Purpose of risk assessment is to determine appropriate control strategy to mitigate potential risk to safety, purity and efficacy of a drug product. First question to ask in any risk management strategy: What are the potential risks that can be introduced throughout the life cycle of a product? Answer to these questions depends on type of a product. For example, in biologics produced using mammalian cells there is risk of introduction of adventitious organisms at each step of subculture of the cell line. Therefore, initial master cell banks created to produce working cell banks will require extensive testing. In contrast, in the case of small molecules, utilization of compendial material and testing can be easily used to confirm the quality of ingoing raw materials and final product. However, risks in a manufacturing process are not limited to raw materials, all steps of a process need to be considered to come up with a list, and level of potential risks.
Manufacturer can use quality risk management (QRM, ICH Q9) tools to rank and select quality attributes, including material and process parameters that should be further evaluated and/or controlled within appropriate ranges to ensure the desired product quality. Critical quality attributes (CQA) are established based on the previous knowledge of the product and scientific justification. Relationship between CQA and process parameters is established using appropriate DOE and available models. Prior knowledge obtained from developmental studies and scientific literature to be considered during risk assessment, can be tabulated in a concise form. Some common examples of known risks factors include degradation, solubility, interactions with excipients, risk of presence of BSE/TSE, carcinogens, nitrosamines and microbial contamination. In addition to devising controls to mitigate highly ranked risks, the identification of potential residual risk that may remain after the implementation of the proposed control strategy should also be considered. These risks may include scaling up to commercial scale that will require a validated plan for managing the risk. Plan will entails conducting the evaluation of relationship between CPPs, CQAs, and overall quality of product. Furthermore, the effect of large-scale commercial equipment will require production of engineering batches to optimize CPPs.
Control strategies indicated by validation studies are incorporated in the batch records and all other relevant documents are revised accordingly. For example, if a mathematical expression is used for determining a process parameter or a CQA, the batch record should include the input values for variables and the calculated result. Ranges of process parameters are clearly tabulated in the batch record and control charts can be used to monitor the movement of process parameters.
Additional data gained through manufacturing campaigns are collected and trended. Any shift within the approved design as defined in the ICH Q8(R2), does not call for a regulatory filing. However, movement outside the design space, requires the use of risk assessment in determining the impact of the change on quality, safety, and efficacy. This type of change will warrant appropriate regulatory filing to the agency as prescribed by regional requirements.