be acceptable (justification required). Any available studies carried out on the medicinal product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively. 2.2.4

Design of formal stability studies: Specification

Specification for formal stability studies Section General requirements Specifications should comply with recommendations of VICH GL39 and GL40. Stability studies should include testing of attributes susceptible to change during storage and likely to influence quality, safety, and/or efficacy (physical, chemical, biological, and microbiological attributes). Validated stability-indicating analytical procedures should be applied. 2.1.5/ 2.2.5 Other specific requirements for drug substances Specification for degradation products in a drug substance should comply with VICH guideline GL 10. 2.1.5

Specification for formal stability studies Section Other specific requirements for medicinal products List of tests and analytical procedures: The rationale for the selection of attributes should be stated by the applicant. Stability specification should be established considering:  Compliance of degradation products acceptance limits with VICH guideline GL 11  Testing of preservative content when the formula contains preservative agents (e.g., antioxidant, antimicrobial preservative)  Testing of functionality (e.g., for a dose delivery system) when relevant Shelf life acceptance limits: shelf life acceptance criteria should be derived from the analysis of all available stability information. When relevant, the concept of different acceptance criteria for release and shelf life specification should be applied. Preservative effectiveness of the formula throughout shelf life: any differences between release and shelf life acceptance criteria for antimicrobial preservative content should be supported by data demonstrating preservative effectiveness of a development batch of the proposed formulation artificially prepared to contain the lowest permitted levels of the antimicrobial preservative(s) according to the shelf- life specification. A single primary stability batch should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for verification, regardless of whether there is a difference between the release and shelf life acceptance criteria for preservative content. 2.2.5

Design of formal stability studies: Storage conditions

Storage conditions: WHY RECOMMENDATIONS? Storage conditions of formal stability studies depend on intended storage conditions for storage, shipment and use The concept of having stability studies carried out in accelerated and/or intermediate storage conditions is recommended to: Investigate the effect of excursions outside the long-term storage conditions Support registration with limited data in long-term condition at the time of submission (with scientific justification) VICH GL 3 provides recommendations for this approach

Storage conditions: WHAT ARE THE STANDARD LONG-TERM CONDITIONS? Long-term storage conditions to consider for defining the storage conditions of formal stability studies are: General case (storage not above 25°C or 30°C). For aqueous*-based medicinal products, there are two cases: Containers are impermeable  general storage conditions are applicable Containers are semi-permeable  specific storage conditions may be required to demonstrate that the product withstands low humidity conditions (no significant water loss) Storage in a refrigerator Storage in a freezer Storage below -20°C * Also to consider for other solvent-based medicinal products for which solvent loss may occur during storage.

Storage conditions for formal stability studies Storage conditions: WHAT IS THE CONCEPT OF ACCELERATED AND INTERMEDIATE CONDITIONS (also see definitions in slide 6)? This concept supports early evaluation of re-test periods and shelf lives + label recommendations on temperature excursions (but is not applicable in all cases): * If 30°C is the long term condition, there is no intermediate condition. (1) 6 months may be sufficient (difference with human medicines (ICH) for which 12 months is required) Storage conditions for formal stability studies Intended label long-term storage conditions Long term Intermediate Accelerated General case (Storage not above 25°C or 30°C) 25°C/60%RH or 30°C/65%RH 30°C/65%RH* 40°C/75%RH Aqueous-based product in semi-permeable containers 25°C/40%RH or 30°C/35%RH 40°C/NMT 25%RH Refrigerated storage (5°C) 5°C - 25°C/60%RH Frozen storage (-20°C) -20°C Below -20°C Case-by-case Duration of stability study Until re-test period / shelf life Until min. 12 months Until min. 6 months Minimum results to be provided at the time of regulatory submission Drug substance: 12 months Medicinal product: 6 months (1) 6 months (1) (if significant change at the accelerated condition) 6 months

Storage conditions: STORAGE CONDITION TOLERANCE Actual temperature and humidity* should be controlled and monitored during stability storage. Variations around the target storage conditions cannot be avoided (e.g. short term spikes due to opening of the doors of the storage facility). What are the variations acceptable to obtain valid stability data? Temperature: +/- 2°C for conditions with a temperature above 5°C +/- 3°C for the 5°C condition +/- 5°C for the -20°C condition Humidity: +/- 5% RH* What if equipment failure leads to excursions that exceed the defined tolerances for more than 24 hours? The impact on stability results should be assessed The failure should be described in the study report * Controlled humidity conditions are not required if the medicinal product is packaged in impermeable containers.

