In February of 1965 Professor L.W. Kallings appeared before the Swedish National Board of Health in Stockholm and advised, “We have typhoid fever. We have deaths.” He was asked to write a report, in which he concluded, “it is neither from food nor water, it’s from a medicine.”
We now know that Prof. Kallings had detected strains of Salmonella in a standard oral drug, a dry thyroid powder from domestic animals that was not much changed from the 1940 edition of USP VI. The drug was Thyroideum, U.S.P. In the same year, Prof. Kallings wrote a second report o the Swedish National Board of Health Entitled, “Microbiological Contamination of Medical Preparations”. In 1966 he expanded his investigation of contamination in the Pharma industry and reported that blindness and eye infections were due to opthalmics contaminated with Pseudomonas aeruginosa. In 1967 the Swedish National Board published the first manufacturing guide on Contamination Control, “Production, Hygiene and Bacteriological Control in the Manufacture of Pharmaceuticals.”
In these same years the FDA published surveys of Pseudomonas, serratia and Klebsiella infections, all from aqueous eye makeups, creams, topical drugs, baby lotions, liquid soap, and skin aeseptics. Children died in a Texas hospital following application of baby lotion to the umbilicuas, and iodophor solution in a Massachusetts hospital were found to be contaminated with Pseudomonas cepacia in instances too numerous to count. IN a rapid turnaround, USP 18 (1970) switched its sole attention from sterility tests and antibiotic assays to non-sterile drugs and “Contamination Control,” the subject of this article some 35 years later.
The historic fountainhead for the field of contamination control was the USP 18 Chapter, “Microbial Limits Test”. The fields of “Contamination Control” and “Water Validation” were thus born. Shortly after publication of USP 18, a series of deaths occurred nationwide from a large volume of parenteral, intravenous infections and endotoxin shock from a product that passed the USP sterility test. In court the FDA lost its case against the manufacturer because the manufacturer had performed the sterility test as promulgated in USP 18 (liquid contents) and did not test the screw cap because it “didn’t have to.” By using a swab and not a membrane filtration apparatus, the FDA found that when the bottle was transferred from liner to drug and no one, not even the nurses notice that they were infusing a cloudy suspension into the vein. It was not reported because “they didn’t have to.” Thus the field of “validation” was born. “Process Control” trumped “Final Product Testing” and the modern era of Contamination Control was on the march for all pharmaceutical dosage forms, sterile, non-sterile, prescription or over-the-counter. This is our subject.
Authors: Herbert M. Prince Ph.D. and Daniel L. Prince Ph.D.