An FDA task force has proposed to broaden the agency's response to periodic incidents involving contamination of drugs with diethylene glycol that the World Health Organization estimated have caused more than 500 deaths in the past century.

The task force called for the agency to consider establishing certain controls on other pharmaceutical ingredients that may pose a similar danger, FDA's Edwin Rivera told the IPEC Americas Regulatory Affairs Conference in Alexandria, Va., Sept. 10.

FDA's Center for Drug Evaluation and Research convened the Pharmaceutical Ingredient Safety Task Force in May, the same month it issued guidance recommending that product manufacturers test all containers of all lots of glycerin for DEG ("The Gold Sheet," August 2007, p. 8).

The glycerin guidance followed a September 2006 recurrence of the problem in Panama, where more than 40 people died from DEG-contaminated cough syrup. More than 80 children had died in Haiti in 1995-96 from DEG-tainted acetaminophen syrup. Hundreds more died from DEG poisoning incidents in Argentina, Bangladesh, India and Nigeria.

The task force, which includes representatives from various organizations within CDER's Office of Compliance, has a fourfold mission:

· Recommend ways to prevent and eliminate "DEG-like" contamination of any pharmaceutical raw materials;

· Address the issue of raw material supply chain integrity;

· Recommend ways to help address the risks posed by sourcing of poor quality, adulterated and misbranded pharmaceutical raw materials; and

· Make specific proposals for enhancing FDA's oversight of pharmaceutical ingredient safety.

The task force already has met twice by teleconference on the supply chain integrity issue with members of the International Pharmaceutical Excipients Council Americas, which along with IPEC Europe and JPEC in Japan represent the world's pharmaceutical excipient users and producers.

The task force viewed a demonstration of one potential technology solution, portable Raman testing equipment, and attended a seminar on nondestructive test methods by the Division of Pharmaceutical Analysis in CDER's Office of Testing and Research in St. Louis.

It also provided input to FDA's May 24 revised import alert for glycerin and advised the U.S. Pharmacopeia on adding DEG testing to the identity tests for glycerin, as well as for propylene glycol, sorbitol and food-grade glycerin.

Additional Risks Would Be Identified

The task force's first proposal is to develop a list of pharmaceutical ingredients that are at risk of adulteration, misbranding and economic substitution, or of being marketed as unapproved drugs.

A number of its other proposals hinge on the development of that list, which a multidisciplinary group, along with IPEC and other pharmaceutical associations, would establish.

Criteria for the list would include the potential economic incentive for substitution or counterfeiting. "When we had the Panamanian incident last year, one of the things we were asking is, is there an economic incentive to substitute glycerin with diethylene glycol?" said Rivera, who is the Manufacturing Assessment and Pre-approval Compliance Branch Chief in CDER's Office of Compliance.

"We did some preliminary checks on the Internet on the price of glycerin vs. DEG." For a 50-drum shipment like the one that went to Panama, "the economic incentive for that volume of material came out to about $18,000," Rivera said.

"For most of us in the U.S., $18,000 doesn't sound like much of an incentive to engage in this type of criminal activity. But to somebody in a developing country, $18,000 can go a long way. In many parts of the world, $18,000 can actually be the equivalent of 10 to 15 years of a person's salary. So you can see that, while it may not be an economic incentive in our country, it could be very likely an economic incentive in other countries."

Other criteria the task force considered for the list include:

· The volume of use in pharmaceutical manufacturing; and

· Past experience or a history of problems.

Quicker Testing Sought

The task force also proposed to promote development of rapid testing methods that agency field personnel and the pharmaceutical industry could use for surveillance.

To accomplish this, Rivera said, "We are asking the FDA CDER labs in St. Louis to research and develop rapid nondestructive sampling methods with handheld instruments, such as Raman and near-infrared."

The hope is, he said, "to transfer this technology to our field force, people on the piers, where they can do some of this surveillance testing on pharmaceutical ingredients being imported into the U.S."

Eventually, Rivera suggested that such nondestructive methods could be used for raw material and finished-product testing "at the point of entry - and at the point of entry into your pharmaceutical facility."

Contamination Reporting Requirement Mulled

A third proposal was for enhanced regulations or guidance, Rivera said, while cautioning the audience that, "these are proposals at this point. Please do not report that this is a done deal."

One idea that was discussed, he said, is to require the reporting of pharmaceutical ingredient contamination and adulteration to the FDA.

"We think that by putting in some type of reporting requirement of this nature, that when you folks find out about problems with a particular pharmaceutical ingredient, either adulteration or intentional contamination, that we can get the word out to the rest of the industry," Rivera said, "and we can also follow up with an investigation to try to determine how this occurred and bring those responsible to justice."