Storage conditions: WHAT USE OF ACCELERATED/INTERMEDIATE CONDITIONS RESULTS? What is looked at when analysing results at accelerated and intermediate conditions? The general principle is that, if significant changes of the quality of the drug substance or the medicinal product are observed at accelerated and/or intermediate conditions: Specific instructions may be required on the labelling to address excursions outside the recommended long-term storage conditions Extrapolation of the re-test period/shelf life may be impossible (proposed re-test period/shelf life to be based only on real time data available from the long term storage condition), or Extrapolation of the re-test period/shelf life may be limited Further guidance on statistical analysis and on extrapolation rules (decision tree) are provided in VICH guidance GL51

Storage conditions: WHAT IS A SIGNIFICANT CHANGE? Drug substance: Failure of compliance with specification Medicinal product: 5% change in assay from initial value Any degradation product exceeding its acceptance criterion Failure for appearance, chemical, physical attributes or functionality test (e.g. pH, dissolution, re-suspendibility, hardness…) 5% water (or solvent) loss for medicinal products packaged in semi-permeable containers after an equivalent of 3 months’ storage at 40°C/NMT 25%RH

Design of formal stability studies: Testing frequency

Testing frequency: WHY? HOW? Frequency of testing should be sufficient to establish the stability profile of the drug substance or the medicinal product at each storage condition tested. Study Testing frequency* Long term   1rst year: every 3 months 2nd year: every 6 months Yearly after Intermediate Every 3 months for 1 year. When performed as a result of significant changes at the accelerated condition: 4 time points from a 12 month study is recommended. Accelerated  Minimum three time points (0, 3 and 6 months) *Matrixing, where the testing frequency is reduced, can also be applied for medicinal products, if justified (see VICH GL 45 for more details).

Design of formal stability studies: Particular case of products to be constituted/diluted before use

Design of formal stability studies: Medicinal products to be constituted or diluted before use Particular case of medicinal products to be used after constitution or dilution: Stability testing should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted/diluted product. Testing should be performed on the constituted/diluted product through the proposed in-use period on primary batches as part of the formal stability studies at initial and final time points. If full shelf life long term data will not be available before submission, minimum 12 months testing results of the constituted/diluted product should be provided.

Design of formal stability studies: Reduced designs based on bracketing or matrixing principles

Design of formal stability studies: Use of bracketing or matrixing reduced designs Use of bracketing or matrixing reduced designs: For medicinal products, reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified. Further guidance on bracketing / matrixing designs is provided in VICH guideline GL 45. Further guidance on statistical evaluation of stability data generated using bracketing or matrixing principles is provided in VICH guideline GL 51.

Design of formal stability studies: Use of bracketing or matrixing reduced designs Definition of bracketing: Design of a stability schedule where only samples on the extremes of certain design factors (e.g., strength, package size) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Factors considered for bracketing can be for instance: Dosage strengths: where a range of strengths is to be tested, bracketing is applicable if strengths are identical or very closely related in composition. Packaging sizes: bracketing can be applied to different container sizes or different fills in the same container closure system.

Design of formal stability studies: Use of bracketing or matrixing reduced designs Definition of matrixing: Design of a stability schedule where all factor combinations are tested in the schedule but where, at each specified time point, only some factor combinations are tested. The design assumes that the stability of each subset of samples tested at a given time point represents the stability of all samples. Factors considered for matrixing can be for instance: Different batches Different strengths Different sizes of the same container closure system Possibly in some cases, different container closure systems .

Stability commitment to authorities

Stability commitment to authorities: WHY? A re-test period or shelf life should be ultimately supported by three production batches followed in VICH stability conditions (at long- term/accelerated/intermediate conditions, as appropriate) When full data will not be available before regulatory approval is granted, the applicant should commit to have the VICH stability program achieved post approval

Stability commitment to authorities: WHAT? Commitment should ensure, as appropriate, that: Long-term stability studies will be continued until re-test period/shelf life, intermediate studies until 12 months and accelerated studies until 6 months Additional next production batches will be placed in stability to obtain a total of at least three production batches followed in VICH stability according to the same protocol as primary batches VICH GL 3 guideline details the three types of commitments to be provided to authorities depending on the content of the stability package provided before approval

to establish re-test periods/shelf lives Evaluation of data to establish re-test periods/shelf lives

Evaluation of data to establish re-test periods/ shelf lives: WHAT? What data to evaluate? Evaluation of stability data should consider not only the assay but also the degradation products and other appropriate attributes i.e. physical, chemical, biological, microbiological tests, particular attributes of the dosage form: e.g. dissolution rate of solid oral dosage forms Where appropriate, attention should be paid to reviewing the adequacy of the mass balance and different stability and degradation performance.

