Approval of a new source of an active constituent

New sources of approved active constituents must be chemically and toxicologically equivalent to the first approval of that active constituent. We will assess these against the data package used in the risk assessment of the first approval of that active constituent if the data are not limited in use. If the use of the data is limited, then the data cannot be used for any subsequent applications for the life of the limitation.

1. General information

If a source of an approved active constituent is included in the Record of Approved Active Constituents for Chemical Products, an application for approval of a new source of the active constituent is required.

The APVMA will conduct a comparative assessment of the Declaration of Composition (DoC) of the proposed new source of the active constituent against the profile of the first approval of that active constituent (subject to limitations on the use of data). If the active constituent’s purity and impurity profiles (including those of toxicological significance) are identical or substantially similar, the APVMA may determine that the source is equivalent to that of the first active constituent approval. In this case, the APVMA will grant a new approval and include the new source on the Record of Approved Active Constituents for Chemical Products.

If the data for the first approval is limited in its use, then submission of all appropriate data may be necessary for the approval of a new source of the active constituent.

If the APVMA determines that the new source of active constituent is not equivalent to the first approval of that active constituent (subject to the limitation on the use of the data from the first approval), we will refuse the application and provide a statement of reasons for the refusal. You may lodge a new application for approval of the new source of the active constituent and provide any additional data (for example, toxicological data) that may be needed to satisfy the APVMA of the safety criteria for the active constituent from that new source.

2. Satisfying the safety criteria for a new source of an active constituent

To satisfy us that the new source of an 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 is directly relevant to the current application
  • 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.

2.1. Providing data to satisfy the safety criteria

This section sets out the chemistry and manufacture 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 or organisms that have been genetically modified) will be added to this guideline.

2.1.1. 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 chemical name
  • the chemical structure
  • the Chemical Abstracts Service (CAS) registry number.

2.1.2. Common name

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

Projects Manager, Committee CH-005
Standards Australia International
GPO Box 476
Sydney NSW 2001

Phone: +61 2 9237 6000
Email: mail@standards.org.au
Web: Standards Australia website

2.1.3. Chemical name

You should provide the full chemical name, in accordance with both the International Union of Pure and Applied Chemistry (IUPAC) and the Chemical Abstracts Service Registry (CAS) nomenclature.

2.1.4. 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, record that the number is ‘not yet allocated’.

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

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

2.1.6. 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 existing as salts or hydrates, you should also provide the molecular mass of the free base or anhydrous form. For polymeric compounds, this should include weight average (Mw), number average molecular weight (Mn) 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.

2.1.7. 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 also 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 of ultraviolet (UV) characteristics, including pH dependence shifts
  • any other related information used to confirm the structure (for example, X-ray diffraction).

With each application for approval of a new source of an active constituent, the following information should be provided in full:

  • the confirmation of active constituent identity; for example, spectroscopic (UV, IR, NMR, MS) data
  • the method of manufacture of the active constituent (for example, process, quality control, impurity formation)
  • a Declaration of Composition (DoC)
  • a full five-batch analysis
  • full details of the analytical method(s) used to determine the active constituent, any isomers and the impurities present
  • appropriate validation data for the analytical method(s)
  • a description of the packaging or container.

Full descriptions of these types of data are provided in the guideline: Approval of active constituents.

2.1.8. Method of manufacture of the active constituent

2.1.8.1. Manufacturer and manufacturing site

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

2.1.8.2. Description of the manufacturing process

You should provide an accurate and detailed description of the manufacturing process and process controls, including 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 chemical steps
  • a reaction scheme that outlines the sequence of all the chemical reactions and includes molecular formulae, chemical structure of starting materials, intermediates, reagents, catalysts and the final products formed, key reaction conditions, amounts used or formed, and 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.

2.1.8.3. Quality control

The following information should be provided 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; for example, the analysis to determine the concentration of reactant or product to check the completion of a reaction (for example, gas chromatography or high-performance liquid chromatography)
  • the tests and acceptance criteria (with justification, including 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.
2.1.8.4. 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 present
  • the amount of solvent left after the final purification.
2.1.8.5. Impurities of toxicological significance

If there is potential for the formation of toxicologically significant impurities, by-products or both, 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.

2.1.9. Declaration of Composition

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

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 levels less than 0.1 per cent)
  • if the active constituent is a manufacturing concentrate, include 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), CAS registry numbers (where they exist), empirical formula, molecular weight and structural formula 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, you should include a summary of laboratory studies that demonstrates the unsuccessful effort in the application.

You should specify the minimum purity of the active constituent and the maximum content of each impurity 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 past 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.

Table 1: Recommended format for a Declaration of Composition
Declaration of Composition

[Letterhead of the manufacturer, including name and address]

[Common name of the active constituent]

[Name and address of the applicant]

Compound
(chemical name)

CAS
number

Limits (g/kg or g/L)

Type
A = Active
I = Impurity
T = Toxicologically significant impurity

Upper
limit

Lower
limit

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[Name and title of responsible person]

[Signature of responsible person and date]

2.1.10. 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 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.

For determination of 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 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.

2.1.11. 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
    • method summary
    • sample preparation techniques
    • equipment or reagents (for example, for chromatographic methods, full details of the column, including 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(s) and sample(s), including retention times
    • peak assignment and peak-integration data
    • original printouts from the chromatographic system, including retention times, peak areas and peak-height tables
  • worked examples of all calculations.

2.1.12. 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 and (LOD) for impurities
  • limit of quantitation (LOQ) for impurities.

Please note that LOD and LOQ are not required for the identification and quantitation of the active constituent; they are only required for the determination and quantitation of the impurities.

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

2.1.13. 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.

2.2. 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.

2.3. 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 depending on authority to access such data.

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.

2.4. Using overseas data assessments and decisions

The APVMA may accept data that has been generated overseas in support of the approval of a new active constituent. In using overseas data and decisions, the APVMA 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.

3. Data list

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

4. Template for dossier to support approval of a new source of an 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
    • Full and detailed 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 blank, sample and reference standard
    • All raw data used to generate the final results.
  • Analytical methods
  • A copy of the actual laboratory method; if the method is not in English, please include an English version
  • Validation data
  • Analytical reference standards
  • Including source, batch number, purity and Certificate of Analysis
  • Packaging
  • Data list

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