Residue Studies And GLP In Brazil
15 December 2008 
Different countries have different requirements for the residue studies that form a part of the data required for the registration of a chemical product. At the end of 2006, the Federal Government of Brazil published a set of new pesticide regulations, which contain several important modifications to the previous regulations.
The new regulations are contained in the official document RDC 216/2006 from ANVISA (Brazil’s Ministry of Health).
These new instructions include the establishment of Good Laboratory Practice (GLP) for field and laboratory studies for residue studies. Potential, desirable outcomes of the new regulations are reduced registration costs and faster evaluations. RDC 216/2006 introduces several changes which shall speed up the “me-too” registration process.
The Process
Due to their nature, residue studies are normally multiple-site studies, in which different phases of the study are conducted at different locations. Typically, there is a field phase involving the application of a pesticide to a crop, and the subsequent collection of samples.
Following collection, the field samples are sent to a laboratory where the analytical (laboratory) phase of the study is undertaken. In order to produce data that will meet the requirements stipulated for product registration, all phases of a residue study must be conducted in accordance with GLP. In particular, it must be held in mind that from the viewpoint of GLP, a residue study is always a single study.
A residue study must be under the control of a single study director. The responsibilities of the study director include the overall design of the study, which may have several field sites with analyses performed in more than one laboratory.
Since the field and laboratory phases of the study are normally in different locations, it is standard practice for a principle investigator to be designated for each location. These principle investigators act on behalf of the study director for the various delegate phases (field and laboratory) of the study.
The study director will prepare the study plan, which must be intelligible to all the test site personnel for each phase of the study. The phases will frequently be located in different places, regions, or even countries. This may require the translation of the study plan into other languages, so that at each location the plan will be understood identically and unambiguously.
Plan Of Action
Each residue study will require a unique study plan, with a comprehensive definition of the study requirements, and methods. The requirements will include a study schedule, responsibilities of the different personnel, a description of the test system for the field phase (for example, specification of the crop, the cultivar, the growth stages for pesticide application and sample collection, and soil characteristics), as well as the analytical methods and specific procedures to be followed.
The appropriate selection of the test sites (laboratory and field) for a GLP study is essential. Each site must be able to achieve the specific criteria stated in the study plan.
For the field phase, the biological test system (crop) must be properly characterized and a unique and reliable identification scheme must be established and rigorously followed. It must be possible to reconstruct the trial and associated raw data of the study.
Appropriate equipment and facilities will be necessary to ensure that specimens collected in the field are obtained from the correct locations, uniquely identified, packaged, transported, and stored under conditions which preserve their integrity.
In order to achieve the study objectives, all of these details will need to be considered in the preparation of the study plan.
Every step of the study, from the preparation of the field through the moment of collection of the field samples to the time of their analysis or assessment in the laboratory, must be planned.
Special Cases
In some cases it may be necessary to make special arrangements to satisfy the requirements of the study.
Standard Operating Procedures (SOPs) are among the most important features of GLP studies. The principles of GLP provide a definition, which can be briefly summarized: an SOP gives documented procedures describing how to perform a test activity. SOPs describe procedures that are routinely employed in the performance of test facility operation, e.g., calibration of field trial equipment, preparation and application of the test substance, sampling, test item reception, sample storage and processing, residue extraction and analysis, records to be maintained, and quality assurance inspections.
The level of detail concerning an activity will be far greater in an SOP than will be found in a study plan or test guideline. Study plans will normally reference the key SOPs which describe the procedures for the various activities that comprise a study.
In order to make the correct selection of analytical methods for a study, the analytes which will be determined must be specified. Methods must be selective and with sufficient sensitivity to give a reliable quantification of each analyte at the level specified in the study plan. Validated analytical methods should be used.
Proper Validation
Method validation for residue analysis will establish that the method being used is fit for the purpose. This includes the quantification of a specific compound (active ingredients and sometimes metabolites) in the matrices of the collected samples, at or below the levels stipulated by national and international registration authorities.
Optimum operational conditions will be specified, and method performance parameters such as accuracy, limit of detection, limit of quantification, specificity, linearity, range, and suitability for different matrices will have been evaluated and recorded.
For some residue studies, it may be necessary to develop and validate new analytical methods, depending upon the specific goals of the study.
The Final Submission
Once the analyses have been completed, the study director will prepare and issue a Final Report for the study.
The Final Report will describe both the field phase and the analytical phase of the study. The Report will demonstrate that both phases of the study have followed the previously agreed-upon study plan, as well as that the study has been conducted in accordance with all of the laboratory, testing, and procedural requirements as set out in the principles of GLP.
Recent Changes In ‘Me-Too’ Registrations
The RDC 216/2006 makes significant changes to the procedures for the submission of registration data for “me-too” formulations.
Registration submissions may now be based on already registered products that contain the same active ingredient. No distinction is made between different types of formulations, such as EC, SC, and WP.
There are limitations – the active ingredient applied per unit area with a me-too product must not exceed the coverage for the product of reference for which registration has already been completed.
The new “me-too” rules for the submission of residue studies are also applicable to “ready to use” premixes of two or more active ingredients that have already been registered in Brazil, with the same limitations that typical “me-too” registrations are subject to.
Submissions of prior residues studies for formulations containing each of the active ingredients, either individually or in mixtures with one or more of the other active ingredients, will be accepted. It is not necessary to submit a residue study for the specific mixture of active ingredients in a “ready to use” product premix containing already registered active ingredients.
Other changes in the legislation which have an impact on the ways in which residue studies are conducted include an increase from three to four in the number of required field trials, and the new rule stating that residue trials will no longer be required for seed treatment products which do not contain systemic active ingredients.
Room For Modification
Although these changes have been accepted at the Federal level, each State has the authority to set its own independent registration requirements. These may differ from the Federal legislation, as well as from State to State.
So far, no State has announced that it has intentions of operating under different registration requirements than those set forth by the Federal regulations of RDC 216/2006.
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