FDA Warning Letter Lessons?
By Eric L. Foxman, R.PH., AAHP Secretary
Of all the Warning Letters issued by the FDA, very few go to homeopathic manufacturers or marketers. That’s good. On the other hand, the few that are addressed to members of our industry reveal a wide divide between what is required by 21 CFR parts 210 & 211, and what the Agency sees in the field and on the Internet. Others that are not addressed to our industry members should be simply ignored.
Wait! Not so fast! There are lots of opportunities for learning about FDA’s expectations and solutions by reviewing on-line warning letters.
During a six-week period early this Autumn, FDA issued 75 warning letters. Of these, 22 (30%) addressed issues of general importance to our industry members. Reviewing these tells us two things. First, an overview reveals what issues are of pressing concern to the Agency. A careful reading also uncovers details of how these issues should be satisfactorily addressed.
Of those 22 Warning Letters, the following issues are mentioned in multiple letters (numbers add up to more than 22 because individual Warning Letters often address multiple concerns):
- Microbial contamination or departure from aseptic processing/conditions (seven);
- New drug allegations/prescription-only claims on OTC labeling (seven);
- Quality unit not able to exercise independent authority (four);
- Problems with/lack of written SOPs (four);
- Other GMP failure (four);
- Marketing of products promoted for CoVid-19 treatment (thirteen).
CoVid, sterility, promotion of products for serious illnesses—These all issues one would expect FDA to be looking for and to jump on. That’s no surprise. The wonder (or disappointment) is that these are still happening at all. (A significant side note is that of those 22 Warning Letters, three were issued to homeopathic companies, which is a far greater percentage than usual.)
Reading the individual Warning Letters provides a classroom text of expectations to be met. The following are just some examples of those expectations taken from the 22 Warning Letters (emphasis added):
- A detailed summary of validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures.
- Describe program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
- Include process performance protocols, and written procedures for qualification of equipment and facilities.
- Cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation.
- Describe the steps that must be taken in change management system before introduction of new manufacturing equipment or a new product.
- A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
- In your response, you stated you initiated a stability program. Your response cannot be fully evaluated because you did not include accelerated studies to support the tentative expiry dates or justification for the quality of the product that remains on the market….
- A comprehensive assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of stability program.
- Specifications for drug products and justification for the ranges for each specification including the upper and lower levels, where applicable.
- Conducting at least one specific identity test on each incoming lot of components. (Under 21 CFR 211.84(d)(2), one may not rely on suppliers’ COA to verify the identity of components.)
- A comprehensive review of materials system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
- A comprehensive assessment to ensure quality unit (QU) is given authority and resources to effectively function. The assessment should also include, but not be limited to: A determination of whether procedures used by the firm are robust and appropriate.
- Provisions for QU oversight throughout all operations to evaluate adherence to appropriate practices. (See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211.)
If your company reads through the recent Warning Letters and ensures that it already has in place — or takes the time to put in place — the actions identified in them, your company will have taken a very large step forward in compliance. And your company will save tremendous amounts of resources (employee hours, cash, lost sales, and angst) by addressing these now rather than in the 15-day window permitted by any Warning Letter your company might receive for these or similar violations.
If you don’t already receive email alerts when FDA posts Warning Letters, you can SUBSCRIBE (for free) at the bottom of this page. When I receive an alert, I always check the “subject” column and ignore those for foods, animal drugs, and smoking cessation related warning letters; this significantly reduces how many I feel compelled to review. It takes about 30 minutes (or less) every two to three weeks. That is a small investment to be prepared.