Chemistry and manufacture of veterinary active constituents (Part 2)

1. Introduction

All veterinary actives must be approved by the Australian Pesticides and Veterinary Medicines Authority (APVMA) prior to their use in the manufacture of registered veterinary products, or be covered by an exemption from approval.

This guideline provides guidance on the information to submit to address the safety criteria for veterinary active constituents.

The APVMA has adopted the quality guidelines of International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH). VICH is a programme aimed at harmonising technical requirements for veterinary product registration. Where a VICH guideline specifies that it applies to new veterinary drug substances (active constituents), such as VICH GL10(R) and GL39, the APVMA considers the guideline to be applicable to all veterinary active constituents, not just new substances.

The APVMA will accept data that has been submitted to other regulatory authorities, and associated assessment reports. If you intend to submit such data packages and/or assessments, please see Guidance for applicants—submission of international data, standards and assessments.

For further guidance on submitting chemistry and manufacturing data in support of active constituent approval, you may also wish to consider the guidance for industry documents for active constituent (drug substance) submissions available from the following:

The APVMA risk assessment manual for chemistry and manufacture is available online.

This guideline does not apply to immunobiologicals; see Guideline for the registration of new veterinary vaccines for further information.

If, after reading this guideline you are unsure as to the information that you are required to provide to support your application, it is recommended that you request Pre-Application Assistance to obtain clarification.

New active constituents are active constituents that the APVMA has not yet assessed, including pharmacopoeial actives listed in the BP, EP or USP and non-pharmacopoeial actives.

Existing active constituents are active constituents that have been assessed by the APVMA, with known properties.

New sources of active constituent are existing active constituents produced by an additional site(s) of manufacture to those previously approved.

Acceptable pharmacopoeia include: European Pharmacopoeia, British Pharmacopoeia (including the BP (Veterinary), U. S. Pharmacopoeia/National Formulary, or any other publication the APVMA considers to be appropriate.

Pharmacopoeial active constituents are active constituents that meet all listed test parameters in the relevant EP, BP, or USP/NF pharmacopoeia monograph.

Non-Pharmacopoeial active constituents are active constituents which are not listed in an EP, BP, or USP/NF pharmacopoeia monograph, or do not meet all listed pharmacopoeial parameters.

2. Identification of an active constituent

You should provide details of the nomenclature, structure, identity and general properties of the new or existing active constituent.

2.1. Common name

You should nominate the common names for new active constituents. The preferred common name will be the name specified in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). If an active constituent is not listed in the SUSMP, a suitable common name may be found from:

  • World Health Organization—International Non-proprietary Names (INNs)
  • Therapeutic Goods Administration—Approved terminology for medicines—Chapter 1—Australian Approved Names (AANs) for therapeutic substances
  • British Pharmacopoeia (BP)
  • British Pharmaceutical Codex
  • Australian Pharmaceutical Formulary and Handbook
  • British Pharmacopoeia (Veterinary) (BP (Vet))
  • European Pharmacopoeia (Ph. Eur.)
  • United States Pharmacopoeia (USP)
  • Chemical Abstracts Services (CAS)
  • International Union of Pure and Applied Chemistry (IUPAC)
  • A name descriptive of the nature and origin of the constituent (eg Melaleuca alternifolia oil, citronella oil).

A trademark, or trade name cannot be used as an approved name of an active constituent.

2.2. Chemical name

The full chemical name in accordance with the International Union of Pure and Applied Chemistry (IUPAC) must be provided. CAS nomenclature should be provided.

You should include all accepted and proposed non-proprietary names for an active constituent—for example, the International non-proprietary name (INN), United States adopted name (USAN), British approved name (BAN)—including the names of the approving authorities.

2.3. Chemical Abstracts Service registry number

You should provide the CAS number for an active constituent with a reference to the source of this number. If multiple CAS numbers exist, providing a single, referenced CAS number is sufficient.

