Abstract
Traditional pharmacy compounding involves the modification of a dosage form to fit the needs of a patient, as prescribed by the patient’s physician, and serves a vital need within the health community. Unites States Pharmacopeia–National Formulary (USP-NF) General Chapter <797>, titled “Pharmaceutical Compounding—Sterile Preparations,” is the gold standard to which modern-day pharmacists compounding sterile products are held. In this article, the FDA 483 inspection reports received by sterile compounding pharmacies were divided into 2 categories: facilities in the United States that require compliance with USP <797> and those that do not require compliance with USP <797>. Results revealed no association between the number or category of 483 comments and state requirements to comply with USP <797>. The impact of voluntary registration of compounding pharmacies with FDA in accordance with the 2013 Drug Quality and Security Act (DQSA) has yet to be determined. The author recommends a national database of all pharmacy compounding facilities that lists the types of manufacturing in each facility to increase transparency and target audits, as well as the institution of rewards for quality in the generic industry to help avoid drug shortages.
Introduction
The largest outbreak of fungal meningitis ever recorded in the US began in September 2012, when multiple cases of fungal meningitis, a disease that is rare and not contagious, started appearing, primarily in Tennessee. After a clinician in Tennessee found fungus in her patient’s spinal fluid, the Tennessee health department became involved and traced the possible source of infection to the New England Compounding Center (NECC), a pharmacy compounding facility. 1 The NECC ultimately recalled three lots of injectable methylprednisolone that had visible signs of fungus contamination which was later confirmed by laboratory tests. The Food and Drug Administration (FDA) initiated an audit of NECC in October 2012 and subsequently of other compounding pharmacies that manufactured sterile products. As of February 2014, there have been 64 deaths from fungal infections traced to the tainted NECC product and 751 cases of infection, spread across 20 states in the United States. 2 In addition, patients who have recovered from the initial fungal meningitis are now presenting with secondary infections at the site of injection months after the injection. Since it is difficult to tell the symptoms of the infection at the injection site apart from the symptoms that prompted the injection, the Centers for Disease Control and Prevention (CDC) is recommending MRIs for patients still complaining of pain. 3
As a result of the fungal meningitis outbreak in 2012, US residents were no longer sure if the compounded sterile drugs being administered were safe. Worse yet, physicians and patients alike were unable to tell if the sterile products being administered were manufactured by a pharmacy compounder or if they were manufactured by a facility that had received approval to manufacture and market the product. Questions of “How did this happen?” naturally arose. FDA was urged to step into the world of pharmacy compounding, an area that has traditionally been the purview of pharmacists.
Woodcock and Wosinska 4 suggested that a complex cascade of economic factors may be to blame for the NECC crisis. The bulk of sterile products are manufactured by generic firms, and competition among buyers for the lowest prices is fierce. When considering upgrading sterile manufacturing facilities in order to avoid product sterility failures, manufacturers have a choice to make—maintain competiveness and viability by not performing needed upgrades or performing upgrades needed to improve product quality and increasing prices, which in turn will decrease their market share. In other words, the current economic system does not reward the quality (of sterile products), only the cost. Manufacturers who sell their (sterile) product at the lowest cost garner the business. A quality problem often results in manufacturers discontinuing production of a sterile product, creating a gap for medically necessary sterile drugs. That gap is often filled by pharmacy compounding.
Traditional pharmacy compounding involves the modification of a dosage form to fit the needs of a patient, as prescribed by the patient’s physician. A patient may not be able to tolerate a specific excipient in a marketed product, so the physician fills out a prescription for the pharmacist that does not contain that specific excipient. Another example of pharmacy compounding is the addition of a flavoring to a liquid prescription. How then, did traditional pharmacy compounding, which is regulated by the individual boards of pharmacies in each state, blossom into providing sterile and nonsterile drug products in bulk quantities across the nation without FDA oversight? For an answer to this, we must delve into the history of the law.
