cGMPs / QRM Process

Safe Materials from Overseas: What Tools Does FDA Have?

Material safety is an industry issue, not an Agency issue.

By Emil W. Ciurczak, Contributing Editor

With all the recent interest in the safety of raw materials and intermediates sourced from off-shore locations, what tools are in the pocket of a typical FDA inspector? Having cut my teeth in the pharma world, the phrase “The FDA is coming to audit us” was only slightly less frightening than a kid hearing, “Wait until your father gets home.” The impression we had was of an inspector who could see through closed books, smell anything hidden away, and sense a lie like a polygraph test. What a difference a NAFTA makes!

The Agency’s fearsome aura was based on U.S. companies buying materials from U.S. vendors (also under the FDA’s gaze), processing them within the country’s borders, and selling the product (primarily) to U.S. sources. That was then, this is now. Globalization as we define it today happened, and a new attitude took over in D.C. Without getting (too) political, Mr. Reagan brought a “government doesn’t work and should be dismantled” attitude to Washington.

After laying off all of the nation’s air traffic controllers, he let a large segment of FDA go as well. The “free market” would take care of product safety. And, to a large degree, the U.S. pharma companies did quite well. Unfortunately, much of the rest of the world had few internal laws or traditions for safety, nor do they today. In many cases, the (often totalitarian) governments encourage suppliers of adulterated or counterfeit products with either false documentation or a blind eye. While the law asks the FDA to perform biennial inspections of drug product plants abroad, no statute exists for raw materials.

Thus, not only does our front line of protection’s responsibility continue to increase, the number of inspectors remains constant. (The Agency has been given the green light to add personnel, but the training is not immediate and experience is needed, too.) Foreign production facilities have grown from 1,282 in 2002 to 2,820 in 2007; concurrently, FDA production facility inspections have gone from 249 in 2002 to only 325 in 2007. Clearly, this is a problem.

As far as incoming materials are concerned, the number of lots of finished drug products, APIs, and intermediates has grown from 17,550 in 2001 to 42,983 in 2007. And, we have no more labs for testing them. What about legal help? Right now, 21 CFR 210/211 concerns only the manufacture, processing, packaging and holding of drug products (ID, purity). It does not specify anything about the ingredients used to make those products.

There is ICH Q7A for APIs, but in the U.S., this is a Guidance, not a legal document. The IPEC GMP Guide calls for voluntary GMP standards for excipients, but, again, voluntary. Now 21 CFR 211.84 (finished products manufacturer rules) does require one specific ID test and calls for periodic testing for reliability of Certificates of Analysis (CofA). The cGMPs require manufacturers to assure ID, quality and purity of ingredients they use—as they have since 1978. Of course, in 1978, bell bottoms, the song “Staying Alive”, and bushy sideburns were in style along with titrations and TLC. The law may be dated?

The irony of finding diethylene glycol (DEG) in products from China is that use of DEG was the basis for the Pure Food and Drug Act of 1937. (What goes around comes around?) Until and unless the Agency is given the bodies and laws it needs to protect us, and indeed, even then, we should set up meaningful screening of everything that enters the drug chain (I just thought that sounded akin to “food chain”).

For instance, an RMID program based on NIR would have spotted the melamine in food, the heparin adulteration, and seen the DEG in the products (e.g., toothpaste) imported from China. A serious RMID program does not rely on CofA’s, but includes welldocumented vendor validation site visits. Adding NIR, IR or Raman to routine screenings and following the 1980s EMEA suggestion of 100% raw materials testing will give us a leg up on the (RM) supply chain problem.

Yes, it is good to have a strong police force, but only a fool would leave his doors unlocked and windows open at night. Raw material safety is not an FDA problem, it is an INDUSTRY problem, so let’s all work together and get our heads out of the sand on this issue.

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