The dietary supplement Good Manufacturing Practice (GMP) regulation (21 CFR 111) is effective for companies with 20 or more employees, with the smallest companies due to come under the regulation soon. Inspections began last year on the largest companies and will begin to fold in the smaller companies as the law becomes effective for those organizational sizes. There have been numerous articles, seminars, Webinars and other industry educational opportunities for all of those involved in these companies to learn more about the GMP regulation details, what preparations are advised and on what aspects FDA inspectors might focus. The United Natural Products Alliance (UNPA) actually offered attendees to its May 2009 GMP seminar a chance to meet and question current FDA inspectors, in addition to other speakers detailing how to prepare for GMP compliance and future inspections. While all the education on the regulations finer points can help the basic foundation of compliance, there is much that can be learned from inspections that have already taken place.
If It Isnt Written, It Doesnt Exist; If its Broken, Fix It
In one inspection observations report (form 483), a dietary supplement manufacturer was told it did not establish written procedures for calibrating instruments and controls used in manufacturing or testing a component or dietary supplement. Specifically, the firm conducts in-house calibration on all their electronic weigh scale instruments, the inspector noted. However, the firm does not have written standard operating procedures [SOPs] for conducting their in-house calibration operation.
Every procedure your staff or crew undertakes has to be written down. This means every step in the manufacturing process, from releasing raw material for processing to checking the seal over plastic bottle openings.
In what might be an example of being completely unprepared, relative to written procedures, one dietary supplement manufacturer inspected in September 2009 did not did not prepare a written master manufacturing record for each unique formulation of a dietary supplement it manufactured. In addition, the inspector noted the company did not have procedures for holding and distributing operations, nor did it make and keep written procedures outlining quality control (QC) responsibilities for conducting a material review and making a disposition decision.
On the other hand, even when companies have written procedures for a certain process, they might not be thorough enough to cover all actions involved. Following one inspection, the auditor informed the dietary supplement contract manufacturer its records of examination and testing of raw materials and components did not include records of examination of finished product packaging and closures used for the dietary supplements. In another case, a juice manufacturer was given a 483 report that stated, The written instructions in your master manufacturing did not include instructions for corrective action plans to use when specifications are not met.
Daniel Fabricant, vice president of scientific and regulatory affairs at the Natural Products Association (NPA), which had more than a handful of its members undergo an FDA GMP inspection, echoed the 483s, saying written SOPs, master batch records and corrective action plans are some the key aspects of GMPs companies should focus on.
In fact, the 483 for the same contract manufacturer as above noted the companys batch production records did not include documentation that QC personnel approved and released, or rejected the packaged and labeled dietary supplement. In addition to getting dinged for the absence of a corrective action plan in its master manufacturing record, the company also lacked sufficient documentation for production and process controls, results of testing and examinations, theoretical yields at various manufacturing stages, and periodic review of instrument calibration and controls.
The corrective action focus was evident in other 483 reports, including one where a juice/supplement manufacturer had a record of glass breakages, which it categorized as low risk, but had no record of segregating or evaluating the products after each breakage incident. There was also no corrective action plan for when the product was out of spec, such as when the pasteurization temperature or bottle core temperature did not meet spec.
If Its Written, Follow It
A pharmaceutical company that also makes dietary supplements received a 483 report noting four of five corrective actions in the master corrective action plan for testing minerals werent implemented.
In September 2009, a contract manufacturer of a well-known superfruit multi-level marketing product was informed of several records issues, including failure to perform every step in its master production record, relating to pasteurization and organoleptic testingthe sequence of actions was not specified sufficiently in the record.
One of the many observations on a particularly lengthy 483 report focused on the companys HACCP plan, which included corrective actions. However, the inspector(s) observed company personnel failing to take such corrective action when facing a deviation from a critical limit.
According to an August 2009 483 report, QC personnel at one dietary supplement manufacturer did not perform required operations of product components, using quarantined raw material that did not bear the proper release sticker as directed by the batch record. Another firm did not follow written procedure for pest control. In fact, the inspectors noted observing rodents in several areas of the facility, and indicated trash storage and disposal was inadequate to prevent attracting pests. They also noted capsule products, including alfalfa, were stored in areas that appeared to experience high-rodent activities, as evidenced by existing rodent droppings, and the products were stored in cardboard barrels capped by flexible plastic, similar to shower caps.