If you are unable to supply a CAS number, please indicate the reason (eg not yet allocated).

2.4. Manufacturer’s code numbers and synonyms

Manufacturer, or laboratory code numbers and synonyms should be provided.

2.5. Molecular and structural formula and molecular mass

You should provide the molecular formula, molecular mass and structural formula of a new active constituent. For active constituents existing as salts or hydrates, you should also provide the molecular mass of the free base/acid or anhydrous form. For polymeric compounds, you should provide the molar mass distribution in the form of the mass average molar mass (Mm) and number average molar mass (Mn).

Where relevant, the structural formula should include the stereochemical properties of an active constituent, such as the relative configuration (eg cis/trans, d/l) and absolute configuration (eg E/Z, R/S). Where possible, the structural formula should be given diagrammatically with all known stereochemistry.

2.6. Elucidation of structure and other characteristics

You should provide confirmation of the chemical structure of a new active constituent. The elucidation of structure should be based on appropriate physical and chemical test results. These may include:

  • a description of the synthetic route as evidence of structure
  • an elemental analysis with theoretical values
  • a discussion on ultraviolet spectroscopic characteristics, including pH dependence shifts
  • infrared (IR) spectrometry
  • 1H and 13C nuclear magnetic resonance spectrometry
  • 19F and 31P NMR spectrometry
  • mass spectrometry (MS)
  • any other relevant information to confirm the structure (for example, X-ray diffraction).

3. Physical and chemical properties

You should provide all relevant physical and chemical properties of a new active constituent. The information should include:

  • a general description (appearance, colour, odour and physical state)
  • whether an active is a pure enantiomer, racemate or fixed combination of non-enantiomeric isomers when a new active constituent contains one or more chiral centres
  • specific optical rotation
  • melting point (for solids), boiling point (for liquids), condensation point (for gases)
  • refractive index and density/specific gravity (for liquids)
  • UV absorption maxima and molar absorptivity
  • pH and/or pKa values
  • solubilities in common solvents
  • n-octanol/water partition coefficient (Powor log Pow)
  • dissociation constant, if appropriate
  • if an active constituent can exist in more than one physical form (for example, polymorph, solvate or hydrate), information for the form (or forms) of the constituent that will be used in the manufacture of the product
  • particle-size distribution (including nanoscale particles)
  • the purity of the substance used to generate data.

Provide appropriate descriptions of the methods used to determine the characteristics listed above so the APVMA can be confident in the data supplied. This combined information is needed to satisfy specific aspects of the Agvet Code, including safety, toxicity, composition of degradation products and impurities (Agvet Code Section 5A).

3.1. Nanomaterial properties

A nanomaterial is any substance intentionally produced, manufactured or engineered to have unique properties or specific composition at the nanoscale—that is, in a size range typically between 1 nm (nanometre) and 100 nm—and that is either a nano-object (that is, confined in one, two, or three dimensions at the nanoscale) or 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.

To allow the APVMA to identify and assess the potential risks of nanomaterials, you should or must provide data describing the following characteristics and physical chemical properties:

  • composition and purity (ie specifications)
  • identity
  • morphology
  • structural integrity
  • catalytic or photocatalytic activity
  • particle size/size distribution
  • electrical/mechanical/optical properties
  • surface-to-volume ratio
  • chemical reactivity
  • surface area/chemistry/charge/structure/shape
  • water solubility/dispersibility
  • agglomeration/aggregation (or other properties).

Provide appropriate descriptions of the methods used to determine the characteristics listed above so the APVMA can be confident in the data supplied. This combined information is needed to satisfy specific aspects of the Agvet Code, including safety, toxicity, composition of degradation products and impurities (Agvet Code Section 5A).

