In pharmaceutical manufacturing, assuring that processes are in a state of control and verified is a very important element for both public health and regulatory authorities. To this end, Continuing Process Verification (CPV) is defined as the ongoing monitoring of a routine commercial manufacturing process to assure that it continues to operate in a state of control post-performance qualification. It is a component of the Lifecycle approach for Process Validation as described in the 2011 FDA Guidance (here). In addition, in 2015, many other regulatory authorities (EMA, PICS, and WHO) all have included a requirement for 3 stages of Process Validation: Process Design, Process Qualification, and Ongoing/Continuing Process Verification.
The key to developing a practical approach to all phases lies in the establishment of Critical Quality Attributes (CQA) for the drug product and assignment and monitoring of Critical Process Parameters (CPP) that have a direct effect on the performance of the process with regard to the CQA. Many firms struggle with the establishment of CPP. In most cases, the relationship is assigned empirically and can result in an onerous task of monitoring a significant number of CPP over the life of the product. However, many of these CPPs have little or no impact on product performance as a whole, and may not be statistically significant. Statistical significance should be a starting point for CPP identification.
At the PDA Annual Meeting last week, Scott Bazzone, Senior Manager of Quality Assurance Validation at Pfizer presented the approach that is used there with regards to establishing the risk significance or Z Score of a CPP to the CQA. The first step is the calculation of a Z score, which measures degree of risk that a CPP has in relationship to the specification (CQA).
Dr. Bazzone suggested that the Z score could be an extremely valuable tool when initially assessing the strength of CPP. Shifts in Z Score could indicate process shifts throughout the Product Lifecycle.
The team at Pfizer (including Dr. Bazzone) has recently published this approach (Ke Wang et al., Statistical Tools to Aid the Assessment of Critical Process Parameters, Pharmaceutical Technology Volume 40, March 20016, Issue 3, Page 36-44). The paper includes a flowchart to aid the reader in use of the tools, as well as examples of calculations. In addition, the Process Validation Interest Group of the Parenteral Drug Association has started work on a Technical Report on Continuing/Ongoing Process Verification. More information on the Technical Report and how to participate in the process can be found on the PDA website. Regardless of the dosage form, continuing process verification is an important component to commercial scale manufacturing. It is essential for the industry to develop tools to measure and assess the reproducibility of processes, as it is clearly critical to regulators worldwide.