International GMPs

Drug Quality – Pharmacopoeal Testing

The pharmacopoeia (from Late Greek pharmakopoiia preparation of drugs, from Greek pharmako- + poiein to make) is a book or treatise describing drugs and drug preparations used in medicine; the text is issued by an official authority and considered as the authoritative standard. Originally pharmacopoeias were collections of recipes to assure consistent communication between physician and pharmacists, but have transformed over time into a book of standards describing the quality specifications a raw material and pharmaceutical product. The oldest known pharmacopoeia appears to be the Chinese Pên-ts'ao Ching, dating to about 4,000 BCE, while in Europe the oldest pharmacopoeia appears to be that written in the monastery at Lorsch, Germany in 795 CE.

It is common in most countries that when a pharmaceutical product is sold and does not meet quality requirements of the pharmacopoeia that the drug is considered unfit for use. In many countries the authorities consider such drug products to be adulterated, a criminal offense causing the product to be withdrawn from the market and for sanctions and/or penalties to be applied to the manufacturer.

Modern Pharmacopoeias date from1581 in Spain, with the 1700-1800s witnessing an explosion in the pharmacopoeal publishing business and most countries issuing pharmacopoeias to control drug standards. The first edition of the United States Pharmacopoeia (USP) was issued in 1820, and the first edition of the British Pharmacopoeia (BP) issued in 1864. The USP was the work of the medical profession and was the first book of drug standards from a professional source to achieve national acceptance and ultimately was recognized in law by the United States Congress as the “official book of drug standards”. The needs for an International Pharmacopoeia (IP) were perceived early and work on the IP dates back to 1874.

Today’s pharmacopoeias are legally enforceable standards of pharmaceutical product quality in the country where the pharmacopoeia applies. In the USA the FDA does not establish the standards stated in the USP, in fact it sometimes has issues with the standards stated, but it enforces those standards in its approval of drug applications, and in its inspection of pharmaceutical manufacturers.

The major pharmacopoeias in use world-wide today are:

• the International Pharmacopoeia (IP) – “official” and primarily used in the developing nations;
• the British Pharmacopoeia (BP) – “official” and primarily used in the 54 member countries of the British Commonwealth;
• the United States Pharmacopoeia (USP) – “official” and primarily used in North America and in 27 other countries;
• the European Pharmacopoeia (Ph. Eur.) – “official” and primarily used in the 26 countries which are member states of the Council of Europe.

Additional influential pharmacopoeias worth noting, either due to the sizes of their populations or to the extent of their export trade in pharmaceuticals, are those of China, India and Japan.

While the pharmacopoeias provide extensive specifications and test methodologies for raw materials and drug products, they suffer from two grievous faults when it comes to drug product quality:

• they only require a few samples from a batch to be tested
• many pharmacopoeal tests are old, or based on poor science, or are a compromise on available testing technology available in all countries using the pharmacopoeia.

The deficiency on sampling pans is best illustrated when considering sampling of injectable product for sterility testing. When testing a batch of one million vials to determine that the batch is sterile, only 20 vials are sampled and tested. Similarly with other dosage forms such as tablets, the test for content uniformity typically is the measurement of the weights of ten individual tablets, and then extrapolating from theise data to an entire batch of, say, 10 million tablets. A cursory review of these sample numbers reveals that these sample quantities are below any acceptable statistically based sampling plan to provide adequate assurance as to the true quality of the entire batch. In selecting these sample sizes, the pharmacopoeia assumes that there is uniformity in product manufacture, which is not necessarily true. Even though the pharmaceutical industry is now heavily committed to process validation these small sample numbers still remain in place as the pharmacopoeal sampling schema.

The deficiency of some pharmacopoeal tests is best illustrated by the pharmacopoeal sterility test which has, over the past 20 years undergone significant changes in the growth media used for the test, in the incubation times and temperatures used in the test. Despite this, the test is still considered by many microbiological experts as being seriously flawed and not truly indicative of whether the individual samples tested are free from contamination, and thus not indicative of the quality of the batch from where it came.

Copyright © Globepharm • Website hosted by XO Communications