What are current good manufacturing practices (cGMPs)? Where did they come from? What are the actual "practices" described in the Code of Federal Regulations, 21 CFR. If you are new to the pharmaceutical or biotechnology industries, you may enter your first "GMP Training" session without much context or perspective. A set of arcane rules is presented; you were never taught these in science classes. What is all the fuss about? The emphasis makes you think it is difficult, but the content may seem quite simple... until you go and try to put them into practice.
GMP Rules Are Event Driven
The GMPs are federal regulations that have evolved over the last century, in response to a series of public health disasters. Different sections of the law apply to different industries; this article is concerned with those that apply to drugs, medical devices, and biological pharmaceuticals.
What these products have in common is that they are highly complex and have stringent quality requirements. The consequences of using a product that does not meet its quality attributes can be fatal. Unlike other products, consumers are unable to check the quality before they take a pill. Therefore, the government has stepped in to set minimal standards and define the systems and processes that must be in place to provide reasonable assurance of quality. The GMP regulations define those systems with enough ambiguity to permit each firm to construct its own processes that will meet the requirements. FDA is the US agency responsible for enforcing the regulations.
What is codified in the GMPs? They represent an array of tactics that seek to reduce the probability of harm to the end user of a drug, device, or biological product. Although the risks cannot be reduced to zero, following GMP guidelines greatly reduces risk. Canada, Europe, Japan, and other countries all have similar rules, and any manufacturer must comply with these rules in order to sell its products.
Unlike other products, many of a drug's quality attributes cannot be detected by the consumer. The consumer must be able to trust the quality of the medicine over time and over different production lots. To achieve this, FDA acts as a regulator and formulator of standards, defining an acceptable level of risk. This acceptable risk varies with the patient population, the disease being treated, and the values of our culture. For example, we accept more risk for a late-stage terminal patient receiving last-effort treatment than for a healthy baby about to receive a vaccine. However, we require that all medicines used in humans meet a high standard of safety and consistency.
Table I. GMP Basics
Let's look at some of the key events that led to establishment of some of the GMP rules.
Vaccine Events — Diphtheria, Tetanus, and Others
GMP rules are easier to understand after you realize they are responses to actual historical events. Vaccines were developed empirically, and the critical parameters that assured efficacy and safety were not well understood initially. As a result, the main approach to safety assurance was change control: "The process defines the product." Any change might make the vaccine unsafe, and extensive testing and an application process were necessary to gain approval.
The source of this thinking can be traced back to 1901, when children who received antitoxin for diphtheria treatment died of tetanus. The horse serum that had been used to prepare the antitoxin was contaminated with tetanus. Thus, the importance of high-quality raw materials was graphically demonstrated, along with the ability of animal-derived materials to pass diseases both known and unknown.