Chemistry and manufacture of products (Part 2)

This is a guideline about the types of information you can submit to address the safety criteria for veterinary chemical products. It also provides guidance on how the information might be presented and analysed, and should be considered in conjunction with any guidelines the APVMA has made or adopted that are specific to the type of product for which you intend to demonstrate safety.

This guideline applies to non-immunobiological veterinary chemical products only. The chemistry and manufacturing data that should be provided for immunobiological products can be found in the APVMA’s specific guidelines section.

The information submitted with an application for a veterinary chemical product must satisfy us that the use of the product in accordance with the APVMA-approved instructions is not, or would not be:

• an undue hazard to the safety of people exposed to it during its handling or to people using anything containing its residues
• likely to have an effect that is harmful to human beings
• likely to have an unintended effect that is harmful to animals, plants, things or the environment.

For further information on the safety criteria, see Satisfying the statutory criteria.

1. Introduction

This section sets out the chemistry and manufacturing data that should be provided to the APVMA in support of an application for the registration of a veterinary chemical product.

Different chemistry and manufacturing data, as included in separate guidelines, may be provided for certain product types.

The APVMA has adopted the quality guidelines of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH), subject to certain changes to reflect particular Australian conditions.

Where the VICH guideline specifies that it is for new veterinary drugs substances (active constituents) and new medicinal products (for example, VICH GL11(R) and GL39), we consider that it should be applicable to all veterinary product applications (such as generic veterinary chemical products). You should justify any deviation from the VICH guidelines, including those that are indicated to apply only to new active constituents and veterinary products.

For further guidance on submitting chemistry and manufacture data in support of veterinary chemical product registration you may also wish to view the ‘guidance for industry documents for veterinary chemical product (drug product) submissions’ available from the websites of:

• the US Food and Drug Administration, Center for Veterinary Medicine
• the veterinary medicines area of the European Medicines Agency
• the Veterinary Drugs Directorate of Health Canada.

2. Formulation type/pharmaceutical dosage form

The formulation type/pharmaceutical dosage form is the form in which the product is presented for veterinary use. You should indicate the type of formulation to be registered.

If the product formulation is to be reconstituted before use, the formulation type or pharmaceutical dosage form of the end-use formulation should be indicated.

A nanomaterial is any substance intentionally produced, manufactured or engineered to have unique properties or specific composition at the nanoscale—that is, a size range typically between 1 nm (nanometre) and 100 nm. It is either a nano-object (that is, confined in one, two or three dimensions at the nanoscale) or has a nanostructure (having an internal or surface structure at the nanoscale). Aggregates and agglomerates are considered to be nanostructured substances. Where size distribution shows that, by number of particles, 10 per cent or more of a substance is at the nanoscale, the substance will be considered a nanomaterial for risk assessment purposes.

If the product has nanoscale properties, they should be indicated.

3. Formulation composition

The formulation composition describes the qualitative and quantitative formulation of the product. You should provide:

• the constituent name, which is the common name, the complete chemical name (IUPAC, CA name) if a common name does not exist, or the proprietary name for components that are complex mixtures
• the CAS registry number, if available
• the constituent standard, which allows us to assess the purity, quality and risk associated with each constituent present in the product
• the concentration (including stability overages), which is the amount of each constituent in the formulation
• the purpose in the formulation, which is the function of each constituent.

Batch analyses or certificates of analysis from the manufacturer or supplier of each constituent should be included to allow us to assess compliance with the nominated standard.

If a pharmacopoeial standard exists, the constituent should comply with the recent monograph. The pharmacopoeial standard should be European Pharmacopoeia (Ph. Eur.), British Pharmacopoeia (BP or BP (Vet)), United States Pharmacopeia (USP), or any other pharmacopoeia recognised by the APVMA. Where a pharmacopoeial standard does not exist, you should provide details of the manufacturer’s specifications.

VICH GL39 and GL40 provide test procedures and acceptance criteria for active constituents, raw materials and excipients. The tests and limits in the manufacturer’s specification for an active constituent should include the universal and specific tests described in VICH GL39 (as appropriate). You should consider impurities according to GL10(R) and residual solvents according to VICH GL18(R) .

If any constituent used in the product has nanoscale properties, they should be indicated.

Where an active constituent is formed in situ (for example, by chemical reaction), both the starting material(s) and the active constituent should be described.

If materials (active and non-active constituents) of animal origin are used, you should provide evidence that they are free of bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathies (TSEs). You should provide the biological source, country of origin, manufacturer details and Department of Agriculture, Fisheries and Forestry (DAFF) import permit. Refer to the DAFF guidelines for managing the risk of transmitting BSE and TSEs for more information.

The formulation composition should not include raw materials used in the manufacture that are not present in the final product formulation. For example, if a solvent is used as an aid in the process and removed in the final stages, that solvent should not be included in the formulation composition details.

Desiccants and inert gases should not be included in the formulation composition details.

Overages of constituents should only be included in the formulation composition details if they are included for storage stability purposes. Manufacturing loss overages should be noted in the manufacturing process details only.

4. Manufacturing process

You should provide a detailed description of the production-scale manufacturing process to allow us to establish that the process is capable of consistently delivering high-quality product, that each step of the manufacturing process is appropriately controlled and that the finished product meets all quality attributes including specifications.

The production scale batch size (for example, in litres or kilograms) should be stated. For sterile products, you should describe the sterilisation process in detail. If applicable, you should describe nanoscale processes in the product manufacturing process.

