Trends in Regulatory Actions for 503B Compounders


December 2019 - Vol. 16 No. 12 - Page #22

Managing a health system pharmacy can be a challenging task; drug shortages, product recalls, and unreliable medication availability are only a few of the concerns that must be addressed on a daily basis. Moreover, reports of the fragile supply line of critical active pharmaceutical ingredients (APIs) are commonplace, and highlight yet another uncontrollable variable in pharmacy practice.

As reported in the 2019 Pharmacy Purchasing & Products State of Pharmacy Compounding annual survey, three-quarters of all facilities now outsource at least some of their compounded sterile preparations (CSPs).1 When choosing a 503B outsourced compounder, in-depth due diligence is critical to ensuring the registered outsourcer is compliant and consistently produces high-quality CSPs.

Tracking trends in regulatory actions for 503B outsourced compounders can assist organizations in choosing appropriate 503B partners and in understanding FDA’s current focus for their own compounding programs. As part of our ongoing medication safety and quality management initiatives, LDT Health Solutions (Wayne, New Jersey) maintains the largest database of FDA compounding activities and documents outside of the FDA itself (data is derived from published FDA documents [ie, Form 483s]). It is from this vantage point that we offer the following observations based on FDA Form 483s, which, in some cases, pre-date the November 2013 establishment of the 503B program.

The Current Regulatory Landscape

Beginning with the 2012 New England Compounding Center (NECC) nationwide fungal meningitis outbreak and continuing through October 4, 2019, the agency has published 696 inspection documents (FDA Form 483s) for 470 different establishments (both 503A and 503B), generated by 386 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 Pages (www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities) include documents that are not available to the public. The public can access a total of 202 FDA inspections of 113 different facilities (this number exceeds the total number of 503B-registered facilities listed by FDA to account for establishments that have been closed or chosen to “de-list” as a 503B business), conducted by 218 different inspectors (see TABLE 1).

TABLE 1 illustrates the depth and breadth of FDA inspections of 503Bs since 2012. On average, FDA spends 8.4 days on each 503B inspection with an average of 2 inspectors per case. It is important to note that the FDA is committed 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 and warning letters issued to 503B establishments can be challenging, especially for pharmacists and other health care professionals unfamiliar with these documents. After careful review of the issued FDA document, it is important to obtain additional information from the 503B facility regarding its plan of correction in order to accurately evaluate the compounder’s current 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 September 2018 PP&P article, FDA’s Regulatory Actions for 503B Compounders2 and the February 2017 PP&P article, Evaluating 503B Outsourcing Providers,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 program (see FIGURE 1). In 2012, the FDA focused on broad categories in 2012, but in recent years, observations have become increasingly specific. The number of inspections spiked in 2014 but has since levelled out. Note that the number of 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 503Bs has varied over time; currently, seventy-three 503Bs are listed, and 52 that were registered have dropped out. Some of the latter account for multiple inspections.

2012-2013 Citations

The top five observations included in the released FDA Form 483s for 503Bs indicate that the most frequent citations in 2012-2013 were similar to citations issued to 503A pharmacies. These observations focus on a lack of written P&Ps; shortfalls in release and quality testing; and gowning, gloving, and garbing inadequacies. TABLE 2 lists the most frequent 503B citations in 2012-2013.

2014 Citations

In 2014, FDA’s focus shifted to the cleanrooms and the compounding spaces (ie, the physical plant) producing CSPs, with specific attention paid to including CSP labeling, the testing and interpretation of quality data surrounding these CSPs, as well as gowning, gloving, and garbing inadequacies. TABLE 3 details the most frequently cited 503B citations in 2014.

2015 Citations

In 2015, the agency expanded its inspection methods, and with that expansion came an increasingly technical focus, including citations in the areas of quality documentation and product labeling. Since 2015, FDA continued to inspect for specific activities; more precisely, the agency is routinely citing section 503B(a)(10)(A) and (B) 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 is responsible for CSP quality; in 503Bs, the quality unit is responsible. 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. TABLE 4 shows the most frequently cited 503B citations from 2015.

2016 to the Present

As FDA has released additional guidance documents for both 503A and 503B establishments, ie, 37 regulatory and policy documents (as of September 24, 2019), there has been a shift in regulatory focus from the agency (FDA compounding guidances are available at: www.fda.gov/drugs/human-drug-compounding/regulatory-policy-information). Since this agency adjustment, the observations cited have become more consistent; within the time period of 2016 to the present, the following observations have been noted:

  • Improper CSP labeling
  • Lack of P&Ps established, written, and followed
  • Aseptic processing areas are deficient for monitoring environmental conditions and for the systems for cleaning and disinfecting the rooms and equipment to produce aseptic conditions

TABLE 5 includes the most frequently cited areas from 2016 to the present.

Discussion

It is important to understand 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 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 the introduction:

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe 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 guidances means that something is suggested or recommended, but not required.4

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 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.

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.

Conclusions

It is important to understand FDA’s current areas of focus and be cognizant of your vendor’s compliance efforts. Moreover, regular review of an organization’s 503B providers can help ensure the pharmacy is taking every step possible to validate that patients are receiving safe, effective CSPs.

Gaining broad insight into the patterns of FDA activity surrounding 503B providers can yield benefits beyond creating a simple report card for your outsourced compounder. A thorough understanding of the quality efforts in 503B outsourcing provider programs can help an organization choose the most suitable 503B partner.

References

  1. State of Pharmacy Compounding Annual Survey. Outsourced Compounding. Pharm Purch Prod. 2019;16(4):54.
  2. Diorio L, Thomas D. FDA’s regulatory actions for 503B compounders. Pharm Purch Prod. 2018;15(9):14-16,18-19.
  3. Diorio L, Thomas D. Evaluating 503B outsourcing providers. Pharm Purch Prod. 2017;14(2):10-14.
  4. US FDA. Regulatory Information. Guidance for Industry: Enforcement Policy Concerning Certain Prior Notice Requirements. www.fda.gov/RegulatoryInformation/Guidances/ucm261080.htm. Accessed October 10, 2019.

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.

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