Heparin and Quality by Design

The Wall Street Journal February 19, 2008 published an article on Heparin.

Following are some excerpts.

“Baxter, which supplies about half the U.S. heparin market, said last week it had temporarily stopped production because of about 350 bad reactions, including four fatalities, potentially tied to the drug. About 40% of the reactions were classified as serious, ranging from stomach pain to vomiting and diarrhea, low blood pressure, speeding heartbeats and fainting.”

In pharmaceutical business, the current methodology to produce consistent performance quality drug is to follow “quality by analysis,” which is analyze everything. In the case of Baxter International, casualties and bad reactions are a clear failure of the prevailing “quality by analysis” culture.

Legislators and consumers are demanding increased inspections. The FDA does not have enough staff to inspect every drug that is imported in US. FDA inspects only 7% of the incoming drugs (FDA inspections). It will not only take increased funding but also time to train inspectors to achieve 100% inspection. We have neither luxury.

Even if FDA could do 100% inspection, they would be following “quality by analysis” methods, which FDA wants the pharmaceutical companies to abandon. It is well known that “quality by analysis” is an inefficient and expensive method of producing drugs. Consumer pays for every mistake, rework, and disposal, if the drugs do not meet their respective specifications.

It has been mentioned that USFDA or EU regulatory agencies should be stationed in China, India and/or other countries exporting drugs. This can only happen if there are agreements in place between various governments. We are nowhere close to such agreements.

If a supplier/manufacturer is behind schedule, there is pressure to release the drug to the market as soon as it is produced. In such circumstances, mistakes like Heparin are going to happen. As more drugs are imported in the future, we are going to hear more about the mistakes. Heparin mistake also suggests that there is a failure on part of the pharmaceutical importer to set up strict standards and stringent protocols. Laxity has to be completely eliminated.

Pharmaceutical industry has to move from “quality by analysis” culture to “quality by design (QBD)” methods. Until this happens, increasing FDA inspectorate and passing new legislation is not going to solve situations similar to the current situation. QBD builds quality in the product from onset. It will change the culture, improve quality and will significantly reduce pressure on FDA and/or any regulatory bodies. Someone has to make a move.

Is close good enough? Heparin fiasco.

The recent fiasco of Heparin being sold by Baxter International is going to lay the blame of FDA (lack of inspection) and companies from China and India for making poor quality product and shipping it to US sellers. This is very myopic thinking.

Companies in EU or US who are importing active pharmaceutical ingredients (API) from China and India very well know which manufacturing facilities in these two countries have been inspected by USFDA and EU regulators. If they are importing API and formulated drugs from un-inspected facilities, then the blame of non-compliance has to be squarely put on the companies selling these products in EU and US.

It is well known that the regulatory agencies do not have sufficient staff to be inspecting every facility. With that being the case, the companies that are selling the pharmaceuticals have shrugged their “corporate responsibility” of selling products that have to meet regulatory standards.

We saw the case of melamine being incorporated in the dog food to enhance the superficial nitrogen content to give the analytical people the “good feeling” of meeting the necessary standards. No one has studied the toxicity of a substituted non-food product on human and animal health. Same thing happened with toothpaste.

Baxter International did not set up the proper protocol with their Chinese suppliers. I am sure they had set up the standards that have to be strictly met. However, there were sufficient laxities in the spec and/or the protocol for slightly off-spec API to pass through. I would not be surprised that the API met every spec but was slightly off spec that if not carefully reviewed would meet the set specifications.

Having manufactured products that have dual use i.e. food grade and non-food grade, I can speculate and speak from experience. In the case of Heparin, the API could not be reworked to meet the specs. Since it was marginally off specification and might meet the spec if overlooked must have been the case for the lots imported by Baxter International.

Press, legislators, and consumers have to look at the facts before they jump to conclusion that FDA is not doing its job and companies in China and India are bad. Any company anywhere if gets a similar opportunity will try to use a short cut and reduce rework, which cuts into profits.

Let us think rationally and understand the facts. Right or wrong, the seller has to be blamed no matter what the facts are. They did not live to their responsibility.

Girish Malhotra