History—Pharmacy Compounding Law
In the early 1990s, the FDA began receiving adverse event reports regarding compounded products and wrote a policy statement, Compliance Policy Guide (CPG) (section 7132.16, later renumbered to 460.200). The compounding industry objected to the approach in the CPG and several bills were introduced with the intent of limiting the Agency’s oversight of compounding. 5 In 1996, Dr David Kessler expressed his concerns that the compounding provision would encourage large-scale production of sterile products under the guise of pharmacy compounding, with potentially fatal results. 5,6 As it turned out, Dr Kessler’s comments and concerns were prescient.
In November 1997, despite Dr Kessler’s concerns and objections, S. 830, the Food and Drug Administration Modernization Act of 1997 (FDAMA), was signed into law as Public Law 105-115. FDAMA added Section 503A to the FD&C Act to address FDA’s authority over compounded drugs. Section 503A exempted compounded drugs from 3 critical provisions of the FD&C Act: the premarket approval requirement for “new drugs”; the requirement that a drug be made in compliance with current Good Manufacturing Practice (cGMP) standards; and the requirement that the drug bear adequate directions for use, provided certain conditions are met. These provisions were the subject of subsequent court challenges, which have produced conflicting case law and amplified the perceived limitations and ambiguity associated with FDA’s enforcement authority over compounding pharmacies. 7,8 The wording in Section 503A allowed compounding pharmacies to expand their market to supply sterile products to hospitals and physicians, leading directly to the largest outbreak of fungal meningitis ever recorded.
USP <797> Pharmaceutical Compounding—Sterile Preparations
The Unites States Pharmacopeia–National Formulary (USP-NF) General Chapter <797>, titled “Pharmaceutical Compounding—Sterile Preparations,” is the gold standard to which modern day pharmacists compounding sterile products are held. USP <797> originated in 1992 with USP Chapter <1206>, entitled “Sterile Drug Products for Home Use.” USP <1206> evolved into USP <797> on January 1, 2004. Despite the publishing of USP <1206> and later USP <797>, pharmacists have largely remained resistant to the implementation of USP <797> and other similar guidelines, despite the fact that USP <797> falls into the category of required USP chapters. FDA documented more than 55 quality issues with regard to USP <797> between 1990 and 2000, many of which resulted in drug recalls, patient injury, and death. Factors involved in these incidents included poor employee training, lack of policy and procedure, poor aseptic technique, poorly designed aseptic facilities, and failure to validate sterile processes. 9
USP <797>, under which pharmacy compounding facilities are either supposed to or are required to operate (depends on the state), was intended for individual sterile compounding operations for a specified individual. The cGMPs under which FDA operates apply to drugs that are administered to large numbers of patients. The general public assumes that FDA oversees all drug manufacturing when in reality, pharmacy compounding has been and continues to be regulated by the boards of pharmacy in each state, not by the FDA.
Compounding Quality Act Title I of the Drug Quality and Security Act of 2013
On the heels of the fungal meningitis outbreak of 2012, President Obama signed the Drug Quality and Security Act (DQSA), legislation that contains important provisions relating to the oversight of compounding of human drugs, on November 27, 2013.
