Microbial contamination of parenteral products is one of the most serious issues currently facing the pharmaceutical industry. Injectable drugs, which are administered directly into the circulatory system, bypass a number of innate human immune defenses associated with the gastrointestinal system. Therefore, to ensure the sterility of each of these products prior to patient administration, pharmaceutical companies must adhere to strict government regulations regarding quality control. Maintaining and following a robust quality control program is integral to quality standards and meeting regulatory requirements.
Adding to these pressing concerns are compounding pharmacies that function inappropriately as drug manufacturing companies, but are not legally required to adhere to federal drug manufacturing regulations. Rather, they function under more lenient state policies that govern their operation, but do not enforce quality control analysis. This lack of regulation and oversight has led to several significant microbial outbreaks, which have resulted in multiple deaths from use of contaminated parenteral steroids, cardioplegia solutions, and intravenous drugs. These events highlight the importance of effective pharmaceutical sterility procedures as well as the need for updated regulatory control policies governing the operation of compounding pharmacies. In this article, we will discuss current practices and issues associated with pharmaceutical quality control analysis, how these can affect patient health and safety, and what could be done to remedy the issue.
Pharmaceutical Manufacturing Companies
Pharmaceutical manufacturing companies are licensed facilities that develop, produce, and market drugs. To ensure the sterility of parenteral drugs, several quality control methods are employed, including operation under current Good Manufacturing Practices (cGMPs), sterility testing, and product supplementation with antimicrobial preservatives. When appropriately followed, these processes prevent product adulteration and microbial contamination.
cGMPs are Food and Drug Association (FDA) enforced regulations that govern all pharmaceutical manufacturing companies. They are intended to assure the proper design, monitoring, and control of all manufacturing procedures to confirm the sterility and quality of products. This includes establishing a reputable management system, obtaining high quality raw materials, upholding controlled operating procedures, identifying product deviations, and maintaining reliable laboratories .
To monitor compliance of pharmaceutical companies with cGMP regulations, the FDA routinely performs facility inspections and reviews publically generated product reports. Companies not in compliance with cGMPs are issued a warning and may become subject to regulatory actions. Although the FDA cannot force a company to recall a drug when compliance is not met, violations can be legally addressed and a court order can be granted allowing the seizure and disposal of drugs . However, patient health is still at risk when these pharmaceutical products are not immediately removed from the market. To reduce these risks, it is the responsibility of the pharmaceutical and health care industries to voluntarily cease the production, distribution, sale, or use of all known non-compliant products.
In addition to cGMP compliance, pharmaceutical companies are mandated by the FDA to ensure product sterility through the use of protocols described in the United States Pharmacopeia (USP). Sterility tests commonly used include the methods described in USP Chapter <71> as well as contemporary rapid microbiological methods (RMM). The sterility testing methods described in USP <71> have long been considered the gold standard for detecting microbial contaminants in parenteral drugs. These methods are based on the observation of media turbidity due to the growth of contaminating microorganisms through either direct transfer-immersion sterility testing or membrane filtration[2, 3]. However, these analyses only measure the probable, not actual, sterility of a product lot. Thus, the product administered to the patient is not directly tested for sterility . This presents a major limitation in current sterility testing as it assumes that a small sample is representative of an entire lot. Therefore, these tests can only offer sterility control and assurance; and cannot guarantee product sterility. To fully ensure product sterility, pharmaceutical manufacturing procedures should incorporate sterility protocols, such as filtration procedures, in addition to endproduct microbial contaminant testing.
To supplement USP sterility testing methods, members of the pharmaceutical community often implement RMMs for the routine examination of microbial limit testing, bioburden assessment, environmental testing, raw materials testing, process water testing, sterility testing, and in-process testing. RMMs employed include growthand viability-based technologies, molecular methods, endotoxin testing, and rapid air monitoring. As compared to classical culture methods, such as those described in USP <71>, RMMs can be considerably more sensitive and efficient due to a high degree of automation . However, although these processes offer an enhancement over conventional microbial detection practices, much of the pharmaceutical industry has been reluctant to adopt RMMs. Their unwillingness is primarily centered around a reluctance to adopt new methods due to perceived increased cost, lack of expertise, or fear of the unknown . However, to improve sterility testing methods, RMM detection techniques should be employed in addition to conventional USP <71> sterility testing methods. By combining these sterility practices, pharmaceutical companies can ensure that quality control procedures and products are kept at the highest standards.
