Verifying chemistry of registered technical grade active ingredients and integrated system products

24 June 2024

Purpose

The purpose of this memo to registrants of technical grade products is to communicate the updated process for verifying chemistry of pesticide active ingredients registered in Canada. This memo applies to both types of technical grade products, namely technical grade active ingredients and integrated system products (ISPs).

Background

In response to a federal commitment to strengthen the pesticide review process in Canada and its transparency, the Pest Management Regulatory Agency (PMRA) underwent a Transformation Agenda with initiatives organized under four pillars. Under the Modernized Business Process pillar, the PMRA committed to establishing a life-cycle approach to the oversight of pesticides, referred to as Continuous Oversight.

In January 2024, the PMRA held a Consultation on the proposed policy on continuous oversight of pesticides. A final policy and a summary of comments and responses will be published July 2024. Under the Continuous Oversight of Pesticides policy, the PMRA will collect and consider on an ongoing basis new science information such as published scientific literature, water monitoring data, and regulatory decisions made by other Organisation for Economic Co-operation and Development (OECD) member countries throughout a pesticide's regulatory lifecycle.

The policy also updates the approach to verifying product chemistry information for individual sources of technical grade products. Technical grade products are used as the source material for formulating pesticide end-use products.

Verifying chemistry as part of Continuous Oversight is an important component for ensuring that health and environmental risk assessments are relying on the best available chemistry information. Periodic confirmation that the technical grade products are being manufactured consistent with the approved specifications and methods is important as unreported and unverified changes to the manufacturing process, or specifications of the active ingredient can have implications for the health or environmental risks of the pesticide. Where new scientific information indicates a potential new or increased pesticide risk, the PMRA will take necessary actions to protect public health and the environment.

Going forward, chemistry verification for each active ingredient will occur every 10 years at a minimum and will be separate from the 15-year re-evaluation-based process. Decoupling the chemistry verification from re-evaluation is expected to result in efficiencies at the time of re-evaluation, with the PMRA having updated chemistry information available on file.

Under this updated verification process, registrants will be requested to submit certain chemistry information regarding their active ingredient, including quality control data. When needed, the PMRA will request additional GLP-compliant (Good Laboratory Practice) chemistry batch and/or impurity of concern data to support continued registration. If the chemistry verification determines that the product composition is not within approved specifications, or the manufacturing process has changed without proper reporting, Health Canada may consider appropriate compliance and enforcement actions.

Changes for registrants of registered technical products

Registrants will receive a request to provide chemistry verification information for registered technical products every 10 years at a minimum, with all sources of a given technical product grouped in the same year.
The approach will be flexible to allow for more frequent chemistry verification (for example, less than 10 years or upon request) when required for certain technical products and/or sources. Examples of situations calling for more frequent verification may include, but are not limited to:

• When actives or sources are known to contain impurities or contaminants of health or environmental concern;
• When the PMRA becomes aware of a potential issue that requires further investigation (for example, information from another jurisdiction; concern flagged with one source that may have implications for another source);
• When there is a history of discrepancies in specifications for certain actives or sources.

The PMRA is adopting a two-step approach for verifying the chemistry of technical products. The PMRA will verify the chemistry profile based on a review of manufacturing processes, updated specification form, and recent quality control production data. A requirement for GLP-compliant chemistry batch data and/or impurity data will only be issued when additional information is needed to further assess the product chemistry.

Process description

Step 1 Chemistry Verification

Registrants will receive a letter from the PMRA requesting the following chemistry information be provided for each registered source within 90 days from the date of correspondence:

• DACO 2.11 Manufacturing methods for Technical Grade Active Ingredient: A detailed description of the current manufacturing process that has been validated by the manufacturer within the last five years. This must include details on starting materials, suppliers, chemical equations, amounts used, production conditions, and date the process was last confirmed or obtained from the manufacturing site;
• DACO 2.12 Specifications Form: An up-to-date Statement of Product Specification Form (SPSF) including the concentration of the active ingredient, impurities and/or contaminants to a level of 0.1% and impurities of concern at any detectable level;
• DACO 2.13 Preliminary Analysis: In lieu of GLP-compliant batch data, the PMRA will require quality control data, representing five of the most recent commercial production runs that have been generated within the last ten years. The information can be presented in raw or finished reports or as certificates of analysis and does not have to be GLP-compliant. Each report must include the active ingredient level, manufacturing location and date, and batch size. The PMRA will not accept full chemistry batch data studies through the chemistry verification process.

If the above listed chemistry information to support verification is not submitted within the specified 90 day period, the PMRA may subsequently issue a notice in accordance with Section 12 of the Pest Control Products Act for the submission of five-batch analytical data using GLP-validated methods (batch and/or impurity data) as a requirement of continued registration of a technical product source. If there is no response to the Section 12 notice, the registration of that technical product source will be cancelled, and the registrant will be notified in writing.