You should provide details of the quality control procedures that ensure the batch-to-batch consistency and reproducibility of the product. This includes the in-process quality control checks performed at various stages of the manufacture, processing and packaging of the product. Testing should include the specifications and tests for pivotal and key/critical intermediates.

5. Product specifications

A specification is a list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described. It establishes the set of criteria to which a product should conform. You should provide product specifications to allow us to assess whether the product is of an acceptable quality for its intended use.

The tests (parameters) for product specifications should cover those features susceptible to change during storage and likely to influence quality, safety and/or efficacy. The tests and limits generally applicable to all products and for particular formulation type/dosage forms are given in VICH GL11(R),GL39 and GL40.

Limits of acceptance should relate to the release limits, and shelf-life specifications should allow acceptable and justifiable deviations from the release specification based on the stability evaluation and the changes observed in storage. The acceptance criteria should include suitable upper and lower limits for the active constituent content (assay), and descriptive, lower–upper or maximum limits of other test parameters as appropriate. The specification limits should take into account the use of any overages in the formulation. A clear distinction should be made between the release specification (the limits for each batch at the time of manufacture) and the expiry specification (the limits with which any sample should comply during its shelf life).

You should include the nanoscale properties of the product, if applicable, in the specification.

You may also wish to view the guidance for industry documents for veterinary chemical products (drug) available from the websites of the US Food and Drug Administration, Centre for Veterinary Medicine and the Veterinary Drugs Directorate of Health Canada for further information on specifications for veterinary chemical product registration.

6. Batch analysis

You should provide batch analysis data to allow us to validate the manufacturing and quality control processes and determine whether the product is manufactured consistently to meet the product release specifications at each of the proposed sites of manufacture. Results for a minimum of three pilot or production scale batches of the product should be provided. The data should include test results for all parameters listed in the product specifications.

If applicable, the nanoscale properties of the product should be demonstrated.

7. Stability data

You should provide stability data to allow us to assess how the product varies over time under a variety of conditions, such as temperature, humidity, light and heat. VICH GL3(R), GL4, GL5, GL8, GL17, GL45 and EMEA/CVMP/424/01 provide information on stability design and testing protocols. Because veterinary chemical products are date controlled, a suitable shelf life should be proposed based on the stability of the product in an Australian climate. Australia has climatic conditions encompassing VICH zones I to IV.

Data from stability studies should be provided on a minimum of three pilot or production scale batches of the product. The batches should be manufactured at the nominated site of manufacture. The product should be tested in the same containers (packaging material) and with the same closure system as proposed for registration.

The product label storage instructions relevant to an Australian climate and the recommended temperature and relative humidity design for stability tests are as shown in Table 1.

You should provide a statistical analysis of the stability data in accordance with VICH GL51. The guideline provides recommendations on establishing the shelf life for products intended for storage in climate zones I and II only. You should ensure that the stability data provided are appropriate to support the shelf life of the product under Australian climate conditions (I–IV).

The need for stability overages of constituents in the product should be supported by the statistical analysis of the storage stability data.

You should provide cold temperature stability data for liquid formulations to allow us to assess any adverse impact. You may, as an alternative, consider a label statement warning against exposure to storage at low temperature (for example, freezing).

You should provide stability data after the first opening of the container for parenteral and other sterile products in multi-dose containers to allow us to assess the in-use stability of the product/packaging. You may, as an alternative, consider a label statement that instructs the user to discard any unused product within 24 hours of first broaching the container or in the case of eye and ear preparations four weeks after first opening the container.

You should provide stability data for products that are reconstituted or diluted before use and are claimed or implied to be stable when stored for a certain period.

A shelf life can be approved for certain product types under certain circumstances without stability data being provided. The situations in Table 2 may be applicable.

You should demonstrate the nanoscale stability of the product, if applicable.

You should note that the approved shelf life for the product will only be based on the stability data provided at the time of the application. A commitment to continue the stability studies is not sufficient to support a longer shelf life

8. Analytical method and validation data

You should provide analytical method and validation data to allow us to assess the quality and adequacy of the control processes. Harmonised methods, such as those found in the European, United States and Japanese pharmacopoeia, should be used where applicable. A full description of the analytical procedures used for testing of the product should be provided, including:

• full details of the analytical methods (including method numbers)
• the purity of the reference standards
• where chromatographic and spectroscopic techniques are used, representative chromatograms and spectra of the reference standard, veterinary chemical product and placebo, labelled with batch number, peak identity and peak integration data (if appropriate)
• worked examples of the calculations.

Method validation data should be provided to allow us to assess the suitability of the method for its intended use. Details of the validation of analytical procedures are provided in VICH GL1 and GL2. Typical validation characteristics that should be considered for validation are in VICH GL1.

If we have assessed the analytical methods in a previous application, you may reference the data provided in that application. However, if the formulations are not identical, you should provide specificity and recovery (accuracy) data to demonstrate that the analytical method is appropriate for use on the new formulation.

You should provide the nanoscale aspects of the product analytical methods if they are relevant.

9. Packaging

You should provide a description of the primary container and closure system, including the composition of the construction materials of each primary packaging component and its specification. The pack size(s) should be provided. Any desiccant or inert gas added to the container for stability purposes should be identified. You should discuss the integrity of the container in terms of its compatibility with the product (including sorption to container and leaching) and its performance in protecting the product physically and in protecting it from moisture and light.

The integrity of the container should not be impaired by the product it contains, nor should the product be adversely affected by the packaging material.