While pharmaceutical compounding has existed throughout history, mass production of pharmaceuticals drove down the need for such drugs for much of the 20th century. It wasn't until the 1970s and 1980s, when the demand for chemotherapeutic and total parenteral nutrition regimens increased, that the pharmaceutical compounding industry began to grow. The market has been advancing steadily since — driven by bulk compounding, increases in home infusion therapy, the evolution of personalized medicines, a rise in hormone replacement therapy, and more. Compounding pharmacies also serve a critical role in providing alternate dosage forms of medications. For example, some patients may need an oral liquid versus a tablet or have allergies or dietary restrictions requiring specially formulated drug versions. Despite their unique position in the marketplace, regulations specific to pharmaceutical compounding are relatively recent.
An Evolving Regulatory Landscape
In September 2012, the CDC, FDA, and local and state health officials began investigating a multistate outbreak of fungal meningitis among patients who received contaminated steroid injections. The contaminated medication was traced back to a compounding facility in Massachusetts, which the FDA had previously visited and found sterility issues. The agency lacked the authority to impose or enforce any changes to the site even though facility operations resembled an FDA-regulated drug manufacturer. Instead, due to the regulatory environment at that time, the facility was able to continue operating as a pharmaceutical compounder,subject only to regulation by state boards of pharmacy. As a result of medications being produced under insanitary conditions by the facility, 753 patients were affected across 20 states, and 64 died.
In response, Congress passed the Compounding Quality Act as part of the broader Drug Quality and Security Act in 2013. This legislation defined two categories of compounders — 503A traditional compounding pharmacies and 503B outsourcing facilities.
• 503A: Traditional Compounding Pharmacies
A 503A pharmacy can compound for individual prescriptions only, not bulk production of drugs. They are required to comply with state boards of pharmacy regulations and requirements outlined in USP <795> Pharmaceutical Compounding-Nonsterile Preparations, USP <797> Pharmaceutical Compounding-Sterile Preparations, and any standards referenced within those chapters.
• 503B: Outsourcing Facilities
Once a 503B outsourcing facility voluntarily registers with the FDA, it must comply with USP <795>, USP <797>, and any standards referenced within those chapters. In addition, they are also required to follow cGMP regulations specified in the Code of Federal Regulations Title 21 Parts 210 & 211 and are under the jurisdiction of the FDA.
Any compounding pharmacy not complying with applicable regulations or failing to register as an outsourcing facility may be subject to rules set forth for drug manufacturers in the Food, Drug, and Cosmetic Act.
The Risk of Microbial Contamination
Among the risks compounding pharmacies face, microbial contamination has always been a significant concern. While licensed pharmacists oversee the actual compounding of medications, they are typically not trained on how to set up, run, and monitor a contamination control program.
One of the most considerable risks for 503A compounding pharmacies producing compounded sterile preparations (CSPs) is the lack of proper training and expertise necessary to implement contamination control measures. Ineffective microbial control measures are combined with the fact that these facilities generally do not register with the FDA and are not subject to cGMP requirements. Plus, although 503A compounding pharmacies should be following USP <797> when producing CSPs, they are also under the jurisdiction and quality standards set in state law or policy, and such criteria may differ from state to state.
For 503B outsourcing facilities, the biggest risk lies in the challenge of producing sterile medications themselves. As CSPs become more prevalent, sterility failures can lead to an increase in adverse events.
In both cases, 503A compounding pharmacies and 503B outsourcing facilities need to remain vigilant in understanding the risks of producing CSPs. This calls for hiring highly skilled microbiologists to implement microbial control policies and procedures, train staff, and cover everything from environmental monitoring to cleaning and disinfection to sterility and endotoxin testing (when applicable). Similarly, as the market grows, so will competition.
Producing consistently high-quality, safe, and effective products is an excellent competitive advantage. The bottom line for any pharmaceutical compounder is that while the “cost of quality” is not cheap, investing in quality personnel, processes, and procedures is worth it to increase patient safety and ensure business longevity.
Accurate Microbial Identification
Getting an accurate microbial identification is easier said than done, but it's a critical practice. Correct identification of microorganisms improves reporting capabilities, which facilitates the full investigation of root causes for contamination and informed decision-making. With accurate data, it is possible to fully understand issues that arise and develop meaningful corrective and preventive actions to reduce production downtime and improve patient safety. However, USP chapters have some variability regarding the degree to which microbes should be identified.
In USP <797>, the chapter states isolates should be identified “at least to the genus level.” USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments indicates that an “appropriate level of identification” should be used. On the other hand, USP <1117> Microbiological Best Laboratory Practices states that isolates should be identified “to species level whenever possible” for risk assessments and that confirmatory tests for laboratory QC microorganisms should be performed “at the level of genus and species.”
• Species-Level Microbial Identification
Overall, species-level identifications will provide the best resolution in microbial data sets compared to genus-level identifications. Species-level identifications add value when investigating an environmental monitoring excursion, a sterility failure, or a potentially objectionable organism in your product. As part of your root cause analysis, the value of species-level identifications is realized when you will be comparing your isolate of interest to historical data obtained from the environmental monitoring of your facility. If your historical data is full of genus-level identifications, it becomes very difficult to track the source of a particular species. Additionally, strain-level characterizations may be necessary to provide more evidence linking your investigational isolate to a contamination source.
