Change in Storage Stability Data Requirement for End-Use Products and Manufacturing Concentrates

30 April 2014

Purpose

The purpose of this memo to applicants and registrants is to communicate changes to PMRA data requirements for end-use products and manufacturing concentrates as they pertain to DACO 3.5.10 Storage Stability Data.

Background

Regulatory Directive DIR98-03 (Chemistry Requirements for the Registration of a Manufacturing Concentrate or an End-Use Product Formulated from Registered Technical Grade of Active Ingredients or Integrated System Products) describes the chemistry data requirements required to support applications to register end-use products or manufacturing concentrates, including storage stability data. The purpose of storage stability data is to assess product stability under expected storage conditions. As per Appendix 1 of DIR 98-03, the current recommended protocol is storage at a constant 20 or 25°C, or under warehouse conditions, in commercial packaging material for a period of one year. It is also recommended (but not required) that data for corrosion characteristics (DACO 3.5.14) be obtained at the same time via the same study.

In addition to the standard one-year storage stability study submitted in support of product registration, the PMRA also often receives accelerated storage stability studies (principally storage at 54°C for 14 days in commercial packaging material). Although these accelerated studies are not a data requirement, they are often submitted to the Agency because they are available (i.e., required by other regulatory authorities either in addition to, or in lieu of, longer-term studies).

In an effort to more closely align data requirements with other jurisdictions, the PMRA has recently examined storage stability data received to date where both accelerated and one- or two- year real-time storage stability data have been submitted in support of a product registration. PMRA's analysis indicates that degradation of active ingredients was similar between the accelerated and standard storage stability regimes, but was more frequently observed, and to a greater extent, with the accelerated regimes. The analysis also demonstrated that no significant differences were found in corrosion characteristics of the packaging between the accelerated vs. real-time studies. As a result, the PMRA has concluded that the accelerated regime of 14 days storage at 54°C is a more rigorous test and is sufficient to fulfil the requirements of DACO 3.5.10 ( as well as 3.5.14) when the study is carried out in commercial packaging. Based on this conclusion, the PMRA is now in a position to revise storage stability data requirements.

Changes to Storage Stability Data Requirements

The revised storage stability data requirements for DACO 3.5.10 are presented in Appendix A of this document. These changes will also be reflected in the next version of Guidance for developing a database for conventional Pest Control Products as a follow-up to the original document that was distributed to registrants by e-mail on July 11, 2013. (Note: The guidance for DACO 3.5.14 will also be changed by reference to the changes in DACO 3.5.10).

Scope and Implementation

The revised data requirements for DACO 3.5.10 (refer to Appendix A) apply to new applications to register a new end-use product or manufacturing concentrate, where storage stability and corrosion characteristics data are required.

The revised storage stability data requirements will also be applied to: a) currently open submissions for new products and b) registered products with an outstanding condition to provide storage stability data. In these situations, the following approach will be taken:

1. Open submissions for new products where the requirement of a one-year storage stability study would normally apply:
   1. If a reviewable one-year or accelerated storage stability study has been provided in support of the application and found to be acceptable, no further data for DACO 3.5.10 will be requested and the applicant will be informed as required.
   2. If no storage stability study has been provided in support of the application, the applicant will be informed of the revised data requirements and that an accelerated storage stability study may be provided in lieu of a one-year study.
2. Registered products with one-year storage stability (DACO 3.5.10) identified as a condition of registration:
   1. Registered products with open submissions to fulfil DACO 3.5.10:
      • If an acceptable accelerated storage stability study is already on the registered product file, the applicant will be informed of the revised data requirements and that the outstanding condition has been fulfilled. In this situation, the new storage stability data provided under the open submission will not be reviewed by the Agency.
      • If there is no acceptable accelerated storage stability study on the registered product file, the storage stability data submitted with the open submission will be reviewed by the Agency as per standard process.
   2. Registered products with no open submission to fulfil DACO 3.5.10:
      • If an acceptable accelerated storage stability study is already on the registered product file, the registrant will be informed of the revised data requirements and that the outstanding condition has been removed.
      • If there is no acceptable accelerated storage stability study on the registered product file, the registrant will be informed of the revised data requirements and that an accelerated storage stability study may be submitted in lieu of a one-year study.

Effective Date

The revised DACO 3.5.10 storage stability data requirements take effect immediately.

Questions / Contact

Any questions should be directed to the PMRA Information Service.

Appendix A Revised DACO 3.5.10 Data Requirements

Storage stability data must adhere to the following requirements:

1. A storage stability study shall be conducted under at least one of the following regimes:
   1. at least one year's duration at a constant ambient temperature of 20 or 25°C and, if the package is permeable, at a relative humidity of 50%, with quantitative analysis for the active ingredient(s) at study commencement and following storage periods of 3, 6 and 12 months;
      or
   2. at least one year's duration under warehouse conditions that reflect the expected storage conditions of the commercial product (this may include the need for freeze-thaw studies). Where possible, the storage environment should approximate any extremes of temperature or climate expected to occur under actual storage conditions. Quantitative analysis for the active ingredient(s) is required at study commencement and following storage periods of 3, 6 and 12 months;
      or
   3. of 14 days' duration under accelerated conditions at a constant temperature of 54°C, with quantitative analysis for the active ingredient(s) at study commencement and after 14 days.
2. The study shall be conducted with the product in its commercial package or in smaller packages of the same construction and materials.
3. For long-term ambient studies, the study should be carried out with sufficient replicates and sufficient sampling frequency to establish the actual shelf-life if significant degradation occurs within one year (i.e. the level of active is no longer within the certified limits). If significant degradation is observed under accelerated conditions, a one-year study as described above may be required to determine the shelf life. If a product has a shelf life of less than one year, an expiration date may be required on the product container.
4. The analysis is to be conducted using a specific validated method. For EPs, the same method used to determine the level of the active ingredient for establishing certified limits would typically be employed. However, if the methodology differs from that provided under DACO 3.4.1, it must be fully described as per Appendix I in Regulatory Directive DIR98-03 Chemistry Requirements for the Registration of a Manufacturing Concentrate or an End-Use Product Formulated from Registered Technical Grade of Active Ingredients or Integrated System Products.
5. The storage stability report submitted in support of registration shall include the following information:
   1. a description of test procedures and conditions, e.g., study duration, humidity and temperature
   2. a description of any physical changes, e.g., phase separation or clumping, in the product and any changes to the integrity of the packaging material during the test period, and also the consequences, if any, of such changes for safe handling and use of the product; and
   3. quantitative analytical data for the active ingredient at study commencement and all storage periods.
6. A surrogate study of a similar formulation may be acceptable in lieu of the storage stability study. The formulation used for the surrogate study must be fully described to allow the acceptability of the study to be determined.
7. The stability protocol must contain a test to monitor for the stability of optically pure/enhanced active ingredient(s) towards chiral inversion or other isomerization, if applicable.