Shifts in FDA Policy
Recent Enforcement Trends May Affect Medical Gas Manufacturers
By Bob Yeoman
April 2011
Regulations applicable to finished pharmaceuticals (21 CFR § 210 & 211) are a broad set of requirements relevant to the entire range of drugs manufactured and marketed in the US today. Every manufacturer—from producers of sunscreen products to those creating the latest cancer fighting drugs—are required by law to use these requirements as the basis of their US Food and Drug Administration’s (FDA) compliance programs, including medical gas producers. FDA is willing to carve out exemptions for some types of products, and over the years medical gases have been the beneficiary of some of these. However, formalized exemptions to 21 CFR are rare events. Most exemptions come in the form of what the agency terms “enforcement discretion”—policy level decisions inside the agency that result in a particular class of products being exempted from compliance with an identified set of requirements. The most infamous exemption in our industry is the FDA decision permitting emergency medical service (EMS) squads to fill and distribute medical gases in virtually an unregulated environment.
Over the last 15 years we have seen a number of major shifts in FDA policy regarding medical gases. Some trends begin at headquarters, while others begin within an FDA district, where they gradually spread to other geographies until they eventually become the FDA’s existing viewpoint on compliance at the headquarter level.
Today, medical gas facilities are feeling the pressure of increased compliance with FDA (agency) requirements. The gases industry, because it uses common equipment and practices in the 3,000+ US medical gases operations under FDA jurisdiction, are especially vulnerable to shifts in Good Manufacturing Practice (GMP) policy. What is applicable to one medical gas facility is most likely applicable to nearly every medical gas facility in the nation. Increasingly, the trend is that new compliance practices do not follow from a formal change in federal regulations. More often, changes simply result from a FDA reinterpretation of what the agency believes constitutes “acceptable compliance” with a particular requirement. These changes are manifested in new enforcement policies. Many drug companies become aware of these policy shifts during FDA plant site inspections where citations are issued for something that had been acceptable at their plant for decades. All this can occur without the FDA ever making a single change to the “official written regulations.” These sudden shifts in policy can leave business owners unprepared.
For this reason, it is essential to pay attention to today’s FDA enforcement trends and policy shifts as they can quickly become new FDA requirements. In this article, we examine two recent enforcement trends and what their implications are for the medical gas industry.
Expiration Dating
Medical gases expiration dating is a classic example of how an FDA discretion-based enforcement exemption can literally disappear overnight. In the 1990s, the gases industry presented a logical and justified case to the FDA for exemption from the agency’s expiration dating requirements and the stability studies that support expiration dates. The FDA wrote a letter to the medical gas industry agreeing that expiration dating and stability testing were not warranted for medical gases and our industry began operating under that premise. All that changed in 2003 when the FDA re-asserted those expiration dating requirements in a new Medical Gas Guidance document. To this day no one is really clear exactly what happened to trigger such a dramatic reversal in agency thinking.
Unfortunately, returning to the practice of putting an expiration date on cylinders is not simple. By law, expiration dates must be supported by “appropriate” stability studies. Depending on what, if any, “discretion” is allowed by the FDA regarding these studies and medical gases, there could be a significant cost impact on our industry. The medical gases industry proposed conducting a simple desktop exercise to determine a typical cylinder leak rate and thus derive an expiration date that would be applicable to all cylinders and medical gas firms. That idea was rejected by the FDA as lacking technical sophistication and for not incorporating any “real world” testing to verify theoretical data. A whole series of proposals and counter proposals ensued, ultimately without resolution to the issue.
Expiration dating policy discussions with the FDA continues today. Meanwhile, inspectors in Florida got tired of waiting and began issuing citations to firms requiring them to implement expiration dating on medical gas cylinders. They were within their rights to do so, since the expiration dating requirement is in the FDA regulations and guidance, and there has been no accommodation issued to the industry. Some medical gas distributors are now moving to comply with these new requirements in Florida and the ripple effect is likely to spread across the nation due to the high degree of commonality in processes and procedures in our industry. Large regional and major gas companies, who typically operate under a single set of homogeneous procedures, find it is too resource intensive and costly to have different procedures and training programs for different states. We fully expect that the large companies servicing Florida markets will begin modifying their procedures and start applying expiration dates nationally over time. And as the FDA and state field inspectors begin to see this new practice appear in their locales, they will start to expect other firms in their jurisdiction to follow suit. This is a textbook example of how a change in practice can become the new cGMP (current GMP) policy without the FDA ever changing a regulation in writing. If your firm is issued an FDA form 483 over the next 6 –18 months and it includes a reference to expiration dating, you will know the genesis of the issue.
