In the past twelve months, the U.S. Food and Drug Administration (FDA) has issued more than 25 Warning Letter to manufacturers of finished pharmaceuticals and active pharmaceutical ingredients (APIs) for violations of the current good manufacturing practice (GMP) regulations. A detailed review of these Warning Letters provides a number of useful insights into where the FDA is currently focusing its limited GMP enforcement resources, and where the agency may start to place greater emphasis in the future.  

Some key takeaways from GMP Warning Letters over the past year include the following:  

  • The FDA issued the large majority of GMP Warning Letters (approximately 80%) to domestic facilities, notwithstanding the many concerns that have been raised in the past year about the increasingly global nature of pharmaceutical manufacturing  
  • The FDA issued a similarly large majority of GMP Warning Letters to finished product manufacturers – rather than API manufacturers – again highlighting the fact that the FDA is still primarily focused on final production instead of the global supply chain for pharmaceutical manufacturing  
  • Several GMP Warning Letters incorporated other compliance issues, including allegations of unapproved new drugs, misbranded drugs,1 promotional issues,2 and pharmacy compounding,3 which demonstrates that the FDA is taking a more holistic approach to enforcement when it identifies violative conduct  
  • The letters that we reviewed show that the FDA is taking a more systemic and risk-based approach to assessing GMP compliance and paying particularly close attention to such areas as the quality control unit, manufacturing process validation, and laboratory out of specification (OOS) test results and investigations4  
  • Virtually all GMP Warning Letters address the inadequacies of the company’s reaction to inspectional observations, which serves as an important reminder of the necessity for a company to submit a high quality response to the FDA that demonstrates the company’s commitment to implementing aggressive corrective action in response to the inspectional observations.  

By carefully assessing FDA’s GMP Warning Letters from the past year, we believe that pharmaceutical companies can enhance their quality systems and improve their manufacturing processes, and therefore more effectively manage future FDA establishment inspections.  

Background on FDA’s GMP Regulations  

Although the FDA finalized the GMP regulations for finished pharmaceuticals over 30 years ago, the agency requires the pharmaceutical industry to produce human drug products using current manufacturing standards, specifications, and technologies.5  

Rather than explicitly codifying its current GMP expectations into regulations, which would require frequent amendments to those rules, the FDA relies on a number of less formal communications to publicly disseminate its evolving expectations, including guidance documents and Warning Letters.6 Consequently, when trying to achieve sustainable manufacturing compliance, a company should routinely evaluate recent guidance documents and Warning Letters to understand the agency’s current thinking on GMP.  

Based on our review of the past year’s Warning Letters, we believe that the following areas of GMP compliance merit special attention by pharmaceutical manufacturers.  

Global Supply Chain and Vendor Qualification  

Notwithstanding the fact that in the past year FDA’s GMP enforcement was still primarily directed at U.S.-based manufacturers of finished pharmaceuticals, we believe that this trend will start changing in the near future and that the agency will dedicate a larger portion of its resources to international inspections.

In fact, the FDA has already announced that, as part of its “Beyond Our Borders” initiative, it will establish offices overseas in countries like China, where the agency believes that closer working relationships with its counterpart regulators will be beneficial.7  

However, recognizing that the FDA will have limited resources to devote to international inspections even with inspectors based overseas, we anticipate that the FDA will more carefully scrutinize how domestic manufacturers qualify their international suppliers. The following observation from a 2008 Warning Letter serves as an example:  

Your vendor qualification program should provide adequate evidence that the manufacturer can consistently provide reliable and safe materials. Suppliers should be monitored and regularly scrutinized to assure ongoing reliability. It is your responsibility to ensure that raw materials received are suitable and approved by the quality unit prior to use.8  

More recently, the FDA warned a Chinese API manufacturer and its subcontractor about the inadequate systems they had in place to ensure the safety of raw materials used in their manufacturing of heparin sodium.9 As a result of these GMP deficiencies, and broad concerns with the reliability of information generated at each facility, the FDA placed materials imported from each facility on import alert, thereby refusing those materials admission into the United States.10  

Bundling GMP Enforcement with Other Violations  

As noted above, the FDA appears to have become more aggressive in its use of GMP Warning Letters to notify drug companies about violative conduct in other areas of their business. In some cases, the FDA has alerted companies that some of their products lack the necessary FDA approvals. In others, the agency has raised concerns about a company’s promotional activities. In still other cases, the FDA has notified companies that they are violating FDA’s pharmacy compounding rules.  

We fully expect this trend to continue in the future. As the agency continues to face an increasingly large number of enforcement priorities with limited resources, we believe that this “bundling” approach to enforcement will become more common. In addition to the areas of enforcement listed above, we think it is extremely likely that the FDA will focus on pharmacovigilance systems and adverse event reporting during future GMP inspections. This is especially true in light of the agency’s heightened sensitivity to drug safety.

Quality Systems  

We identified references to deficient quality systems in virtually every GMP Warning Letter that we reviewed. The following quotations from recent Warning Letters illustrate FDA’s concern in this area:  

  • [The observed GMP deficiencies are] indicative of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality and purity of your manufactured product.11  
  • Please explain why your firm’s Quality Control Unit (QCU) did not detect and document these deficiencies during their batch production and control and what actions will be taken to assure these deficiencies do not extend to other batches of the same or other drug product.12  
  • Failure to conduct investigations in a timely manner and to extend the investigations to other drug products that may have been impacted by the same failure while investigations of confirmed cross-contamination (without a probable root cause identified) were ongoing demonstrate the failure of your QCU to provide adequate oversight and ensure procedures are followed.13  

These passages underscore the critical role that Quality Control Units play in pharmaceutical manufacturing and how closely the FDA monitors their performance.  

Effective Regulatory Management  

As noted above, virtually all GMP Warning Letters from the past year address the inadequacies of the company’s inspection response. While there are a variety of acceptable ways to respond to an inspection observation, we have seen many examples of inspection and Warning Letter responses that fail to adequately address FDA’s concerns.  

Given the potentially significant consequences of GMP noncompliance, we strongly encourage our clients to make every effort to ensure that their written responses demonstrate a commitment to manufacturing high quality drug products and to implementing aggressive corrective action as part of a robust pharmaceutical quality system.