• Methods for Microbial Identifications
Phenotypic methods, dependent on the analysis of biochemical reactions of a microorganism, can have subjective test results and often rely on very limited or clinically-focused identification libraries. These methods also rely on ancillary tests, such as Gram stains, prior to analysis, leading to further variability and data integrity concerns.
Proteotypic methods, based on MALDI-TOF analysis of primarily ribosomal proteins in a microorganism, can be very reliable and have a high sample throughput. However, attention needs to be paid to the breadth (number of species) and depth (number of strains) of the identification library to ensure it is pharma-focused to reproducibly obtain the highest rate of species-level calls.
Genotypic methods (DNA sequencing) are the gold standard for microbial identifications. They provide the best chance for accurate and reliable species-level identifications but require complex instrumentation and highly skilled personnel, and the throughput is limited. Experienced scientists are also needed to properly analyze the sequence data and phylogenetic trees to ensure accurate identifications are made. DNA sequencing is usually best left to a trusted outsourcing partner.
Best Practices for Mitigating Risk
Compounders produce drugs under less regulatory pressure while also, paradoxically, being expected to maintain product quality and ensure patient safety to the level at which FDA-approved drugs are held. With that, those looking for quality improvements to mitigate risk may consider implementing processes and procedures often seen in pharmaceutical industry facilities that produce regulated products.
Periodic internal audits conducted by quality assurance departments are an excellent way to identify potential issues and engage in continuous quality improvement initiatives.
Addressing issues internally helps ensure that external audits run smoothly with minimal impact on the facility. This is especially critical given that, although some external audits are scheduled or expected within a certain time frame, some are complete surprises.
The types of policies, procedures, or systems being audited depend on the auditing entity. Auditors may be potential clients, current customers, state boards of pharmacy, FDA or DEA, and city or county officials. More detailed audits may include an examination of organizational structures and responsibilities, training and quality policies, corrective and preventive actions, facility operations, equipment qualification, incoming material receipt and testing, finished product testing and release, and environmental monitoring. Regardless of the audit type, it is essential to be ready.
Identifying a trusted, reliable outsourcing partner offers many advantages for a pharmaceutical compounding facility. Most importantly, outsourcing provides compounding pharmacies access to qualified, compliant products and services that help them protect patients and their businesses while improving microbial control programs.
A highly experienced consultant in microbial control can help identify gaps in a facility's quality processes and procedures and define a plan for quality improvement. The cost per reportable result also decreases while the accuracy of identifications increases without having to make capital investments and maintain expensive identification equipment — helping improve operational efficiencies while reducing compliance risk. One factor often overlooked in the cost analysis of partnering with an outsourcing company is the cost of inaccurate identification. Processes that result in inaccurate, inconsistent, or no identification must be repeated using other methods to get successful identification. In addition to adding time and operational costs, it can lead to misdirected remediation efforts and pose a threat to patient safety. Outsourcing microbial identifications also frees up your quality control microbiology staff to work on other critical tasks.
What to Look for in an Outsourcing Partner
When choosing an outsourcing partner, it is imperative that you start by conducting a comprehensive supplier verification audit to assess the quality of their products and services. After all, their data is your data, and you must be confident that your chosen outsourcing partner is generating compliant, audit-ready information to support your business.
First and foremost, outsourcing partners should have the industry knowledge and technical expertise to provide value to the organization to ensure the safe supply of compounded medications. Whether you're a 503A pharmacy or 503B facility, look for companies that:
• Are cGMP-compliant, FDA-registered, and maintain one or more ISO certifications for quality testing, such as ISO 17025.
• Have FDA-licensed products used for compliance with compendial test methods.
• Have extensive, quality reference databases with respect to microbial identification that are validated and updated frequently.
• Offer integrated cGMP-compliant data management tools for tracking and trending microorganism information so you can access data whenever needed.
• Provide access to a capable technical support group to assist with everything from routine identifications to microbial investigations.
More than anything, however, you should look for an outsourcing partner you feel confident will be with you every step of the way, from sample submission to identification to technical support.
The unique position of compounding pharmacies in the drug production and regulatory landscape enables them to help combat supply chain disruptions during catastrophic events.
This was seen most recently in 2017 with Hurricane Maria's impact on pharmaceutical production in Puerto Rico and, of course, COVID-19. During the pandemic, the FDA temporarily allowed commercially available drugs to be compounded by pharmacy compounders not registered as outsourcing facilities. With this, market growth is expected to accelerate as these pharmacies continue to play an increasingly important role in the industry as it relates to the rising costs of commercial drugs, decreasing drug accessibility, and drug shortages.
Dr. Doug Botkin
Technology and Market Development Manager
~ Charles River Laboratories
Dr. Doug Botkin is a Technology and Market Development Manager at Charles River Laboratories. He is a subject matter expert in the Microbial Solutions group, focusing on Accugenix products and services for microbial identifications. Doug has over 24 years of experience in infectious disease research, spaceflight microbiology, and pharmaceutical microbiology. He holds a bachelor’s degree in Biological Sciences from Illinois State University and earned his PhD in Microbiology and Molecular Genetics from The University of Texas Health Science Center at Houston.
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