FDA Warnings: Mistakes to Avoid

june23_posts FDA

What Is Your Company Paying Attention To?
And what is the FDA paying attention to?

In a recent 30-day period, FDA sent 33 warning letters addressing all product categories under their jurisdiction. Forty-five per cent were for drug products; of those, 12 of 15 were for cGMP violations.  While only one of the twelve involved a facility that contract manufactures homeopathic products, every company in our industry can learn what the agency is focusing on; FDA is certainly learning what to look for!  The list is not so very long.

A major focus now is microbial contamination due to unsanitary conditions. Some of the Agency’s observations involve circumstances so familiar that one ends up overlooking them – until too late: peeling paint; a plastic bag on a HEPA filter blocking adequate airflow; broken tiles at the base of a wall with product residue on them; improperly patched holes in walls; masking tape on the walls of manufacturing rooms.  When read about, they are obvious glaring problems, but when at the edge of one’s field of vision day after day, they become invisible.  More systemic problems are also observed: poor on-going maintenance of the manufacturing environment and inadequate environmental monitoring.  An important take-away: all staff should be trained and expected to observe with critical eyes for problems as soon as they arise and not forestall remedial efforts for the sake of today’s production schedule.  It may very well be today that the inspector arrives.

Other observations are noted in multiple warning letters; it seems like companies might not know what is required or might be cutting expenses.  Yet the remediation efforts, the lost sales, the expenses of a recall, and the blow to a company’s reputation far outweigh any short-term savings. The following five areas the where agency has been focusing inspection efforts, and each company should proactively ensure these will stand up to regulatory review: the Quality Unit failed to ensure that manufacturing operations complied with CGMP; the firm performed insufficient reviews and control over data integrity; the Quality Unit failed to confirm deviations in testing methods were investigated and resolved; the firm lacked proper oversight of manufacturing operations and adequate procedures for production and process control; the Quality Unit failed to ensure adequate document control. Knowing FDA will be looking for these lapses means every company is already in a position to address these issues long before the agency does in an inspection. There is no excuse for such warning letter observations.

Some in the homeopathic industry flatly state that identification of incoming active ingredients is not possible for homeopathic materials. This is certainly not true for every incoming component at every facility in the supply chain.  There is no reason why homeopathic companies should be part of an observed increasing trend of a) reliance on suppliers’ certificates of analysis (COA) without proper verification or qualification of those very suppliers, and b) inadequate validation of manufacturing processes whether in one’s facility or in that of a contract manufacturer. In more than one of the 12 Warning Letters noted above, the agency clearly spells out:

“FDA regards contractors as extensions of the manufacturer…. You are responsible for the quality of your drugs regardless of agreements in place with your contract facility. You are required to ensure that the drugs you distribute are not adulterated. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/media/86193/download.”

It is unacceptable to attempt to shunt blame to a manufacturing partner.  Every company is responsible for its actions and for those performed on its behalf.  Anything less is an abdication of ones duty to the company’s customers.

FDA has posted their concern regarding an observed and disturbing increase in fabricated and unreliable laboratory data. While the posted document is focused on data used for medical device applications, the observations also show up in more than one recent drug product warning letter. During one inspection, differing and conflicting answers were provided regarding documentation of results in accord with the company’s own SOPs. Upon deeper investigation, personnel acknowledged depending on their memory for later reporting of lab test results.

 The warning letter emphasizes the necessity to contemporaneously document laboratory results rather than the observed practice in which staff did not document test results, but instead excused their actions by "I haven't written it yet" and "It's in my head."  One outside review of that circumstance concludes:

“While the Warning Letter appears relatively restrained, it contrasts sharply with the related Form 483 inspection report, which strongly implied systemic dishonesty among the company's staff and a waste of investigators' time.” [RA/QA News Roll: Late February 2024; email sent 29 February 2024 from The FDA Group]

Personnel must be expected and trained to take responsibility for contemporaneously recording all relevant and required information.  Facilities must be provided with adequate and appropriate materials/equipment and space for accurate and timely documentation of laboratory and processing results.  FDA has posted their concerns, thus each company can proactively address potential shortcomings.

Perhaps the most challenging cGMP requirement is process validation.  How, one might ask, does one validate the attenuation process? As each company has a different process, a single answer is not possible.  But each company must recognize this is a question to be both asked and answered.  One warning letter to a homeopathic company plainly states:

“You have not validated your manufacturing process used to produce homeopathic drug products…. During the inspection, you indicated that you were not aware of the requirement.”

The agency goes on to instruct:

“In your response, you commit to performing process validation…. Your response is inadequate because you must assure that your production process is capable of assuring all of your drugs are of acceptable quality, identity, strength, and purity. During process validation, the process design should be evaluated to determine if it is capable of reproducible commercial manufacturing…. In addition, your response did not consider a retrospective assessment of potential impact to product quality. Without adequate process validation, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.”

The HPCUS has posted a series of draft White Papers on perceived technical gaps in cGMPS. One of the White Papers addresses process validation for Hahnemannian Liquid Attenuations. Review of this draft White Paper can stimulate an intra-company discussion on ways in which such process validation can be achieved in a meaningful and effective manner.  The public comment period for the posted White Papers ends April 22, 2024, after which comments will be reviewed and the drafts updated as appropriate, before taking them the next step.

What should your company be paying attention to? Part of the answer is paying attention to what FDA is paying attention to.