This article presents a common understanding of both Fresenius Kabi and bioMérieux for good compounding practice, and reviews microbiological testing as related to sterile compounding. Topics discussed include environmental and personnel monitoring, media fills and the release testing of compounded sterile preparations. Although the topic is approached from a US point-of-view, the information will be useful for benchmarking by European compounding pharmacists, and for consideration for improving compounding practice.
Sponsored by the Business Unit Compounding of Fresenius Kabi (in collaboration with bioMérieux).
Sterile compounding can be defined as the preparation of an individual drug to meet a physician’s prescription that is administered directly to the patient. In the US, compounding is performed or supervised by a pharmacist licensed by a state board of pharmacy. A compounded sterile preparation (CSP) meets the unique needs of an individual patient when commercially available drugs do not meet those needs in terms of dosage, mode of administration and formulation. A patient might not be able to take the commercially available drug, or might require a drug that is currently in short supply or discontinued.
In the Autumn of 2012, a multi-state fungal outbreak associated with a compounded sterile preparation manufactured in a large scale for interstate commerce changed the global regulatory landscape in both the US and Europe. On 21 September 2012, the US Federal Center for Disease Control and Protection (CDC) was notified by the Tennessee State Department of Health of a patient with the onset of fungal meningitis approximately 19 days following epidural steroid injection at a Tennessee ambulatory surgery centre. On 28 September, investigators identified a case outside Tennessee, possibly indicating contamination of a widely distributed medication.
On 4 October 2012, out of an abundance of caution, the CDC and FDA recommended that all health care professionals cease use and remove from their pharmaceutical inventory any product produced by the New England Compounding Center (NECC), located in Framingham, MA. The Massachusetts Department of Public Health collaborated with the CDC and FDA on a multi-state investigation of fungal meningitis among patients who received an epidural steroid injection to control back pain. The pharmacy involved NECC and recalled three lots consisting of a total of 17,676 single-dose vials of the steroid, preservative-free methylprednisolone acetate (MPA).
The contaminating fungus was established as Exserohilum, a fungus so rare in human infection that the Tennessee State Health Commissioner described it as a fungus most physicians never see it in a lifetime of practising medicine. According to the ASM Manual of Clinical Microbiology, phaeohyphomycosis of the skin, subcutaneous tissue, cornea, nasal sinuses and the brain have been documented with this fungus. As of the final CDC update in October 2015, this multi-state outbreak resulted in 753 fungal meningitis infections in at least 20 states and 64 deaths due to Exserohilum rostratum from contaminated preservative-free MPA steroid injections.
Establishing an environmental monitoring programme might be a new activity for some sterile compounding pharmacies. This review briefly summarises the requirements for microbial monitoring as well as associated release testing. These will differ by regulation responsibility in the United States; for example, a state board of pharmacy expects the compounding pharmacies to comply with USP <797> (following Section 503A sterile compounding pharmacies), and the US FDA regulates compounding pharmacy that have to comply with pharmaceutical good manufacturing practices (following Section 503B outsourcing sterile compounding facilities).
Sterile compounding pharmacies in the US
Section 503A sterile compounding pharmacies must comply with the requirements found in USP <797> Pharmaceutical compounding: sterile preparations in terms of the location and frequency of environmental monitoring in their sterile compounding and support areas. These general requirements are summarised in Table 1.
Frequency of sampling
According to the current chapter <797> air sampling shall be performed at least semi-annually (that is, every six months) as part of the re-certification of facilities and equipment. USP <797> is currently undergoing revision and it is likely that the frequency of monitoring will be increased from semi-annually to monthly routine monitoring. Contrast this frequency to every manufacturing shift in pharmaceutical drug product manufacturing.
Selection of sampling sites
USP <797> requires that an appropriate environmental sampling plan is developed for airborne viable particles based on a risk assessment of compounding activities performed. The risk assessment should take into consideration the compounding processes and the compounding products. The focus should be on high-risk locations where significant movement of people, airflow, or product exposure occur during the compounding. Selected sampling sites shall include locations within each ISO Class 5 environment (Grade A) and in the ISO Class 7 and 8 environments (Grades B and C), and the segregated compounding areas at greatest risk of contamination (for example, work areas near the ISO Class 5 environment, counters near doors, pass-through boxes). The plan should include sample location, method of collection, frequency of sampling, volume of air sampled, and time of day as related to activity in the compounding area and action levels.
