cGMP compliance, time bombs and the ‘ten-ton elephant in the room’
In a note recently circulated to supplement makers, James Neal-Kababick - director of Oregon-based Flora Research Laboratories – said the FDA is “looking much more closely at the use of all analytical techniques to assure they are being used properly”.
Citinga warning letter sent to Ion Labs last month criticizing its sampling procedures, he said: “Now let’s look at the other ten ton elephant in the room: Sampling plans and protocols….
“I have repeatedly warned industry stakeholders that you must have a scientifically valid sampling plan that produces lot representative samples for laboratory testing.
“First you must establish the program for sampling based on scientifically valid plans and you must validate the sampling plan. Then you must sample and test the sample composite or composites depending on the target analyte and limitations of the test and specification.”
High costs of kit or testing no excuse for failure
He added: “For instance, you can’t test for trace level adulteration and get lot representative data by taking one 10g composite of a million capsules. You must take approximately 30 pulls and separately analyze these, then aggregate the data to obtain data that is lot representative.”
He added: “You must test finished batches of supplements to assure that they meet their specifications for potency, purity, strength, composition, and limits on reasonably anticipated contaminants.”
Firms should also note that the FDA does not consider the high costs of equipment or testing as a justification for laxity in this regard, he warned.
Reprocessing: ‘A time bomb waiting to go off?’
Meanwhile, the issue of reprocessing dietary supplements without proper protocols – also highlighted in the Ion warning letter - was “a time bomb waiting to go off ” in the sector, claimed Neal-Kababick.
“I see it all the time under the microscope when testing products. You can’t just mill up failed material and re-blend it again without proper protocols or it will be declared adulterated.”
Similarly, firms cannot “just arbitrarily change formulation ingredients without the proper documentation”, he claimed, citing FDA’s observation that batches it tested deviated from the master manufacturing record (MMR) and yet Ion “did not provide documentation of any material review and disposition decision and follow up for these deviations”.
For example, the FDA concluded that a batch of Ion’s wintergreen content mints was adulterated because a small change in the level of an excipient (magnesium stearate powder) from the MMR was not signed off and documented properly.
Reference standards: ‘I knew this was going to happen’
The FDA also alleged that Ion failed to establish criteria for selecting reference materials used in tests, adding that “non-compendia reference standard materials should be of the highest purity by reasonable effort and should be thoroughly characterized to ensure their identity, purity, quality, and strength…”
Said Neal-Kababick: “I knew this was going to happen. You must characterize your standards to assure that you have proper quantitative values and proper identity.”
RACs: Ignorance is no defense
Finally, Neal-Kababick stressed the importance of testing for reasonably anticipated contaminants (RACs), and that ignorance of what the relevant RACs might be, or reference to past form, is no defense.
“If an FDA inspector asks you how you know for certain that the lead level in the finished product is within specifications, answering ‘because it was never out of spec before’ is not going to cut it.”
He added: “FDA is not going to have much mercy for those that say ‘I did not know…’ when it comes to hot topic, high-risk groups of products considering that they are the subject of numerous news stories, warning letters, trade association talks and symposia sessions.”
Stay on top of the issues
The overriding message is that manufacturers must up their game, said Neal-Kababick.
“The FDA is enforcing the cGMP regulations and they are doing so at increasingly detailed levels. Moving from HACCP-like inspections to detailed evaluation of the analytical methods and standards, the inspections are becoming more involved and thus we are seeing more and more cGMP issues arise.
“I can’t stress enough that it is imperative that you study the warning letters and keep on top of the issues at hand.
“If you do not have the time to do this, you must get someone who can (hire someone or get a consultant) because FDA will eventually make it to your facility and you do not want to be the umpteenth person in a row with the same violations.”
The American Herbal Products Association (AHPA) is hosting an educational tele-seminar on cGMP inspections to assist companies in targeting compliance efforts on February 23.
Click here for more details.
