Approval of a new active constituent

The Agvet Code requires the APVMA to approve active constituent(s) contained in an agricultural chemical product intended for distribution, sale or use in Australia. This applies regardless of whether the product is formulated in Australia or overseas. The Agvet Code also requires us to keep a Record of Approved Active Constituents for Chemical Products and to enter particulars and any conditions of the approval into it.

The Agvet Code Regulations provide that the APVMA may establish standards for approved active constituents. We will establish and publish a standard for the active constituent when we approve it. The standard establishes the minimum purity of the active constituent and the maximum contents of the relevant impurities (particularly those of toxicological significance). All approved active constituents used in agricultural chemical products for which an APVMA active constituent standard exists must comply with the standard on an ongoing basis as a condition of their approval.

The APVMA active constituent standards are available on the APVMA website.

An application for approval of an active constituent may be submitted before an application for registration of a new agricultural chemical product or may be made at the same time.

If an application requires submission of data held by third parties (eg active constituent manufacturer or product formulator), arrangements should be made with the third party to provide the data directly to the APVMA—preferably at the same time as the application is lodged—with a covering letter including details of the application to which the data relate.

1. Satisfying the safety criteria for a new active constituent

To satisfy us that the new active constituent meets the safety statutory criteria, applicants may provide any of the following, either singly or in combination:

• data
• valid and relevant scientific argument
• reference to previously submitted data that are directly relevant to the current application
• reference to previous APVMA reports that are directly relevant to the application and meet the validity criteria
• reference to overseas assessments and decisions that are directly relevant to the application.

Further information about each of these approaches is available in the guideline, Putting your application together—approval, registration and variation.

1.1. Providing data to satisfy the safety criteria

This section sets out the chemistry and manufacturing data that you should submit to the APVMA to satisfy the safety criteria in an application for approval of a new active constituent (or as a manufacturing concentrate). These data are applicable to all active constituents prepared by chemical synthesis. Details about approval of active constituents derived from living organisms (plants, animals, microorganisms plus organisms that have been genetically modified) will be added at a later date.

1.1.1. Identification of the active constituent

You should provide the following details of the identity of each active constituent:

• the common name
• the International Union of Pure and Applied Chemistry (IUPAC) chemical name
• Chemical Abstracts Service (CAS) registry number
• the manufacturer’s code number(s) and/or synonyms
• the chemical structure.

1.1.1.1. Common name

You should provide the common name given in the Australian Standard (AS1719: Recommended Common Names for Pesticides), if this is available.

If Standards Australia has not published or otherwise approved a common name for a particular active constituent, you should provide the International Organization of Standardization (ISO) common name, or proposed ISO common name, and where relevant, other proposed or accepted common names (synonyms), including the name (title) of the nomenclature authority concerned.

Inquiries may be directed to Standards Australia for approval of a new common name for a new active constituent:

• by mail:
  Projects Manager Committee CH-005
  Standards Australia International
  GPO Box 476
  Sydney, NSW 2001
• by telephone: 02 9237 6000
• by email: mail@standards.org.au
• on the web: Standards Australia website

1.1.1.2. IUPAC chemical name

You should provide the full chemical name, in accordance with both the IUPAC and the Chemical Abstracts (CA) nomenclature.

1.1.1.3. Chemical Abstracts Service registry number

If available, you should provide the CAS number of the active constituent. If the CAS number has not been allocated, you should record that the number is not yet allocated.

1.1.1.4. Manufacturer’s code number(s) and/or synonyms

The manufacturer or laboratory code numbers and/or synonyms should be provided, as applicable.

1.1.1.5. Chemical structure

1.1.1.5.1. Molecular and structural formulae and molecular mass

You should provide the molecular formula, molecular mass and structural formula of the active constituent. For active constituents that are salts or hydrates, you should provide the molecular mass of the free base or anhydrous form. For polymeric compounds this should include weight average (M_w), number average, molecular weight (M_n) and molecular weight distribution.

