Redator Kivalita em 1 de April de 2021 em Articles

What RDC 301/2019 requires facing the toxicological evaluation and ADE/PDE in cleaning validation

Cleaning validation in the production of medicinal products is essential to avoid risks of cross-contamination between products and to ensure the efficacy and safety of these products.

In the European Community, since 2015, in addition to aspects related to the physical-chemical characteristics of products and analytical methodologies, this risk analysis mainly considers the toxic potential of the product, increasing product safety for patients and also for operators on the production line. In Brazil, by the publication of RDC 301/2019, ANVISA incorporated this same rationale, in which toxicological evaluation and application of risk analysis should be applied both in cross-contamination management and cleaning validation.

In the toxicological risk analysis, health based exposure limits (HBEL) of each product are estimated. Usually, permissible daily exposure or PDE (Permitted Daily Exposure) isestimated, a value that represents the specific dose (mg/person/day) of the substance that is unlikely to cause adverse effect in individuals exposed to the dose itself, or lower doses, every day throughout life.  

  1. Daily Exposure Allowed

A) The calculation of the Permissible Daily Exposure begins with an extensive literature review, collecting all data on the pre-clinical and clinical toxicology of the product.  

B) All information obtained in the review is critically analyzed for completeness, robustness and relevance. Only the data considered valid are used in the pde calculation. Only results of studies considered valid and relevant will be selected as the starting point for the PDE calculation.  

C) From the evaluated data, dose values are extracted, which are applied in a calculation that includes the standard weight of a person and a series of uncertainty values that take into account issues such as difference between species and severity of the observed effect, among others. This calculation needs to be performed by experienced toxicologists with knowledge to critically analyze the studies, select the relevant information and correctly apply the uncertainty factors.


D) The final value corresponds to the dose that a person can ingest of the product every day throughout their life without any toxic effects happening. And for this reason the PDE is a more appropriate value for input into cleaning validation calculations, as it provides for chronic exposure.

2. The PDE Report ANVISA Technical Note 276/2020 details minimum requirements that need to be addressed in the PDE report, including all studies evaluated, starting points and uncertainty factors used with justification for use, pharmacokinetic data and identification of responsible toxicologists, including their experience in PDE calculation.

3. Application in cleaning validation The PDE deve value be used as a value related to health within the cleaning validation equations. In this way, it is important to know the PDE value  of all  pharmaceuticals and cleaning agents that share the manufacturing line to conduct validation assertively.

InnVitro Research & Development is a toxicology consulting company with extensive experience in conducting PDE reports. | Linkedin Inn Vitro

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