What are the regulatory expectations with respect qualification and experience of a toxicologist?

Toxicology being an inter-disciplinary science, an understanding of the physiology, biochemistry, pathology, endocrinology, pharmacology, clinical pharmacology, genetics, etc., is a must in order to make an integrated assessment of findings of toxicology studies and to identify potential signals from the clinical studies. Masters or PhD degree in the area of toxicology, veterinary medicine, human medicine, pharmacology etc. represents a relevant qualification that teaches these subjects. The depth and breadth of toxicology subjects covered in these courses vary. Certification by professional bodies in the field of toxicology is an endorsement of a person’s relevance of qualification and experience in the field of toxicology. Some of these certifications are based on successful completion of a written examination (ex: Diplomate of American Board of Toxicology), while others may be based on relevance of qualification and demonstration of actual practice of toxicology, and adequacy of experience in the toxicology field (ex: European Registered Toxicologist). In summary, the most critical attribute that a person should process in order to be able to derive a PDE is combination of relevant educational qualification, understanding of basic science of toxicology, and adequate experience in the field of toxicological risk assessment.

What competencies are required for the person developing the Health-Based Exposure Limits (HBEL)?

Health-Based Exposure Limits should be determined by a person who has adequate expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determination of health-based exposure limits such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE).

Is the use of LD50 to determine health based limits acceptable?

No, LD50 is not an adequate point of departure to determine an HBEL.

Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

Yes, HBELs should be established for all products. HBELs for highly hazardous products are expected to be completed in full as per the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) or equivalent.

What purpose PDE is used in the context of cleaning validation?

PDE is used to determine the acceptable amount of a previous drug that may be allowed in the next drug as carry over cross contaminant. This acceptable level is called MACO (Maximum Allowable Carryover). The MACO is then used for the calculation of the maximum safe surface residue or rinse concentration (the operational cleaning limit), which takes into account the shared equipment surface areas or volumes of the rinse of equipment between products A and B. MACO = PDEPrevious x MBSnext TDDnext Where, MACO (Maximum Allowable Carryover): Acceptable transferred amount from the previous product into your next product (mg). PDE- Permitted daily exposure. MBSnext- Minimum batch size for the next product(s) (where MACO can end up) (mg) TDDnext: Standard therapeutic daily dose for the next product (mg/day). As evident from the equation, larger the PDE value, higher will be MACO. This means more amount of a relatively safe drug may be allowed as a cross-contaminant while highly toxic compound can be allowed only a minute amount in the next product.

What is PDE and why it is needed in the context of cleaning validation?

ISPE-Risk MaPP, ICH Quality guidelines, EU GMP, and EMA guidance recommends a risk-based decision making in the pharmaceutical manufacturing. When different medicinal products are produced in shared facilities, the potential for cross-contamination is a concern. Medicinal products provide a benefit to the intended patient or target animal; however as a cross contaminant, they provide no benefit to the patient or target animal and may even pose a risk. Hence, the presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations. To this end, health based limits through the derivation of a safe threshold value should be employed to identify the risks posed. The derivation of such a threshold value (e.g. permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data. PDE is a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. It is synonymous to ADE (Acceptable Daily Exposure). PDE is a reflection of toxic potential of the compound; higher the PDE lower is the toxic potential. PDE is derived by a toxicologist from a structured scientific evaluation of relevant data.

What is cleaning validation?

Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product used in the equipment below the scientifically set maximum allowable carryover level in a shared manufacturing facility.