The structural formula should include (where relevant) stereochemical properties of the active constituent; for example geometric isomerism (cis/trans, E/Z), the number of chiral centres and the configuration at each centre. Where possible, the structural formula should be given diagrammatically with all possible or known stereochemistry.

1.1.1.5.2. Elucidation of structure and other characterisation of structure

You should provide confirmation of the chemical structure of the active constituent and impurities. The elucidation of structure based on the spectroscopic data should be provided, along with their interpretation, and all other appropriate physical and chemical test results. This may include using at least three of the following techniques:

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

1.1.2. Physical and chemical properties

All relevant physical and chemical properties of the active constituent and/or manufacturing concentrate should be provided. The information should include, as appropriate:

• a general description, for example, appearance, colour, odour, physical state
• the stereochemical properties of the molecule, for example geometric isomerism, number of chiral centres and configuration at each centre
• if a new active constituent contains one or more chiral centres, a specification of whether the active constituent is a pure enantiomer, racemate or fixed combination of non-enantiomeric isomers
• if a new active constituent contains geometric isomers (cis/trans, E/Z), a specification of whether the active constituent is a pure geometric isomer, or a fixed combination of geometric isomers
• if the active constituent is optically active, a specific optical rotation measurement with limits
• the melting point or range (for solids)
• the boiling point or range (for liquids)
• if the melting and/or boiling point cannot be determined because of decomposition or sublimation, the temperature at which decomposition or sublimation occurs
• the condensation point (for gases)
• the refractive index (for liquids)
• the density or specific gravity(for liquids)
• the UV absorption maxima and molar absorptivity
• the pH and pKa values
• the vapour pressure
• Henry’s Law Constant
• the solubility in water expressed as g/L or mg/L, in the neutral range, acidic range (pH 4 to 6) and in the alkaline range (pH 8 to 10)
• the solubility in various organic solvents expressed as g/L or mg/L
• the n-octanol/water partition coefficient (K_ow)
• the hydrolysis in aqueous solution under acid, neutral and basic conditions
• the dissociation characteristics including dissociation constant, if appropriate
• the flash point (where the melting point is below 40˚C)
• the flammability including auto-flammability
• explosive properties
• photochemical properties
• oxidising properties
• the auto-ignition temperature
• corrosion characteristics
• the dangerous goods classification as per the Australian Dangerous Goods Code (ADG Code), available through the Department of Infrastructure and Regional Development website, if applicable.

The purity of the test substance used to generate the physical and chemical properties should be stated.

You should also describe the methods used to generate the data provided. Where the method used is described in a scientifically recognised publication or manual—for example, those by the Organization for Economic Cooperation and Development (OECD), the Collaborative International Pesticide Analytical Council (CIPAC), or the American Society for Testing Materials (ASTM)—a reference to the relevant publication will suffice.

It is desirable that physical properties such as solubility in water and vapour pressure be determined from tests conducted at ambient temperature (20–25˚C). However, if data are available at another temperature, these may be provided. The temperature at which these tests were conducted, or other relevant test conditions, should be stated.

1.1.3. Stability data

You should provide the results of stability studies (long-term and/or accelerated conditions) conducted on at least one batch of the active constituent.

Stability studies should establish the inherent stability of the molecule; in particular the degradation pathway and the identity of any degradation products, especially toxicologically significant impurities formed during storage.

For storage stability studies, samples of the active constituent should be stored for a minimum of 14 days at 54˚C and/or, for long term testing, for up to two years at room temperature (30˚C or under normal Australian warehouse conditions). If the active constituent is unstable at 54˚C and 30˚C, it may be stored at lower temperatures of 0–5˚C and 2–8˚C respectively.

The content of the active constituent and, if appropriate, any toxicologically significant impurities, should be monitored initially, at sufficient sampling intervals and at the end of the stability study.

The submission should include:

• the actual stability results (that is, raw data)
• details of the analytical methods employed for the determination of the active constituent
• details of any toxicologically significant impurities and degradation products
• a summary of the results and conclusion.

