As D-day approaches for the final round of GMP compliance, a preliminary review of what inspectors have found so far gives small-tier companies an insight of what to expect.
Paper. Inspectors are going to want to see lots of it, in the form of master manufacturing plans, standard operating procedures, and records of all sorts.
"FDA takes a risk-approached approach. What are the areas of risk right now for FDA? Let's look at (contamination), and that the products are made as they are written up to be made, and that there aren't accidental overages that could potentially raise a red flag," said Daniel Fabricant, scientific affairs vice president for the Natural Products Association.
"White mounds of paper," Fabricant said. "If you don't write it down, it didn't happen."
On June 25, the third and final phase of tougher GMP rules goes into effect. Those companies with 20 or fewer employees must be in full compliance with the Food and Drug Administration guidelines.
The Good Manufacturing Practices rule was first rolled out in draft form by the FDA in June 2007. The final rule was introduced in October 2007. The first deadline in June 2008 for compliance applied to companies with 500 or more employees, followed a year later by companies with 21 to 499.
FDA officials began inspections of larger-sized companies in 2008, and the number of inspections is increasing every year. The agency completed 12 inspections in fiscal year 2008, 28 in fiscal year 2009, and is doing many more now.
"It is too early, based on this limited data, to identify or publicize any trends," Reynolds said. "My last information is that there had been one untitled letter, and one warning letter that has been issued so far. But there are a number of regulatory recommendations that are under review in the centre for possible regulatory action."
"Quite honestly, some of the smaller and medium firms are not there yet," said Carl Reynolds, senior advisor in the Division of Dietary Supplement Programs at FDA's Center for Food Safety and Applied Nutrition.
Amy Caplette, a group leader at Nutrilite Labs in Lakeview, Calif. who spearheaded that company's GMP compliance effort, said inspectors are looking to see if information in the form of documentation flows through your facility along with your raw materials.
"Most auditors want to see things from beginning to end, from the receipt of the raw material to the shipping of finish product," she said.
Inspectors will want to be assured that the documents that control that process are easily available to line workers and that you can verify that they are up to date.
"How do you control that document?" Caplette said. "Is there a revision number? Is there a date to it?"
"They will want to know how you store the record," she added.
No one argues that this new required level of documentation will add complexity and cost. But it is an achievable and necessary step, industry insiders have said.
"Whatever your documentation is, it is finite. It has beginning, a middle and an end," said Michael McGuffin, CEO of the American Herbal Products Association. "Whatever (the documentation requirements are), you can get there. Once you're there, it's more of a headache than an obstacle."
The FDA generates documents of its own in the inspection process, including a 483 letter detailing the shortfalls they found. Companies can expect to get one of these.
"It's very, very rare for an inspectors to come into a facility and spent six to ten days there and say, 'Gee, that was perfect,'" McGuffin said.
"We don't see the fact that companies are likely to receive a 483 as evidence of failure. The failure would be if you can't fix what's on the 483," he said.
There is no formal requirement that a company respond in writing to action taken on 483 line items. But McGuffin, Fabricant and others say a company would be foolish not to document when has been done and forward a copy to FDA.
"It's better to give the agency the info they need to close the file, rather than keep the file open," McGuffin said.
Reynolds discussed how the FDA is monitoring GMP compliance at a special educational session at SupplySide East in late April.
"What are they (the inspectors) seeing? Well, ladies and gentlemen, investigators are documenting almost everything and some are so basic it is a little bit troubling to me. … Insect and rodent activity in manufacturing and food ingredient storage areas. How on earth can that be!? Insects and rodents in your storage areas? It surprises me."
Other failures include a lack of written procedures for how to handle rodent and vermin problems; a lack of master manufacturing and batch records, or they are incomplete or don't contain the information required; a lack of corrective action plans for when specifications the company set are not met; and a lack of or incomplete identity testing.
In other words, Reynolds said, the failures run the gamut.
Joysa Winter contributed to this report.