Editor’s note:This is the first in a two-part series examining violations of cGMPs (current good manufacturing practices) in fiscal year 2017 (FY17) based on data INSIDER obtained through a Freedom of Information Act (FOIA) request. The second article will look at the FY17 data from the perspective of industry stakeholders and others outside FDA.
Dietary supplement companies cited last year by FDA for cGMP violations are still coming up short meeting fundamental requirements, an FDA official said in an interview.
“Unfortunately, what we’re still seeing is that the most frequently reported observations during the inspections are deficiencies in some of the fundamental aspects of the cGMP compliance system," said Cara Welch, Ph.D., senior advisor to FDA’s Office of Dietary Supplement Programs (ODSP).
In FY17, nearly one quarter of inspections that received a Form 483 for cGMP violations or “observations" allegedly failed to establish product specifications for the identity, purity, strength and composition of the finished dietary supplement, INSIDER learned through a FOIA request. The aforementioned observation was the most common cGMP infraction in FY17.
“The citation is used when investigators observe either a complete lack of product specifications, or it can be used when they’re incomplete or inadequate," Welch explained in a phone interview. “Sometimes, we walk in and there are no specifications. Sometimes, there are some barebones specifications that are not sufficient to meet the requirements."
In discussing cGMP violations fundamental to the 10-year-old regulations, Welch referenced failure to establish and meet product specifications, failure to establish and follow written procedures for quality control (QC) operations, and deficiencies related to batch production records and master manufacturing records.
“These requirements," she said, “are really critical to ensuring that the product leaving a particular facility has been consistently manufactured in a quality manner."
More than 60 inspections resulted in an observation for failing to establish and follow written procedures for the requirements to review and investigate a product complaint, reflecting the third most common cGMP violation for the fiscal year that ended on Sept. 30, 2017.
The cGMP data provides a snapshot of compliance with regulations adopted in 2007 to ensure dietary supplements are manufactured based on quality standards.
Although the data reflects information queried from FDA’s inspection observation database, it includes certain limitations. Some 483s are manually prepared and not entered into FDA’s inspection observation database. The results also may not reflect all final 483s issued to a firm following an inspection.
Top five cGMP observations in FY17
1. 21 C.F.R. 111.70(e) (89 inspections) (23.48% of inspections with Form 483)
- You (firm) did not establish product specifications for identity, purity, strength and composition of finished dietary supplement.
2. 21 C.F.R. 111.103 (70 inspections) (18.47%)
- You did not establish and/or follow written procedures for quality control operations.
3. 21 C.F.R. 111.553 (63 inspections) (16.62%)
- You did not establish and/or follow written procedures for the requirements to review and investigate a product complaint.
4. 21 C.F.R. 111.75(c) (60 inspections) (15.83%)
- You did not verify the finished batch of dietary supplement meets product specifications for identity, purity, strength and composition and/or limits on contamination that may adulterate or lead to adulteration of the supplement.
5. 21 C.F.R. 111.205(a) (50 inspections) (13.19%)
- You did not prepare and/or follow a written master manufacturing record for each batch size of a dietary supplement that was manufactured.
Source: FDA based on FOIA request of FY17 cGMP inspections
For several years, dietary supplement firms inspected by FDA were frequently cited for failing to test their ingredients. The FY17 data shows some improvement in this area—45 firms were cited for failing to conduct an appropriate test or examination to verify the identity of a dietary ingredient prior to use, reflecting the eighth most common observation. (The same number of firms were cited for failing to establish and/or follow written procedures for holding and distributing operations.)
By comparison, INSIDER previously reported nearly one in five facilities that received a Form 483 in FY14 failed to verify the identity of a dietary ingredient prior to use through a test or examination. The latter observation was the most common infraction cited by FDA inspectors that year.
Welch said it was nonetheless frustrating that roughly 12% of firms that received a 483 in FY17 were cited for failing to confirm the identity of a dietary ingredient prior to use.
“It’s a big, complicated rule," Michael McGuffin, president of the American Herbal Products Association (AHPA), said, commenting on the cGMPs incorporated in 21 C.F.R. 111. “It’s not perfectly clear. It’s not the best use of English language anybody ever crafted, and companies have 100 percent responsibility to comply with it.
“It sounds like there’s some improvement," McGuffin continued. “And it sounds like there’s still plenty of work to do."
FDA enforcement strategy
Asked whether FDA is moving aggressively in its post-inspection enforcement against firms cited for fundamental cGMP violations, Welch responded, “I think enforcement will continue to be a big component of our work. That said, enforcement is resource-intensive, and enforcement alone is not a realistic path to industry-wide compliance."
She said FDA is exploring ways to improve the educational resources available to firms regarding cGMP compliance.
“We recognize that many firms have made—and continue to make—the necessary investments in cGMP compliance, and we have a commitment to working with firms that after an FDA inspection demonstrate a commitment to coming into compliance," Welch said.
However, she pointed out FDA will continue to take actions to remove products from the market tied to firms that show an inability or unwillingness to comply with the regulations. Products that haven’t been made according to cGMPs, Welch reminded the dietary supplement industry, are “adulterated."
FY17 cGMP inspections: 656
Inspections Receiving Form 483: 379
Total number of observations: 1,949
Average number of observations per Form 483: 5.14 (calculated using inspections issued a Form 483)
Source: FDA based on FOIA request of FY17 cGMP inspections