Audit Checklist

GMP Update: Total Compliance

Now that this last deadline, which was for the smallest companies per number of employees, has passed, are manufacturers ready to prove compliance?

Requiring supplement manufacturers to have proper controls in place to ensure dietary supplements are processed and handled in a consistent manner and meet high-quality standards is not too much to ask. This is the definition of good manufacturing practices (GMPs) for dietary supplements, which, thankfully, FDA put forth in its long-awaited release of these requirements. While called for by DHSEA in 1994, the GMPs took a while to come to fruition under FDAs creation, and a three-stage staggered compliance schedule meant all companies subject to the rule were not necessarily required to comply until June 2010. Now that this last deadline, which was for the smallest companies per number of employees, has passed, the big questions remaining include: Are manufacturers ready to prove compliance? And, is FDA going to inspect and enforce the GMP regulation to help improve the quality of the industry and force out rogue companies not interested in long-term commitments to quality and integrity?

Since these arent easily answered questions, it can be helpful to look at all the work, resources and effort put into the race to prepare for the compliance deadline. From the announcement of the GMPs in  June 2007, the industry has bound together to organize seminars and workshops; consultants with FDA GMP experience in other areas offered advice and a third-party partnership toward compliance; and industry media continued to find ways to inform and educate manufacturers and others facing some level of GMP scrutiny.

The GMP regulation (21 CFR Part 111) actually covers more than just manufacturing; it also mandates minimum requirements for packaging, holding and labeling supplements. Its provisions cover the physical plant design (safety, functionality, etc.), cleaning methods and frequency, testing of incoming and outgoing products, quality control (QC) and manufacturing procedures, complaint handling and how it is all recorded and documented. In fact, recordkeeping is a large part of GMPs.

As the 483 reports from FDAs early inspections of companies in the initial stage of compliance (i.e. large companies) showed, documentation was a point of deficiency and worry for companies trying to reach compliance. Standard operating procedures (SOPs), master batch records and corrective action plans were among the documentation giving companies GMP challenges. The related problem was companies having such records, but not following them consistently.

The issue of testing is also a troublesome point, as Daniel Fabricant, vice president of scientific and regulatory affairs at the Natural Products Association (NPA), noted tests must be specific and selected. He also highlighted the ongoing importance of test methods, as early FDA reports indicated selecting the right method was important not just for a specific incoming ingredient or outgoing formula, but also for ensuring bottles or packages are properly sealed.

Joy Josephs, founder of Joys Quality Systems, reported the main trouble spots are raw material and finish product testing. Most companies are having interpretation problems with reduced testing by sub-set testing based upon statistical sampling plans of batches, she said, noting others are unclear on vendor qualification for raw materials. Most are running identity test only without the pre-requisite of vendor verification of Certificates of Analyses. Also qualified laboratory personnel are hard to come by.

The reports from the field add to the education for the rest of the industry yet to face an FDA GMP inspection. As Casey Coy, NSF International, noted one of the key areas that give dietary supplement companies difficulty is in the interpretation of the regulation, along with defining the criteria needed for their specific operations to be considered compliant. The path to compliance is paved with knowledge, and this has not been a road built overnight.

The journey to bring industry manufacturers on board with GMPs began before FDA coughed up its final rule on supplement GMPs. NPA established its own GMP standards for dietary supplements in 1999 and has updated them over the year. In a move to stay relevant, NPA recently updated its GMP certification program to at least cover the requirement of 24 CFR 11, while leaving in place prior NPA GMP standards that were higher than FDAs GMPs. Fabricant noted some areas where NPAs GMPs were higher included requirements for expiration dating, stability testing and dedicated QC personnel.

In the NPAs program, companies strive for an A rating, which allows the use of the NPAs GMP certification mark. Achieving this top rating requires completion of several steps: NPA member companies registered for the GMP certification program must have key QC people attend a GMP training seminar conducted by NPA. Based on this seminar and the NPA self-assessment questionnaire, the companies must conduct an internal self-assessment of its current operations compliance with NPA GMP standards. A gap analysis will identify areas of non-compliance, and a corrective/preventive action plan should be devised to address deficienciesNPA offers resource materials to its GMP program participants to help them achieve compliance. Hiring an industry consultant is another option.