Modified chemistry requirements will be applied to the following scenarios:

• Food-grade active ingredients: Registrants of food-grade active ingredients can provide an updated product specification form and a completed attestation form confirming no change to the source's food-grade status. Where applicable, the letter to the registrant initiating the chemistry verification process will clarify if the source has previously been confirmed by the PMRA as food-grade. If a source was not previously confirmed as food-grade, the registrant may request consideration for food-grade status under this chemistry verification process.
• Sources of technical grade active ingredients that are 100% repacks of another (parent) technical product source: Registrants of the 100% repack will provide an updated product specification form and a completed attestation form that there has been no change in source. If the registrant of the parent technical product source fails to provide the required chemistry information within 90 days or concerns arise during the process, the repack registrant will be required to either provide the required information or discontinue their registration; otherwise, the registration of that technical product source will be cancelled and the registrant will be notified in writing.

Once the PMRA has completed its assessment of the chemistry information, a letter will be sent to the registrant indicating either that the chemistry verification process has been completed and is deemed acceptable, or that additional chemistry batch and/or impurity of concern data will be required to support continued registration.

Step 2 Chemistry Batch Data

If, upon review of the chemistry information submitted for verification (Step 1), the PMRA determines that additional chemistry information (for example, batch and/or impurity data) is required, the PMRA will issue a notice in accordance with Section 12 of the Pest Control Products Act. Registrants will be required to comply with the notice by submitting a Category B submission to further assess the product chemistry.

Examples of changes in chemistry information that will trigger a requirement for batch or impurity data may include, but are not limited to:

• Identification of a new or previously unidentified impurity of concern;
• Significant changes to the previously approved manufacturing process;
• Increase in the level of an impurity of concern beyond the established certified limits;
• Lowering of a Virtual elimination target (in other words, more conservative) for a Toxic Substances Management Policy Track 1 substance;
• Significant changes to the PMRA-approved product specifications; or
• Levels of the active ingredient that are outside of established certified limits.

The PMRA will issue a notice, in accordance with Section 12 of the Pest Control Products Act, outlining the requirements and timeframes for submitting the batch and/or impurity data as a condition of registration. Registrants will be given one year to submit the batch and/or impurity data via a Category B submission, with the associated application fees. The PMRA will then review the batch and/or impurity data and decide on the continued acceptability of the product chemistry.

Transparency and Predictability

All registered active ingredients will follow a ten-year schedule, with the flexibility to require chemistry verification sooner where and when warranted. The PMRA will establish and maintain a transparent and scheduled five-year chemistry verification work plan outlining the planned schedule to submit chemistry information for all sources of registered technical grade active ingredients. The chemistry verification workplan will be published on the Canada.ca website.

Scope and Implementation

The chemistry verification process applies to all sources of registered active ingredients, at a minimum of once within a 10-year period.

Implementation will begin in 2024-25 fiscal year, with 44 active ingredients (Appendix I). The PMRA will contact the implicated registrants to formally request the chemistry information within 90 days.

Microbial active ingredients will not be in scope for this first year of implementation. Instead, the PMRA will initiate a pilot project in 2024-25 to explore a comparable chemistry process for microbial active ingredients.

For some recent re-evaluation decisions, the PMRA indicated at the time of decision that registrants would be required to submit confirmatory chemistry data under the future Continuous Oversight approach. These active ingredients will now be incorporated into this chemistry verification process.

During the transition period, registrants may continue to receive requests for chemistry information through the re-evaluation process (in other words, active ingredients where re-evaluation was initiated before 1 April 2024). For re-evaluations scheduled for initiation in 2024-25, these active ingredients will be transitioned over to the updated process described herein.

Questions/Contact

Any questions should be directed to the PMRA Information Service.

Appendix I: Active ingredients subject to chemistry verification in fiscal year 2024-25

• Acibenzolar-s-methyl
• 3-(Trimethyoxysilyl)propyldimethyloctadecyl ammonium chloride
• 3-(Trihydroxysilyl)propyldimethyloctadecyl ammonium chloride
• Butoxypolypropylene glycol
• Citric acid
• Castor oil
• Dichlorprop-p (present as dimethylamine salt)
• Dichlorprop-p
• Dichlorprop p-isomer (present as 2-ethylhexyl ester)
• 1,4-Dimethylnaphthalene
• Diodofon
• Diquat
• Dried eggs
• Fish meal mixture
• Fish oil mixture
• Flonicamid
• Garlic oil
• Garlic powder
• Hexahydro-1,3,5-tris(2-hydroxyethyl)-s-triazine
• Imazethapyr
• 3-Iodo-2-propynyl butyl carbamate
• Iron (present as FeHEDTA)
• d-Limonene
• Meat meal mixture
• Mesosulfuron-methyl
• Metconazole
• Metrafenone
• Naphthalene
• Oxalic acid dihydrate
• Paradichlorobenzene
• Saponins of Chenopodium quinoa (food grade)
• Sodium fluoride
• Tefluthrin
• Tembotrione
• Thiabendazole
• Thymol
• Tralkoxydim
• Wintergreen oil
• Gibberellic acid
• Gibberellins A4 and A7^{Footnote *}
• Calcium hypochlorite^{Footnote *}
• Putrescent whole egg solids^{Footnote *}
• Sodium chloride
• Sodium hypochlorite^{Footnote *}