Health system pharmacies are rife with challenges that must be addressed daily. From drug shortages and product recalls to reports of the fragile supply chain of critical active pharmaceutical ingredients (APIs), there are many uncontrollable variables in pharmacy practice.
To combat some of these challenges, approximately 71% of all facilities now outsource at least some of their compounded sterile preparations (CSPs), as reported in the 2021 Pharmacy Purchasing & Products State of Pharmacy Compounding annual survey.1 When choosing a 503B outsourced compounder, in-depth due diligence is critical to ensuring the registered outsourcer is compliant and consistently produces safe and high-quality CSPs.
A firm understanding of trends in regulatory actions for 503B outsourced compounders can assist organizations in choosing qualified 503B partners. As part of our ongoing medication safety and quality management initiatives, LDT Health Solutions (of Wayne, New Jersey) maintains the largest independent database of FDA compounding activities and documents outside of the FDA itself (with data derived from published FDA documents [ie, Form 483s]). It is from this vantage point that we offer the following observations based on the FDA Form 483s, which, in some cases, pre-date the November 2013 establishment of the 503B program.
Of note, FDA form 483s are written from an “industry” (manufacturer’s) inspection point of view. Because of this, the FDA form 483s group both pharmacy (503A) establishments and 503B outsourcing facilities into manufacturing operations instead of compounding operations. Another point of confusion is that the meaning of terms widely used by practicing pharmacists is generally different than the meaning that an FDA inspector would assign to that same term use in a manufacturing context. This can result in miscommunication and is therefore important to be mindful of.
The Current Regulatory Landscape
Beginning with the 2012 New England Compounding Center (NECC) nationwide fungal meningitis outbreak and continuing through November 1, 2021, the agency has published a total of 802 inspection documents (FDA Form 483s) for 508 different establishments (both 503A and 503B), generated by 416 different FDA inspectors. For 503B compounders (outsourcing facilities), we know that the data in this area is incomplete, since the updated postings to the FDA Registered Outsourcing Facilities Page (www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities) include references to documents that are not available to the public. The public can access a total of 233 FDA inspections conducted by 233 different FDA inspectors of 110 different facilities (this number exceeds the total number of 75 currently 503B-registered facilities listed by FDA to account for establishments that have been closed or chosen to “de-list” as a 503B business) (see TABLE 1).
TABLE 1 illustrates the depth and breadth of FDA inspections of 503Bs since 2012. On average, FDA spends 8.8 days on each 503B inspection with an average of 2 FDA inspectors per site visit. It is important to note that the FDA is committed statutorily to inspecting each and every 503B facility; if a 503B has not yet been inspected, it should prepare for what is an inevitable FDA inspection foretold by their voluntary registration status and outlined within the Drug Quality and Security Act (DQSA).
Evaluating FDA Form 483s, FDA Untitled letters, FDA Warning letters, FDA Recall Requests, Alerts, Voluntary Recalls, Establishment Inspection Reports (EIRs), Warning Letter Closeouts, and Regulatory Meeting requests issued to 503B establishments can be challenging, especially for pharmacists and other health care professionals unfamiliar with these documents. Response documents such as FDA form 483 Responses, FDA Untitled Letter Responses and FDA Warning Letter Responses are not routinely posted to the FDA’s website unless the 503B provider specifically requests these documents to be publicly posted. After careful review of these issued FDA documents, it is important to obtain additional information directly from the 503B facility regarding its formal plan of correction to accurately evaluate the compounder’s current regulatory compliance status. Ongoing monitoring of an outsourcing partner’s compliance with all prevailing statutes, rules, and regulations is not only essential, but a fiduciary responsibility of every organization that purchases CSPs from 503Bs. Thus, each organization must commit the time and resources required to obtain clarity from the provider any time citations are issued, or other questions are raised.
See the December 2019 PP&P article, “Trends in Regulatory Actions for 503B Compounders”2 and the February 2019 PP&P article, “Due Diligence Drives 503B Compounder Selection,”3 for more information on understanding FDA Form 483s and warning letters.
Evaluating 503B Data Trends
Our ongoing analysis of FDA observations indicates a shifting inspection focus since the start of the 503B outsourcing facilities program (see FIGURE 1). In 2012, the FDA focused on broad general categories, but in recent years, observations have become increasingly specific. The number of FDA inspections spiked in 2014 but has since decreased. Note that the number of FDA inspectors listed is based on the reduced sizes of the inspection teams and the fact that NECC’s team was so large it skewed the earlier data.
