Why Controlling CQAs Isn't Good Enough For Gene & Cell Therapies

One of the most frequent statements made in the biopharmaceutical industry is the need to “control a product’s critical quality attributes (CQAs) by controlling the process’ critical process parameters (CPPs).” While the statement is accurate literally, it does not convey the true technical requirements for controlling product quality.  The statement leaves many important aspects of controlling a manufacturing process to achieve high product quality buried within the following two important ICH Q8 definitions:¹

• Critical Quality Attribute (CQA) – 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.
• Critical Process Parameter (CPP) – A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired product quality.

The definitions contain several regulatory ambiguities that make using them as design criteria very difficult, frequently resulting in much confusion and a lack of transparency in developing complex processes for manufacturing complicated products such as gene and cell therapies and advanced therapy medicinal products (ATMPs). Since CQA and CPP form the basis of almost everything that is done to develop biopharmaceuticals, especially gene and cell therapies, these definitions should be analyzed very carefully, and more functionally precise working definitions should be established to aid the industry. By examining and understanding the definitions’ terms, perhaps better manufacturing processes can be developed that result in better overall product quality.

Especially for gene and cell therapies, measuring all the necessary CQAs of any product to assure complete safety and efficacy is impossible. Although a number of CQAs can be identified to define some aspects of a product’s safety and efficacy, many of the product’s important attributes are and will always remain essentially unknown or unmeasurable. The industry typically regards CQAs as those product attributes that can be measured to establish and document product quality, with little thought given to controlling unknown product attributes.

Ultimately, the true measure of product quality is established during clinical trials by the product’s impact on people. Those products that demonstrate sufficient clinical safety and efficacy during clinical trials with the defined and controlled measurable CQAs are regarded to be safe and effective. Long-term control of the unknown CQAs (u‑CQAs) is left to controlling the process and is the origin of the old but frequently forgotten saying “the process defines the product.” Failure to adequately control u‑CQAs during the product’s development, scale-up, and commercial manufacturing may be a significant source of Phase 3 and post-launch product failures.²

To more accurately describe all CQAs, an alternative definition of a critical quality attribute might be:

• Critical Quality Attribute (CQA)* – A measurable or unmeasurable physical, chemical, biological, or microbiological property or characteristic that should be controlled by the manufacturing process to be within an appropriate limit, range, or distribution to ensure the desired product quality.

The key concepts in the new definition are that CQAs can be both measurable and unmeasurable and that u-CQAs can only be controlled and therefore must be controlled by the manufacturing process.

Turning to the ICH Q8 definition of CPP, there are two ambiguously defined types of process parameters. The first are output parameters that reflect the performance of the process. To enhance the understanding of important non-product attribute process outputs and their role in defining and controlling the process’ performance, these parameters can be defined as critical process responses (CPRs) as follows:

• Critical Process Response (CPR)* – A output process parameter whose variability has or may have an impact on a measurable or unmeasurable critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired product quality. A measurable CQA may be used as a CPR.

One would think that the difference between an output variable and an input variable would be obvious.  However, defining and clearly understanding all the variables that connect complex sequences of manufacturing processes is frequently a significant challenge leading to considerable confusion unless very precise process flow diagrams are carefully developed and analyzed.

The second type of parameters are input parameters. The inputs for all manufacturing processes can be placed into three categories. Each category is controlled using different control strategies developed and defined during process development. Placing each input parameter into one of the three categories provides for a better understanding of each parameter’s impact on the CQAs and CPRs when developing process unit operations. The three types of input parameters are:

• Operating Parameters (OPs) – the input process variables that are manipulated manually or by automated control systems during process development and manufacturing operations to control the process’ performance and thus product quality.
• Material Parameters (MPs) – the attributes of the raw material or in-process materials that feed the process. Examples of MPs include the physical, chemical, biological, or microbiological property or characteristic of the incoming materials such as impurities and contaminants, along with chemical composition. For a manufacturing process, some of the MPs could be the critical quality attributes from the prior process unit operation.
• Equipment Parameters (EPs) – the parameters of the equipment, including size, capacity, materials of construction, etc. EPs are usually defined in the equipment’s user requirement specification (URS). Particular attention should be paid to EPs that might change during operation, such as heat transfer capabilities that might change because of fouling. Some EPs should be monitored and controlled by a variety of maintenance control strategies.

Both the measurable and unmeasurable critical quality attributes are controlled by the performance of the manufacturing process during their formation. In order to better understand and control unmeasurable CQAs, the CPP definition can be expanded for a better understanding of how to develop the wide variety of control strategies and systems required to control and monitor all the different critical process parameters. Expanding the definition of CPP to address the issues discussed above results in:

• Critical Process Parameter (CPP)* – An input or output process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired product quality. Output parameters represent the performance of the manufacturing process during the formation of all critical quality attributes and should be appropriately monitored and controlled to assure product quality.  Input parameters include material attributes of incoming raw materials, input operating parameters that control the process’ critical output parameters and product quality, and equipment parameters that may impact directly or indirectly the product quality as reflected by critical quality parameters, critical input operating parameters, or critical process output parameters.

