Chemistry and manufacture requirements for registration of an agricultural chemical product

The Agvet Code requires the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register agricultural chemical products intended for distribution, sale or use in Australia, regardless of whether the product is formulated in Australia or overseas. The Agvet Code also requires us to keep a register of agricultural and veterinary chemical products and to enter particulars and any conditions of the registration into the register.

If your application is to be accompanied by data held by third parties (for example, a product formulator), you should make arrangements with the third party to provide the data directly to us, preferably at the same time as your 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 agricultural chemical product

Applicants may satisfy us of the safety statutory criteria for a new product by providing any of the following, either singly or in combination:

• Data that allow us to be satisfied of the statutory criterion
• Nominating a relevant registered reference product
• 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, including the data that were provided to make that decision

1.1. Providing data to satisfy the safety criteria

This section sets out the chemistry and manufacturing data that should be submitted to us in support of an application to register a new agricultural chemical product. These data are applicable to products that are prepared by chemical synthesis. Details about information to support applications to register products that are of biological origin (that is, from plants, animals, micro-organisms and organisms that have been genetically modified) will be added to this guideline.

1.1.1. Distinguishing product name

The distinguishing product name is the name by which the product is (or is to be) known, registered, labelled, advertised and sold. It should include such descriptive words or phrases as are needed to distinguish the product from other products and to identify the purpose for which it is to be used. Full information on the requirements relating to the distinguishing name is provided in the Agricultural Labelling Code.

1.1.2. Formulator and formulation plant details

You should provide the name and address of all manufacturing facilities – including the GPS coordinates – involved in any step of the manufacture of the product. This includes toll or contract manufacturers and subcontractors involved in packaging and labelling, and testing, up to and including release for supply.

1.1.3. Formulation type

You should indicate the type of formulation to be registered (for example, wettable powder, emulsifiable concentrate, suspension concentrate, soluble concentrate, granule, dustable powder, bait, ultra-low-volume spray or aerosol).

The list of formulation type codes used by the APVMA for different formulation types is available in a separate guideline. If a description of the formulation type does not appropriately describe your proposed formulation type, refer to the Manual on the Development and Use of FAO and WHO Specifications for Pesticides (2016) to provide a formulation type.

1.1.4. Formulation composition

The formulation composition describes the qualitative and quantitative formulation of the product. You should provide a full description of the formulation of the product to be marketed or supplied for the purposes covered by the application including:

• the common or chemical names of the constituents and their identification or composition (trade names alone are not acceptable and should be accompanied with common or chemical names) –
  • in some cases, safety data sheets (SDS) may be submitted in lieu of the manufacturer’s CoA
  • for proprietary non-active constituents, specifications from the supplier – supplied directly to the APVMA
• the Chemical Abstracts Service (CAS) Registry Number (if available)
• the concentration of all active and non-active constituents in the formulation
• reference to the quality standards (for example, the APVMA approval number for the active constituent, and the manufacturer’s specifications for non-active constituents – for proprietary non-active constituents, the supplier can provide specifications directly to the APVMA)
• the purpose of the constituents in the formulation (for example, whether it is the active constituent, a surfactant, an emulsifier or a filler).

Based on the actual purity or potency of the active constituent and all non-active constituents, you should adjust the formulation composition by calculating the concentration of constituent(s). For example, if the theoretical concentration of an active constituent in a batch of product (that is, the label claim) is 275 grams per litre (g/L), and the purity of the technical active constituent being used is 950 grams per kilogram (g/kg) (95% weight per weight), then the factorised concentration of the technical active constituent to be added would be:

275 g/L÷(950/1000)=289.5 g/L

Concentrations of technical active constituents, together with the stated nominal concentration of active constituent (and any overage), adjuvants, and inert constituents should be expressed in g/L for liquid formulations and g/kg for solid formulations. If these units are not appropriate for a particular formulation, the applicant should propose suitable units (for example, a biological unit).

Table 1 provides an example of an adequate formulation composition statement.

_{MS = manufacturer’s specification}

1.1.5. Active constituent standard

The active constituent(s) proposed for use in registered agricultural chemical product(s) must be approved active constituent(s). Active constituent sources included in the Record of Approved Active Constituents for Chemical Products comply with the APVMA active constituent standards and may be used in registered products as per the conditions of registration. The active constituent in a product may also be listed on the list of active constituents not requiring evaluation. Active constituents on this list have been evaluated by the APVMA and approved under section 14A of the Agvet Code. These active constituents can be obtained from any reputable supplier.