4. Stability data

Data describing the inherent stability of a new active constituent should be supplied. The content of an active constituent, any degradation products including toxicologically significant impurities, and other critical characteristics should be monitored initially, and at sufficient sampling frequency during storage to provide an accurate stability profile of an active constituent. The resulting data will be used to determine the appropriate composition and purity of an active constituent over the retest interval, and to determine the safety criteria as required by the Agvet Code, Section 5A.

The results of stability studies (long-term, accelerated, and under various conditions of stress such as heat, light, humidity, acid/base hydrolysis and oxidation) should be provided.

If the active is imported into Australia for local product manufacture, you should propose a suitable re-test period based on the stability of an active constituent in the Australian climate. Australia has climatic conditions encompassing VICH zones I to IV. VICH GL3(R),GL5, GL10(R), GL18(R), GL39, GL45 and GL51 provide information on stability design and testing protocols and data evaluation.

Stability data should address specific aspects of the Agvet Code, such as Section 5a, and Regulation 15(1)(d).

5. Method of manufacture of an active constituent

5.1. Manufacturer and site of manufacture

For any active constituent, you must provide the name and business address of the manufacturer(s) of an active constituent, and the street address of the manufacturing plant(s) in which an active constituent is manufactured.

A manufacturing site should be listed on the approval with their name and manufacturing site address, along with the step or steps of manufacture that the manufacturer undertakes in the manufacturing process if a manufacturer:

  • undertakes a substantial chemical transformation in the manufacture of the active constituent (including the final chemical reaction producing the active constituent, and any steps producing intermediates that are not readily available in the market)
  • undertakes a step that directly affects whether or not an active complies with one or more of the parameters in the specification (for example, a site conducting sterilisation for an active that is specified as being sterile, or a site conducting micronisation for an active manufactured to a specified particle size range should be included. Sites conducting only analysis and testing of the active do not need to be included, as these sites do not themselves affect the quality of the active).

If you are unsure or unable to determine whether a site should be included in your application, please contact the Chemistry section for further guidance.

If an active constituent is to be manufactured at multiple sites with equivalent manufacturing processes manufacturing to the same specifications, you have the option of either submitting subsequent Item 17 applications referring to the file and application numbers of the primary application submitted, or requesting multiple site approvals under the one file and application number (via a variation application under an Item 18). This will depend on whether you wish to have a single approval covering all sites, or an approval for each individual site. You are not required to submit the full data package again, only batch analysis results for each site.

5.2. Description of the manufacturing process

For any new active constituent, or a new source of an existing non-pharmacopoeial active constituent, you should provide a detailed description of the manufacturing process to allow the APVMA to establish that the process is capable of delivering an active constituent of known quality.

5.2.1. Active constituents produced by chemical synthesis

Each step of the manufacturing process should be appropriately controlled. An active constituent is required to meet all quality attributes set out by the manufacturer, including specifications and retest intervals.

The batch size (in litres or kilograms) and scale (pilot or production) should be provided, along with full details of the quality control procedures that ensure batch-to-batch consistency and reproducibility of an active constituent.

You should describe the in-process quality control checks performed at various stages of the manufacture, purification and packaging of an active constituent. Testing should include the specifications and tests for key intermediates.

An appropriate description of the manufacturing process will usually include:

  • an introductory paragraph detailing the number of chemical steps, whether the process is a batch or continuous process, and detail on significant purification steps
  • a detailed description and flow diagram of the synthetic processes, including molecular formulae, chemical structures of starting materials, intermediates, reagents
  • chemical equations of the reactions involved, reflecting stereochemistry, and in-process quality control steps
  • the relative amounts of each starting material and their order of addition
  • reaction conditions (for example, temperature, pressure, pH and reaction times) and the duration and yield of each step of the process
  • information on intermediates that are isolated and purified
  • information on any catalysts used in the manufacturing process
  • if a manufacturing concentrate is produced, details on the final concentration of an active constituent present, the methods used to confirm this concentration, and details of any diluents or additives used.

You should describe the nanoscale processes of an active constituent manufacturing process, if relevant.