Mind the Gap

Quality expert Amy Caplette, Nutrilite, advised companies to read the GMP preamble, which provides insight into the regulations, then read section by section and compare the regulation against your companys practices.   This will identify gaps and identify areas for continuous improvement, she assured.

 

When ready, the company contacts an authorized third-party auditor to conduct the GMP audit. Much like an FDA GMP inspection, the NPA-approved auditor will inspect all areas of the facilities that are involved with the manufacturing, packaging, labeling, testing, warehousing and/or distributing of dietary supplements. Cleanliness, adherence to procedures and the movement of materials through the facility are focal points, and a substantial part of the audit will involve review of GMP-related documentation. Just as with an FDA inspection, the member supplier must have a qualified representative available to answer the auditor's questions during this facilities inspection.

Corrective actions to address deficiencies found in the audit will help lead to the prized A rating. NPA reviews the new A rating and supporting audit before sending a certification letter to the company. This is not the end, however, as certified companies are required to not only maintain the GMP standards and NPA membership, but also must be re-audited every two years.

Supplement manufacturers and others facing GMP compliance have also turned to the private firm NSF International, which offers a GMP registration process. Under this program, manufacturers can become independently registered by NSF as complying with GMP requirements. NSF relies on Section 8 of NSF/ANSI Standard 173-2008, which covers operation processes, procedures and documentation involved in the identity, strength, composition, quality and purity of a product.

NSFs DBA Analytical developed the official SupplySide East GMP training program, which featured two courses. Documentation Management for GMP Compliance was a full-day training course covering SOP creation and implementation, batch production records (BPR) and master manufacturing records (MMRs). FDA GMP Inspection Readiness outlined the FDA inspection process, including critical considerations and steps to consider pre-audit, managing the process and any issues during inspection, and follow-up actions that could decide the post-audit future of the company. These interactive events were good opportunities for company leaders to get hands-on experience at tackling some of the documentation and personnel challenges GMPs present.

Companies are still seeking certifications by third-party programs, Joseph said. They believe FDA will consider them serious about compliance and be less aggressive with certified compliant companies. Also in high demand, she noted, are numerous experienced industry consultants, which often have FDAs ear and have stockpiled years of experience in both GMPs and FDA actions. In addition to her regular consulting duties, Joseph has offered GMP informational seminars at industry events such as SupplySide trade shows.

Under the banner of consulting firm EAS Consulting, Carl Reynolds presented industry seminars at SupplySide and other events, detailing the key parts of the FDA GMP regulation manufacturers need to pay special attention to. His practical approach gets right to the point and hammers it home with emphatic mantras, such as records, records, records and documentation, documentation, documentation. Reynolds has rejoined FDAs Center for Food Safety and Nutrition (CFSAN), but still offers his time to the industry at trade shows and educational events to keep companies updated on what FDA expects in audits.

Given all these resources, how have companies been faring in pursuit of GMP readiness? Based on the early 483 reports, many companies had some concrete areas they knew needed more attention to move closer to compliance. This was no big surprise because, as Fabricant pointed out, the first few years of FDA auditing is expected to be a learning experience and reconnaissance for both FDA and industry. Still, there werent many huge names among those available 483 reports, so it is hard to say if cleanliness will be a key deficiency industry wide as it was for one supplement manufacturer, or if following documentation will prove as challenging as it did for another manufacturer.

Over the past couple of years, the FDA has provided additional training and guidance to the FDA auditors, which increased their knowledge and expectations of compliance of supplement manufacturers, said Amy Caplette, group leader of Nutrilites quality assurance department. 

