Providing the complex polypharmacy therapies required for hospitalized patients in an efficient, cost-effective way is a challenging daily mandate for hospital pharmacists. Over the past decade, to accomplish this goal reliance on outsourcing facilities for some portion of a hospital’s compounded sterile preparations (CSPs) has been steadily increasing and represents a significant volume of the preparations provided to patients. The 2016 Pharmacy Purchasing & Products’ State of Pharmacy Compounding Survey cites that following a dip in outsourcing usage between 2013-2015, seven of 10 (69%) health systems utilize some degree of outsourcing to meet their daily needs.1 As such, routine, formalized screening and evaluation of these outsourcing providers has become an essential element of the initial vetting and ongoing compliance processes for all hospitals and health systems utilizing these providers.
The Regulatory Landscape
Managing CSPs for patients subsequent to the September 2012 meningitis outbreak resulting from contaminated steroid injections from the New England Compounding Center (NECC) can be daunting. The incident made abundantly apparent the importance of caution when purchasing outsourced CSPs, and it is no accident that CSPs have become the most scrutinized area of pharmacy practice. Since the NECC tragedy, most state boards of pharmacy have taken action to revise, modernize, or overhaul their pharmacy practice acts with respect to compounding.
With the November 2013 passing of the Drug Quality & Security Act (DQSA), some of the regulatory confusion that led to the NECC tragedy has been clarified. On November 14, 2012, FDA commissioner Margaret Hamburg told lawmakers that although the problems uncovered during NECC inspections were very serious, the agency was obligated to defer to Massachusetts authorities, which have more direct oversight over pharmacies. The challenge noted by commissioner Hamburg was that “There is a patchwork of legal authorities that oversee the action we can take.”2 As the FDA continues to define the remaining portions of the DQSA, transparency will similarly increase.
Since the NECC case, the FDA has been actively inspecting pharmacy compounders of all sizes. The majority of these inspections have not occurred in 503B outsourcing providers, but in retail pharmacies, compounding pharmacies, home care pharmacies, and hospitals, even though the state boards of pharmacy are the inspection authority for non-503B pharmacies.3 The catalyst for these inspections varies and ranges from routine 503B inspections, to MedWatch complaints, to requests by a local board of pharmacy or health department for agency support. Since Congress voted funding for FDA in excess of $2.75 billion in appropriations for 2017, this activity is well within the reach of the agency’s resources. FDA has recently released a summary document highlighting its progress over the past 3 years.4
Form 483s and Warning Letters
Because most practicing pharmacists have never participated in an FDA inspection, a great deal of mystery and confusion exists regarding the process and interpretation of the public documents generated by these inspections. The two most common documents issued pursuant to inspections are the FDA’s Form 483 (Inspectional Observation) and the FDA Warning Letter.
A Form 483 is issued to notify a compounder’s management of objectionable conditions.4 Compounders are encouraged to respond to FDA in writing describing their corrective action plan to remedy these objectionable issues. While drug manufacturing companies issued a Form 483 by FDA are rarely published to the FDA Web site, the FDA has changed this practice for compounding pharmacies and publishes the majority of the FDA Form 483s issued to these pharmacies. On the FDA Web page for 503B facilities (FDA maintenance of this Web page is required by the DQSA), it is noted that four outsourcing facilities (503Bs) have been issued Form 483s, but those Form 483s have yet to be publicly posted. Form 483 responses may or may not be posted to the FDA site, and rarely are the Form 483 and Form 483 response posted together.
An FDA Warning Letter most assuredly follows the issuance of the Form 483 and is posted to the FDA’s Web site for public review.3 Since the NECC tragedy, the FDA has conducted more than 350 inspections, with more than 120 of these visitations “for cause.” In almost all of these inspections, whether routine, follow-up, or “for cause,” the agency has issued a Form 483.5
Challenges in Evaluating Form 483s and Warning Letters
Since both Form 483s and Warning Letters are generally unfamiliar to pharmacists, administrators, and the general public, and because they utilize structured, formal language, interpretation and evaluation of these documents can be a difficult and confusing exercise. Therefore, informed understanding of the information contained therein is critical to properly evaluate their implications.
It is important to understand that both of these documents are crafted using the vernacular and rely on terminology taken directly from the Food, Drug, and Cosmetic Act (FDCA, CFR 21, parts 210 and 211),6 with current Good Manufacturing Practices (cGMPs) as their investigative basis. This may not always be the most accurate lens through which to evaluate a pharmacy compounder, so there could unintentionally be some misapplication of regulatory standards. For example, the FDA routinely applies cGMP standards for garbing, which exceeds current USP and local pharmacy statute requirements. Adding to the confusion is the inconsistency by the agency in the use of some of the terms appearing in these documents. For example, in describing the type of compounding establishment the FDA is inspecting, the agency has utilized 42 different naming terms, most of which cannot be found either in the regulation or in the FDA’s own standard lexicon (see TABLE 1. FDA 503A and 503B Pharmacy Establishment Naming).3 The confusion caused by the use of this loose terminology often touches off further regulatory questions with the local board of pharmacy or other local licensing agencies.
