Compliance Risk Management Using a Top-Down Validation Approach 2

These incidents resulted in deaths and serious injury to patients. Specific regulations in the US and elsewhere were instituted to force conformance to basic canons of pharmaceutical GMPs. Globally, firms must adhere to a defined set of CGMPs that ensure product safety. These practices can be summarized by seeking the following characteristics in all development and production activities:
  • Safety—a drug does no harm to the patient
  • Purity—a drug is free of contamination
  • Efficacy—a drug works as intended
  • Identity—a drug is what its supposed to be
  • Strength—a drug is sufficiently potent.

These qualities are briefly stated in FDA's CGMPs:
... this chapter contain[s] the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess (6).
If we focus our intention on those elements of pharmaceutical operations that directly affect those concerns and pay reduced attention to activities whose effect is less apparent, the validation activities will have true meaning and purpose and be inherently risk-based. Addressing process and product validation properly
The product is the result of the process. The process exists only to make the product. The two are unalterably linked. We cannot speak of validating a process without evaluating the product, nor could we somehow support the efficacy of a product without knowledge of its underlying process. They exist in combination and must be evaluated in the same fashion. A product results from the process through the procedures applied to materials in a piece of equipment. In its simplest form, the product might be a single material such as an active pharmaceutical ingredient (API) transformed by a process such as sterilization, which, when filled into a suitable container, results in a parenteral dosage form. More commonly, the product is composed of many materials and undergoes several transformational processes before it is considered a drug product. The drug product can be considered the consequence of three primary elements:
  • Materials and components—the API, excipients, and its final product container
  • Batch records, standard operating procedures, and test methods—the instructions and practices that define the process steps and are the means for evaluating the product
  • Equipment and facilities—the mechanical systems that effect the material transformation.

Figure 1
The production of the drug product takes place in a CGMP environment under quality systems that provide the necessary controls to ensure the required quality attributes are attained (see Figure 1). The validation effort provides documented evidence of the controls' effectiveness. To properly validate any product or process, we must focus on the critical quality attributes of the specific drug product and the parts of the overall system that directly affect those attributes. To the extent that a material, piece of equipment, process utility, control system, or operating procedure affects one or more of those critical attributes, it requires greater attention in the overall validation exercise. Treated in this manner, the validation effort is inherently risk-based.

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