5.2.2. Active constituents produced by fermentation

Information on active constituent produced by fermentation should describe the fermentation process in detail, including:

  • the source and strain of microorganism used in the fermentation process
  • strain improvement procedures
  • purity and stability checks
  • cell banking arrangements
  • storage
  • propagation seeding procedures
  • whether or not the microorganism has been deposited in a recognised culture collection such as the American Type Culture Collection, the United States Department of Agriculture or the World Federation for Culture Collections
  • the composition of the media, and details of how the reaction conditions are controlled (times, temperatures, pH, rates of aeration, and name and composition of preservatives)
  • a detailed description of the isolation and purification procedure for an active constituent, including in-process controls used to ensure freedom from potentially pathogenic agents, such as viruses and prions.

5.2.3. Semisynthetic active constituents derived from fermentation

If the starting material for a semisynthetic antibiotic is obtained by fermentation, the description of the starting material should be provided as detailed under section 6.2.2. The information for the synthesis of the final active constituent from the starting material should be provided as described under section 6.2.1.

5.2.4. Feed-grade active constituents produced from fermentation

Feed-grade active constituents are permitted as components of feed—additive drug premixes, which are used in the manufacture of medicated feeds. A feed-grade active constituent is usually derived from fermentation and are usually marketed as unpurified or partially purified products. They commonly contain a large percentage of carbohydrates, amino acids, fatty acids and nucleotides, but may also contain small amounts of toxic components that are not readily isolated or identified.

For this reason, the microbial fermentation process should be described in detail, including specifications for all components of the media and all procedures and precautions employed to prevent contamination or abnormal fermentation. You should include a description of all the in-process tests used to determine quality and yield.

5.2.5. Active constituents of plant origin

For an active constituent of plant origin, the full details of the manufacturing procedure (such as extraction and purification) of the active constituent(s) should be supplied. Your submission should also include:

  • a description of the botanical species
  • the part(s) of the plant used (such as leaf, flower or root)
  • the geographical origin of the plant
  • where relevant, the time of the year harvested.

Due to seasonal variations, it is recommended that you provide data from five or more batches spanning three or more years. These data will provide a reasonable understanding as to the variation of individual components, and a valid base from which to determine the limits of related compounds.

The details of chemical fertilisers, pesticides, fungicides and other agents used during cultivation should be described, if possible.

If there is a pharmacopoeial standard for the plant-origin active, the active should comply with all aspects as stated in that standard.

It may be appropriate to include limits for pesticide residues resulting from such treatments in the active constituent specifications. The absence of toxic heavy metals should also be confirmed.

Normalisation of chromatograms can be undertaken to gain upper and lower concentration variations of the components present. As actives derived from plants are expected to have a significant number of components equal to or greater than 1 g/kg, the main components should be characterised.

You may consider applying for Pre-Application Assistance regarding information that is required prior to generating this information.

5.2.6. Sterile active constituents

For sterile active constituents, the sterilisation process should be described in detail.

5.3. Quality control

You should provide the following information on the measures taken to assure the quality of an active constituent:

  • control of all raw materials
  • tests and acceptance criteria performed at critical steps of the manufacturing process to demonstrate that the process is controlled
  • in-process quality control of intermediates and operations.

5.4. Animal-sourced material

For starting materials of animal origin used in the manufacture of an active constituent, you should provide information on:

  • biological sources
  • country of origin
  • manufacturer
  • specifications.

You should also provide evidence that the material is free of bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathies (TSEs).

For information about importing biological agents, refer to the Department of Agriculture and Water Resources website.

5.5. Genetically modified organisms

For starting materials that consist of or contain genetically modified organisms (GMOs), the APVMA consults with the Office of the Gene Technology Regulator (OGTR) as required by the Agricultural and Veterinary Chemicals (Administration) Act 1992 (see our website for more information).

For approval of a GMO, you should also refer to OGTR guidelines on data required for a risk analysis relating to the use of the GMO.