If the active constituent or the source of the active constituent is not included in the Record of Approved Active Constituents for Chemical Products, you should submit an application for approval of a new active constituent or a new source of an approved active constituent, respectively.

Product registration holders must ensure the active constituent used in an agricultural chemical product complies with the APVMA’s active constituent standards, available from our website.

You should provide the following information about the active constituent:

• The name of the manufacturer and the street address of the manufacturing plant(s), and the approval number, where available
• The batch analysis data for the batch of the active constituent (analysed within the last 2 years) to be used in product formulation. The batch should be analysed for active constituent content and impurities listed in the APVMA’s standard for that active constituent and analysed for any toxicologically significant impurity(ies) at any level
• Full details of the analytical methods used for the determination of the active constituent, any isomer and impurities
• Appropriate validation data for the analytical methods used for the determination of the active constituents and relevant impurities and toxicologically significant impurity(ies) or reference to an application number where these data have been provided and assessed

1.1.5.1. Reference to previously submitted data of active constituent

If the data have been assessed and accepted by us in a previous application, you may reference the analytical method and method validation 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 request that you resubmit any or all the referenced data previously submitted. This is usually the case where previously submitted data are older than 5 years.

1.1.6. Formulation process and quality control

You should provide a description of the method of formulation of the product and the sequence of operations, plus an indication of the typical size of the production-scale batch.

Full details of the quality control procedures used by the formulator to ensure batch-to-batch reproducibility of the product should also be provided. Information should include details of the control checks performed at various stages of the manufacture, processing and packaging of the product. The description of the in-process testing should include the specifications and tests for pivotal and key or critical intermediates. A description of the process to deal with a product that does not comply to release specifications should be provided.

1.1.7. Cleaning of manufacturing equipment

You should provide a description of the methods and quality control measures for cleaning of manufacturing equipment between batches of different products.

1.1.8. Physical and chemical properties of the product

The following data on the physical and chemical properties of the product should be provided:

• Appearance, colour, odour, physical state
• Acidity, alkalinity or pH value
• Bulk density (solids)
• Density or specific gravity (liquids)
• Viscosity and surface tension (liquids)
• Relevant characteristics applicable to the particular formulation type (for example for wettable powder: suspensibility, wet sieve test, wettability and persistent foam)
• Flash point
• Flammability
• Explosive properties
• Oxidising properties
• Corrosive hazard
• Dangerous goods classification as per the Australian Dangerous Goods Code (ADG Code), if applicable

1.1.9. Potential for the formation of impurities of toxicological concern

You should monitor and report toxicologically significant impurities present in the active constituent and non-active constituents in the product, or formed during the formulation of the product and storage or by migration of packaging material into the product.

Note that a general list of toxicologically significant impurities is available on our active constituent standards page.

1.1.10. Product specifications

You should provide product specifications, with suitable upper and lower limits for the active constituent and the toxicologically significant impurities, and the relevant physical characteristics of the product.

The specification limits should take into account the use of any overages in the formulation.

Specifications should address the test parameters for the particular formulation types, as outlined in the separate guideline on generation of storage stability data for agricultural chemical products.

Table 2 provides an example of a suitable format for product specifications.

1.1.11. Batch records of active constituent

The product registration holders and/or the active constituent supplier are required by a condition of product registration to maintain analysis records for each batch of the active constituent used in their registered products. We may audit the active constituent batch records held by agricultural chemical product registration holders.

1.1.12. Content of active constituent – allowable variations

The difference between the stated label amount or concentration and the actual content of the active constituents should not exceed the statutory limits for chemical products.

The Agvet Code Regulations establish the means for determining the maximum allowable variation for active constituent content based on the nominal label amount or concentration and the composition of the product. In the case of an agricultural chemical product or constituent, these allowable variations are those specified in the FAO specifications for plant protection products (Table 3).

_{EC = emulsifiable concentrate; SC = aqueous suspension concentrate; SL = soluble concentrate; GR = granule; WG = water-dispersible granule}

_{Note: In each range the upper limit is included. (Sourced from JMPS, 2010)}

1.1.12.1. Comments for Table 3

The allowable variations (tolerances) refer to the average analytical result obtained and take into account manufacturing, sampling and analytical variations, except where an overage is required. Positive deviations from the upper limits given in the table may be utilised if the formulation is manufactured with an overage to compensate for degradation in storage.

