Chemistry and manufacture of active constituents (Part 2)

This is a guideline about the types of information you can submit to address the safety criteria for veterinary active constituents. 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 active constituent for which you intend to demonstrate safety.

This guideline applies to non-immunobiological veterinary active constituents 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 active constituent 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 approval of an active constituent. This guideline applies to active constituents of synthetic, semisynthetic or natural origin only and excludes immunobiological active constituents.

The APVMA has adopted the quality guidelines of International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH), with certain conditions to reflect particular Australian conditions. Where the VICH guideline specifies that it is for new veterinary drugs substances (active constituents) (such as VICH GL10(R) and GL39), we consider that it should be applicable to all veterinary active constituent applications. You should justify any deviation from the VICH guidelines, including from those indicated to apply only to new active constituents.

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

2. Identification of the active constituent

You should provide details of the nomenclature, structure, identity and general properties of the 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 the active constituent is not listed in the SUSMP, the common name may be found in one of the following:

  • World Health Organization—International non-proprietary names
  • Therapeutic Goods Administration—Approved terminology for medicines—Chapter 1—Australian approved names 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)
  • Standards Australia (AS 1719-1994: Recommended common names for pesticides)
  • International Organization for Standardization
  • British Standards Institution
  • Chemical Abstracts (CA)
  • International Union of Pure and Applied Chemistry (IUPAC)
  • the name descriptive of the true nature and origin of the constituent.

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 both the International Union of Pure and Applied Chemistry (IUPAC) and the Chemical Abstracts (CA) nomenclature, should be provided.

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

2.3. Chemical Abstracts Service registry number

You should provide the Chemical Abstracts Service (CAS) number of the active constituent. If the CAS number has not been allocated, state ‘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 the 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 the 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 the active constituent. The elucidation of structure should be based on appropriate physical and chemical test results. This may include:

  • a description of the synthetic route as evidence of structure
  • an elemental analysis with theoretical values
  • a discussion on ultraviolet (UV) characteristics, including pH dependence shifts
  • infrared (IR) spectrometry
  • 1H and 13C nuclear magnetic resonance (NMR) 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 the active constituent. The information should include the purity of the substance used to generate the data and the methods used for each test parameter. The information should include, as appropriate:

  • a general description (for example, appearance, colour, odour and physical state)
  • when a new active constituent contains one or more chiral centres, whether the active is a pure enantiomer, racemate or fixed combination of non-enantiomeric isomers
  • specific optical rotation
  • melting point (for solids)
  • boiling point (for liquids)
  • condensation point (for gases)
  • refractive index (for liquids)
  • 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 (Pow or log Pow)
  • dissociation constant, if appropriate
  • if the 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).

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 us to identify and assess the potential risks of nanomaterials, you should provide the following characteristics and physical chemical properties:

  • composition
  • identity
  • purity
  • 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)
  • descriptions of the methods used to assign these determinations.

4. Stability data

You should provide stability data to demonstrate the inherent stability of the active constituent. The content of the active constituent, any degradation products (especially toxicologically significant impurities), and other critical characteristics should be monitored initially and at sufficient sampling frequency during storage. 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. You should propose a suitable re-test period based on the stability of the active constituent in an Australian climate. Australia has climatic conditions encompassing VICH zones I to IV. VICH GL3(R),GL5GL10(R)GL18(R)GL39GL45 and GL51 provide information on stability design and testing protocols and data evaluation.

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

5. Method of manufacture of the active constituent

5.1. Manufacturer and site of manufacture

You should provide the name and business address of the manufacturer or manufacturers of the active constituent and the street address of the manufacturing plant(s) in which the active constituent is manufactured. If a toll or contract manufacturer is involved, their details should also be provided.

5.2. Description of the manufacturing process

5.2.1. Active constituents produced by chemical synthesis

You should provide a detailed description of the manufacturing process to allow us to establish that the process is capable of consistently delivering quality active constituent in a process in which each step of the manufacturing is appropriately controlled and the active constituent meets all quality attributes, including specifications. The batch size (for example, in litres or kilograms) and scale (pilot or production) should be stated.

