Variation of the particulars or conditions of approval of an approved active constituent

Approval holders may apply for a variation to the particulars or conditions of approval of an approved agricultural active constituent, including changes to the quality, specifications, or manufacturing process of the active constituent.

1. General information

The active constituent approval holder is responsible for notifying the APVMA of any proposed changes to the manufacturing process and/or observed change to the impurity profile of an active constituent. We must assess these changes, as change to the manufacturing process has the potential to alter the impurity profile, which may in turn impact the toxicity of the active constituent. Changes to the toxicology profile may invalidate previous assessments we have undertaken on the active constituent.

If we determine the variation of active constituent is not equivalent to the original approval of that active constituent, additional data (for example, toxicological data) will be required to allow us to be satisfied that the constituent, as varied, meets the safety criteria.

2. Satisfying the safety criteria for a variation to an approved active constituent

Approval holders may satisfy us of the safety statutory criterion through provision of any of the following, either singly or in combination:

• data that allow us to be satisfied of the statutory criterion
• valid and relevant scientific argument that satisfies us of the statutory criterion
• reference to previously submitted data that are directly relevant to the current application
• reference to directly relevant overseas assessments and decisions.

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

2.1. Providing data to satisfy the safety criteria

You should provide the following information with each application for variation to particulars or conditions of approval of the approved active constituent, where applicable:

• method of manufacture of the active constituent (for example, process, quality control, impurity formation)
• a new Declaration of Composition (DoC)
• a new full five-batch analysis
• full details of the analytical method(s) used for the determination of the active constituent, any isomers and the impurities present
• appropriate validation data for the analytical method(s).

2.2. Providing valid and relevant scientific argument

You may use valid and relevant scientific argument to satisfy us of the safety criterion for a variation to an approved 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 refer to the data provided in that application.

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

2.4. Using overseas data assessments and decisions

We may accept data that have been generated overseas in support of a variation to an approved active constituent. In using overseas data and decisions we will consider:

• the relevance of the data to Australian manufacturing systems
• 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. Method of manufacture of the active constituent

4.1. Description of the manufacturing process highlighting the relevant changes

You should provide an accurate 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 includes
  • molecular formulae
  • the chemical structure of starting materials, intermediates and reagents
  • chemical equations of the reactions involved, reflecting stereochemistry where relevant
• the relative amounts of each starting material and their order of addition
• reaction conditions (temperature, pressure, pH and reaction times, etc.), where these are critical
• 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, 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 of toxicological significance.

4.2. Quality control

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

• specifications or purity data for all starting materials, reagents and key intermediate products
• the measures used to monitor and assess the performance of an ongoing manufacturing operation (for example, analysis to determine the concentration of reactant or product to check the completion of a reaction)
• 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.

4.3. Impurities

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

The submission with respect to impurities must 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.

4.4. Impurities of toxicological significance

If there is potential for the formation of toxic impurities and/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 toxic impurities.

A general list of toxicologically significant impurities is listed in the APVMA’s active constituent standards.

5. Declaration of Composition

You should provide a comprehensive DoC for the active constituent. The DoC should be signed and dated 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
• 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 (solvent or additive free) basis, and the content of diluents and/or any additives in g/kg
• the chemical names with
• company code numbers (where applicable)
• Chemical Abstracts Service (CAS) registry numbers, where they exist
• empirical formula
• molecular weight
• structural formula for all identified impurities

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

You do not need to identify the impurities that are not of toxicological significance and are below levels of 0.1 per cent.

Table 1 provides an example of the DoC for an active constituent.

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 proof of control of the new process.

If data on commercial-scale batches are not available, you should provide batch analyses for pilot-scale batches manufactured using the revised process as intended for commercial-scale batches.

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)
• detailed 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 and peak integration data
  • X and Y axes
  • clearly readable scales
• a copy of all raw data used to generate the final results.

For determination of impurities present in the active constituent, reference standards should be prepared for each of the identified impurities, particularly those known to be of toxicological significance, and the concentration of impurities quantitated against their own reference standards

It is acceptable to use the active constituent as an external standard to estimate the levels of impurities, 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. Normalisation is not appropriate.

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 associated errors in the preparation and analysis associated with each analytical procedure; however, the mass balance should be in the range of 98–102 per cent.

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 (at any level) in the active constituent.

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

• principle of the method
  • method summary
  • sample preparation techniques
  • equipment or reagents
    • for example for chromatographic methods, details of the column
    • eluent (including gradients, where applicable)
    • temperature
    • detector
    • retention times
• purity of reference standards
  • source of the standard
  • batch number
  • purity
  • certificate of analysis
• where chromatographic techniques are used, relevant chromatograms for
  • blank
  • sample
  • standard
• for chromatograms
  • retention times
  • peak assignment
  • peak integration data
  • clear and readable X and Y axes with appropriate scales
• worked examples of the calculations.

8. Validation data

You should provide validation data for the method(s) used to assay the active constituent and impurities. If there is no change to the methods, you only need to refer to the relevant method identifier. If the method has changed, address the following parameters, where appropriate:

• specificity
• linearity
• precision
• recovery (accuracy)
• limit of detection for impurities
• limit of quantitation for impurities.

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

9. Data list

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

10. Template for the dossier to support an application for variation

The dossier you submit to support an application for variation of the particulars or conditions of an approved active constituent should contain the following sections:

• Table of contents
• Overall summary
• Method of manufacture of the active constituent
• Quality control
• Impurities
• Impurities of toxicological significance
• Declaration of Composition (DoC)