The Biologics Control Act was passed in 1902, to improve the assurance of safety and purity of sera, vaccines, and other biological
products. The Food and Drugs Act was first passed and put into law in 1906 and revised as the Food, Drug and Cosmetic Act
of 1938. The original law focused on misbranding and adulteration of foods, drinks, and drugs, and only restricted interstate
commerce. At the time, the main target was patent medicines and foods that often contained toxic ingredients and made unsupported
claims of effectiveness. The 1938 revision extended control to cosmetics and therapeutic devices, required that a new drug
be shown to be safe, authorized factory inspections, and required that specifications be set for any unavoidable poisonous
substances in drugs.
In 1937, thousands of people were exposed to toxic cough syrup, and 107 people died. The culprit was diethylene glycol, which
had been used in lieu of the safer propylene glycol. A lack of control and standards for choosing ingredients that were low
in toxicity was the root cause of this and other, similar events.
Both deliberate and accidental use of inappropriate raw materials has been documented. For example, jake leg, a neurological
disease found in consumers of moonshine whiskey, resulted from addition of an ingredient thought to be safe. Other errors
have occurred when unsuitable raw materials were used by accident. Identity mix-ups continue to be a leading cause of medical
errors today. Items with similar names, packaging, or labels are easily confused with each other. Many sections of the GMP
regulations seek to assure that different medicines are easily distinguishable from each other, that labels are legible, and
that they contain all the relevant information.
Resulting regulations include 21CFR 211: 184, which requires that the identity of each shipment of each raw material be confirmed
before it is put into use; requirements that tablets and capsules have distinctive shapes and colors and sizes that permit
them to be easily distinguished by appearance; and requirements to check and double-check labels during risky operations where
mix-ups are more likely to occur. For example, detailed requirements are explicitly stated in the GMP regulations for weighing
raw materials and packaging drug products.
Potency: Activity per Unit
Insulin, a life saving treatment for diabetics, demonstrated the importance of controlling and accurately measuring potency,
which is the ability of the drug to exert its biological effect. The dosing of insulin must be tightly controlled because
both too-high and too-low levels can be life threatening. Variation in insulin potencies between product lots caused many
safety events and led to the Insulin Amendment of 1941. For the first time, this required that both the manufacturer and FDA
test and release drug product on a per-lot basis for purity and potency. The federal laboratory thus vetted the quality control
laboratory within the firm and served as an additional checkpoint. This requirement was extended to many other biological
products and phased out only after an extensive track record of consistency was established. Today, we also see the effects
of the insulin experience in the rigor with which analytical release methods must be validated for linearity, selectivity,
accuracy, robustness, and precision.
Vaccines: Process Validation
In the Cutter incident of 1955, two polio vaccine lots resulted in at least 250 cases of polio. The vaccine, supposedly
inactivated, still contained active virus for unknown reasons. Certain lots of other vaccines, including those for yellow
fever and rabies, also gave the recipients the disease instead of protecting them from it. In some cases, these incidents
were traced to process changes or variances that were believed to be insignificant but actually resulted in incomplete virus
These and other events marked the emergence of strict process validation. Ranges must be defined within which the process
has a high probability of yielding a product that meets its specifications. The 1987 Guidelines for Process Validation are
currently in revision. Numerous guidance documents, including FDA "Points to Consider" and International Conference on Harmonization
guidelines have addressed the special issues of virological safety and methodologies for evaluating processes for freedom
from adventitious agents. The Division of Biologics Control was created within NIH to oversee vaccine safety. Today this is
the Center for Biologics Evaluation and Research (CBER), now part of FDA.
The 1972 Devonport, UK, incident resulted in at least five deaths when drug products designed to be sterile became contaminated
and recipients developed infections. An unwritten change to autoclave operation, communicated orally between operators, resulted
in dextrose IV solutions that were not uniformly sterile. The Clothier inquiry, which examined the causes and contributing
factors, identified several violations of what we now consider basic GMP.