You should provide the effect of metal or metal ions on the stability of the active constituent if there is a likelihood that the active constituent will come into contact with metals or metal ions during its storage or use.

Guidelines suitable for the generation of such data have been prepared by the APVMA (please see guideline on Generation of storage stability data for agricultural chemical products). We emphasise that testing should be undertaken in the proposed commercial packaging or in smaller packages of the same construction and materials.

1.1.4. Method of manufacture of the active constituent

1.1.4.1. Manufacturer and manufacturing site

You should provide the name and business address of the manufacturing plant of the active constituent and the street address in which the active constituent is manufactured. If a toll or contract manufacturer is involved, please provide their name, and business address of the manufacturing plant of the active constituent and the street address in which the active constituent is manufactured.

1.1.4.2. Description of the manufacturing process

You should provide an accurate and detailed description of the manufacturing process and process controls and include the following information:

• an introductory paragraph detailing the number of chemical steps, whether the process is a batch or continuous process, and significant purification steps
• a flow diagram of the synthetic processes that outlines the sequence of all the steps
• a reaction scheme that outlines the sequence of all the chemical reactions and includes
• molecular formulae
  • chemical structure of starting materials, intermediates, reagents and catalysts
  • the final products formed
  • key reaction conditions
  • amounts used or formed
  • yields obtained
  • the relative amounts of each starting material and their order of addition
• the reaction conditions (temperature, pressure, pH, reaction times and addition rate etc.)
• the duration and yield of each step of the process
• information on intermediates that are isolated and purified
• a description of any purification procedures for the active constituent, including procedures to recover starting materials, intermediates or the final product
• 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 synthetic process in sufficient detail to enable us to assess the potential presence of impurities and impurities of toxicological significance.

1.1.4.3. Quality control

You should provide the following information to ensure the quality of the active constituent:

• specifications or purity for all starting materials, reagents, catalysts and key intermediate products
• the measures used to monitor and assess the performance of an ongoing manufacturing operation; such as the analysis to determine the concentration of a reactant or product to check the completion of a reaction (for example, gas chromatography or high-performance liquid chromatography)
• tests and acceptance criteria (with a justification that includes experimental data) performed at critical steps of the manufacturing process to ensure that the process is controlled
• representative data relating to in-process quality control.

1.1.4.4. Impurities

You should identify and report on the impurities that are or may be present in the active constituent at levels of greater than or equal to 0.1 per cent—note that toxicologically significant impurities at any level must be identified, characterised and quantified.

Information provided with respect to impurities should include structural formulae and, if possible, a scheme for the formation of the impurity, followed by a text discussion of its formation.

Potential sources of impurities or related substances include:

• impurities in the starting materials, from incomplete or side reactions, or isomerisation
• residual solvents, reagents and immediate precursors
• trace elements arising from the use of catalysts or other sources
• the degradation of the active constituent that may occur after manufacture
• the amount of water or moisture present
• the amount of solvent left after the final purification.

1.1.4.5. Impurities of toxicological significance

If there is potential for the formation of toxicologically significant impurities or by-products this must be declared and quantified. You should also provide details of the conditions leading to their formation and the steps taken to control the formation of toxicologically significant impurities.

A general list of toxicologically significant impurities is available on the APVMA Standards for active constituents page on the APVMA website.

1.1.5. Declaration of Composition

You should provide a comprehensive Declaration of Composition (DoC) for the active constituent—Table 1 provides an example. The DoC should be signed and dated by the person responsible for it and include the following information:

• the minimum purity of the active constituent (in grams per kilogram [g/kg] or grams per litre [g/L], as appropriate on a dry-weight basis) as well as the ratio of the content of isomers or diastereoisomers (where relevant)
• the maximum content of all impurities present in quantities of 0.1 per cent or more including water
• any toxicologically significant impurities present at any level (including less than 0.1 per cent)
• if the active constituent is a manufacturing concentrate, the minimum concentration of the active constituent in the manufacturing concentrate as well as the minimum purity of the active constituent and the maximum content of all impurities on a dry-weight (diluent or additive free) basis, and the content of diluents and/or any additives in g/kg or g/L
• the chemical names, with company code numbers (where applicable), Chemical Abstracts Service (CAS) registry numbers (where they exist), empirical formulae, molecular weights and structural formulae for all identified impurities.

