FDA Posts its First Dietary Supplement GMP Warning Letter

By Ricardo Carvajal & Wes Siegner –

FDA recently posted what appears to be the first warning letter to a firm for violations of the dietary supplement good manufacturing practice ("GMP") regulations in 21 CFR Part 111.  The warning letter marks a point of transition for the agency and industry, from developing and issuing the regulations, to enforcing them.  It is in the context of enforcement that FDA’s interpretation of undefined terms such as “appropriate” (as in “appropriate test or examination”) and “representative” (as in “representative samples”) will be elucidated. The warning letter is also a timely reminder that failure to comply with any required step, including even the signing of a required document, causes the products at issue to be adulterated and therefore unlawfully marketed.  Because the Federal Food, Drug, and Cosmetic Act ("FDC Act") is a strict liability criminal statute, such violations are also misdemeanor criminal violations.  Although the federal government has seldom brought such actions in recent decades, there are signs that the agency may be considering bringing such cases again against senior management to emphasize the need to comply with FDC Act requirements.

The letter is required reading for industry, as it provides insight into the types of issues on which FDA inspectors can be expected to focus, as well as the types of corrective actions that FDA expects.  Among the violations cited in the letter: 

• Failure to “conduct at least one appropriate test or examination to verify the identity of a dietary ingredient.”  FDA judged the appearance and other testing conducted by the firm for its aloe ingredient to be “not appropriate.”  Further, FDA demanded adequate identity testing not only of aloe used after the firm’s proposed correction date, but also of aloe used before that date.

• Failure to “make and keep documentation for why meeting in-process specifications, in combination with meeting component specifications, helps ensure that the dietary supplement meets the specifications for identity, purity, strength, and composition; and for limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement.”  The firm had no documentation explaining the rationale for its raw material specifications.  Although the firm claimed to be implementing a new product development SOP to address this issue, FDA did not credit that effort because the firm didn’t submit the SOP to FDA for its review.

• Failure to follow the firm’s written procedure for “collecting representative samples of each unique shipment of components.”  It appears that the firm used a sampling frequency that FDA found inadequate.  Although the firm revised its SOP to address this issue, FDA judged the firm’s response inadequate because it did not address staff training. 

• Failure to have an adequate quality control program, including (1) failure to “periodically review calibration records for production equipment,”  (2) failure of inclusion in the master manufacturing record of written instructions requiring one person to verify the addition of a component, and (3) failure to properly document release of finished product in the batch record.

• Failure to include in the master manufacturing record and batch production records a statement of the theoretical yield and percentage of theoretical yield, respectively, at “appropriate phases of processing.” 

• Failure to include in the master manufacturing record “corrective action plans to use when a specification is not met.”