The details outlined in these documents may override directions given in other level documents. Level 4 documents provide step-by-step instructions for production-related tasks and activities as well as provide a means for documenting such tasks using, for example, data sheets, forms, or batch records. They apply to a specific department, product, equipment, or process. These documents are the most specific in nature, (e.g., batch record, test methods, validation procedures). The last level of documents in a document hierarchical structure are level 4 documents. The current requirement for ’documented evidence’ may be driven by this event of Devenport. Preventing errors is more effective than finding rejects because it is not possible to detect all rejects. In other words, how you make something helps to define its level of quality. The concept that quality must be designed into the process and cannot be achieved only by testing remains a central tenet of current good manufacturing practice (cGMP).

Validation was developed as a means of documenting systematic evaluation of the sterilization cycle - building in a safety factor - and identifying the critical parameters that need to be controlled to assure process performance. Processes and requirements for equipment validation were created, and legal right of inspection was explicitly given to the agency. This incident helped to define sterility assurance in an operational way. Together, these factors resulted in a sterilization cycle that did not assure that all vials in the autoclave were sterilized thus, some doses were safe, while others led to sepsis in patients who received them. The chain of events that compromised the safety of the drug product included inadequate maintenance, inadequate understanding of autoclave operation, and regular deviations from the written production instructions (often as an attempt to compensate for equipment malfunction).

The Clothier inquiry, which examined the causes and contributing factors, identified several violations of what we now consider basic good manufacturing practice (GMP). An unwritten change to autoclave operation, communicated orally between operators, resulted in dextrose intravenous solutions that were not uniformly sterile. The 1972 Devonport, UK, incident resulted in at least five deaths when drug products designed to be sterile became contaminated and recipients developed infections. So, too, with the issue of drug safety and drug quality. It is a truism that it takes a disaster to happen for people, and especially regulators, to wake up and review the accepted way of doing things.

Best trace able drawings