Registering Generic Agrochemicals in the EU - Technical Equivalence
Oct. 14, 2013
- Dr John McKenzie
Dr John McKenzie has worked in China for over 5 years and currently is Business Development Manager for Harlan Laboratories. John has a doctorate in Chemistry f...
The EU has a complex array of legislation and guidance on Agrochemicals (Plant Protection Products). If an active substance is currently approved in the EU, approval for each new source of the same active substance must also be granted before the new source is placed on the market. This is more commonly known as a Generic Agrochemical.
There are some basic milestones in gaining authorisation for a Generic Agrochemical in the EU:
All active substances ‘as manufactured’ must be granted Technical Equivalence to the existing registered source(s) in the EU.
Technical Equivalence is the process where the technical specification of a new source of an existing active substance is compared by an EU Member State to the technical specification of the existing source or sources of the active substance as included in Regulation (EC) 1107/2009.
Before starting a program of technical equivalence, it is essential the manufacturing process is proven and constant. The technical equivalence report will show inconsistency in manufacture and can be the messenger of bad news - `poor control of manufacturing process`, or good news `good control of manufacturing process`. To start off a technical equivalence program is, with manufacturing, to understand all the components of the manufacturing process and to build knowledge of what the active ingredient may contain.
For Technical Equivalence:
1. A GLP 5-batch report of the material as manufactured is required. The material should be from full scale production, recently manufactured and taken from non-consecutive batches. This is to demonstrate and confirm the true extent of the manufacturing variability
2. From the GLP 5-batch report, a technical specification for the active substance can be proposed by the applicant. The technical specification is the profile of the technical active substance that covers the manufacturing variability. The technical specification includes the minimum purity of the active substance and the maximum content of any impurities present at > 0.1% w/w.
3. All impurities present at >0.1% w/w should be identified and quantified. In addition, impurities that are particularly undesirable because of their toxicological, ecotoxicological or environmental properties, shall be considered as relevant. The limits for relevant impurities may be set at levels lower than 0.1% (Refer to Figure 2 for a summary of assessments below 0.1%). The analytical methods must be validated in accordance with EC Guidance SANCO/3030/99 Rv4. Refer to Figure 1 for a summary.
4. It is recommended that the minimum purity of the active substance is not lower than the existing registered source. When setting a technical specification it should be considered that it is this specification for active substance and impurities that will have to be met and passed by Quality Control when placing on the market in the EU.
5. For submission, a Confidential Information document must be submitted. In addition to the technical specification this document contains the Confidential Information on the starting materials, detailed manufacturing process and impurity formation.
6. Submission is made to one Member State. All EU Member States are able to comment but must agree on the equivalence report.
7. The objective of the evaluation is to identify whether there is an unacceptable hazard increase for the new source when compared to the reference source as a result of:
a. Any new impurities
b. Increased levels of relevant impurities. A relevant impurity is one of toxicological and/or ecotoxicological or environmental concern compared to the active substance.
c. Increased levels of non-relevant impurities present at >0.1% w/w. Non-relevant impurities occur due to process variability.
8. If the certified minimum purity is not lower than the reference source and there are no new impurities or existing impurities present at increased levels the new source is deemed equivalent and no further data is needed.
9. If there are new or increased levels of impurities in the new source compared to the reference source then additional data may be needed. The data required for each new source has to be assessed on a case-by-case basis. The necessary data could consist of (Q)SAR analysis, genotoxicity testing, scientific argumentation and/or toxicity data.
The technical specification of the existing active substance is not known to the applicant at the point of submission, this data is confidential to the existing authorisation holder. The Member State opens the file on the existing active substance to carry out the evaluation for Technical Equivalence, the data from this file is not released at any point to the applicant of the new source. Therefore it can be difficult to determine prior to a submission the exact data necessary for a submission and it is sometimes necessary to make a follow up submission with the additional data.
Being assessed as being Technically Equivalent is the first milestone, however it does not mean you can immediately place your source of active substance on the market in the EU unless you have access to the necessary active substance data.
• Access must be gained to the active substance data package (also known as the Annex II data package).
- Such access could be gained through various options, such as Letter of Access (LOA), or referring to data that is out of data protection (it should be noted that it is determined on a case-by-case basis if this data is out of data protection), or the potential applicant could even create a ‘matching dossier’, which although is the more costly option, may create a longer sales period.
- Potential applicants should also consider what implications the on-going Annex I Renewal (AIR) programme may have on the data protection of the active substance in the future. AIR is the process of renewing the existing active substance approvals in Europe.
• In most EU Member States the new source must be notified in writing to the relevant ministry as a source of technical material that will be used, some Member States require formal registration of the new source in each individual formulated product placed on the market.
Figure 1 – summary of analytical requirements
Figure 2 – assessments of impurities below 0.1%