The recent meningitis outbreak due to tainted compounding is a catastrophic example of the importance of quality assurance for compounded sterile products (CSPs). The CDC investigation concluded that a total of 48 deaths have resulted to date from patients receiving contaminated methylprednisolone acetate (MPA) compounded injections.1 This event is just one of several incidents in recent years that have linked contaminated CSPs to patient deaths. With hospital pharmacies increasingly outsourcing sterile compounding to vendors, these tragedies emphasize the need for continued diligence by both pharmacists and pharmacy technicians to ensure that proper quality assurance measures are strictly adhered to when compounding sterile products.
Market forces have led pharmacies to find creative ways to control costs and improve efficiencies, particularly with CSPs. Some hospital pharmacies are considering incorporating methods to evaluate and validate beyond-use-date (BUD) extensions, defined as the date at which a CSP should not be used, as a way to control costs and decrease waste.2 To take this approach, pharmacists must be certain that CSPs within their institution retain both stability and sterility; however, most pharmacies are not equipped to perform robust stability and end-product sterility tests. Therefore, many have opted to use contracted analytical laboratories to fulfill these testing requirements. These suppliers offer a wide range of laboratory and analytical testing services to address hospital pharmacy needs, including sterility testing, stability versus potency testing, quality assurance, accreditation, and regulatory compliance.
Sterility Testing: Membrane Filtration vs Direct Inoculation
Sterility testing is an essential component of compounding safety. USP Chapter <71> states that both direct inoculation and membrane filtration are suitable tests for examining a product for sterility.3 Direct inoculation involves the transfer of a test solution directly to a growth medium. Membrane filtration, the commonly accepted standard for examining CSPs, involves pouring a sample through a membrane filter, then placing the membrane on a recovery medium to incubate for cell recovery. Membrane filtration allows laboratories to test more samples using less medium, produces fewer false positives, and has a greater sensitivity of microbial detection than direct inoculation.4
Many laboratories highlight their state-of-the-art instruments for sterilitytesting (eg, rapid membrane filtration) that enable increased automation, higher detection and accuracy rates, and shorter incubation durations. While sterility tests are becoming more accurate and efficient with improved technology, it is important to evaluate whether the laboratory’s entire sterility process is validated according to compendial standards.3 USP Chapter <1223> states that, “In an event of a dispute, only the result obtained by the compendial test is conclusive.”3
Stability Testing vs Potency Testing
When researching analytical laboratories for BUD services, it is important to determine the types of stability tests performed and whether a stability-indicating method (SIM) is used—this is a validated quantitative analytical procedure that measures the amount of active pharmaceutical ingredient free from potential interferences. Drug stability is a critical component in BUD extension. While potency testing can include a variety of tests, such as titration, only a SIM determines stability.5 The typical instrument used to separate and quantitate drug samples for both potency and stability is high-performance liquid chromatography (HPLC). There is a common belief that potency testing is suitable to determine BUD, and depending on the type of method done, this may be true. The key is whether the potency test uses a SIM. This is important because both stability-indicating and potency tests can use similar instruments, but only SIM incorporates forced degradation, a process that applies external stress to increase the speed of a product’s degradation rate, allowing the active ingredient to separate from degradants, impurities, and excipients.4
Evaluating the Laboratory
Evaluating the quality assurance and quality control of a laboratory’s service is one of the most important parts of researching analytical laboratories. Similar to that of a compounding pharmacy, laboratories should have quality assurance and quality control steps in every testing and validating process. It is important to ask potential vendors if the laboratory has an established quality assurance program. If they do not have such a program, the laboratory should have documents explaining in detail their standard operating procedures, personnel training, verification methods, testing methods, and instrument calibration history. These documents should be readily available, easily retrievable, and the laboratory should be willing to share them with potential customers. You should also consider whether there is a quality assurance officer and whether the quality assurance team is a separate entity within the organization. In regards to testing the final CSP, the laboratory should provide a certificate of analysis that demonstrates each of their performed tests, description of the end products tested, and final results.
Laboratory accreditation is the process by which a third party assesses the competence of a laboratory on a specific test. It is important to note the scope of accreditation; accreditation does not necessarily include all laboratory testing instruments and methods. As a potential customer, you may need to determine if the accreditation includes the testing methods you are seeking.