Quality Control
There is another FDA enforcement trend beginning to appear that involves Quality Control (QC) and how medical gas firms organize and manage their QC unit activities at manufacturing sites. Like the change in expiration dating, this trend may signal a significant shift in FDA compliance policy. Recently, the FDA issued a handful of citations to medical gas firms for what the agency perceived as the QC unit’s lack of independence from the company’s operating group. The FDA appears to be once again pushing the concept of a dedicated and independent QC unit organization at medical gas facilities.
The FDA’s paradigm for quality control is that a properly organized and managed QC unit serves as the cornerstone of a well-run compliance program. To the agency, a firm without a strong and well-managed QC Unit operation simply cannot have an effective compliance program. During inspections the FDA takes a careful look at the influence the operational side of the business can exert on the quality function. Simply put, the FDA believes if the QC unit reports to the group responsible for producing and delivering product (the profit center), quality and FDA compliance issues and programs (cost centers) are likely to be the lesser priority. While obviously not true in all cases, there is enough historical evidence to indicate that the FDA’s concerns are well founded. To avoid this potential conflict of interests the FDA “prefers” that a company’s QC unit be independent of the operations group.
For traditional pharmaceutical firms this is not a problem. They usually have well defined and organized QC units with lots of resources dedicated solely to quality control. Since 100 percent of the products produced at traditional pharmaceutical sites are cGMP regulated products and the production volumes are sufficient to satisfy the needs of a continent (or two), these facili ties tend to be well staffed. Seen from this perspective, the commitment to a dedicated QC unit organization at a pharmaceutical site makes sense in terms of both manpower utilization and cost.
Medical gases plants, on the other hand, typically only have a handful of employees and tend to service customers inside a 200–300 mile radius. The volume of medical products produced at an average cylinder gas facility is usually a small percentage of the total volume of all gas products manufactured at the facility. To produce medical products at these sites cost effectively, firms cannot afford a dedicated QC unit structure to support conducting what may end up being only six to eight hours of QC analysis in a typical work week. For this reason, operations personnel in a medical gas facility routinely execute QC unit related tasks, and many other tasks as well. Up to this juncture the FDA has accepted this practice with the following caveats.
1. The QC unit should not report to, or be, the production supervisor. At independent firms the QC unit often reports to the business owner. At larger firms, there are typically other options, which do not include having the local QC unit report to the plant manager.
2. The QC unit should have a specific and detailed set of Standard Operating Procedures that cover its tasks, responsibilities for quality, and its authority to suspend shipments if needed.
3. The QC unit should have a specialized and on-going training program in place that annually reinforces the QC unit tasks, responsibilities, and authority.
The issue of how best to manage the QC unit function at medical gas facilities is not new. It has bubbled to the surface at least twice over the last 20 years and appears to be making its way back into the agency’s spotlight. Recently, a few FDA districts began using the inspection processes to push the implementation of a dedicated QC unit function at cylinder plants. Some firms have resisted the FDA’s “push,” while others appear to have acquiesced. At this point the jury is out as to where this trend is headed—is it isolated to a specific FDA district, or the iceberg tip of a new and significant shift in FDA medical gas industry compliance policy.
One thing is absolutely clear. If the FDA eliminates its current enforcement discretion regarding the QC unit function at medical gas facilities, it will have a major impact on our industry and the potential availability of medical gases nationwide. We at B&R Compliance will be watching this issue very closely. In the meantime, to create the best possible defense against a recommendation to implement a dedicated QC unit at your medical gas facility, we strongly recommend firms are in full compliance with the three caveats listed above.
What’s Ahead
In the evolution of FDA compliance policy, the Compressed Gas Association (CGA) has played an essential role in communicating to government regulators the issues and impacts of government decisions. This communications process has allowed the medical gas industry an opportunity to present additional details on issues, which regulators may not have fully considered initially. Historically, CGA has also helped the FDA discern the potential benefits and/or pitfalls of the different options under consideration by providing industry data not typically available to the agency. Maintaining this communication portal involves the long term commitment of time and resources by industry leaders in order to keep the whole process alive and working. Compliance with FDA regulations is one of the many hidden costs medical gas firms face as a consequence of participating in the pharmaceutical market of the 21st century, with non-compliance the most costly of them all.
Bob Yeoman is President and CEO of B&R Compliance Associates LLC (Lehigh Valley, PA), a consulting firm specializing in medical gases, safety management, and other regulatory compliance management issues relating to the compressed gas industry. He can be reached at (610) 868-7183; Email bob.yeoman@brcompliance.com.