Ingredient Tracing Could Be Required

Another idea is to require that agents, brokers, traders, distributors, importers, repackers and relabelers maintain complete traceability or pedigree of pharmaceutical ingredients they sell or distribute.

"These are similar to expectations for APIs in Section 17.20 of the ICH Q7A guidance for active pharmaceutical ingredients," Rivera noted.

He called attention to existing pedigree requirements for U.S. exports of pharmaceutical goods that come into play when someone tries to re-import those goods.

"Essentially, whoever is trying to bring those U.S. goods back into the U.S. has to provide documenttation to FDA showing where those materials have been, in whose hands they have been, and why are they coming back," he explained.

Perhaps No CoA for High-Risk Ingredients

Another proposal is to require in-house testing by dosage form manufacturers of high-risk pharmaceutical ingredients.

"We are saying that if we come up with a list of high-risk pharmaceutical ingredients, perhaps this acceptance of a valid certificate of analysis may not suffice for some of those high-risk pharmaceutical ingredients," Rivera said.

"We may actually require, depending on the nature of the material, that you actually do testing of that pharmaceutical ingredient and not accept the CoA."

Labeling Requirements for All Components

The task force also proposed "to require the country of origin, the name of the manufacturer labeling for all components of drugs," Rivera said. "Again, it might be limited to a list of the high-risk pharmaceutical ingredients."

Investigators to Check Ingredient QA

While the proposals Rivera described are just for review and discussion, there is one regulatory change that he said is almost certainly going forward: a new emphasis on raw materials in facility inspections.

"The one thing that I can assure that we will most likely do is we will be revising the drug process inspection compliance program, Compliance Program 7356.002, to emphasize more detailed coverage of the raw materials system and this includes the vendor qualification program."

Rivera elaborated that the agency will be instructing its investigators "to spend more time during a systems-based inspection to cover vendor qualification programs and what procedures a company has in place to assure the quality of pharmaceutical ingredients before they are actually used by that company."

International DEG Meeting Proposed

The task force also is proposing a DEG pharmaceutical ingredients open public meeting, followed by one or more workshops, Rivera said.

FDA is looking to organize the meeting in conjunction with the Pan American Health Organization, the World Health Organization, the European Medicines Agency and the U.S. Pharmacopeia.

The meeting, which would be in or near Washington, would be similar to the WHO/FDA DEG workshop that was held in Washington after the 1996 DEG contamination incident in Haiti.

One difference from the previous meeting is that this time FDA hopes to work with worldwide regulators and other trade associations "to come up with solutions on how we can avoid DEG contamination incidents."

Instead of just discussing general recommendations like they did last time, "we would like to have this meeting to actually put an end to any DEG contamination incidents around the world."

It is possible, Rivera added, that the conference might be expanded beyond glycerin to address pharmaceutical ingredient safety issues in general.

International Cooperation Proposed

The workgroup also proposed to work with the Pharmaceutical Inspection Cooperation Scheme and other regulatory bodies.

Although FDA's request to join PIC/S is still under consideration, "we can still work with PIC/S as we have done in the past, and perhaps this might be an area where we can explore what regulators can commonly do with respect to pharmaceutical ingredient safety issues."

Import Controls Could be Strengthened

Another possibility raised is to establish new or enhanced import controls. "This would be essentially to deal with high-risk pharmaceutical ingredients and also high-risk drug products," Rivera said. "A lot depends on coming up with this list that I initially mentioned."

The task force also made a glycerin-specific proposal that all bulk containers of glycerin should be labeled with a caution statement saying that glycerin has been implicated in numerous DEG contamination incidents around the world, "and it would emphasize the importance of testing each container for DEG contamination, and of course, this may be considered also for propylene glycol and sorbitol."

Such a caution statement is important "to remind folks of the danger of not testing many of these sweeteners for DEG contamination," Rivera stressed.

Education and Training Needed

Also FDA needs to work with associations such as IPEC, PhRMA and GPhA to develop continuing education and training for its own staff and external stakeholders. "Without this important training element, we are not going to have much success in ensuring the quality and safety of pharmaceutical ingredients."

Import Safety Study Could Impact Process

Rivera noted that President Bush on July 18 issued an executive order directing Health and Human Services Secretary Mike Leavitt to establish an interagency working group on import safety.

"I bring it up here this afternoon because the final recommendations of this presidential task force may influence what we do in FDA with respect to imported pharmaceuticals" (see next story).

- Bowman Cox (b.cox@elsevier.com)

FDA Considers Range of Measures to Enhance Safety of High-Risk Excipients

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