On June 2016 will be coming into effect for veterinary medicaments EMA’s guideline (EMA/CHMP/CVMP/SWP/169430/2012) already implemented for human medicaments. This document follows the review of chapter 3 and 5 (currently into effect since March 2015), with the purpose of determine a new risk analysis methodology for shared facilities: It is necessary a dedicated facility? and how can we establish a theoretical threshold of cleanness?
EMA (EMA/CHMP/CVMP/SWP/169430/2012) guideline establishes as first step, the development of toxicology reports and scientific calculation of the Permitted Daily Exposure (PDE) based in pharmacological, toxicological and pharmacokinetical data.
2. Maximum residue levels versus PDE
Why shouldn’t veterinaries use Maximum Residue Levels (MRLs) (described in CR (EU) No 37/2010) instead of PDE value?
MRLs are threshold values, specific for any API that allows evaluating if withdrawal times are being fulfilled. The main objective is to protect consumers against residual treatment exposures. Although MRLs are very useful as a reference, it cannot be extrapolated to cleanness validations and risk analysis in shared facilities, because there are some differences in objectives and applications:
- To determine MRL values it’s considered that previous animal exposure to the API is controlled. We know the dose, application time, effects, etc. In cross-contamination exposure are accidental and therefore unknown.
- To establish MRLs values, although livestock can receive the treatment through any route (parenteral, oral, intramamary, topic…), population exposure to the residue is always through feeding from a contaminated animal (oral route). However, risk analysis in shared facilities, must be consider always the indicated route of the medicament produced in plant (oral in premixtures for medical feeds, topic for external antiparasitic manufacturing, etc.).
- It is critical for MRL calculation to take into account pharmacological behavior of the substance in target species. Factors as differences of toxicity between the active principle and its metabolites or residues, speed and route of excretion, etc. should be taking into account because population exposure to the substance is always produced after a previous metabolism by the animal body. On the other hand, cross-contamination of an active principle is produced when manufacturing; and that means that contamination will not be produced by either a residue or metabolite; but with the primary API.
3. Exposure limit definition
How to define exposure limits.
Exposure thresholds will be determined from Permitted Exposure Limits (PDE), defined as the amount of substance that can penetrate daily in the organism, all life long without harm.
PDE determination is specific for each API and it is derived from scientific evaluation of all pharmacological and toxicological pre-clinic and clinic data.
For PDE determination in veterinary, it is necessary take into account specific features and differential factors regarding humans.
- Shorter life-cycles and treatments.
- Weight differences between species: From a hundred times lower in poultry or fish farming toa hundred times higher in cattle, than human PDEs.
- Physiological differences of each species that can affect to the pharmacokinetics and pharmacodynamics: Ruminal pH inactivation may reduce toxicity for some APIs if the contaminated animal is a ruminant, instead of a monogastric.
- Exclusive routes of administration (intramamary, slow release oral bolus) etc.
For veterinary medicaments, EMA’s guideline of November 2014 (EMA/CHMP/CVMP/SWP/169430/2012), establish that it is possible to use the PDE approach to establish different limits for different target species. However, this would be highly impractical. Consequently, it is considered pragmatic that PDE should be derived assuming human exposure and data.
Since we have an unique PDE for each API(calculated from human weight and corrective factors) we can classify and categorize according to the risk, with a standard rule for all of them.
In case of APIs for non-food animals (horses, dogs, cats, etc.) EMA’s guideline is less specific because there was no direct risk for human population. However a categorization of cross-contamination risk is required as well as a threshold values establishment. In these cases, detailed bibliographical research and expert criteria are critical points in standardization values and control measures. It would be always necessary to take account specific considerations of each target species
Toxicological value determination in risk analysis follows general guidelines that it allows to compare between standardized value of different products; enabling the categorization of any substance to define technical and organizative measures.
As a practical approach according to EMA/CHMP/CVMP/SWP/169430/2012 guideline, human PDE values can be used for cleanness validation in veterinary medicaments.
However, some APIs and veterinary medicaments have differential features. So, bibliographical research and analysis are critical steps for threshold determination. Therefore, this work requires specialized staff in veterinary toxicology for select the starting point and corrective factors that must be applied.