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.
CQA identification. 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