The most telling information could be the focused effort and willingness to continuously assess and reassess QC and GMP elements that some companies have undertaken. Coy confirmed companies serious about achieving GMP compliance have invested in additional personnel to set-up and maintain compliant quality systems, and some may also be utilizing a third-party certification program to assist with the compliance and maintenance of their quality systems.  These companies have taken an important step in risk management, and although the upfront costs for GMP implementation and compliance may be higher than what was previously being performed, the costs of manufacturing an adulterated product and undergoing a recall would be much more costly, she said. While some companies were indeed desperate and serious about becoming compliant, Coy noted others initially balked at the financial commitment necessary for compliance; some of which then realized its importance and see it as a solid investment in the security of their company as a whole. Meanwhile, some continue to ignore the GMPs altogether, she said, but as FDA continues to educate itself on supplement manufacturing, inspect facilities and enforce the regulation, those companies that have chosen to ignore compliance requirements will likely be forced out of the industry through regulatory force or self-policing of the industry.

Still, despite all the right intentions and efforts, there are some companies that have and will struggle to bring their firms into GMP compliance. Smaller companies have difficulties due to lack of resources, including personnel, of which the regulation clearly requires separation of the quality unit from the production personnel, Coy explained, adding larger companies can have less flexibility than small- to mid-sized companies, thereby often creating difficulties in implementing the regulations organization wide.  Mid- to large-sized dietary supplement companies that have been involved in the pharmaceutical and OTC space have not been as impacted by the regulations due to the fact that they have already had to comply with pharma GMPs.

Fabricant said NPA has recognized small companies have and may continue to struggle economically with the personnel and tasks needed to run a GMP-compliant manufacturing operation in this new supplement world. He highlighted recent consolidations in the supplement market, and suggested this trend would continue, as companies look for ways to keep their brands and products alive in the face of limited resources. We will continue to see this trend over time, he speculated. It makes sense to be bigger.

Joseph reported most of her cold calls now are coming from small companiesless than 20 employees; some less than 10 employeeswho have decided to hang in there and try to become compliant. They are no longer complaining about the cost of cGMPs, she said Most are lacking in onsite testing capabilities, but are willing to use third-party labs.

According to Caplette, smaller companies may specifically struggle with subpart E of the regulation: Requirement to Establish a Production and Process Control System. Smaller manufactures need to establish activities to ensure the identity, purity, quality, strength, and composition of components, ingredients, and the dietary supplement, she explained. For some manufacturers that did not conduct appropriate testing in the past, this requirement may be financially difficult especially if they do not have an in house laboratory.  In addition, manufacturers must provide adequate documentation of how the company determined the appropriate sampling and testing to ensure that the finished batch meets all the product specifications. She further stated smaller manufacturers that rely on certificate of analysis records will need to develop and maintain documentation for a supplier qualification program.

GMPs are clearly having some effect on the industry, as companies have undergone inspections and corrective actions, and third-party certifications have been running in high gear, in addition to the reported consolidation for improved financial ability to manufacture in the GMP environment. I absolutely am finding that the desired effect is being realized, Joseph quipped. Management is becoming aware of their individual vulnerability and is supporting GMP implementation.

There is an expectation the dividing line will further sharpen between manufacturers investing heavily in GMP preparations and those who slip by the regulations due to a lax FDA.

Supplement GMPs bring another level of control over the manufacturing process that ensure products are made consistently, meets quality standards, appropriate labeling, and is safe for consumers, Caplette said. This helps the industry weed out non compliant manufacturers and while keeping innovative and quality manufacturers.

However, much is still to come in this GMP saga. It is going to get a lot tougher, Fabricant warned. We are kidding ourselves if we dont realize there is more to do in the coming years.

Joseph also issued caution, saying many companies are still not ready. A high level of implementation has been completed among the first two tiers, however there are still gaps, particularly related to interpretation, she noted. Unfortunately the last tier is just getting started, many of whom did not know they were subject to the final rule or had decided to opt out of the industry before their compliance date became effective.

Due to the nature of the dietary supplement industry, and the fact that there are still many vague areas in the GMP regulation, several industry guidelines are being developed to help provide some clarity to how the GMPs should be interpreted and implemented for a dietary supplement companys specific operation, Coy offered. Responsible companies have always striven to meet these quality standards, but as industry guidelines are developed, there may need to be modifications in how these standards are met.

Thus, the word is still out on what specific long-term effects GMP will have; but the stage has been set, and the players are all warming up for their spotlights.        

 

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