Over the last several weeks there has been a veritable avalanche of dietary supplement related GMP headlines, including posted 483 reports, GMP warning letters and even a criminal indictment for active pharmaceutical ingredient (API) adulteration.

I’ll ignore the latter for now, as it is complicated and the story is available elsewhere. I will also put aside NDI-related issues and leave out the action taken against companies whose claims pushed their products into the realm of unapproved new drugs. But the 483 reports and GMP violation warning letters that remain are fodder for this column, as these items largely revolve around product quality and GMPs.

CFR 21 Part 111 Section I. “Background and Related Information,” clearly indicates the intention of the Dietary Supplement GMP by stating, “The final rule establishes, in part 111 (21 CFR part 111), the minimum cGMPs necessary for activities related to manufacturing, packaging, labeling, or holding dietary supplements to ensure the quality of the dietary supplement.”

Manufacturers are expected to establish for their products what FDA has determined to be the minimum manufacturing practices required to produce a quality product. Simply put, manufacturers must produce what they intend to produce and have in place controls that demonstrate they consistently achieve their desired outcome in product manufacture. FDA goes on to further clarify the intent by defining “quality” in Part 111 Section III. “What does the final rule do?” to mean, “that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic Act.”

Now go to http://www.fda.gov/ICECI/EnforcementActions/ucm255532.htm#foods and use the “find” function in your browser to look for “21 CFR 111.” What do you see?

Ok, it is time-consuming slagging through all the piles of information on the FDA website, but quickly it becomes overwhelmingly apparent that companies are not being criticized for the quality of their products and product specifications or even the appropriateness of the methods used to demonstrate they meet specifications. Worse; they are getting caught with a complete lack of specifications and documentation!

Summarizing Recent Inspection Findings

There are people in the industry who have been keeping track of this information over the last few years and some even created handy summaries (Thank goodness!). I steer you to a couple sources I perused:

Michael McGuffin of the American Herbal Products Association (AHPA) gave a lecture entitled, “21 CFR 111 Compliance: A review of recent inspection records” at the Covance Symposium, September 15th, 2010. The presentation can be found on the AHPA website at http://www.ahpa.org/Default.aspx?tabid=193.

Marian Boardley of the FDA Compliance Group LLC has put together useful summaries of FDA GMP inspection activities over the past couple of years and I noticed that she added an update on Oct 4th, 2011. Her charts (copyright Marian Boardley 2011) can be found at http://marianboardley.com/13811.html.

Ms. Boardley presents a very jarring view of the data from 2009-2010 in the form of four pie charts: Inspectional Observations by GMP Subpart; Warning Letter Items by GMP Subpart; Subpart E Inspectional Observations by Topic; and Subpart E Warning Letter Data by Topic. There are a total of 15 subparts in the GMP but 64% of the cited warning letters were from just four of those subparts, with 29% from Subpart E (Process and Production Control). Subparts I (Batch Records) and H (Master Manufacturing Records) tied for second place with 13% each, while Subpart F (Quality Control) came in third at 9%. The remaining 36% of the warning letter citations came from the other 11 subparts combined. Within those warning letters related to Subpart E (Process and Production Control), 37% concerned specifications, 20% finished product testing, 17% identity testing, 17% sampling plans, 7% supplier qualification and finally 2% material review.

As fascinating as the big picture overviews are, it is within the actual warning letters themselves that the fine grain of the supplement industry’s GMP problems are revealed.

Remember the rumor that the acronym GMP actually stands for “Great Mountains of Paperwork”? The truth is when FDA pays a visit to a facility it is charged with visually inspecting the facility to ensure it is clean and well-maintained AND reviewing your alpine paperscape. Not only do they want to see that you have that mountain of paperwork, but they will proceed to go over it with a fine tooth comb.

In many (far too many) cases the warning letters contain wording such as:

“You have not established specifications for purity for ingredients used in dietary supplements produced by your contract manufacturer.”

“You did not [establish] [follow] written procedures for quality control operations.”

“Your batch production record did not include complete information relating to the production and control of each batch.”

“You did not [prepare] [follow] a written master manufacturing record for each batch size of a dietary supplement that you manufactured.”

“You did not [establish] [follow] written procedures for maintaining, cleaning, and sanitizing, equipment, utensils, and any other contact surfaces that are used to manufacture, package, label, or hold components or dietary supplements.”

…and my personal favorite… “You did not conduct at least one appropriate test or examination to verify the identity of a dietary ingredient, prior to its use.”

As far as I’m concerned, the key phrase in these excerpts is “you did not.” These weren’t nit-picking critiques of the adequacy of the written materials and documentation that procedures were followed. Inspectors didn’t say “you’re specifications aren’t good enough;” they said, “You don’t have any specifications.”

Come on people, a complete absence of written materials and documentation? The joke is “Great Mountains of Paperwork,” not “Generally Minimal Paperwork” or “Galling Molehills of Paperwork.” I’ve heard of turning molehills into mountains, but never the other way around.

I can imagine a fictional conversation between an FDA inspector and a QA person going something like this:

FDA inspector to QA person: “Let me see your training file that documents your qualification for this job.”

(QA person gives blank look.)

FDA inspector: “Ok, Let me see your written purity specifications for this dietary component.”

QA person: “Here is the C of A from the supplier.”

(FDA inspector writes something down.)

FDA inspector: “Show me the written vendor qualification plan for that vendor.”

QA person: “Here’s the C of As from the last five times we bought from them over the past 10 years.”

FDA Inspector: “Hmmm, these all say the same thing. They don’t have dates or lot numbers, and they all have the same photocopy machine stripes on them.”

(FDA inspector writes at more length.)

FDA inspector: “Show me the written identity specification and identity testing SOP for this incoming dietary ingredient.”

QA person: “Here’s the catalog we use and the shipping manifest for the last batch… See? Same catalog number.”

FDA inspector: “uh huh”—scribbling furiously—“and the SOP?”

QA person: “We don’t have anything written down, we just show the stuff to George, he’s been in the business since 1983.”

(FDA inspector runs his hand slowly down his face…)

Write Down What You Do & Document You Are Doing It

I was asked to evolve the quality discussion through this column, so how about this… You must have written specifications for all aspects of everything. Incoming bottles, cotton for the bottles, labels, non-dietary ingredients like excipients, the capsules you put the products into, closures, dietary ingredients, the machines you mix with, the machines you wash with, the machines you make capsules or tablets with, the conveyor belts, ovens, refrigerators, scoops, scales, shipping containers, and more. Specifications should describe what the thing you’re specifying is and how you can tell that it is what it’s supposed to be or working the way it should.

Specifications should describe the quality of the materials you wish to use to make the product, including how you verify identity, the machines used in the product manufacture, and there should be a different set of specifications that describe the quality (identity, purity, composition, strength) of the finished product, including how you can tell (prove) that your goal was met. You also have to have specifications for all the processes you use to make your product, including the process you use to clean up between batches/products.

Did I mention that all this stuff has to be written down? Once you have the specifications, you have to follow those specifications and you must prove, in writing, that you have followed the specifications (i.e., documentation).

This is obviously a short list of the stuff you need to do. No matter how you say it, no matter who says, it is the law and if it isn’t written down, it didn’t happen.