Medication production for patient use has always traditionally come from one of two sources: large scale pharmaceutical manufacturers, typically producing tens of thousands of doses daily under the jurisdiction of the Food and Drug Administration (FDA) and distributed via traditional retail or mail order pharmacies, and compounding pharmacies, extemporaneously preparing doses based on individual patient needs under the jurisdiction of their home state’s Board of Pharmacy. The growth in the number and size of compounding pharmacies, both producing sterile and non-sterile products, over the past twenty years has improved patient access to specialized, non-commercially available drugs but has also exposed quality concerns. Issues with sterility, stability, and potency especially in a few pharmacies engaged in large scale production has raised significant concerns with the FDA (see New England Compounding Center meningitis outbreak – Wikipedia). These concerns were addressed in the Drug Quality and Security Act of 2013, in which Congress created a new category of compounders known as outsourcing facilities. In contrast to “traditional” compounders, outsourcing facilities can, subject to satisfying relevant legal requirements, compound and distribute drugs without receiving prescriptions for individual patients, and without limitation on the quantity of drugs that they ship interstate. These outsourcing facilities, also known as 503B compounding pharmacies under the new section titled 503B of the Food, Drug & Cosmetic (FD&C) Act, must register with and agree to oversight by the FDA. These facilities often prepare medications that are temporarily unavailable from the manufacturer, medications no longer produced by manufacturers, or unique formulations not commercially available. The customers of outsourcing facilities are commonly hospitals, clinics and physician offices. Drugs compounded by outsourcing facilities are subject to current good manufacturing practice (cGMP) requirements, similar to those that pharmaceutical manufacturers are subject to and much more stringent than the regulations applied by State Boards of Pharmacy (Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry | FDA). Currently, there are less than 75 total FDA registered outsourcing facilities operating in the United States.
A Core Pillar of cGMP is the Design and Construction of the Facility
The design must address efficient and controlled workflow, segregation of sterile and non-sterile environments, and safe storage of components and final product. Special consideration is given to the air handling and environmental quality (HVAC system) to assure proper airflow and cleanliness to reduce particulate and microbial contamination of delivered air and prevention of cross contamination within and between operating spaces. No compromises are admissible when it comes to sterile manufacturing. Due to their nature of use, sterile products are manufactured under controlled environments in order to control contamination. This is done through special facilities called clean rooms. Clean rooms within outsourcing facilities are A and B graded. A-Graded clean rooms are considered high-risk operation areas. These areas are the highest controlled as they involve the exposure of the final product to the environment within the clean room. B graded clean rooms are the background environment for the main production area. The main difference in the different graded clean rooms is the air cleanliness. Each area must meet specific standards of a clean air classification. Essentially, how many microorganisms are allowed per cubic foot of air of the room.
Although there are various sterilization precautions from cleaning supplies all the way to how staff dress when they enter a clean room, the main way a sterile plant controls its environment is by controlling the air. A moderate temperature and low humidity are maintained throughout the production area so that the environment is not hospitable for microorganisms. High-Efficiency Particulate Air Filters (HEPA) are utilized to reduce particles and microorganisms from entering rooms even further. Then, the air flow is controlled at a specific velocity, this is known as unidirectional air flow. Constant parallel streams of air are uniformly swept over the entire surface of the production area of the clean room. The objective of this is for the air directional flow to collect particles and transport them out of the clean room through ducts and another filtration system.
Within the cleanrooms is where individual ingredients are combined in under precise control, often utilizing specialized equipment not found in traditional pharmacies but more akin to that seen in pharmaceutical manufacturing. These apparatuses often have specific functions involving mixing, blending, final dose forming, sterilization, and packaging. This equipment must be routinely cleaned, maintained, and validated, often several times per day between batches. Due to the precision required, this equipment often costs tens of thousands to hundreds of thousands of dollars per device and requires extensive operator training.
Are Quality Control and Quality Assurance Core Tenets of cGMP?
Core tenets of cGMP are quality control and quality assurance, and oftentimes this team of staff is referred to as the Quality Unit (QU). They are responsible for constant testing and evaluation of all equipment, chemicals, staff, and critical air environments that are involved in drug production. Testing performed by the QU includes confirmation of all drug ingredients (APIs, binders, and water) potency and stability, sterility of the drug production areas, cleanliness of all equipment used, operator technique and sterility, container and closure integrity and sterility, and, of course, final product potency and sterility. The actions of the QU are similar, if not identical, to their counterparts in the pharmaceutical industry because cGMP doesn’t compromise or distinguish between large and small operations (Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations | FDA).
Though, well designed outsourcing facilities often are state-of-the-art, it is the staff and their training and adherence to cGMP that is the heart of operation. In addition to the business managers, these facilities require skilled technicians, chemists, plant engineers, pharmacists, quality assurance personnel, microbiologists, statisticians, and administrative personnel. A typical medium sized outsourcing facility with four to eight separate product lines (each producing a particular medication) may employ forty or more people with salaries ranging from $20 per hour for warehouse support to over $200,000 annually for the PhDs and Pharm.Ds.
The advent of the outsourcing facility has opened a new avenue for the production of medications. These facilities fill the gap between the large pharmaceutical manufacturers and the patient specific compounding of community pharmacies. They provide for the manufacture of large volumes of doses of FDA approved drugs that are either in short supply or not currently available and are often the only source for hospitals and clinics across the country. With the reliance of the national healthcare system on an often-international single source of specific medications, the outsourcing facility is becoming the safety net. Growth of this sector of pharmaceutical production is only limited by the investment costs and acquisition of trained and talented professionals.
If you or your organization is interested in building, adding, or acquiring a 503b compounding pharmacy or outsourcing facility, please contact us online now, or call us at (877) 503-7687 to discuss how we can help guide you in this highly complex and regulated industry. Our inhouse experts have decades of direct hands-on experience in the fields of drug compounding and manufacturing.
