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.
The key steps to selecting CPPs and their application to process control are as follows:
- Identify critical quality attributes (CQAs) for drug-product and substance
- Select API, excipients, materials, and container closure
- Define all unit operations and process flow
- Define all product and process specification limits
- Achieve acceptable results for method validation of all analytical methods
- Complete quality risk management for factor/response selection for all critical unit operations and materials
- Explore the design space for all key factors identified during the risk assessment using design of experiments (DOE) or other
- Determine the factor effect size and select all CPPs
- Evaluate CPPs for ease of control and practical application to process control.
These steps are considered in detail below.
CQAs are those attributes that are important to the quality of the drug product and that remain consistent with those used
in clinical studies. The industry generally associates them with ICH parameters, such as identity, purity, potency, stability,
and safety. CQAs provide the justification and rationale of what is critical to function and what ultimately needs to be controlled
to assure compliance and fit for use. CQAs are the foundation upon which the CPPs must be associated. Line-of-site between
CPPs and CQAs is considered a major component of the drug-development strategy.
Ingredient, materials, and container closure.
Key parameters and analytical methods that measure the attributes of the API, excipients, key materials, and packaging/container
closure must be examined using a quality risk-management (QRM) approach. This approach focuses on finding those attributes
that will be crucial to maintaining the quality and stability of the drug substance and drug product. Key findings of this
review will be added to the list of candidate process parameters that need to be controlled. Output of a QRM material assessment
can help to generate candidate CPPs.
Unit operation process definition.
Identification of all unit operations and their associated equipment sets and equipment capabilities in upstream and downstream
processes are crucial when selecting those parameters that need to be controlled to assure potency and drug lot consistency.
Small changes in time, temperature, pH, and other variables may result in changes to API characteristic, yield, and impurity
profiles. Output of a QRM unit operation assessment will generate some candidate CPPs. Because biologics are extremely sensitive
to processing, it is important that each unit operation is carefully evaluated for possible impacts to the large molecule