Critical process parameters (CPPs) and their associated process controls are crucial to drug development and process validation
and to the evaluation of every manufacturing unit operation. Although every manufacturer and regulator requires effective
process control systems, few companies are satisfied with the performance of their internal and/or CMO's controls. In many
cases, process controls fail to perform adequately due to the fragmented nature of selection, application, and implementation.
Partially implemented process controls, for example, will not adequately cover the range of capabilities that are required
for the drug-substance and/or drug-product development and are likely to result in a lack of control of the process and product.
Failure to control the process can result in difficulties with regulatory submissions and lot release. A lack of efficient
controls can also lead to extensive product loss and a loss of regulatory and customer confidence.
The systematic approach for CPP selection and use discussed in this article was developed in line with the International
Conference of Harmonization (ICH) Q8, Q9, Q10, and Q11 guidelines, which recommend quality risk management and the identification
of CPPs as part of drug quality and process control development (1–4).
Specifically, ICH Q8(R2) Section 2.5 on Control Strategy (1), states:
".... These controls should be based on product, formulation and process understanding and should include, at a minimum, control
of the critical process parameters and material attributes.... A comprehensive pharmaceutical development approach will generate
process and product understanding and identify sources of variability. Sources of variability that can impact product quality
should be identified, appropriately understood, and subsequently controlled. Understanding sources of variability and their
impact on downstream processes or processing, in-process materials, and drug product quality can provide an opportunity to
shift controls upstream and minimize the need for end product testing. Product and process understanding, in combination with
quality risk management (see ICH Q9), will support the control of the process such that the variability (e.g., of raw materials)
can be compensated for in an adaptable manner to deliver consistent product quality."
CPP selection has traditionally been difficult because of a lack of a systematic approach to the problem. CPPs can be found
in media, upstream and downstream unit operations, and drug-product processing. Due to the large number of unit operations
and media complexity, it is easy to overlook processing parameters and materials that may impact drug-substance and drug-product
variation and CQAs. Failure to identify critical parameters can result in unexplainable variation during batch processing
and lot acceptance.