Evaluation of data to establish re-test periods/ shelf lives: HOW? If data show so little degradation and so little variability that it is apparent from looking at the data that the requested re- test period/shelf life will be granted it is normally unnecessary to go through formal statistical analysis. Providing a justification for the omission should be sufficient If an evolution or a variability of a quantitative attribute is observed further analysis is necessary

Evaluation of data to establish re-test periods/ shelf lives: HOW? How further analyze stability data? An approach for analyzing data is to determine the time at which the 95% one-sided confidence limit intersects the acceptance criterion: Batches can be combined for analysis if intercepts and/or slopes are not significantly different. If not possible, the re-test period/shelf life should be based on the worst case batch Limited extrapolation of real time data from the long-term storage condition can be undertaken at approval time if justified (based on knowedge of degradation mechanism, results under accelerated conditions, goodness of fit of the mathematical model, existence of other supporting data, adequacy of mass balance…). Further guidance on statistical analysis and extrapolation rules is provided in VICH guideline GL 51

Statements/Labeling

Statements/Labeling A storage statement should be established for the labeling in accordance with relevant national/regional requirements The storage statement should be based on the evaluation of stability data. Where applicable, specific instructions should be provided, particularly when freezing cannot be tolerated Terms such as “ambient conditions” or “room temperature” should be avoided A re-test or expiration date should be displayed on container labels of drug substances if appropriate An expiration date should be displayed on the container label of medicinal products

Guideline GL 4 – Stability Testing for New Veterinary Dosage Forms (Annex to GL 3 guideline)

NEW DOSAGE FORMS: Why a guideline? Scope of the guideline: It addresses the recommendations on what should be submitted regarding stability of new dosage forms by the owner of the original application, after the original submission for new drug substances and products. Why a guideline? New dosage forms can be developed using prior knowledge gained on medicinal products using the same active substance.

NEW DOSAGE FORMS: Definition Definition of a New Dosage Form: A new dosage form is defined as a drug product which is a different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority. Such pharmaceutical product types include products of different administration route (e.g., oral to parenteral), new specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) and different dosage forms of the same administration route (e.g. capsule to tablet, solution to suspension).

NEW DOSAGE FORMS: What to provide? What stability package to provide for submission? In principle, stability protocols for new dosage forms should follow the guidance in the parent GL 3 stability guideline. However, a reduced stability database at submission time may be acceptable in certain justified cases.

Annex to the general presentation of VICH GL 3: VICH stability package to provide for registration For each case of label long-term storage condition

Minimum time period covered by data at submission VICH storage conditions for stability studies of products intended to be stored at 25°C or 30°C General case (storage not above 25°C or 30°C) Study Storage condition Minimum time period covered by data at submission Drug Substance Medicinal Product   Long term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months 6 months Intermediate** 6 months*** Accelerated 40°C ± 2°C/75% RH ± 5% RH * It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. ** If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition. *** If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Testing at the intermediate storage condition should include all tests, unless otherwise justified

Minimum time period covered by data at submission VICH storage conditions for stability studies of products intended to be stored at 25°C or 30°C Aqueous (or solvent)-based medicinal products packaged in semi-permeable containers (storage not above 25°C or 30°C) Study Storage condition Minimum time period covered by data at submission Drug Substance Medicinal product   Long term* 25°C ± 2°C/40% RH ± 5% RH (1) or 30°C ± 2°C/35% RH ± 5% RH (1) - 6 months Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months*** Accelerated 40°C ± 2°C/NMT 25% RH ± 5% RH (1) * It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH. ** If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition. *** If long-term studies are conducted at 25°C ± 2°C/40% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted. (1) An alternative approach to testing in low humidity conditions is to perform the stability studies under higher relative humidity and deriving water loss at the reference relative humidity through calculation (experimental determination of the permeation coefficient of the container closure system or use of water loss rates indicated in section 2.2.7.3 of the guideline).

Minimum time period covered by data at submission VICH storage conditions for stability studies of products intended to be stored in a refrigerator Drug substances or medicinal products intended for storage in a refrigerator Study Storage condition Minimum time period covered by data at submission Drug Substance Medicinal product   Long term 5°C± 3°C  12 months 6 months Accelerated* 25°C ± 2°C/60% RH ± 5% RH If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition, the proposed re-test period or shelf life should be based on the real time data available at the long term storage condition. If significant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during shipping or handling. This discussion can be supported, if appropriate, by further testing on a single batch of the drug substance or the medicinal product for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to test a drug substance through 6 months when a significant change has occurred within the first 3 months.

Minimum time period covered by data at submission VICH storage conditions for stability studies of products to be stored in a freezer or below -20°C Drug substances or medicinal products intended for storage in a freezer Drug substances or medicinal products intended for storage below -20°C: storage conditions should be treated on a case-by-case basis Study Storage condition Minimum time period covered by data at submission Drug Substance Medicinal product   Long term -20°C± 5°C  12 months 6 months The re-test period or shelf life should be based on real time data obtained at the long-term storage condition. In the absence of an accelerated storage condition for drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted, e.g., during shipping or handling. to address the effect of short term excursions outside the proposed label storage condition