Since Form 483s and Warning Letters do not represent an all-inclusive finding of law or deviation from regulation, to fully evaluate the compounder, more data is essential. FDA’s own disclosure on the Form 483 states:
This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations, and do not represent a final Agency determination regarding your compliance. If you have an objection regarding an observation, or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA at the address above. If you have any questions, please contact FDA at the phone number and address above.
Obtaining Additional Information
Upon the issuance of a Form 483, compounders are encouraged to submit a written response to FDA within 15 business days of the inspection’s closing. Posted Form 483 documents can be found on the FDA’s Office of Regulatory Affairs Freedom of Information Act Electronic Reading Room Web site, at www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htm. However, as noted previously, these documents are not always released publicly or posted on a timely basis to the FDA’s Web site.
Part of the standard due diligence of any organization that utilizes outsourced compounding services should be to routinely request the vendor provide these documents or any other regulatory action or formal communications from all city, state, and federal agencies with jurisdiction over the compounder. This due diligence should be included in the standard contract language between the organization and the outsourcing compounder, and routinely incorporated into the regular quality management process of the organization.7
Keep in mind that the existence of such documents does not in and of itself constitute a catastrophic problem with the outsource provider, since the FDA publicly acknowledges that it is unusual not to issue a Form 483 during each inspection. However, it is critical that the organization review an unredacted copy of the Form 483, along with the compounder’s response document, in order to identify the regulatory shortfall, evaluate how the compounder has responded to the 483, and consider any possible patient impact for each observation cited.
The assistance of a competent, qualified third-party resource familiar with these documents and the FDA process may be helpful for the pharmacy to determine both a short- and long-term course of action to safeguard the organization and its patients. In some circumstances, the application of a tiered approach to establish the severity of each observation may be helpful in understanding the possible impact to the compounded preparation (see TABLE 2). Nevertheless, no citation should be dismissed outright without a full assessment of its cause and the potential impact on the patients receiving these medications. It also is important to note that the FDA has issued multiple Form 483s to some establishments—61 pharmacies have had multiple inspections (45 have had two inspections, 15 have had three inspections, and one has had four inspections).3 It is particularly important to closely review any compounder that has been issued repeat citations, since this could indicate an unresolved or unaddressed problem, or a lack of understanding by the establishment’s leadership of a key quality or safety metric.
To gain a comprehensive understanding of the situation surrounding a given FDA action, the pharmacy must conduct a thorough inquiry. Most critical to remember is that the final responsibility for the quality and safety of all CSPs provided to patients rests with the pharmacist-in-charge (ie, the supervising pharmacist or manager of record) of the dispensing pharmacy. Therefore, proceed with an abundance of caution in order to protect patient safety at all times.
The temporary suspension of the procurement and use of these preparations is a reasonable first step should any doubt exist regarding product quality or safety. An outsourcing facility is not a manufacturer—it is essentially a contract compounding pharmacy. Although these compounders follow some cGMPs, they are not true drug manufacturers, and as such, do not offer the same regulatory protections and product liability safeguards as a drug manufacturer. Careful evaluation of the 503B’s safety practices is essential to assuring your patients’ safety, as well as protecting your professional licensure.
The maze of local, state, and federal statutes, rules, and regulations for the provision of compounded preparations in the modern health care system is undoubtedly challenging to navigate. Careful selection of an outsourcing partner to supplement an organization’s capabilities is key to ensuring long-term success and patient safety. Ongoing monitoring of an outsourcing partner’s compliance to all prevailing regulations is not only essential, but also a fiduciary responsibility of every organization that purchases these preparations. As such, pharmacy must commit to investing sufficient time and resources in the pursuit of clarity of any FDA communication and regulatory actions issued to the organization’s outsourcing providers.
Diorio L, Thomas D. Ensure outsourcing quality during shortages. Pharm Purch Prod. 2011;8(12):14-17.
Diorio L. Evaluating compounding practices. Pharm Purch Prod. 2012;9(12):12-13.
Lou Diorio, RPh, FAPhA, is a principal of LDT Health Solutions, Inc, an international medication safety and quality management consulting company celebrating its 10th year of practice. Lou 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. He serves as a member of the NY 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. In addition, Dave served 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.