GROTON, CT — Imagine asking an FDA inspector this question: “If I switch to a new contract testing facility for sterility testing and the first test is a failure, can I invalidate it because it was the first?”

If you think you&#39d be asking for trouble by posing a question like this, guess again. Steven Souza, resident-inspector-in-charge of the U.S. Food and Drug Administration (FDA)&#39s Hartford, CT-based branch, fields these types of anonymously submitted inquiries in an effort to better inform the industries the FDA serves.

Souza says he usually gets a plethora of questions, some of which have sparked lengthy debates when he makes presentations before pharmaceutical field professionals. But at the ISPE New England Chapter meeting, held in September at Pfizer Central Research in Groton, CT, the 35 people who gathered there were apparently there just to listen.

Informing Constituents

Presentations like Souza&#39s are just one way the Modernization Act of 1997 allows the FDA to keep its constituencies informed. The agency also heavily relies on the Internet. Several Web sites provide regulatory guidelines and compliance documents for not only the FDA, but also the Center for Drug Evaluation and Research and the Center for Biologics and Research. There is also a site for the Adverse Event Reporting System, through which the agency receives and processes safety reports electronically.

“We are trying to open up the FDA as much as possible. If we can make information available to the industry, it will make our jobs easier as inspectors,” Souza says. “And most firms want to do the right thing and produce a good product.”

Souza&#39s presentation outlined what the FDA looks for when performing inspections. The regulatory considerations are:

• Requirements for validation or verification
• Control of microbiological contamination
• Sampling and testing of in-process and drug products
• Testing and release for distribution and laboratory controls
  

Some of these considerations require separate validation procedures. “There are only a couple of places in the requirements where the word “validation” comes up. Control of microbiological contamination is one of them, and we really want to see tight controls on in-process sampling and testing,” Souza says. By mandating such controls, laboratory, in-process, operator, and equipment errors can be minimized, he says. The considerations also have many caveats to overall investigations, including methodology, calculations, instrumentation performance, documentation review, corrective actions, equipment, and personnel.

Retesting Samples

According to Souza, one of the greatest problems the agency runs across is that many drug manufacturers believe that if a test on a product sample turns up a failure, then all they need to do is retest subsequent samples until it passes into compliance. Without naming names, Souza points to one particular instance in which a lot of “XXXX injection” revealed a potency of 131.2 percent, which was over the 90 to 125 percent limit for this particular drug. The manufacturer did not reveal a cause for the failure and released the drug to the market. “This is inappropriate. The company saw the numbers and sent it out the door anyway. We have a problem with that,” he adds.

In another instance, one of three units failed a moisture test. According to the manufacturers&#39 records, no cause for the failure was found, and an analyst retested the failed unit, while a second analyst tested all three of the units. The drugs passed the second tests and were released. “This is a sterility issue, and you cannot just retest,” Souza says. “You need to determine if the HEPA filter was compromising sterility or if someone touched something they were not supposed to. You have to find out these things out before letting a product go out the door.”

When it comes to testing, Souza says it is important not just to test one tablet in what is commonly referred to as an out-of-specification (OOS) test. “If there&#39s a problem with the test equipment, scrap it and start over. Document everything, and if a test comes up with a failure, find out how and if other batches were affected,” he says.

Errors in the laboratory, process, and manufacturing are a given, and one specific way to minimize errors and subsequent product failures is to ensure that employees are well trained, Souza says. One case in point: An employee working at the end of a production line for a medical device used to measure sleep patterns thought he was doing the right thing by wiping residue left on the equipment from injection moldings. “He thought he was doing a better job by shining it up, but what he was really doing was creating an electrostatic charge, and ruining the devices,” he adds.

Many in attendance said Souza&#39s presentation lifted the ambiguity that sometimes surrounds a government agency. “He is letting people know what is involved in an inspection. The FDA wants to help fix the problem, and presentations like this provides a more personal side of the FDA,” says Dr. Shawn Kinney, president of Hyaluron, Inc. in Wayland, MA. Hyaluron is a recently incorporated company that provides aseptic filling and formulations of viscous solutions containing hyaluronic acid.

Phil Sumner, an engineering manager at U.S. Filter in Plantsville, CT, agrees, saying Souza provides an excellent snapshot of the FDA&#39s approach to inspections. “There is a mystique with the FDA that was somehow lifted with (Souza&#39s) overview. He puts a face on the agency,” Sumner says.