FDA is disappointed with continuing violations of “basic” manufacturing requirements applicable to the dietary supplement industry.
In fiscal year 2019 (FY19), dietary supplement manufacturing facilities issued an inspection report—or so-called Form 483—for violations of cGMPs (current Good Manufacturing Practices) were most commonly cited for failing to establish specifications for finished dietary supplements, according to FDA data.
Other top violations or “observations” related to failure to establish written procedures for quality control operations, and batch production records that did not include complete information, Natural Products INSIDER learned through a Freedom of Information Act (FOIA) request to FDA.
“It’s disappointing that we’re still talking about such frequent noncompliance with these basic cGMP requirements,” Lindsay Haake, an FDA spokesperson, said in an email.
The top observation suggests “a firm has failed to properly document the nature of the product it is intending to produce,” Haake said. “It’s extremely important that manufacturers have clear expectations of what the product should be at the end stage.”
FDA, she added, expects manufacturers to have considered “the levels of each ingredient and documented reasonable ranges of these ingredients as acceptance criteria;” and documented “the appropriate methodology to then verify the specification because, of course, the expected results don’t mean much if you can’t test the product to verify the specification has been met.”
That a little over half of dietary supplement firms inspected in FY19 received an inspection report for alleged violations of cGMPs suggests “the industry still has a lot of work to do to improve compliance” with the 12-year-old regulations and 25-year-old Dietary Supplement Health and Education Act of 1994 (DSHEA), said Tara Couch, Ph.D., senior director of dietary supplement and tobacco services for EAS Consulting Group LLC, in an email.
“An effective cGMP system builds quality into a product,” Haake said, “so that consumers can be confident that the products they purchase contain what it on the label.”
Based on interviews with industry experts and FDA data obtained by INSIDER through numerous FOIA requests, the most common violations have largely remained the same over the past several years, including failure to establish product specifications.
“That’s not a trivial concern,” said Peter Lurie, M.D., president of the nonprofit advocacy group Center for Science in the Public Interest (CSPI), commenting in an interview on the requirement to establish product specifications. “If you don’t have proper specifications, you don’t have proper assurance that you’re making the product appropriately.”
“Sadly for the industry, it has been the same since 2009 when the FDA started tracking the top citations for the supplement space,” said Larisa Pavlick, vice president of global regulatory and compliance with the United Natural Products Alliance (UNPA).
“Obviously, there’s some communication failure there,” she added later in an interview.
But Pavlick—a former FDA investigator who inspected dietary supplement manufacturing facilities—isn’t necessarily surprised. She said a compliance program guide used by FDA inspectors focuses on six major areas, including product specifications.
Pavlick identified a gap between what industry understands specifications to be and what FDA intended as reflected in preamble to the cGMP regulations incorporated in 21 C.F.R. Part 111.
Product specifications being used by firms may include such components as chemistry, particle size and physical characteristics, Pavlick noted. “But FDA only cares about five elements, which is identity, purity, strength, composition and limits for potential contaminants. Anything else on the specification sheet, the FDA investigator isn’t going to care or worry so much about.”
In FY19, 12% of firms issued a 483 were cited for failing to conduct an appropriate test or exam to confirm the identity of a dietary ingredient prior to its use. That compares to 16% of 483s in FY18 and 12% in FY17, according to FDA data obtained by INSIDER. Haake also pointed out 12% of 483s in FY19 included an observation of failing to establish identity specifications for components.
“These requirements are tied together because if a manufacturer does not have an identity specification, it’s not possible to then verify the identity of an ingredient before it is used,” the FDA spokeswoman explained.
Haake expressed concerns about the second-most common observation: failing to establish/follow written procedures for quality control operations.
“Quality control is integral to a cGMP system and incorporates steps from the initial design of a product, through its production, and includes the requirement to document when a product can and cannot be released, as well as the review of complaints about the product and an assessment of how they might relate to manufacturing,” she said.
FY19 cGMP data
Number of inspections: 598
Number of inspections issued Form 483: 305
Number of inspections not issued 483: 293
Average number of observations per 483: 4.99
Most common observation: You did not establish product specifications for the [identity] [purity] [strength] [composition] of the finished dietary supplement (77 inspections, or 25% of 483s).
Second-most common observation: You did not [establish] [follow] written procedures for quality control operations (66 inspections, or 22% of 483s).
Third-most common observation: Your batch production record did not include complete information relating to the production and control of each batch (46 inspections, or 15% of 483s).
Source: FDA via Freedom of Information Act request
Merle Zimmermann, Ph.D., is chief information analyst of the American Herbal Products Association (AHPA). After studying the FOIA data and separate FDA data he obtained, Zimmermann said he noticed an increase in violations related to requirements to establish master manufacturing and batch production records.
Annual FDA cGMP data requested by separate entities may yield different results depending on the nature of the request, when it was made and other factors. Responding to INSIDER’s FOIA request, FDA cautioned the results reflects data queried from a database. Some 483s are manually prepared and not entered into the database.
According to Zimmermann, the most common infractions relate to requirements to establish specifications and determine whether they have been met.
“These [requirements] are all related to tracking and recording how the process and facility work and are independent of those sections which identify problems which directly affect the consumer,” he said in an email.
About half of firms inspected in FY19 did not receive a 483 for alleged cGMP violations. In FY18 and FY17, 46% and 42% of firms did not receive a 483, respectively, according to FDA data obtained by INSIDER.
Daniel Fabricant, Ph.D., president and CEO of the Natural Products Association (NPA), said the relationship between industry and FDA investigators may have improved—negating the need to leave paper documentation in cases in which the agency has “a few knits to pick.”
“Clearly, people [at FDA] are thinking some of this stuff is not worth writing down to some degree in terms of the observations,” said Fabricant, who previously led the Division (now “Office”) of Dietary Supplement Programs, in an interview.
Asked about firms that didn’t receive a 483, Haake said FDA inspections reflect “a snapshot in time of a firm’s compliance with the regulatory requirements.”
“We know that there are many firms in this industry that take compliance seriously, and we want to see this become the norm for dietary supplement cGMP inspections,” she said.