All impurities present at or above the 0.1 per cent level should be identified and reported. If identification of an impurity is not feasible, a summary of laboratory studies demonstrating the unsuccessful effort should be included in the application.

You should specify the minimum purity of the active constituent and the maximum content of each impurity based on the previously and recently manufactured batch analysis results from the manufacturer. We recommend that you provide an analysis of at least five batches manufactured within the last five years, as this provides some statistical certainty on the reliability of the data and also demonstrates that the manufacturer is currently capable of producing the active constituent.

1.1.6. Batch analysis data

You should provide batch analysis results (analysed within the last five years) for at least five commercial-scale production batches of the active constituent to demonstrate routine compliance with the DoC and to demonstrate that the manufacturer is in control of the process.

If data on commercial-scale batches are not available, you should provide batch analyses for pilot-scale batches manufactured using the same process as intended for commercial-scale batches. Laboratory-scale batches are not appropriate as they do not demonstrate the capability of full-scale manufacture.

The results should include:

• batch size
• batch number
• date of manufacture
• date of analysis
• results of the analytical determination for the content of the active constituent and each impurity present at a concentration of 0.1 per cent or more using specific methods—actual numerical results should be provided rather than vague statements such as ‘within limits’ or ‘conforms’
• content of toxicologically significant impurities (present at any level)
• information on the analytical methods used to generate the data and the validation of these methods
• where applicable, chromatograms of the batches showing separation of impurities. Chromatograms should be clearly labelled with
  • batch numbers
  • peak identity
  • peak integration data
  • a software-generated table with retention time and peak area of associated peaks
• a copy of all raw data used to generate the final results.

To determine impurities in the active constituent, reference standards should be prepared for each of the identified impurities, particularly those known to be toxic, and the concentration of impurities should be quantitated against their own reference standards.

It is acceptable to use the active constituent of known purity as an external standard to estimate the levels of impurities (diluted to the appropriate concentration), provided the response factors of those impurities are sufficiently close (90 per cent or more) to that of the active constituent. In cases where the response factor is not close, it may still be acceptable to use the active constituent provided a correction factor is applied. You should provide the rationale for when and how a correction factor is used.

The sum of the quantitative level of the 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, it is expected to be in the range of 98–102 per cent.

1.1.7. Analytical methods

You should provide full details of the test methods used for determining the active constituent, all impurities at or above 0.1 per cent and toxicologically significant impurities (even when present at less than 0.1 per cent) in the active constituent.

The following information should be included in a written analytical method:

• a copy of the actual laboratory method. If this laboratory method is not in English, please include an English version
• the principle of the method
• the method summary
• sample preparation techniques
• equipment or reagents (for example, for chromatographic methods, details of the column include column name, manufacturer, packing material and dimensions)
• eluent (including gradients, where applicable)
• column temperature
• detector and retention times of all components
• purity of reference standard(s), source and batch number of reference standard(s)
• where chromatographic techniques are used
  • relevant chromatograms (blank, standard and sample) including retention times
  • peak-assignment and peak-integration data
  • original printouts from the chromatographic system which include retention times, peak areas and peak-height tables
• worked examples of all calculations.

1.1.8. Validation data

You should provide validation data for the method(s) used to assay the active constituent and impurities. Address the following parameters, where appropriate:

• selectivity or specificity
• linearity
• precision
• recovery (accuracy)
• limit of detection (LOD) for impurities
• limit of quantitation (LOQ) for impurities.

Note that LOD and LOQ are not required for the quantitation of the active constituent, only the determination and quantitation of the impurities.

