Infractions continue to hamper the GMP process, especially as it relates to contract manufacturing.
In the dietary supplement industry, good manufacturing practices (GMPs) are the lynchpin principles responsible for conveying confidence and trust at all points along the supply chain. The industry at large has made great strides toward complete GMP compliance, yet there are still some infractions that continue to hamper that process, especially as it relates to contract manufacturing.
“A review of FDA cGMP inspection records reveal that contract manufacturers are generally in compliance with the broad intent of cGMP requirements that are designed to ensure what is in the product is on the label,” says Merle Zimmerman, chief information analyst, American Herbal Products Association (Silver Spring, MD). “When contract manufacturers are not in full compliance, FDA inspection records usually document minor, technical details that are relatively easy to address rather than more serious compliance issues.”
Minor recordkeeping infractions, such as missing signatures, are the most common issues identified by inspectors. “This suggests that contract manufacturers have generally adopted policies, procedures, and practices needed to be cGMP compliant, and some are fine-tuning their practices to eliminate these minor, technical issues,” he says. “To ensure compliance, contract manufacturers should focus on their recordkeeping policies and procedures and train employees to ensure every T is crossed and every I is dotted.”
Lisa Thomas, general manager of dietary supplement programs for NSF International (Ann Arbor, MI), says there is increased industry interest in moving toward GMP compliance and summed up the overall state of affairs across the industry in one word: improving. “The number of compliant facilities in the NSF GMP program has significantly increased since January 2010, from 169 to now over 300 NSF GMP-compliant facilities listed today,” she says. “Additionally, there are over 100 other facilities in the initial stages of the NSF GMP program. Many are working to improve their quality processes and correct non-conformances found during the first three-day NSF GMP audit at their facility.”
There continues to be plenty of room for improvement, though. “NSF collected data from all initial audits-these are first-time audits of facilities not yet registered under the NSF GMP program-from November 2012 to the present and found that 66% of all facilities were not compliant with NSF GMP requirements,” she says. “Furthermore, many of these companies were not able to correct non-conformances and bring these facilities into compliance with 45 days after the initial audit.
“This tells us that although companies are interested in getting their facilities GMP compliant, they may not be able to do so in a timely manner because of resource constraints, a lack of training and expertise, or, in some cases, little or no commitment from senior management.”
As of July, FDA had issued 13 warning letters in 2014, citing a variety of infractions ranging from aforementioned recordkeeping details to lack of ingredient and finished-product testing, improper testing methods, and insufficient batch and master manufacturing records.
“Manufacturers have been quicker to comply than the private-label distributors, many of which still are failing to realize their obligations to ensure that products are being manufactured pursuant to cGMPs,” says Justin Prochnow, shareholder, Greenberg Traurig LLP (Denver, CO). “The FDA’s position with respect to private-label distributors that contract out manufacturing is outlined in detail in a number of warning letters issued this year.”
For instance, in one warning letter, FDA stipulated that distributors who contract with other manufacturers to manufacture, package, or label dietary supplements have an overarching and ultimate obligation to ensure that all phases of production are in compliance with dietary supplement GMP requirements. In short, a company that outsources dietary supplement manufacturing, packaging, and labeling is still responsible for the product’s overall GMP compliance.
Overall, Thomas says GMP facility registration is growing as companies seek better suppliers with lower risk due to a raised commitment to quality. “Facilities outside the United States are also looking to comply with U.S. regulations to facilitate importation and separate themselves from competitors,” she said. “Ingredient suppliers in Asia are slowly adapting to third-party GMP registration as well, driven mostly by buyers that understand the important role third-party GMP facility registration plays in helping ensure continued quality and safety throughout the supply chain.”
NSF continues to observe one aspect of the process that would benefit from greater expeditiousness: the average 40-day response time to correct non-conformances. “Considering the turnaround time demand placed upon facilities dealing with FDA warning letters, this particular observation was alarming,” Thomas says. “If an FDA audit identifies non-conformances in any facility, a 40-day turnaround time for corrections just isn’t going to cut it.”
Steve Holtby, president and CEO, Soft Gel Technologies Inc. (Commerce, CA), says contract manufacturers face unique challenges when it comes to both growing their business and keeping pace with regulatory issues. He advocates formal training programs to ensure personnel have a thorough working knowledge of GMPs and SOPs, he says.
And although it can be an arduous task, recordkeeping and documentation continue to be critical to safeguard GMP compliance and continued certification. “Dealing with the qualification of raw ingredients and their suppliers is difficult, because raw-ingredient suppliers are not held to the same regulations as the dietary supplement manufacturers,” Holtby says. “For example, it’s common for distributors of raw ingredients to not perform all the necessary testing needed. In this case, we would perform-or arrange-the testing ourselves.”
Testing on a whole has become more comprehensive and time-consuming, not just because of GMPs but also for other reasons, such as evolving requirements under Proposition 65. “A lot of companies are struggling to comply with the heightened requirements of the FDA GMPs, which take a lot of resources-both time and money,” Holtby says. “A well-rounded contract manufacturer may be able to offer some services and knowledge as part of its customer-service package, thereby freeing companies from having to outsource or hire internally.”
Spiked ingredients and testing continue to be additional areas of concern. Tim Bray, vice president, Pharmachem Laboratories Inc. (Kearny, NJ), says that the increasingly overseas origin of raw materials has necessitated that the industry undertake the responsibility (and the cost) for double-checking assay results. “Previously, from proven suppliers over many years, the industry had taken results supplied by the manufacturers’ certificates of analyses,” he says. “Now there is a double-check in place to ensure that quality.”
There are two critical parts to testing: inbound raw-materials testing and outbound finished-goods testing. “Different laboratories use different test methods, especially with botanicals, and currently not all test methods being used are accurate or appropriate,” says Robin Koon, executive vice president, Best Formulations (City of Industry, CA).
Michael Schaeffer, president, Pacific Nutritional Inc. (Vancouver, WA), says allowing adequate time for test method development has been a struggle; however, he’s witnessed greater client flexibility as it relates to testing. “Clients [have been] willing to make label or formulation changes to reduce the analytical costs and…discontinue products that are not as successful as other products in their offerings,” he says.
While the industry has made many positive strides, the playing field still isn’t level, according to Schaeffer. “There are still differences in interpreting the GMP requirements in the industry,” he says. “Our industry should develop standards for the parts of the GMP regulations that are not defined-particularly, in the area of specifications.”
Moving forward, contract manufacturers should continue to advocate for and educate companies about the benefits of making the corrections necessary for compliance. “For industry, the messaging of GMP compliance needs to continue, and companies need to work with legislators and regulators to ensure legitimate products are available for consumers,” Schaeffer says.
Top 10 GMP Infractions Leading to an FDA Warning Letter
Tips for Improving GMP Compliance in a Contract Manufacturing Relationship
Photo © iStockphoto.com/06photo