Let’s talk about CPPs and CQAs
Updated: Aug 22, 2019
As per ICH Q8, when a systematic approach to drug development is applied, scientist and researchers must begin with predefined objectives and emphasize product/process understanding and process control based on sound science and quality risk management. That is the definition of Quality by Design (QbD), which can be further expanded with additional key terms:
The Quality Target Profile (QTPP) is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into consideration safety and efficacy. The QTPP provides an understanding of what will ensure the quality, safety, and efficacy of a specific product for a patient, and furthermore, describes the design criteria for the product. Prior to any consideration for commercial scale manufacturing, it is the QTPP what sets the basis for development of the CQAs, CPPs, and control strategy.
TPP: labeled use, safety and efficacy
QTTP: Quality Characteristics to ensure safety and efficacy, as promised in the label.
What is a CQA? It’s a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8). Keep in mind the following:
All desired product quality attributes; physical attributes identification, assay, content uniformity, dissolution and drug release, degradation products, residual solvents, moisture, microbial limits, etc.
CQAs are identified based on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute.
CQAs must be identified before taking into account risk control and does not change as a result of risk management.
Manufacturing processes often go through a series of ‘process steps’, or unit operations to achieve a desired product or output. Unit operations involve a physical change or chemical transformation such as separation, crystallization, evaporation, filtration, polymerization, and other reactions. It is here where the CPPs come to the scene.
Critical Process Parameter (CPP) is a process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process yields the desired quality. (ICH Q8).
Critical Material Attribute (CMA) - A physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of output material.
CQAs = f (CPP1, CPP2, CPP3 … CMA1, CMA2, CMA3…)
Sometimes, in each Process Step and identify “Intermediate CQAs” that could impact the drug CQAs. Intermediate CQAs are quality characteristics that are not necessarily describing the final product, but will give us confidence that a specific process step (or unit operation) is providing the desired quality results as we move forward in the process. Then, is a matter of identifying the Process Parameters (and material attributes) that may impact the intermediate CQA of that particular Process Step.
The industry still has a long way to go as many pharmaceutical operations started manufacturing their products before this systematic approach we call QbD was on the scene. These products are sometimes referred to as “legacy products”. One can still find many pharmaceutical operations where the CPPs (and CMAs) are not properly identified, but rather, the information is scattered in many different R&D, Process Development documents, including also the many Investigations and CAPAs they had to implement as they accumulated knowledge and process learning over the years. Here is a good rule you should follow: if a Process Parameter can have an impact to a CQA (or an intermediate CQA), then this parameter should be considered a Critical Process Parameter.
ICH Q8 / ICH Q9
Yu, et al. Understanding Pharmaceutical Quality by Design, The AAPS Journal, 2014, 16(4): 771-783