10
The following is a direct excerpt from the FDA on compounding
10
: Title I of this new law, the Compounding Quality Act, removes certain provisions from section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) that were found to be unconstitutional by the US Supreme Court in 2002. Section 503A describes the conditions under which certain compounded human drug products are entitled to exemptions from three sections of the FDCA requiring: Compliance with current good manufacturing practices (cGMP) (section 501(a)(2)(B)); Labeling with adequate directions for use (section 502(f)(1)); and FDA approval prior to marketing (section 505). By removing the unconstitutional provisions, the new law removes uncertainty regarding the validity of section 503A, which will be applicable to compounders nationwide. In addition, the new law creates a new section 503B in the FDCA. Under section 503B, a compounder can become an “outsourcing facility.” An outsourcing facility will be able to qualify for exemptions from the FDA approval requirements and the requirement to label products with adequate directions for use, but not the exemption from cGMP requirements. Outsourcing facilities: Must comply with cGMP requirements, Will be inspected by FDA according to a risk-based schedule, and Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound. If compounders register with the FDA as outsourcing facilities, hospitals and other health care providers can provide their patients with drugs that were compounded in outsourcing facilities that are subject to cGMP requirements and federal oversight. If a compounder chooses not to register as an outsourcing facility and qualify for the exemptions under section 503B, the compounder could qualify for the exemptions under section 503A of the FDCA. Otherwise, it would be subject to all of the requirements in the FDCA applicable to conventional manufacturers. FDA anticipates that state boards of pharmacy will continue their oversight and regulation of the practice of pharmacy, including traditional pharmacy compounding. The Agency also intends to continue to cooperate with State authorities to address pharmacy compounding activities that may be violative of the FDCA.
Materials and Methods
The laws of all 50 US states were researched (cutoff date: September 28, 2015) to determine if a state required compliance with USP <797>. Only states that required full compliance with USP <797> were counted as requiring compliance with USP <797>. The states were separated into 2 categories, those that required compliance with USP <797> and those that did not. Using the list of 483s issued for compounding pharmacies on the FDA website, 11 the FDA 483s issued for compounding pharmacies were reviewed and categorized into states that do and do not require compliance with USP <797>. FDA 483 citations were further slotted into 12 categories: (1) no potency, sterility, or endotoxin testing; (2) procedures to prevent microbial contamination are not written or followed; (3) deficient gowns and gowning; (4) facility and equipment design insufficient for the prevention of microbial contamination; (5) deficient cleaning and disinfecting systems for aseptic processing areas; (6) deficient environmental monitoring (EM) in aseptic processing area; (7) deficient control of room air pressure; (8) deficient validation of the sterilization process; (9) out of specification (OOS) and complaints not investigated or followed up; (10) no beyond-use date (BUD) and/or expiration date and/or stability program; (11) deficient labeling, labels, or label control; and (12) batch manufacturing records (BMRs) absent and/or not followed and/or deficient.
Results
As of September 2015, a total of 39 states require the implementation of USP <797> in regards to the compounding of sterile products. In addition, 56 pharmacy compounding facilities have registered since the implementation of the Compounding Quality Act Title I of the Drug Quality and Security Act of 2013. 7 The proportion of registered outsourcing facilities (75%) is about the same as the proportion of states that require adherence to USP <797> 78% (Table 1).
States That Do and Do Not Require the Implementation of USP <797> for Compounding Facilities Versus the Number of Registered Outsourcing Facilities (as of September 2015).
aPercentage of the total number of states.
bPercentage of registered outsourcing facilities as of September 28, 2015.
The dates of the FDA inspections of the presented pharmacy compounding facilities that produce sterile products range from October 2012 to the cutoff date of September 28, 2015. All inspections occurred after the fungal meningitis outbreak and are continuing. Although there were a greater number of sterile product facilities audited in states that require adherence to USP <797> than in states that do not require adherence to USP <797>, the average (±SD) number of FDA 483 citations across the 12 categories was identical for both groups (7 ± 2). This indicates that mandating compliance to USP <797> is important, but that in itself does not translate directly to increased compliance. Compliance to USP <797> is multifaceted. Refer to Tables 2 and 3.
The Number of FDA 483s Received in States That Require Compliance With USP <797> (as of December 2013).
aSome facilities were audited on 2 different occasions.
The Number of FDA 483s Received in States That Do Not Require Compliance With USP <797>.
aSome facilities were audited on 2 different occasions.
Table 4 lists the types of FDA Form 483 citations in the 12 groups listed in the methodology section, received by states that require the implementation of USP <797>. Table 5 lists the types of FDA Form 483 citations received by states that do not require the implementation of USP <797>. The exact wording on the FDA Form 483 is noted for many of the violations.
