The chain of events that compromised the safety of the drug products included inadequate maintenance, inadequate understanding
of autoclave operation, and regular deviations from the written production instructions (often attempting to compensate for
equipment malfunction). 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. This incident
helped to define sterility assurance in an operational way. Processes and requirements for equipment validation were created,
and the legal right of inspection was explicitly given to the agency.
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. The concept that
quality must be designed into the process and cannot be achieved only by testing remains a central tenet of cGMP. In other
words, how you make something helps to define its level of quality. Preventing errors is more effective than finding rejects
because it is not possible to detect all rejects.
One of the saddest events in the pharmaceutical industry occurred in the early 1960s. Thalidomide, prescribed for sleep problems,
was shown to be safe in clinical trials in healthy adults and was subsequently prescribed to patients, including pregnant
women, in Europe. Although safe in adults, thalidomide was toxic to fetuses, and thousands of victims were born with major
birth defects. Because FDA hesitated to approve thalidomide, its impact in the US was much less severe than in Europe.
This incident demonstrated that the choice of subjects in pre-clinical and clinical trials is critically important for evaluating
safety. Regulations now require reproductive studies in two or three species of animals prior to human clinical trials; newer
requirements also require the consideration of gender, race, age, and other characteristics in the design of clinical trials.
The data have shown that not only safety, but also efficacy, can vary among sub-populations, and are shedding new light on
genetic differences between individuals. In reaction to the thalidomide epidemic, the US Congress passed the Kefauver-Harris
Drug Amendments, which required that a manufacturer prove effectiveness as well as safety before marketing products.
In 1982, several consumers of over-the-counter Tylenol capsules suddenly died of cyanide poisoning. An intensive investigation
of the production records showed that this was not the result of a raw materials mix-up during manufacturing. Rather, tampering
apparently occurred on store shelves. A new vulnerability was identified in the supply chain.
The manufacturer, Johnson and Johnson, notified the public and voluntarily recalled its entire product in what is now a textbook
case of how to respond to a health disaster. Their development scientists went into overdrive to re-design the capsule to
make tampering more difficult and more detectable. The industry as a whole re-evaluated the means of delivering over-the-counter
medicines. Regulations were updated starting in 1982, and they now require tamper-resistant packaging that aids in the detection
of tampering. Without these steps, over-the-counter pharmaceuticals could have become an unacceptable safety risk.
In 1989, an outbreak of toxic reactions to over-the-counter L-tryptophan, a dietary supplement, resulted in 38 deaths and
probably thousands of less severe reactions. The event was the result of a manufacturing process change that increased the
level of a harmful byproduct. Doses that had previously been safe now caused toxicity. One response to this event was the
clarification of requirements for characterizing drug impurities and new requirements for evaluation of minor impurities.
In the biological products area, extensive policy and guidances have been issued on how to establish comparability when process,
facility, or other changes are made.
Organization and Personnel
The most basic section of the GMP regulations, 21 CFR 211:80, can be paraphrased to state, "Thou shalt have written procedures,
and thou shalt follow them." This remains the most-cited violation of the GMPs — not because it is difficult to understand
but because it is such a challenge to comply. The consistency of any product results from the ability to repeat the procedures
faithfully over a long period of time, despite changes in equipment, staffing, and other factors. Batch record review, performed
by a quality assurance group, is one means of checking the fidelity with which the recipes are followed. Training programs
seek to prevent inconsistencies from occurring and should be repeated periodically to reinforce the importance of following
procedure exactly as written. The GMP regulations spell out basic qualifications and training requirements for all individuals
engaged in GMP functions, including consultants.