Laboratories may also be accredited on their compliance with the International Organization for Standardization (ISO) standards. Laboratories accredited under ISO 9001 standards have been evaluated and shown to meet the criteria for a quality management system.6 Another ISO standard to consider is ISO 17025; it addresses the general requirements for competence of testing and calibration laboratories. ISO 17025 certification encompasses part of the ISO 9001 standardization categories plus a more rigorous audit for verifying instrument calibration.
This is not to say that non-accredited laboratories should not be used. Accreditation and maintaining accreditation status is a costly undertaking for laboratories. Some laboratories may not have the resources for accreditation, but have excellent standard operating procedures that exhibit best practices. Conducting onsite visits and understanding quality assurance and quality control measures will help in these situations. Pharmacies may want to partner with their epidemiology team to evaluate the efficiency of a laboratory’s standard operating procedures.
Although not required, most laboratories are registered with the FDA, which provides some comfort to potential customers in assuring that the laboratory is complying with federal regulations. By registering with the FDA, laboratories are opening their doors to FDA audits. However, FDA audits are not all-inclusive, and may not audit the entire laboratory or processes without specific reason. For example, the result of an FDA audit may show that a company was deemed compliant. However, the company is deemed compliant only in what the FDA audited. This does not necessarily mean that the analytical laboratory’s entire service line, including end-product sterility and stability testing, are in fact compliant.
The additional benefit of a laboratory having FDA registration is it provides the ability to review that laboratory’s public records. The FDA website includes the registration information and any warning letters (FDA Form 483) issued to registered laboratories. (For more information regarding warning letters, go to http://www.fda.gov/ICECI/EnforcementActions/ucm256377.htm.)
Good Laboratory Practices (GLPs) is a federal regulation (21 CFR 58) that ensures the quality and integrity of safety data for nonclinical laboratories.7 This regulation provides criteria for items such as laboratory operations, personnel training, procedures, testing articles, and records. It is important to note that the FDA does not certify GLP laboratories. However, the FDA is the governing body that oversees compliance and is authorized at any time to audit a laboratory. It is in the best interest of analytical laboratories to be compliant, and most laboratories have stringent standard operating procedures to ensure compliance with the federal code.
In addition to sterility and stability testing, some laboratories offer further testing and validation services, including endotoxin testing, pH testing, specific gravity testing, and dissolution validation. Online services are also available from some laboratories that allow customers to submit and track samples, receive certificates of analyses, and access useful data graphs and time charts. These are attractive services for customers who require data accessibility and quick turnaround time for test results.
Some laboratories also offer consulting services such as USP <797> compliance, standard operating procedure guidance, and quality improvement initiatives. These programs are intended to highlight the laboratory’s expertise in building programs that meet standards and regulations. In addition, these services are advertised as a means for customers to increase revenue and decrease cost by discovering new opportunities, improving current practice, and removing deficiencies with one’s practice.
Closing the Gaps
Recent contamination tragedies highlight the disastrous consequences of allowing gaps in quality assurance and quality control measures when compounding sterile products. Analytical testing laboratories offer services that allow end-product testing for BUD extensions; utilizing such services can help to ensure that compounded sterile products are safe and efficacious to patients.
Christian S. Conley, PharmD, is a first year health-system pharmacy administration resident at the University of North Carolina Hospitals and is a graduate student at the UNC Eshelman School of Pharmacy. He received his doctoral degree from Samford University, McWhorter School of Pharmacy in Birmingham, Alabama.
Robert Granko, PharmD, MBA, is the associate director of pharmacy at the University of North Carolina Hospitals. He graduated with a BS in pharmacy from Long Island University School of Pharmacy, Brooklyn, New York, and received his PharmD from the University of North Carolina at Chapel Hill and his MBA from Pfeiffer University School of Graduate Studies.
Proposed FDA Regulations Target Nontraditional Compounding
Following the recent meningitis outbreak, the FDA is pursuing new regulations for increased federal oversight of high-risk and high-volume compounding pharmacies. The proposed regulations will categorize such entities as performing nontraditional compounding. Under the proposed regulation, pharmacies that conduct nontraditional compounding will likely be required to comply with current Good Manufacturing Practices (cGMP), federal code 21 CFR 211. While most laboratories are GLP compliant, cGMP compliance is less common. In fact, few laboratories claim cGMP compliance; nonetheless, their standard operating procedures may abide by cGMP standards. For pharmacies researching laboratories to provide BUD testing, cGMP compliance will likely become increasingly important, especially for those pharmacies that outsource CSPs to nontraditional compounding pharmacies.
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