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International GMPs

The Advent of GMPs

It is a truism that it takes a disaster to happen for people, and especially regulators, to wake up and review the accepted way of doing things. So, too, with the question of drug safety and drug quality.

It was the “Elixir of Sulfanilamide” disaster in 1937 in the United States that alerted US authorities to the concept that a drug needed to be proven to be safe. In this situation, Sulfanilamide, the first of a new generation of "wonder drugs" and a popular and effective treatment for diseases such as strep throat and gonorrhea, was formulated into an Elixir of Sulfanilamide and marketed for use in children. But the liquid formulation contained a poison, the same chemical used in antifreeze (polyethylene glycol), and it killed 107 people, most of them children. Following the scandal caused by this tragedy, American law was changed to require drugs to be proven to be “safe”. The need for drugs to be proven to be “effective” would, remarkably, have to wait for another 50 years.

It was the issuance of contaminated intravenous fluids in the United Kingdom in 1972 that killed 6 people (the Davenport Disaster, which became the subject of a British Parliamentary Enquiry), that provided the British Department of Health (now known as the Medicines and Healthcare Regulatory Agency) with the powers to perform mandatory GMP inspections of pharmaceutical manufacturers.

It was not until the marketing in 1972 in the United States of contaminated large volume intravenous fluids manufactured by Abbott and McGaw Laboratories, two large multi-national manufacturers, that the US FDA realized the 1963 GMPs were not of sufficient rigor to prevent quality mishaps occurring in pharmaceutical product manufacture and testing and embarked on a revision of the GMPs resulting in the 1976 GMP regulations, which are still virtually unchanged today (in 2004).

It was the Haitian disaster of 1997, where 87 children died following ingestion of anti-fever medication contaminated with polyethylene glycol, rather than being what the pharmaceutical manufacturer thought it was (glycerol), but never tested, that any real concern was given to the source, origin and the quality of active pharmaceutical ingredients (APIs) and pharmaceutical excipients. In this case, the material had been bought by a Haitian company, Pharval, from a German supplier, because to quote the president of Pharval “every one knows that the Germans manufacture good quality product”. This also being the rationale for why Pharval did not test the incoming raw material for its correct identity and quality and instead relying on the accompanying certificate of analysis.

The Haitian government asked the US FDA to assist their investigation by tracing the faulty material back to its source. It was found that the excipient had indeed been purchased from a German company, but what the Haitians did not know was that the material had in turn previously been purchased from a source in Holland that had purchased the material from a source in Germany that had purchased the material from a source in China. The material was accompanied by a certificate of analysis attesting to its nature and its quality and stating that the material was Glycerol USP grade. When the US FDA tried to track the material to its original Chinese source the Chinese government refused to cooperate with the investigation, and the FDA was unable to find out who exactly was either the manufacturer or the testing laboratory of the material. Indeed the investigation never revealed where the adulteration and fraud had occurred.

At this time, many countries and industry organizations had promulgated GMPs covering the manufacture of Active Pharmaceutical Ingredients (APIs) and Excipients. GMP codes were in place from FDA, WHO, CEFIC (the European Association of Chemical Manufacturers), PIC (the Pharmaceutical Inspection Convention), the PMA (US Pharmaceutical Manufacturer’s Association), but in no case except for the US FDA were regulatory inspections required as part of compliance with any of these codes – the FDA having routinely performed such API inspections as part of their routine for product registration since 1979.

In the wake of the Haitian incident, and the lack of clear GMP guidelines for API manufacture, the International Conference of Harmonization (ICH) – a group consisting of the European Union, Japan and the United States – enacted an international set of GMPs governing the manufacture, testing, and distribution of Active Pharmaceutical Ingredients (APIs) – the ICH-Q7A guidelines), which have since been adopted as law in the United States, the European Union, Japan, and many other countries. Inspections by national authorities under the ICH-Q7A guidelines began by the EU and Japan in May 2004. The FDA will continue its API inspections using these clarified API GMPs in continuation of their 30 year old international inspection program, begun in 1979.  

The adoption of GMPs by the pharmaceutical industry, and the world-wide regulations, codes and directives mandating their implementation follows the dictum expounded by John Juran in the 1950s his seminal text “Quality Control Handbook” (published by McGaw-Hill), where he stated that product quality depends on the following three principles:

  • Quality, Safety and Effectiveness must be designed and built into the product;
  • Quality cannot be tested into the product
  • Each step in a manufacturing process must be controlled, to maximize the probability that the finished product meets all its quality and design specifications.

When he wrote these principles in the late 1950s, Juran did not have the pharmaceutical industry specifically in mind, but the pharmaceutical industry has well embraced these principles, and they are exactly reflected in the GMPs, especially the last of the three principles.

All GMP codes (guides, directions, regulations – call it what you will), are concerned with drug quality, safety, purity, strength, and identity. With the exception of the format of the Japanese GMPs, all GMP codes have the same basic sections covering all aspects of manufacture and testing to result in a quality pharmaceutical product.



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