Further information on the validation of analytical methods is available in a separate guideline.

1.1.9. Analytical reference standards

Applicants for approval of new active constituents must provide the following samples to the Australian Government National Measurement Institute:

• 1 gram of the analytical reference standard of each pure active constituent, or where the active constituent is a mixture of major isomers which can be separated, 1 gram of each isomer
• 100 grams of active constituent as manufactured (the percentage purity and the method provided to the APVMA in the approval of the active constituent should also be provided).
• 10 milligrams of analytical reference standards for all toxicologically significant impurities present in the active constituent
• 100 milligrams analytical standard for all metabolites identified and for which a maximum residue limit applies.

Please note, you may provide justification to us that you should supply less than 1 gram of analytical reference standard and/or less than 100 grams of active constituent as manufactured. We will consider such arguments on their merits.

Storage instructions and information on the recommended shelf life of the analytical reference standard and active constituent are required, especially if degradation is likely to occur under transport or storage.

The samples should be sent to:

Chemical Reference Materials
National Measurement Institute
Riverside Corporation Park
105 Delhi Rd
North Ryde NSW 1670
Australia

telephone: 02 9449 0191
fax: 02 9449 0292
email: chemref@measurement.gov.au

Samples must be accompanied by a letter stating:

• the reason for submitting the samples including the application and active constituent numbers
• the purity of each of the materials supplied with a separate Certificate of Analysis for each
• the storage instructions
• the acute oral and dermal toxicities of the materials, or the appropriate safety data sheet.

Care should be taken 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 National Measurement Institute before approval of a new active constituent. When standards are supplied to the National Measurement Institute, documentation to this effect should be forwarded to the APVMA for confirmation purposes.

From time to time we may request that active-constituent approval holders provide replacement material to maintain our inventory of reference materials.

1.1.10. Packaging

The packaging, or storage or shipping containers must be appropriate for the characteristics of the active constituent.

A description of the packaging materials used for the active constituent and information regarding the corrosive effect, if any, of the active constituent on the packaging materials should be provided. This information is not required if the active constituent is formulated into a product at the site of manufacture.

1.2. Providing valid and relevant scientific argument

You may use valid and relevant scientific argument to satisfy us that you have met the safety criteria for the approval of an active constituent. Argument may also be used in conjunction with data.

1.3. Reference to previously-submitted data

If the manufacturing process or the analytical methods have been assessed and accepted by us in a previous application, you may reference the data provided in that application.

The reference should include the active constituent approval number, application number and the data reference number. We reserve the right to ask you to resubmit any or all the referenced data previously submitted.

1.4. Reference to overseas data assessments and decisions

We may accept data generated overseas in support of the approval of a new active constituent. In using overseas data and decisions, we will consider the relevance of the data to Australian manufacturing systems and any differences between the approaches and legislative responsibilities of the Australian and the overseas regulatory decision-making authority.

2. Data list

You should provide a data list, irrespective of whether data are eligible for limitation on use.

3. Template for the dossier to support the approval of a new active constituent

• Table of contents
• Overall summary
• Identification of the active constituent
  • Common name
  • Chemical name
  • CAS registry number
  • Manufacturer’s code numbers and/or synonyms
  • Molecular and structural formula and molecular mass
  • Elucidation of structure and other characteristics
• Physical and chemical properties
• Stability data
• Method of manufacture of the active constituent
  • Manufacturer’s name and site address
  • Description of manufacturing process
  • Quality control
  • Impurities
  • Impurities of toxicological significance
• Declaration of Composition
• Batch analysis data
  • Batch size, batch number, date of manufacture and date of analysis
  • Results of the analytical determination
  • Content of toxicologically significant impurities (present at any level)
  • Detailed information on the analytical methods
  • Chromatograms of the sample and reference standard
  • All raw data used to generate the final results
• Analytical methods
• Validation data
• Analytical reference standards
• Packaging
• Data list