You should provide full details of the manufacturing process quality control procedures that ensure batch-to-batch consistency and reproducibility of the active constituent. You should describe the in-process quality control checks performed at various stages of the manufacture, purification and packaging of the active constituent; testing should include the specifications and tests for pivotal and key/critical 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 significant purification steps
  • a detailed description and flow diagram of the synthetic processes, including molecular formulae, chemical structures of starting materials, intermediates, reagents and 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
  • if a manufacturing concentrate is produced, details of the final concentration of the active constituent present, methods used to confirm the concentration, and details of the diluents and/or any additives used.

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

5.2.2. Active constituents produced by fermentation

The information about an 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 (for example, times, temperatures, pH, rates of aeration, and name and composition of preservatives)
  • a detailed description of the isolation and purification procedure for the 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 Active constituents produced by fermentation (above). The information for the synthesis of the final active constituent from the starting material should be provided as described under Active constituents produced by chemical synthesis (above).

5.2.4. Feed-grade active constituents

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

For this reason, the microbial fermentation 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 in-process tests used to determine quality and yield.

5.2.5. Active constituents of plant origin

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

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

If they are known, you should record the nature of chemical fertilisers, pesticides, fungicides and other agents used during cultivation. 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.

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 the 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 the 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 seeks advice from the Office of the Gene Technology Regulator (OGTR). For approval of a GMO, you should also refer to OGTR guidelines on data for a risk analysis relating to the use of the GMO.

6. Active constituent specification

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 an active constituent should conform. You should provide active constituent specifications to allow the APVMA to assess whether the constituent is of an acceptable quality for its intended use.

If a pharmacopoeial standard exists, the active constituent should comply with the recent monograph. If a pharmacopoeial standard is not available, you should provide a manufacturer’s specification. VICH GL39and 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 VICH GL10(R) and GL40 and residual solvents according to VICH GL18(R).

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

7. Batch analysis data

You should provide batch analysis data to allow us to validate the processes (manufacturing and quality control) and determine whether the active constituent is manufactured consistently to meet the proposed quality standard. 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 be the same as that described in VICH GL3(R). You should consider the presence of impurities according to VICH GL10(R)GL39 and GL18(R).

The results should include:

  • batch size, number, date of manufacture and date of analysis
  • analytical determinations (for quantitative tests, such as of active constituent contents, individual and total impurities, provide the actual numerical results rather than vague statements such as ‘within limits’ or ‘conforms’)
  • information on the analytical procedures used to generate the data, and validation of those procedures
  • where applicable, chromatograms of the batches, showing the separation of impurities (chromatograms should be clearly labelled with batch numbers, peak identity and peak integration data)
  • a copy of all raw data used to generate the final results.

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

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

8. Analytical methods and validation data

You should provide analytical methods 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. You should provide a full description of the analytical procedures used for the testing of the product, including:

  • full details of the analytical methods (including method numbers)
  • the purity of the reference standards
  • where chromatographic (such as HPLC) and spectroscopic (such as NMR) 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.

You should provide method validation data to allow us to assess the suitability of the method for its intended use. Typical analytical validation methodologies and characteristics are provided in VICH GL1and GL2.

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

9. Analytical reference standards

If you are applying for approval of new active constituents, you should provide the following samples to the Australian Government National Measurement Institute (NMI):

  • 1 gram of analytical reference standard of each pure active constituent or, if the active constituent is a mixture of major isomers that can be separated, 1 gram of each isomer
  • 100 grams of the active constituent as manufactured (the percentage purity and the method used to determine purity should be provided)

    You may provide justification that you should supply less than 1 gram analytical reference standard and/or less than 100 grams of active constituent as manufactured. We will consider your argument on its merits.
  • 10 mg of analytical reference standards for the toxicologically significant impurities present in the active constituent
  • 100 mg of analytical standard for all metabolites identified and for which a maximum residue limit (MRL) applies.

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.

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: (02) 9449 0111
Fax: (02) 9449 1653
Email: info@measurement.gov.au

Samples should be accompanied by a letter stating:

  • the reason for submitting the samples
  • the purity of the materials supplied, with the certificate of analysis
  • storage instructions
  • acute oral and dermal toxicities of the materials, or the appropriate material safety data sheet (MSDS).

Take care to ensure that samples are properly packed. Samples that arrive leaking or otherwise 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.

10. Packaging

The packaging or storage/shipping containers should be appropriate for the characteristics of the active constituent. You should provide a description of the packaging materials used for the active constituent and information about the corrosive effect, if any, of the active constituent on the packaging materials. This information is not required if the active constituent is formulated into a product at the site of manufacture.

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