In addition, the number of 503B establishments has varied over time; currently, seventy-five 503B establishments are registered and listed with FDA, and 79 establishments that were registered in the past have dropped out of the 503B program. Some of the latter account for multiple inspections.
2016 to 2019 Citations
In 2016, the agency continued its general inspection methods with a technical focus as seen in the year prior; citations were commonly in the areas of quality documentation and preparation labeling. The FDA continued to inspect for specific activities; more precisely, the agency routinely cited section 503B(a)(10)(A) and (B) of the Federal Food, Drug & Cosmetics Act (FDCA) with respect to CSP labels. In addition, there was a proliferation of citations that should have been addressed by the 503B’s quality control unit (as defined in the Code of Federal Regulations).
In pharmacy practice, the pharmacist-in-charge (PIC) is responsible for CSP quality; in 503B establishments, the quality unit is responsible to mimic the convention established by cGMP pharmaceutical manufacturers. Examples of citations that should have been addressed by the quality control unit include the rejection of unsuitable in-bound API, rejecting drugs and materials that did not meet the outsourcer’s specifications, and early launching of recalls or preparation withdrawals. Beginning in 2019, FDA has increased scrutiny of the CSPs being compounded and cited CSPs that are essentially a copy of one or more approved drugs within the meaning of sections 503B(a)(5) and 503B(d)(2) of the FDCA. Please note that some of the CSPs deemed a copy of an approved drug were being administered via a completely different route of administration or method or the approved drug could not be used in the given situation.
TABLE 2 shows the most frequently cited 503B citations from 2016 to 2019.
2020 to Present
Based upon documents posted by the FDA, there was an expected decrease in the number of onsite visits during the COVID-19 pandemic for 2020 and 2021. In 2020, there were five FDA form 483s posted for 503B establishments, and there have been six FDA form 483s posted in 2021. However, the regulatorily required postings to the FDA’s Registered Outsourcing Facilities webpage (https://www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities) have listed that two 503B outsourcing facilities received FDA form 483s in 2020 and ten 503Bs outsourcing facilities received FDA form 483s in 2021—but there is no active web link to view these documents, and they are not publicly posted anywhere else on the FDA‘s website.
This lack of information makes it difficult to make objective comments as to the FDA’s overall enforcement strategy. But the FDA continues to release additional guidance documents for both 503A and 503B establishments (48 regulatory and policy documents as of October 6, 2021 in total).4 Since the publication of this collection of agency guidance documents, the observations cited have become more consistent—from 2016 to present, the following observations have been noted:
TABLE 3 shows the most frequently cited 503B citations from 2020.
TABLE 4 includes the most frequently cited areas from 2021 to the present.
Based upon the verdicts resulting from the NECC debacle, it is apparent that company was running a criminal enterprise and not operating a viable pharmacy as they represented. This enterprise was fueled by what the FDA refers to as “economically motivated adulteration.” As such, this operation did not reflect the lawful provision of the essential pharmacy services provided by conscientious professionals. Notwithstanding this distinction, it could be argued that based upon the documents publicly available, the FDA continues to aggressively inspect pharmacies looking for similar illegal “NECC-like” operations, a noble idea. But 10 years later, there have been few instances identified that can be argued as being even close to that blatant criminal conspiracy. The puzzling part of this aspect of the post-NECC universe is that contrary to the public statements by the agency, the level of general cooperation and communication between FDA and state boards of pharmacy is inconsistent and generally poor. There is universal agreement that rooting out “bad actors” that use the pharmacy banner to hide illegal and dangerous compounding practices must be identified and stopped in the interest of public health. But the tenor of the collective FDA form 483s delivered to 503A providers is permeated with a certain guilty-until-proven-innocent view.