Further information on requirements relating to active constituent concentration on product label is provided in the in the labelling code.

1.1.13. Batch analysis data

Results from a current batch of the product are required to demonstrate that the product is formulated within specifications. The data should address all parameters listed for the product specifications.

Note: The initial results from stability trials may be sufficient.

1.1.14. Toxicologically significant impurities

Where the concentration of toxicologically significant impurities is known to increase as the active constituent degrades upon storage, the level of these impurities should be analysed at the commencement and completion of the relevant product storage stability study. The concentrations found after product storage should be in a proportionally appropriate concentration to meet the APVMA standard for the active constituent. Examples of such products are those that are date-controlled (mancozeb, zineb, diazinon, dimethoate). However, where toxicologically significant impurities are the result of ‘carry-through’ from raw materials and/or as a by-product of the manufacturing process for the active constituent and do not increase on storage, then no analysis of these impurities is needed in the relevant product stability study.

1.1.15. Stability data

You should provide data that shows stability during storage to demonstrate that the product continues to meet its specifications for the shelf life of the product. Stability testing may be conducted on laboratory-, pilot- or production-scale batches of the product (stability data generated on batch sizes of less than 5 kilograms or 5 litres are normally not acceptable as they are not adequately representative). The formulation should be the same as that proposed for registration in Australia. The samples should be stored in the proposed commercial packaging, or in smaller containers of the same packaging material. You should provide batch size and identity, packaging material, pack size and the quantity of the product it contains.

Agricultural chemical product containers have an important effect on storage stability or shelf life. If the product is corrosive, lids, liners, seals, seams or container sides may be damaged over time, causing the contents to leak during storage, transportation, handling and use. The condition of the containers should be examined at the beginning and end of the study to determine any obvious signs of package failure or deterioration. You must note and discuss any adverse effect of formulations on the containers in the stability report.

You should demonstrate that the product remains within specifications when stored under normal conditions. Typically, agricultural chemical products should remain within specifications for up to two years under normal conditions.

Storage stability data from accelerated and/or long-term testing at or above 25°C (ambient testing) should be provided for the product stored in the proposed commercial packaging (or smaller packages of the same construction and material).

Stability testing may include one or more of the following, as appropriate:

• Accelerated testing
• Real-time testing
• Cold-stability testing for liquid products

These test are explained in more detail below.

1.1.15.1. Accelerated testing

An accelerated storage stability test is designed to increase the rate of chemical and physical change of a product. The currently preferred method for accelerated storage stability testing is the Collaborative International Pesticides Analytical Council (CIPAC) MT 46.3: accelerated storage procedure.

This CIPAC method examines samples stored at 54˚C over a period of 2 weeks, unless other temperatures and periods are specified in the FAO/WHO specifications for particular formulation types. For products, that are unstable at these temperatures, alternative periods and temperature regimes are available (for example, 6 weeks at 45˚C; 8 weeks at 40˚C, Table 4).

1.1.15.2. Real-time testing

Stability tests at elevated temperatures are designed to increase the rate of chemical degradation or the physical change of a product. Data from an accelerated study can give a useful indication of a product’s stability, but note that products may pass this test and yet still be unstable on long-term storage. Therefore, it is recommended that applicants provide stability data generated at ambient temperatures over a period of 2 years. For example, if the proposed product has the ability to cake over time or is subject to contamination from bacterial or fungal growth, accelerated stability would not be suitable to demonstrate the stability of the product; in this case, real-time stability testing would be appropriate.

Note: Real-time data are required for date-controlled agricultural chemical products.

1.1.15.3. Cold-stability testing for liquid products

Liquid formulations (for example, emulsifiable concentrates, oil-in-water emulsions, micro-emulsions, soluble concentrates and suspension concentrates) may be adversely affected by storage at low temperatures. Cold-stability testing should be carried out at 0 ±2˚C or lower for 7 days (CIPAC method 39.3).

Note: Cold-stability testing is not necessary if the product label contains a warning against exposure to low temperatures.