Another quality control method employed by pharmaceutical manufacturing companies is the addition of antimicrobial preservatives. These substances are added to products to protect them from the growth of microorganisms that are introduced during the manufacturing process or through multiple withdrawals of the product from its container. For these preservatives to be effective, the stability of the preservative, interactions with the parenteral drug product, the minimal inhibitory concentration, and optimum pH for antimicrobial activity must all be considered [6, 7]. Antimicrobial efficacy is routinely analyzed using the antimicrobial effectiveness test (AET) described in USP Chapter <51> . When properly performed, the AET provides a general gauge of antimicrobial effectiveness at levels that are non-toxic to the consumer.However, this analysis does not guarantee that a preservative system will never allow the growth of a contaminant in a product .
Overall, the quality control methods used by pharmaceutical manufacturing companies, in addition to strict FDA regulatory oversight, ensure that manufactured parenteral drug products are sterile prior to administration. However, associated regulatory procedures should be updated or modified to truly guarantee the sterility of all products. For example, when cGMP compliance is not met, products should be removed from the market immediately upon discovery and a recall issued to ensure they are not used. Additionally, sterility testing methods and protocols used to test preservative efficacy should be updated to include more sensitive assays. Maintaining high standards in manufacturing and quality practices provide customer assurance that a product is indeed safe to use.
Pharmaceutical Compounding Companies
Compounding pharmacies are companies that combine or process FDA approved drug products to produce individualized medications to fit the unique needs of a single patient. They are often called upon when patients require limited dose strength, a unique or specialty formulation, or allergenfree medication. Presently, compounding facilities are predominantly regulated by individual state Pharmacy Boards with oversight by the FDA. Under this guidance, compounding pharmacies are required to adhere to preparatory and sterility practices as described in the Federal Food, Drugs, and Cosmetics Act (FDCA) and the USP, respectively.
Section 353a of the FDCA defines the purpose of drug compounding and what practices compounding pharmacists must follow. Further, this section indicates that compounding can only be performed with a valid prescription order that indicates the customer’s need for an individualized medication. Furthermore, this law clarifies that compounded products must be prepared in limited amounts and should not be produced when commercially available drug products exist. However, due to the limited volume of compounded products produced in each lot, this law exempts legitimately prescribed and prepared compounded drugs from review, approval, adverse event reporting, and placement of storage and labeling requirements on product vials . Problems arise when compounding pharmacies function outside the FDCA regulations by operating as drug manufacturers. By functioning in this inappropriate capacity, compounding companies risk producing large quantities of adulterated drugs that are not manufactured under cGMPs, not properly controlled for quality, and are not FDA-approved. Thus, the sterility of compounded products received by patients cannot be guaranteed.
To help maintain the sterility of compounded parenteral drugs, compounding pharmacists are required to adhere to USP<797>. This standard details sterility testing procedures including sampling the air, preparation surfaces, and gloved fingers for viable microbial particulates. In these particular tests, any colony forming unit counts that exceed the respective action level require identification of the source of contamination and subsequent re-evaluation of personnel work practices, cleaning procedures, operational procedures, and air filtration efficiency. However, due to lenient state regulations, many compounding facilities do not routinely perform USP <797> testing procedures.