6. Active constituent specifications

These are important, as they effectively comprise the composition and purity of an active constituent, one of the relevant particulars required for an active approval according to the Agricultural and Veterinary Chemical Code Regulations 15(1)(d).

If a relevant pharmacopoeial standard exists, an active constituent should in general comply with the monograph. A valid scientific argument may be provided for not using an available pharmacopoeial standard. For example, if the active constituent is a mineral for use in a feed premix, food or feed quality material may be sufficient to ensure the quality, safety and efficacy of the product.

If a certificate of suitability from the European Directorate for the Quality of Medicines (EDQM) is available confirming suitability of the European Pharmacopoeia monograph as a specification for the active constituent from the nominated site, it is strongly suggested that you include this in your application.

If a pharmacopoeial standard is not available, you should provide a manufacturers’ specification, which should include parameters such as identification, a minimum purity, isomeric composition (where applicable), maximum limits for key impurities (refer to VICH GL10 for guidance), and key physicochemical properties.

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

For actives of plant origin; specification of the main components will generally suffice (see section 8 below).

The nanoscale properties of an active constituent, if relevant, should be incorporated into an active constituent specification.

7. Batch analysis data

You should provide batch analysis data from at least three commercial-scale batches manufactured within the previous two years. This allows the APVMA to validate processes (manufacturing and quality control) and determine whether an active constituent is manufactured consistently to meet the proposed quality standards. The data should include test results for all parameters listed in the specifications.

The selection of batches to demonstrate routine compliance with the pharmacopoeial monograph or manufacturer’s specifications should comply with those described in VICH GL3(R). You should also consider the presence of impurities according to VICH GL10(R), GL39 and GL18(R).

The batch analysis data should include:

  • batch size, batch number, date of manufacture and date of analysis
  • numerical analytical determinations (ie quantitative tests such as active content or impurities, provide numerical results rather than ‘within limits’ or ‘conforms’ statements)
  • information on the analytical procedures used to generate the data, and validation of those procedures
  • where a chromatographic method is used, chromatograms of the batches, showing the separation of impurities (please clearly label chromatograms with batch numbers, peak identity, peak integration data, X and Y axis labels and scales)
  • all raw data used to generate the final results should be provided or available on request. At least an example calculation should be provided.

The sum of the quantitative level of active constituent and impurities is referred to as the ‘mass balance’. Mass balance is an important parameter in a batch analysis to ensure that all major impurities have been detected. The mass balance need not add up to exactly 100 per cent due to analytical error associated with each analytical procedure; however, the mass balance should fall within 98–102 per cent.

You should demonstrate the nanoscale properties of an active constituent, if relevant.

8. Analytical methods and validation data

You should provide validation data and details on analytical methods to allow the APVMA to assess the quality and adequacy of the control processes. Compendial methods, such as those found in the British, European, or United States Pharmacopoeia, should be used where applicable. A full description of the analytical procedures used for the testing of the product should be provided, including:

  • full details of the analytical methods (including method numbers)
  • the purity of the reference standards or Certified Reference Material along with a Certificate of Analysis
  • 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) where chromatographic (HPLC, GLC) and spectroscopic (NMR, FTIR) techniques are used
  • worked examples of the calculations.

You should provide method validation data to allow the APVMA to assess the suitability of the method for its intended use. Typical analytical validation methodologies and characteristics are provided in VICH GL1 and GL2.

You should describe the nanoscale aspects of an active constituent analytical methods, if relevant.

9. Analytical reference standards

If you are applying for approval of a new active constituent, you should provide the following samples to the Australian Government National Measurement Institute (NMI, Agvet Code section 57 and section 169):

  • 1 gram of analytical reference standard of each pure active constituent or, if an active constituent is a mixture of major isomers that can be separated, 1 gram of each isomer
  • 100 grams of an active constituent as manufactured (the percentage purity and the method used to determine purity should be included
  • 10 mg of analytical reference standards for any toxicologically significant impurities present in an active constituent
  • 100 mg of analytical standard for all metabolites identified and for which a maximum residue limit (MRL) applies (metabolites included in the residue definition for enforcement).

