Where did Pharmaceutical GMP start - the "Cutter" episode?
6/02/01
David Buckley

What is "quality"?
When did the concept of Good Manufacturing Practice start? Can one trace the origins back to the 1930s, or back as far as the pyramids? We'd find evidence of it there too I think.

Quality was in the hands of the individual craftsman prior to the industrial revolution. They controlled quality from beginning to end, and had a personal stake in the result. The craftsman and customer probably knew each other very well and dealt with each other on an individual basis. A bad craftsman, as well as blaming his tools, probably went hungry very quickly. And when I met some of my wife's relatives and friends in a small village in Wales the tradition was still alive as they knew each other not by name alone but by nickname, such as Williams the Plumber, or Bruce the Carpenter. The concept of Dave the Microbiologist was puzzling to them as what I did then was a little peculiar for them to fathom. Dave the Bug I became, then, boy-oh!

When Henry established the modern factory early last century everything changed. Poorly educated folk flooded into the cities to work on Ford's assembly lines. Their output was so variable that the pioneers of management had to develop an approach to work that solved the problem - the division of labour into managers, who thought, and operators, who did. Appropriate at the time, for the quality of the product improved. But it was to have a miserable effect on industry for years and reverberates in industry today.

In the mid 1920s a team of researchers at the Western Electric Company headed by Shewhart began using statistics to control product quality by analysing the process by which it was produced.

Shewhart published "Economic Control of Manufactured Product" in 1931, the start of modern process control, the popularisation of control charts (not to be confused with run charts, which control nothing) and the development of sampling techniques and plans for incoming products.

These quality control techniques and off shoots ("MilSpecs"!) were the growth industry during the 40s when the War effort required large numbers of suppliers to provide product of similar, acceptable levels of quality. Indeed, it must have been disappointing to have received ammunition to find it wouldn't fit properly into the gun if the enemy was advancing on you.

Polio
Then in the 50's I have personal recollection of the summer scares that surrounded outbreaks of polio, poliomyelitis. It was a frightening time as the school playgrounds at little lunch would resound with the scare stories of the paralysis that awaited you or even the slow death with victims housed in an iron lung. The evidence was always there of friends who had had a brush and had returned with leg irons, never to be really part of the scene again.

Polio was then called infantile paralysis, a viral disease which strikes quickly. Enter the virus. By nose or mouth, travelling to the intestines, incubating for a few days. Then the bloodstream; 10% of infected people develop symptoms and 1% develop the paralytic form of polio. A few die. The horror of the disease is the paralysis. The younger you are when exposed the less serious the disease. 1921 saw a young man named Franklin Delanor Roosevelt hit by the virus. Roosevelt exposed as a teenager, was never to walk again. (But never-the-less he became one of the US's greatest presidents.)

Legs can be left permanently paralysed. If it affects the lungs the patients cannot breathe. Can strike brain and spinal cord. It escapes the immune system by hiding in the myelin sheath around the nerve cells (hence ".myelitis"). After a severe attack of polio in its paralytic form, there is no treatment. There was an urgency to develop a vaccine, as early as the 20s. These efforts failed, partly because researchers did not know there was more than one strain of virus, there are three.

Jonas Salk was the first to develop a successful vaccine, some wags called the anti-Sabine vaccine. Sabine was Salk's bitter rival but Salk was much more popular and media-genic. In '52 Salk used a mixture of the three types grown in monkey kidney cultures and killed by formaldehyde. The so-called "inactivated virus vaccine". Connaught Medical Research Laboratories at the University of Toronto was nominated to provide all vaccine for a large field trial set to begin in the 1954 northern spring. 1,800,000 were given the vaccine, a placebo or nothing at all.

On April 12, 1955 the result of the field trial was published, news rushed by the media to a public who would not care to hear of any niggling doubts. American vaccine producers rushed to release their vaccine but with little government control. Six companies were authorised to produce it in the United States including Cutter Laboratories in Berkely, California. Around 5 million children by the end of April 1955 had been inoculated with commercially produced vaccine but some of the firms had difficulty in safely inactivating the polio virus because two weeks later, the first problems arose.

The public elation was shattered when children given vaccine from Cutter contracted polio because Cutter's vaccine contained live virus. Live polio virus was being injected into children. It is estimated the Cutter vaccine gave polio to 79 recipients who in turn went on to spread the disease to another 120 playmates and relatives; 3/4 of the victims were paralysed and 11 died (some say 10); 260 cases of polio would eventually be traced to Cutter's vaccine. The Cutter vaccine was taken off the market, although the general vaccination program continued for a time. Investigation revealed problems in inactivation of one of the strains of the virus. On April 27, 1955, the US Surgeon-General heavily criticised one of the six companies, charging that its manufacturing lines had failed to kill the polio virus before the vaccine was disseminated. Cutter Labs was ordered to halt production and recall batches of its vaccine. But was it only Cutter?

The U.S. Surgeon-General halted the vaccination program and a technical committee of virologists developed more stringent specifications for the manufacture of the vaccine.

Salk publicly criticised some of the manufacturers, claiming the problems arose not from the manufacturing directions but from their application. The controversy simmered with the manufacturers denying the claim, blaming instead the poorly worded manufacturing directions. The US FDA also came in for heavy criticism for not taking a more cautious overview of the trials and the manufacture of the vaccine. However, in the hysteria to get the vaccine on the market it would have been a brave regulator who would have tried to delay the launch of the trial or, later, the sale of the vaccine in order to spend a little more time evaluating the clinical trials or reviewing the manufacturers GMP.

Whatever, the results were 11 (or 10 depending on who you read) unnecessary childhood deaths. The FDA stung into action, put GMP on the roadmap with increased regulation of the manufacturing process through their Current Federal Register (CFRs), the World Health Organisation through committee work developed its first guidelines on GMP in the 60's. followed by Australian licensing of manufacturers in the early 70's at state level with NSW leading the way.

1. Paul JR. A history of poliomyelitis. Yale University Press, New Haven, 1971.
2. Gould T. A summer plague. Polio and its survivors. Yale University Press. New Haven, 1995.