Pharmacy Compounding Companies Within States That Require Compliance With USP <797> and Received FDA 483 Citations.
Source (483s): http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm378645.htm.
Abbreviations: BMR, batch manufacturing record; BUD, beyond-use date; Cpdg, compounding; EM, environmental monitoring; OOS, out of specification.
Pharmacy Compounding Companies Within States That Do Not Require Compliance With USP <797> and Received FDA 483 Citations.
Source (483s): http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm378645.htm
Abbreviations: BMR, batch manufacturing record; BUD, beyond-use date; Cpdg, compounding; EM, environmental monitoring; OOS, out of specification.
Overall, the FDA cited the 12 categories listed in Tables 4 and 5 at roughly the same rates and rankings in states that do and do not require compliance with USP <797>. Specific 483 comments were also similar across all compounding facilities that received an FDA 483, regardless of the state of residence.
The summarized comparisons across the regulations governing outsourcing facilities, facilities that manufacture sterile product for approved drugs, and USP <797> in Table 6 are not meant to be exhaustive, but they highlight the differences between USP <797> and drug products manufactured under an NDA or abbreviated new drug application (ANDA). As can be seen from Table 6, USP <797> is a useful guidance for the small sterile compounding operations for which it was intended—mixing of a sterile drug into a sterile bag of saline and other similar operations intended for immediate delivery to one patient. USP <797> was not designed to ensure the sterility and potency of sterile drugs compounded on a large scale and shipped in large quantities. For example, USP <797> does not require potency testing prior to release of the sterile compounded drug to the patient. This practice makes sense when the sterile drug is compounded under sterile conditions using proper sterile technique and is then delivered directly to the patient within a matter of minutes or several hours. The lack of potency testing of a sterile compounded drug product that has been manufactured in bulk, stored for a period of time, and then shipped in large quantities to multiple locations not only does not make sense but puts patients at risk. In this scenario, there is no assurance that the compounded drug product contains the correct amount of active ingredient or is sterile and free from endotoxins and objectionable organisms.
Brief Comparison Between OSF, USP, and cGMP Guidelines and Regulations.
Source: USP <797>, 21 CFR 210 and 211, Guidance for Industry; Current Good Manufacturing Practice—Interim Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act July 2014.
Abbreviations: ANDA, abbreviated New Drug Application; BUD, beyond-use date; CAPA, corrective and preventative actions; CSP, compounded sterile product; DP, drug product; EM, environmental monitoring; cGMP, current Good Manufacturing Practice; OSF, outsourcing facility; QC, quality control; NDA, New Drug Application; USP, United States Pharmacopeia.
Discussion
The value of pharmacy compounding to both hospitals and community pharmacies and ultimately patients is not disputed. The types of cGMP violations noted in Tables 4 and 5, however, raise serious questions as to the safety of compounded products purported to be sterile. Many of the violations listed in the FDA Form 483s in Tables 4 and 5 provide evidence of poorly constructed facilities, homemade equipment (biological safety cabinets constructed of particle board instead of the industry standard of stainless steel), poor aseptic technique, little to no environmental monitoring, lack of training, and failure to validate aseptic processes. These violations are eerily similar to those noted in the early 1990s, over 2 decades ago. 9 Some sterile compounding facilities have no walls between “clean” areas, and thus there is no way to ensure that the “clean” area is actually clean. Others allow gowns used in the preparation of sterile products to be worn while taking out the garbage and then to be reused in the “clean” room while manufacturing sterile products. About half of the firms in Tables 4 and 5 do not investigate laboratory failures (potency, stability, sterility, endotoxin) even when complaints are received. The majority of firms do not even test their products for potency, sterility, or endotoxins. Most firms in Tables 4 and 5 do not have validated aseptic processes and have deficient gowning practices.