A supplement and conventional food manufacturer was called out for worse rodent problems, as inspectors found rodent excreta pellets (REPs) all over the facility, along moldings, on a sink drain board, on the mechanical table in the blending room and in the corner of the blending room. The inspectors wrote, the northwest corner of the warehouse where whey protein concentrate was stored, showed apparent urine staining and REPs. They further said the apparent REPs in the southwest corner of the blending room were too numerous to count.
Cleanliness is Godliness
Looking through the inspection observation reports for dietary supplement companies, numerous issues were related to cleaning/hygiene or the documentation for such. A major supplement manufacturer got word from inspectors that it did not make and keep documentation for the date of use, cleaning and sanitizing of the equipment used to prepare coating solutions for dietary supplement tablets. The auditors also noted the manufacturers QC personnel did not use sufficient hygiene practices to prevent contamination of supplement ingredients. Then during blending, company associates were seen touching drums, outer bags and box cutters before touching the raw materials without refreshing their gloves.
Another manufacturer was called out for its hand-washing water not being a sufficient temperature for sanitationthe automatic sinks used for hand sanitation only generated cold water.
Sometimes, the cleanliness was visibly apparent, but the record of such was deficient. A juice and supplement manufacturer was told its liquid processing equipment is cleaned and sanitized daily, and deep-cleaned and sanitized once a week, but [your] firm does not maintain any record of the daily cleaning process."
Testing, Testing 1,2,3
Fabricant noted identity testing is a big deal in GMPs. Make sure your tests are specific and selective, he advised, adding test methods are going to be an important issue going forward, as will maintaining and using high-quality reference standards.
Inspectors appear keenly in-tune to testing issues. They told a pharmaceutical company the lab and test methodologies used in its dietary supplement operation do not appear to be appropriate for their intended use. The specific problem, as noted, was the method used produced negative trends that report equipment drifts, OOS CV standards and/or invalid results that required re-test on several mineral lots, but this test method continues to be used and has not been replaced with a more reliable method.
The focus on methods might even seem microscopic, as the same manufacturer was cited for failing to use an appropriate method to test the seal over its plastic bottles to ensure a uniform sealing process. According to inspectors, the current method involved pressing the seal with a finger while visually inspecting the seal. The problem was, in fact, there was no specification for how much pressure and time of press was needed to adequately test the seal, nor was there any requirement for a tool that could test the integrity of the seal.
The same manufacturer was using a certain monograph for its ginseng ingredient, but inspectors noted the monograph requires verification of the suppliers certificate of analysis (COA) that pesticide testing was conducted, yet no results for this testing were included, nor was contact information for the lab responsible for supplying this information.
Yet another company, a food, drug and cosmetic manufacturer which makes a major brand aloe-base digestive supplement, was told it failed to conduct at least one appropriate test to verify the identity or maintain documentation showing the tests that were performed were sufficient to ensure the identity of the aloe raw material.
Of all the manufacturing areas discussed in preparation for GMPtesting, records, training, diligent performance, etc.how the facility is designed might have slipped under the radar. GMP inspectors, however, are on top of this aspect, according to some design observations they made on 483 reports. One manufacturer was informed: The plant is not constructed in such a manner as to allow floors to be adequately cleaned and kept clean. Perhaps suggesting more of a maintenance issue than design, the specific observation was on a section of floor that had missing parts, thereby enabling standing water to get under the floor and escape regular cleaning efforts. The same company was also told a lack of appropriate design to enable, manufacturing systems to be maintained in an appropriate sanitary condition. It seems a spray deflector used behind a bottle rinser was made of cardboard rather than an appropriate material.
Overall, most of the observations in the 483 reports available appeared to be easily corrected problems, such as not following a documented process, failing to clean and sanitize certain areas, and failure to wear appropriate and sanitary clothing. Problems of a greater scale included lack of testing protocol, deficiencies in master batch/production/manufacturing records, and failure to safeguard raw materials and product from contamination.
The reports viewed ranged from three to 22 observations. For those companies with 20 or more employees, time is running out to address similar problems your company might have. For companies with fewer than 20 employees, the sooner they address these types of issues, the better their chances of having their first GMP inspection generate fewer 483 observations. The dietary supplement industry has offered numerous seminars, Webinars, conferences and workshops on how to interpret the GMP regulation and how to prepare for inspections. UNPA has held mock inspections; NPA has long offered its own GMP inspection program, and many other trade associations and laboratories have offered education and expertise, including access to former FDA officials and inspectors. With all this information and resources available, there ample opportunity to prepare for the inevitable inspection and take advantage of the observations of inspections already conducted.
The Quality Control section is sponsored by Ethical Naturals; however, the company does not review or approve editorial content.