The above definition of CPP is rather cumbersome. Output parameters have already been described using the CPR definition. The remaining input parameters can be split into the three different types of input parameters using the following four definitions:

• Critical Operating Parameter (COP)* – An input process parameter defined and validated during process development used to define and control the process’ behavior, whose uncontrolled variability may have a negative impact on a critical quality attribute and/or critical process response and therefore should be monitored and controlled to ensure the process produces the desired product quality.

Examples of COPs include media composition, buffer concentrations, mixing rates, gas addition rates, etc. COPs used to actively control the performance of the process, or critical process responses (CPRs) in real time, are defined as:

• Critical Control Parameter (CCP)* – A critical operating parameter (COP) that is manipulated based on a measured critical process response (CPR) or other input parameter to control the process’ performance such that it remains within appropriate limits, ranges, or distributions to ensure the desired product quality.

CCPs are a very important subset of COPs typically used in a feedback loop with a CPR or in other sophisticated advanced control systems required to control product quality.  An example of a CCP is the base addition rate or quantity to control a bioreactor’s pH (a CPR).

Continuing with the other two types of input parameters not always adequately identified during process development results in the following two definitions.

• Critical Material Parameter (CMP)* – A measurable or unmeasurable physical, chemical, biological, or microbiological property or characteristic of an input material whose value and variability has an impact on a critical quality attribute and/or critical process response and therefore should be appropriately monitored or controlled to ensure the process produces the desired product quality.

If the definition of a CMP sounds a lot like the definition of a CQA, it’s because the CQA of the prior process is frequently a CMP of the next process.  The raw material attributes, such as chemical composition, impurities, and contaminant levels described in the definition can have a significant impact on the CQAs of the product produced. 

The last type of input parameter is frequently not addressed because its impact is often underappreciated when the processes are initially designed and validated.

• Critical Equipment Parameter (CEP)* – A process equipment design parameter whose value or variability has an impact on a critical quality attribute and/or critical process response and therefore should be appropriately defined, monitored, or controlled to ensure the process produces the desired product quality.

Examples of EPs include volumes, materials of construction, agitator type, heat transfer area, etc. These parameters are usually part of the equipment’s user requirements specifications when the equipment is defined for selection and acquisition during process development and engineering design.

In designing and validating processes, especially for gene and cell therapy products, the three types of input parameters can significantly impact both types of outputs through many complex interactions.  For example, the oxygen transfer to the cells in a bioreactor can be a complex combination of agitator types (CEP), oxygen flow rates (COP), and media composition (CMP).  The oxygen transfer defined by these inputs can have an important impact on both the CQAs of the product produced by the cells and the process’ performance (CPR), which in turn may impact many u-CQAs.

Conclusion

Although applicable to any pharmaceutical product, the concepts and enhanced definitions for CQAs and CPPs are critical to understanding the development and manufacturing of gene and cell therapy products. The restructuring of the definitions of CQA and CPP is part of evolving ICH Q8 into a well-structured design space to better define and understand unit operations for using process‑based risk analysis and life cycle process development and validation methods.³ While regulatory agencies may not change or modify their current definitions of CQA and CPP, understanding their underlying concepts as expressed in the alternative definitions is critical to properly developing complex biopharmaceutical processes like those required to successfully commercialize gene and cell therapy products.

References:

1. ICH Q8 (R2) – Pharmaceutical Development, September 2009
2. Witcher, M. F., “Phase III Clinical Trials – Ever Wonder Why Some Products Unexpectedly Fail?  ISPE iSpeak Blog, Pharmaceutical Engineering, Aug. 7, 2019.  https://ispe.org/pharmaceutical-engineering/ispeak/phase-iii-clinical-trials-ever-wonder-why-some-products-unexpectedly-fail
3. Witcher MF. Integrating development tools into the process validation lifecycle to achieve six sigma pharmaceutical quality. BioProcess J, 2018; 17. https://doi.org/10.12665/J17OA.Witcher.0416

About The Author:

Mark F. Witcher, Ph.D., has over 35 years of experience in biopharmaceuticals. He currently consults with a few select companies. Previously, he worked for several engineering companies on feasibility and conceptual design studies for advanced biopharmaceutical manufacturing facilities. Witcher was an independent consultant in the biopharmaceutical industry for 15 years on operational issues related to: product and process development, strategic business development, clinical and commercial manufacturing, tech transfer, and facility design. He also taught courses on process validation for ISPE. He was previously the SVP of manufacturing operations for Covance Biotechnology Services, where he was responsible for the design, construction, start-up, and operation of their $50-million contract manufacturing facility. Prior to joining Covance, Witcher was VP of manufacturing at Amgen. You can reach him at witchermf@aol.com or on LinkedIn.