Introduction
Preserving patient safety is a priority for the healthcare industry and regulatory authorities.Regulatory guidance states and industry best practices encourage drug safety specification include data to address potential issues that are not addressed during clinical studies.Patient safety has emerged as a distinct healthcare discipline to deal with these concerns.
The pharmaceutical industry is witnessing a swift change towards the use of single use systems to manufacture drugs. Along with this change is an increasing awareness of the potential for harmful substances to migrate from these single use systems into the drug product and compromise patient safety. Patient Toxicological Risk Evaluations are being performed to mitigate this risk and realize the benefits of single use systems.
Low and middle-income countries (LMIC) are increasingly manufacturing and supplying their own drugs to domestic markets utilizing single use process technology, and they too will want to conduct these evaluations.
Patient Toxicological Risk Evaluations consider all the components in the process train from the bioreactor to the final filling assembly. These evaluations identify and quantify all the potential compounds that may leach into the drug product and then correlate the toxicity of these compounds to patient safety with respect to a specific drug.
Risk Evaluation
Toxicological risk evaluations determine whether or not a product poses a potential risk for the toxicological endpoints measured. Regulatory guidance requires identification and quantification of the impurities and characterization of their toxicological profile to determine impact on patient safety. The Parenteral Drug Association (PDA) technical report No 26, states that "It is the user’s responsibility to demonstrate that the product does not contain objectionable levels of extractables from the filter. . . . The filter user is responsible for obtaining extractable data for the drug product formulation". This assessment utilizes extractable and/or leachable data from the drug manufacturing process to evaluate the toxicological risk for patients exposed to potential leachables. The risk evaluation considers the quantity of extracted or leached compounds, patient population, patient dose, frequency of dosage and route of administration.
The toxicological evaluation of impurities and the determination of acceptable levels in the final product is a challenge not described in detail in any guideline or reference. In the absence of such data usually needed for the application of one of the established risk evaluation methods, i.e. data from long term carcinogenicity studies or data providing evidence of threshold mechanisms of genotoxicity, implementation of a generally acceptable approach as defined by application of the Threshold of Toxicological concern(TTC) is proposed.
While guidance documents establish high level strategies, practical implementation is problematic because it suggests that all extractables/leachables, regardless of their accumulated levels, must undergo full toxicological safety evaluation. Such an evaluation would be necessary even when the concentration is so low that there is no adverse effects to humans. However, some extractables may not be detected in the final drug product(i.e., they do not leach)and some leachables may be at so low a level that they have no effect on patient safety. This evaluation is not productive since the regulatory and industry resources are most effectively used when they are focussed on substances that are present at high levels that affect patient safety.
With the aim of balancing absolute safety risk and the level of effort required to establish that risk, it is reasonable to propose dose thresholds for extractables or potentialleachables, combined with a risk evaluation of the manufacturing process.
Approach and Process
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