The Chemistry section will keep applicants informed of any reference standards required for toxicologically significant impurities or residue definition components as the Health and Residues assessments become available.

You should also submit storage instructions and information on the shelf life of the analytical reference standard and active constituent, especially if degradation is likely to occur during transport or storage.

If those amounts of material are excessive please discuss this with the APVMA to negotiate an appropriate amount of material to be provided.

The samples should be sent to:

National Measurement Institute
105 Delhi Road, North Ryde NSW 2113, Australia
PO Box 138, North Ryde NSW 1670, Australia

Phone: +61 22 9449 0111
Fax: +61 2 9449 1653

Email: info@measurement.gov.au

Samples should be accompanied by a letter stating:

  • the reason for submitting the sample
  • if the sample is commercial in confidence material
  • the purity of the material supplied
  • certificate of analysis
  • storage instructions
  • acute oral and dermal toxicities of the material, or the appropriate safety data sheet (SDS).

Take care to ensure that samples are well packed. Samples that arrive damaged will be destroyed and replacement samples will be requested.

Samples should be provided to the NMI before approval of a new active constituent. When standards are supplied to the NMI, documentation to that effect should be forwarded to the APVMA.

From time to time, the APVMA may request replacements for some or all of the above samples to maintain the inventory.

The National Measurement Institute stores these materials which are used as required by the APVMA. The National Residues Survey uses these materials in order to monitor residue levels in food producing crops and animals. The National Residues Survey may contract out analytical residue testing. Reference material is not released to any other party for any other use.

10. Packaging

You should provide a description of the packaging materials used for a new active constituent and information about the corrosive effect, if any, of an active constituent on the packaging materials. This information is not required if an active constituent is formulated into a product at the site of manufacture.

11. Existing actives

Applications for a new source of an existing active may qualify for reduced data requirements.

11.1. New source of an existing active that complies with a recognised, pharmacopoeial standard

Applications for a new source of an already approved active may qualify for reduced data requirements if an active is listed in the acceptable pharmacopoeia, and complies with all aspects of the relevant pharmacopoeial standard, and any limits for residual solvents (other than those specified in the pharmacopoeial standard) comply with VICH GL18(R).

In these cases, you are required to submit three certificates of analysis (COA) that demonstrate compliance with the relevant pharmacopoeial standard (and VICH GL18(R) if applicable) for each manufacturer.

If a certificate of suitability from the relevant European Pharmacopoeia monograph/standards (CEP) as granted by the European Directorate for the Quality of Medicines (EDQM) is available for the proposed new source of an active, you are strongly encouraged to include it in your application.

11.2. New source of an existing active that does not comply with a pharmacopoeial standard

In cases where an active is listed in an acceptable pharmacopoeia but does not comply with all aspects of the relevant pharmacopoeial standard, or where no pharmacopoeial standard exists for an active, you are required to provide data and/or argument to support the approval of that the proposed site of manufacture.

An active manufactured to a non-compendial standard may not be suitable for specific types of veterinary products, such as injections or oral medications.

The following data points will need to be addressed by data (from a drug master file, for example) or scientific argument:

  • identification of the active constituent
  • active constituent specifications
  • stability data (where there are known issues arising from the stability of an active likely to affect the safety or quality of an active—eg diazinon and malathion, which are used in some ectoparasiticide products, can form toxicologically significant degradation products)
  • methods of manufacture of the active constituent
  • batch analysis data
  • analytical methods and validation data.

Scientific argument used to support applications may include documentation on particular points of difference where an active does not comply with a particular pharmacopoeial standard, with reasoning provided as to why these differences would not affect the safety, stability or efficacy of the active constituent.

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