The results obtained are identical across all states, regardless of a mandated adherence to USP <797>. What is unclear is why. Kastango and Bradshaw 10 reported that there may be either a reluctance by pharmacists in compounding facilities to comply with basic aseptic processing standards or a misunderstanding of aseptic processing standards and techniques, or both.
Note that this research includes only compounding pharmacies that were audited by FDA and received an FDA 483. It is possible that pharmacy compounding facilities were audited but did not receive an FDA 483. While FDA 483s are public, a list of facilities inspected but that did not receive a 483 is not made public. Why FDA audited the facilities that received 483s is clear as all produce sterile products; FDAs audit plan targets compounding facilities that manufacture sterile products as those pose the highest patient risk. However, it is not known if FDA chose to audit one compounding facility over another. Since there is no comprehensive list of all compounding facilities in all states that manufacture sterile products, it is also not known if FDA targeted sterile compounding facilities in one state versus another.
On November 27, 2013, President Obama signed the Drug Quality and Security Act (DQSA), legislation that contains important provisions relating to the oversight of compounding of human drugs, including voluntary registration of outsourcing facilities. According to this new law under section 503B, a compounder can become an outsourcing facility and as such must comply with cGMP requirements, will be inspected by FDA according to a risk-based schedule, and must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound. Since registering with FDA as an outsourcing facility is voluntary, it is unclear if new legislation will improve the safety deficits in the pharmacy compounding of sterile products. As of September 2015, only 66 sterile pharmacy compounding facilities have voluntarily registered with FDA. A national database that lists all the compounding pharmacies in all states and what they compound would go a long way to helping both FDA and state boards of pharmacy with targeted inspections. Making state inspection records public would also help increase transparency between FDA and compounding facilities.
Currently, only outsourcing facilities and all facilities in Arkansas and Colorado are required to label compounded products in such a way that the patient who receives them knows they have been compounded and not manufactured by an FDA-approved facility. This makes it difficult for physicians, patients, and pharmacists alike to know if the sterile drug they are about to recommend or consume is actually sterile. Physicians, pharmacists, and consumers could do a quick search on the Internet to determine if the manufacturer is one that is well known or is a compounding pharmacy. But is anyone really going to do that in the cases where the product is lifesaving, part of a drug shortage, and needed immediately, such as epinephrine?
The wisest course of action seems to be what has already been launched—locating compounders of sterile product that manufacture large quantities and/or ship across state lines and ensuring their products are safe via the FDA inspection process and registration of these facilities as outsourcing facilities. This should be coupled with incentives for pharmaceutical manufacturers to upgrade their sterile manufacturing lines and thus continue to manufacture lifesaving sterile products versus discontinuing manufacture and creating a drug shortage. Economic incentives that support product quality would enable the manufacturers who have the most experience with the sterile, lifesaving medication to continue with manufacturing, thus increasing the safety of the medication and preventing possible infections in consumers, some of which may be fatal. It seems ironic that the desired outcome, decreased medication costs resulting from the introduction of generic medications, is what is a likely contributor to drug shortages and thus to the increased use of pharmacy compounders. A better balance between economics and quality/safety is needed.
Conclusions
Sections 503A and 503B of the FD&C Act were implemented largely in response to the NECC crisis in Massachusetts. Under Section 503B of the FD&C Act, FDA has clear jurisdiction over compounding facilities that register as outsourcing facilities. However, registration as an outsourcing facility is voluntary. Compounding facilities that fall under Section 503A of the FD&C Act are regulated by state boards of pharmacy, although FDA can inspect these facilities. Given the sheer number of sterile compounding facilities FDA has audited since the NECC crisis in 2012, most of which were not registered outsourcing facilities, it seems that FDA is not leaving the safety of the American people entirely up to audits performed by state boards of pharmacy; this is in line with the finding that there is no difference in the types of 483s issued in states that require adherence to USP <797> and states that do not.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.