Compliance Risk Management Using a Top-Down Validation Approach 1

Validation has been an established fact of life within the pharmaceutical and healthcare industries since the mid-1970s. It has evolved from a poorly understood concept into a major source of difficulty for manufacturers. Initially conceived in response to specific sterility problems in the large-volume parenteral industry, it has morphed into a broad-based regulatory expectation for a myriad of activities. In the healthcare industry, the difficulties associated with validation have much to do with its origins. Validation in the pharmaceutical industry was imposed on the pharmaceutical industry by regulators as an appropriate means to establish the sterility of large-volume parenterals where the earlier control methods had proved inadequate (1). Because it was first associated with the preparation of sterile materials, validation has always been pursued with a near-absolutist mentality in all aspects. It has never been considered a valuable activity, likely because of its regulatory origins, but one that is largely associated with maintaining compliance.
Where did we go wrong?
Nearly every early validation effort was focused on sterilization and depyrogenation processes, and this focus continued to predominate until the 1990s. Real consideration of the need to validate pharmaceutical products with respect to their critical quality attributes did not begin until the US Food and Drug Administration began its preapproval-inspection program (2). This initiative brought attention to what had largely been missing in validation efforts previously. What are the true objectives of validation in the broadest sense? The answer is rather simple: patient safety considerations must be the focus of validation activities. The sterility concerns of the 1970s might represent the most direct evidence of that focus, but other relevant patient-protection items must be addressed. Validation efforts must be properly defined and focused to the extent that they support patient needs. The value of validation diminishes markedly when it fails to focus on factors that clearly affect the patient's well-being. Excessive levels of documentation of systems with little link to the patient are all too commonplace. Risk, as it relates to how the validation effort should be shaped, has not been fully considered until quite recently (3, 4). The result is that costs are excessive, timelines are extended unnecessarily, and an entire industry is developed around preparing massive documents qualifying and validating increasingly irrelevant components of the overall manufacturing process.
An excellent example of this trend might be the delayed introduction of isolation technology into the US healthcare industry. Early implementation of the technology was hampered by efforts to eliminate leaks in the system, evaluate the microbial resistance on every substrate, sterilize the interior to a 1 in a million probability of a nonsterile unit, and other matters of little import. These endeavors wasted resources and greatly delayed the implementation of what is widely acknowledged to be a superior aseptic processing technology. These tasks were considered important for ensuring the sterility of the materials produced using isolators.
Although a degree of caution is always necessary, these concerns were clearly off target. Cleanrooms, which have never been sterile, have always leaked, and there are a myriad of substrates treated in a much less effective manner. In pursuit of the perfect isolator, firms lost sight of the real point: the substantial improvement in patient safety that isolation technology afforded. Isolators are inherently safer than cleanrooms and preferable in every way as an aseptic production technology. The hours spent on resolving these allegedly important issues delayed isolator implementation by nearly a decade. The perceived "problems" with isolators persist to this day, and FDA's 2004 aseptic processing guidance contains several misconceptions regarding isolators (5). Lack of awareness about how isolators benefited patients served no one's purposes.
Regulatory perspective
Globally, regulators understand their mission to be one of safeguarding patient health by ensuring that drugs are safe to administer. In the US, a steady evolution of drug regulation shaped the current environment in which the industry operates. The landmark events that resulted in the current good manufacturing practices (CGMPs) industry follows include:

• Nostrums in the late 19th century that led to FDA's creation in 1906
• Diethylene glycol erroneously used in drug products in the 1930s
• Thalidomide administration to pregnant women outside the US in the 1950s
• Large-volume parenteral sterility failures in the 1970s
• Tylenol poisoning in the 1980s.