Compliance Risk Management Using a Top-Down Validation Approach - Pharmaceutical Technology

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Compliance Risk Management Using a Top-Down Validation Approach
Patient safety must be the primary concern of any validation effort. The author explains how a risk-based approach to validation and compliance follows naturally from this premise.

Pharmaceutical Technology

What is PQ?

The term "performance qualification" (PQ) was developed to clarify the distinction between the process and product efforts and those related to equipment. It was a way to distinguish between the equipment-focused activities (e.g., installation, operational, or equipment qualification) and those related to the product or process (i.e., PQ). Certain firms call the product and process effort "process validation," but this term is by no means universal. Coincidently, PQ can also stand for "process qualification" or "product qualification." Fortunately, though these terms have been expressed, neither has seen widespread use. It might be advisable to consider yet another definition of the acronym PQ: "product quality." The author believes it best to use the term "performance qualification" for activity that focuses on the essential quality attributes of the product as delivered by the process. It must be recognized that the process and product cannot be separated. One is the result of the other, and knowledge of their interaction is critical to success.

The PQ of a pharmaceutical process must demonstrate how the process ensures product quality. The completed effort must demonstrate how the independent variables of the process (i.e., temperature measurement, addition rate, mix speed, and mix time) result in a product that meets its defined quality attributes (i.e., content uniformity, viscosity, and color).

The recommended approach to PQ considers process parameters, product attributes, and their interrelationship. Only in combination can a process or product validation be properly addressed.

The link between process parameters and quality attributes should be established during the developmental process and documented in technology-transfer reports. The development must determine the relationship between the important process parameters and product attributes such as:

  • Drying time and moisture content
  • Mixing time and content uniformity
  • Reaction conditions and impurity levels.

Establishing the link between parameters and attributes during the developmental process facilitates the execution of the process on the commercial scale. Kenneth Chapman's classic article, "The PAR Approach to Validation," provides an excellent example of the need to link the independent process parameters and the resulting dependent quality attributes (8). Independent variables are established by the pharmaceutical manufacturer as necessary for successful process operation and include aspects such as equipment operating set points, operating instructions, material and equipment specifications, required in-process tests, mole ratios, and addition rates. Each of these can be chosen to realize the desired outcome as defined by the dependent variables. The dependent variables are product attributes that are the result of applying the selected independent variables. The goal of the development is to determine the relationship between the independent and dependent variables and use that knowledge to ensure an acceptable outcome. The more that is known about that relationship, the more robust the process and the more likely that the performance qualification will be a success.

Successful performance qualification is a largely a result of sound development and adherence to CGMP on the commercial scale. To accomplish this, it is critical that firms understand the importance of a development effort that increases their process knowledge. A trendy term for this information is the "design space," and the overall effort has been termed "quality by design." Much of these ideas were embodied in FDA's recent initiative on risk-based compliance, which declared the attainment of process knowledge to be essential (9). That this effort and new terminology are necessary only indicates how misguided validation efforts have become in recent years. The following modest paraphrase of an early definition of validation is an appropriate way to consider process development efforts: "The goal of development (validation) is to identify the process variables necessary to ensure the consistent production of a product or intermediate (10)."

Development is not about great science; it's about robust processes that make quality products consistently.

The product- and process-qualification activities should be the centerpiece of the any firm's validation effort. Any loss of focus wastes resources and risks patient safety. We must maintain a clear link between what we are doing and what we are trying to achieve.


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