Because of the continued regulatory leniency over quality control and sterility testing procedures, there have been multiple microbial outbreaks associated with compounded parenteral products. A recent example includes numerous hospitalizations and deaths attributed to contaminated parenteral steroids produced by the New England Compounding Center (NECC) . Patients who received the tainted steroid product were documented to have primarily suffered from fungal meningitis as well as strokes, spinal osteomyelitis, epidural abscesses, or fungal infections associated with peripheral joints [10, 11]. In addition to this recent outbreak, there have been other past incidences of contaminated compounded parenteral drugs resulting in patient sickness and death. These include tainted cardioplegia solutions produced in 2005 by Central Admixture Pharmacy Services Inc. and bacterial-contaminated intravenous medications produced in 2011 by the Advanced Specialty Pharmacy [12, 13].
Regardless of the increasing number of hospitalizations and deaths associated with contaminated parenteral drugs, regulations governing the quality control of pharmaceutical compounding have yet to be legally updated; however, it is not from a lack of trying. In the past decade, there have been several efforts to establish additional FDA oversight on pharmacy compounding. One example includes an attempt in 2007 to introduce the Safe Drug Compounding Act, which would have provided the FDA with authority to restrict when doctors could order injectable drugs from compounding pharmacists, limit interstate distribution of compounded drugs, and establish requirements for sterile compounding. However, the Safe Drug Compounding Act, like many other attempts at increasing FDA oversight, was never passed. In this case, it was primarily due to the efforts of many compounding pharmacists who argue that forcing additional regulations on compounding companies would “negatively impact patient access to necessary compounded prescription medications,” as described in a March 2007 letter reviewed by Reuters . Moreover, those opposed claim that the FDA does not have the right to impose a ban on traditional compounding practices, as the FDA Modernization act of 1997, which amended the FDCA, was created to ensure the continued availability of compounded drug products .
Though it is unlikely that the FDA will be able to legally enforce some of the aforementioned quality control regulations, the safety concerns associated with compounded parenteral products must be addressed and minimized. First, all compounding pharmacies that are functioning outside of FDCA regulations and operating as manufacturing companies should be required to register with the FDA and operate under FDA regulated cGMPs and sterility testing procedures. This will ensure that any pharmaceutical facility that manufactures a drug is regulated by a minimal set of quality control standards. Second, compounding companies should be required to report any adverse drug problems, such as microbial contamination or calculation errors, with the FDA. This would ensure that all patients who had been exposed to the product would be immediately notified and assisted. Lastly, all clinical health care facilities that purchase and distribute compounded medications should be required to provide a disclaimer to their patients. This warning would warrant that patients are well informed of the risks associated with compounded medications, which may lead to more individuals to immediately seek help upon use of a contaminated product.
Though it is the responsibility and ethical obligation of each pharmaceutical facility to produce parenteral medications of confirmed sterility, companies may fall short of their obligations. Over the past decade, failure of regulatory compliance has resulted in numerous hospitalizations and deaths attributed to contaminated products. In response to these outbreaks, both the enforcement of and the quality control regulations that pharmaceutical companies currently operate under must be scrutinized and updated.
Currently, registered pharmaceutical manufacturers operate under strict FDA regulatory control. In contrast, compounding pharmaceutical companies are minimally regulated, do not require drug approval, and are not legally required to report the production of an adulterated parenteral drug. Additionally, many of these compounding companies regularly operate outside the boundaries of the FDCA by functioning inappropriately as a drug manufacturer. Because of lax oversight regarding product preparation and sterility, the quality of the drug supply is diminished. Thus, it is essential that the policies governing the sterility, operation, and production of all pharmaceutical products be addressed. Only with updated, effective regulations, procedures, and robust manufacturing and quality practices can patients be assured of the sterility of their medications.
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Cara N. Wilder, Ph.D., is a microbiology specialist at ATCC. She received her Ph.D. from Oregon State University and was a postdoctoral fellow at the University of Maryland.
Elizabeth Kerrigan is the Director of Products, Services, BioCollections and Standards at ATCC in Manassas, Virginia. She also directs the ATCC Standards Development Organization and is the ATCC representative to the United States Pharmacopeial Convention, American National Standards Institute, Clinical Laboratory Standards Institute, Stakeholder Panel on Agent Detection Assays, as well as a member of PDA, ASM, USP, ISBER and AMP.