Toxicology services for pharmaceutical manufacturing
Pharmaceuticals, by nature, are intended to act on human body and bring about their effects, which can be beneficial if it is the intended effect in intended patients; however, it can be adverse if it is exposed unintentionally.
Whether you are about to introduce a new product or continue to manufacture existing products, following two indispensable requirements need to be met: ensure safety of plant workers and limit cross contamination into subsequently manufactured product to limit unwanted patient exposure. This is achieved by putting in place appropriate measures to control the exposure to a level that is not harmful, which is achieved by way of risk-based manufacturing practices.
Cross contamination risk and PDE
In a shared facility, the risk of cross contamination is minimized by appropriate cleaning process, which needs to be validated. In the context of cleaning validation, it is a regulatory and scientific expectation that health risk of a contaminating drug residue is identified using toxicologically defined exposure limit called Permitted Daily Exposure (PDE). It may also be called health-based exposure limit (HBEL). The term Acceptable Daily Exposure (ADE) is synonymous to PDE. This has been mandated by the EMA in: Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (EMA/CHMP/ CVMP/ SWP/169430/2012). This applies to both human and veterinary API and drug products. Similar risk-based and science-based approach has been recommended in ICH Q9, cGMP guidelines, both EU and US FDA (21 CFR 211.67), and in ISPE-Risk MaPP.
Exposure limits such as 10 ppm, 1/1000th minimum therapeutic dose, or a fraction of LD50 are considered arbitrary, not science-based, and are no more acceptable to regulatory agencies.
What is PDE?
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. When derived correctly, PDE is a reflection of toxic potential of the compound; lower the PDE, higher is the toxic potential. PDE is derived by toxicologist from a structured scientific evaluation of relevant data.
Where is it used?
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 MSCO (Maximum Safe Carryover), a terms sometimes incorrectly referred as Maximum Allowable Carry Over (MACO). The MSCO 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 previous product and subsequent product.
Unlimited exposure to pharmaceutical and intermediates in the manufacturing plant may adversely affect the health of the exposed workers. Local and national legislation on worker safety expects every employer to identify the level of risk and put in measures to minimize such risk. The assessment is primarily driven by the toxicity potential of the compound, the assessment of which ends up in establishment of an health based exposure limit called OEL.
What is OEL?
OEL represents an airborne concentration (expressed as time-weighted average for a conventional 8 h work-day and a 40-h work week) of a substance to which it is believed that nearly all workers may be repeatedly exposed (day after day, for a working lifetime) without adverse effect.
Where it is used?
OEL is used to decide the containment requirement and worker safety measures to be put in place in a manufacturing facility. OEL should be interpreted as a safe level of exposure without the use of respirator or other protective equipment. Since the derived OEL is health-based, when the compound concentration in the working environment is kept below the OEL, workers are protected from all toxicological and pharmacological effects of the compound. In order to ensure the compound concentration in the surrounding air is within the OEL, the work environment and compound handling practices should be commensurate with the target OEL.
What is OEB?
At times there may not be enough toxicology data to derive OEL. This is addressed by way of a qualitative assessment of potential effects of the compound using the minimum available information using the concept of OEB. Occupational exposure banding, also known as hazard banding, is a process intended to quickly and accurately assign chemicals into specific health hazard categories (bands) of increasing severity based upon their inherent pharmacological and toxicological properties. These categories also correspond to predefined strategies known to provide the necessary degree of control to protect employees and the environment. Typically, in a manufacturing set up, each band will have associated guidelines that define the best practice for the facility, equipment, and exposure controls required to keep the OEL at a level that complies with health and safety regulations.
The health-based exposure limits such as PDE and OEL are based on the same principle of toxicological risk assessment however the data is applied in two different context targeting two different population.
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