Samples from all stability tests should be tested before (the initial analysis at the start of the study) and after storage for the content of active constituent and the relevant physical properties of the formulation type. Real-time stability results should include testing at suitable intervals.

Further information regarding the storage stability testing is available in a separate guideline on generating storage stability for agricultural chemical products.

1.1.16. Analytical methods

You should provide a full description of the analytical methods used for testing the product. The methods of analysis should be appropriate for the type of active constituent and the formulation matrix of the product. You should provide the following information to demonstrate the suitability of the analytical methods used to generate data for product registration:

• Full details of the analytical methods used for determining the active constituent and, where appropriate, relevant toxicologically significant impurities in formulated agricultural chemical products during stability testing
• A description and purity of the reference standards
• Where chromatographic techniques are used, representative chromatograms of the:
  • blank
  • reference standard
  • product sample.
• Chromatograms labelled with
  • batch number
  • peak identity
  • peak integration data
  • X and Y axis labels.
• Worked examples of the calculations

1.1.17. Validation data

You should provide validation data for the methods used for the determination of active constituent and, where appropriate, relevant impurities.

The following parameters should be addressed:

• Selectivity or specificity
• Linearity
• Precision
• Recovery (accuracy)
• Limit of detection (LOD) and limit of quantitation (LOQ) for relevant impurities and all toxicologically significant impurities

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

Note: If we have assessed the analytical methods in a previous application, you may refer to the data provided in that application. However, if the formulations are not identical, you should provide specificity and recovery (accuracy) data to demonstrate that the analytical method is appropriate for use on the new formulation.

1.1.18. Packaging

Packaging details should include details of the size, shape, construction and lining of suitable containers that will be used for the product. The integrity of the container should not be impaired by the product it contains, nor should the product be adversely affected by the packaging material.

Potential changes to the integrity of the packaging materials should be monitored during the storage stability studies.

1.2. Using a reference product

You may nominate a reference product that is suitably similar to the product being registered in order to satisfy us that the product being registered satisfies the safety criteria. If the reference product has a limitation on its use or we require access to confidential commercial information for the reference product, you must provide written consent from the authorising party for us to access the protected or confidential commercial information data.

1.3. Providing valid and relevant scientific argument

You may use valid and relevant scientific argument to satisfy us of the safety criteria for registration of an agricultural chemical product. Argument may also be used in conjunction with data.

1.4. 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. The reference should include the product registration number, application number and the data reference number. We reserve the right to request the applicant to resubmit any or all the referenced data previously submitted.

1.5. Using overseas data assessments and decisions

We may accept data that have been generated overseas in support of registration of an agricultural chemical product. In using overseas data and decisions, we will consider the similarity of the Australian and overseas products, the relevance of the data to Australian climatic and environmental conditions, agricultural 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 the data are eligible for limitation on use.

3. Template for the dossier to support the registration of a new agricultural chemical product

• Table of contents
• Overall summary
• Distinguishing product name
• Formulator and formulation plant details
• Formulation type
• Formulation composition
  • Common or chemical names of the constituents
  • CAS registry number (if available)
  • Concentration of all active and non-active constituents in the formulation
  • Reference to quality standards
  • Purpose in the formulation of the non-active constituents
• Active constituent standard
  • Manufacturer and manufacturing plant details (includes name of manufacturer, street address, GPS coordinates of the manufacturing plants and the approval number (where applicable))
  • Analytical methods used for the determination of the active constituent
  • Validation data for the analytical methods
• Batch records
• Formulation process and quality control
• Physical and chemical properties of the product
• Potential for the formation of impurities of toxicological concern
• Product specifications
• Batch analysis data
• Stability data
  • Accelerated testing
  • Real-time testing
  • Cold-stability testing for liquid products
• Analytical methods
  • Analytical methods
  • Purity of the reference standards
  • Chromatograms of the sample and reference standard
  • Worked examples of the calculations
• Validation data
  • Specificity
  • Linearity
  • Precision
  • Recovery (accuracy)
  • Limit of detection (LOD) and limit of quantitation (LOQ) for relevant impurities
• Packaging
• Draft label
• Data list

4. References

JMPS 2010, Manual on the development and use of FAO and WHO specifications for pesticides, second revision of first edition, FAO/WHO Joint Meeting on Pesticide Specifications, the Food and Agriculture Organization and World Health Organization of the United Nations, Rome.