In the absence of criminality, this stance by the agency could be seen as damaging to the profession of pharmacy as it erodes public trust. Furthermore, in a time when COVID deaths are still occurring in unacceptably high numbers, we cannot afford to diminish the value of these vital frontline health care professionals. The aggressive enforcement stance by FDA, using a cGMP standard rather than the respective state’s Board of Pharmacy (BOP) regulations effectively excludes the BOP from the conversation. Once an FDA form 483 is issued, a BOP is unlikely to contradict a federal agency to avoid creating a weak optic as to the board’s stance on regulatory compliance and public safety. Further complicating this situation is the fact that the application of appropriate quality standards (cGMP vs BOP regulations) is a complex subject not well understood by the general public. What is lost in the application of cGMP standards—which leaves us debating “how clean is clean?”—is a clear discussion around which standard is best applied to pharmacy operations. Pharmacy by its very nature is a profession fraught with risk; our collective duty is to make sure that what we do, and how we do it, does not present an unreasonable risk to public health. Without this key distinction there would be no public access to care.
Understanding how FDA surveys the 503A pharmacy universe helps clarify the process for reviewing and interpreting the FDA form 483s issued to your current or prospective 503B outsourcing provider. Since these businesses have voluntarily registered with FDA and have agreed to follow prescribed cGMP regulation (currently outlined only in FDA guidance), the application of cGMP to these providers is appropriate. But it is essential to remember that while these outsourcing providers use cGMP as their roadmap, they are not pharmaceutical manufacturers. As such, they do not offer the same product liability protections as would a conventional pharmaceutical manufacturer, so it is this shared responsibility that you are surveying for compliance. Critical to this survey process is your understanding of how solid science, the provider’s standard operating procedures, and current practices intersect with FDA guidance to impact the quality of the preparations they provide to you.
It is important to recognize that FDA guidance documents represent the thinking of the agency at the time of issuance and that they may be amended by FDA at any time. Furthermore, without the referencing of specific, legally enforceable applicable regulations, these guidance documents should be viewed as conditional recommendations based on current FDA thought and regulatory discretion. In fact, each document includes the following text in its introduction:
In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidance describes the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.5
Because not every FDA inspection document is publicly released (for a wide range of reasons), lessons learned from this data must be tempered with the understanding that multiple factors are involved in each inspection, and that the trending data presented here is a broad overview of the field activities currently ongoing at 503B outsourcing facilities. Even so, the valuable lessons learned by examining this data from the FDA form 483s presented here can provide important insight into a provider or prospective provider’s level of compliance, compounding diligence, and overall understanding of the service model in which they are engaged.
Repeated citations over time at any single facility may indicate a lack of focus by its leadership on corrective actions, while citations for apparently simple items, such as package labeling, could indicate a lack of understanding of the regulations. In either case, citations should trigger monitoring of your 503B provider’s quality management activities more closely.
When surveying a 503B provider, require definitive confirmatory documentation of any remedial or corrective actions taken. Robust follow-up can help verify that these corrections have become part of the outsourcer’s daily practices. Determine your key quality indicators; if they are not part of your vendor’s standard reports, you can request customized reports. Once the proper reports are in place, be sure to regularly review the information to ensure the CSPs provided for your patients are safe and effective.
It is important to understand FDA’s current areas of inspection focus and be cognizant of your vendor’s compliance efforts. Moreover, regular review of an organization’s 503B provider(s) can help ensure the pharmacy receiving these compounded preparations is taking every step possible to validate that their patients are receiving safe, effective CSPs.
Gaining broad insight into the patterns of FDA activity surrounding 503B outsourcing providers can yield benefits beyond creating a simple report card for your outsourcing compounder. A thorough understanding of the quality efforts in 503B outsourcing provider programs can help an organization choose the most suitable 503B partner(s).
Lou Diorio, RPh, FAPhA, is a principal of LDT Health Solutions, Inc, an international medication safety and quality management consulting company celebrating its 13th year of service. He is a graduate of Long Island University’s Schwartz College of Pharmacy, where he is also an adjunct professor of pharmacy practice, a member of the college’s Alumni Board, and preceptor of pharmacy students. Lou serves as a member of the New York State Council of Health-System Pharmacists’ Research and Education Committee and also is a member of the New Jersey Society of Health-System Pharmacists’ Industry Relations Committee.
David Thomas, RPh, MBA, is a principal of LDT Health Solutions, having previously served as the director of information technology operations for SoluNet, LLC, and as a manager of implementation and technology development for Baxter Healthcare. Prior to his 15-year tenure with Baxter, Dave held hospital practice and management positions for 5 years. He is a graduate of St. Louis College of Pharmacy.