Qualification and re-evaluation of compounding personnel
All compounding personnel working in ISO Class 5 and 7 environments (Grades A and B) shall successfully complete an initial competency evaluation and gloved fingertip/thumb sampling procedure (zero CFU) no less than three times before initially being allowed to manufacture CSPs for human use. More specifically to ISO Class 7 environment (Grade B), the garment can also be sampled (for example, forearms, chest, head). This can be slightly different for compounding in isolators. Re-evaluation of all compounding personnel for this competency shall occur at least annually for personnel who compound low- and medium-risk level CSPs and semi-annually for personnel who compound high-risk level CSPs using one or more sample collections during any media-fill test procedure before they are allowed to continue compounding CSPs for human use.
Microbiological growth media
A general microbiological growth medium such as soybean–casein digest agar (also known as trypticase soy broth agar (TSA)), is used to support the growth of bacteria, yeast and mould. Media used for surface sampling shall be supplemented with additives to neutralise the effects of disinfecting agents (for example, TSA with lecithin and polysorbate 80) that may persist on surfaces. The media is subject to growth promotion testing using the recommendations found in USP <61> Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests. The plates used in environmental monitoring are incubated between 20 and 35°C for 5–7 days. A commonly used incubation schema in the pharmaceutical industry is 20–25°C for 2–3 days followed by 3–5 days at 30–35°C to promote fungal growth.
Monitoring methods
Acceptable methods for monitoring the microbiological quality of the environment include surface monitoring product contact on surfaces, floors, walls, and equipment with swabs and contact plates, active air monitoring with impact or centrifugal air samplers and passive air monitoring with settling plates.
Contact plates are used to detect and enumerate microorganisms on flat, non-porous surfaces such as the stainless steel working surface in a laminar flow hood or biological safety cabinet. They may be used for personnel monitoring of cleanroom gowns, sleeves, and gloves. Disposable plastic plates, with a 55-mm diameter, are filled with TSA with the convex meniscus of the agar above the rim of the plate to make contact with the surface being sampled. Alternatively, regular-sized plates may be used for full palm imprints. When the surfaces samples have been disinfected, neutralising agents are incorporated in the medium. Tween 80 (0.5% polysorbate) is used to neutralise residual phenolic disinfectants and 0.07% lecithin is used to neutralise quaternary ammonium compounds. The sampling is achieved by touching the entire meniscus on the surface and using a rolling uniform pressure on the back of the plate to effect contact. After incubation, the number of CFUs are counted and the results expressed as CFU per plate or per square centimetre.
For active or passive air monitoring 90-mm diameter TSA plates are exposed during sample collection. High-efficient air samplers are available from multiple vendors that may sample a cubic metre of air (1000 litres) in the order of 10 minutes. After incubation, the number of CFUs are counted and the results expressed as CFU per cubic metre of air (active air sampling) or after a four-hour exposure (settle plate or passive exposure).
Media fills
USP <797> requires that after successfully completing hand hygiene and gowning qualification that all compounding personnel have their sterile technique evaluated using a media-fill test using the worst-case compounding procedure and processing conditions they encounter during a work shift by replacing the CSP with soybean–casein digest broth. Personnel are re-qualified at least annually.
Outsourcing sterile compounding facilities
In the US, so-called Section 503B outsourcing sterile compounding facilities must comply with the requirements of the US federal good manufacturing practices regulations found in 21 CFR Part 211 that require facilities to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilisation processes (21 CFR 211.113(b)) and establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). Recommendations on how facilities can comply with these GMP requirements are found in the 2004 FDA Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. The industry practice in ISO 5 (Grade A) areas is to conduct air, surface, and personnel monitoring each shift, and in ISO 7 (Grade B) areas it is daily. Other surrounding support areas would be monitored weekly.
Environmental monitoring excursions
When environmental monitoring results exceed the action levels (see Table 1) or the trending rules and alert levels established in your facility, the excursion should be investigated to determine if there is a loss of environmental control within the facility, a disinfection failure or poor aseptic practices. Once the probable root cause of the excursion is found, corrective and preventative actions should be taken in the areas of environmental control and aseptic practices.
UK situation
What is the situation in the UK? In 2003, the British Government modernised the hospital pharmacy manufacturing unit (PMU) network.
The network was rationalised from small hospital-based operations into a network of 13 large lead units and support units.
These units have a diverse range of activities including:
- Sterile manufacturing of terminally sterilised products
- Aseptic manufacturing of pre-filled syringes, eye-drops and other items
- Non-sterile manufacturing
- Aseptic compounding, that is, total parenteral nutrition, chemotherapy, centralised intravenous admixture services and diagnostic radio-pharmaceuticals
- Extemporaneous dispensing services.
In addition to the PMU network, there are about 120 aseptic compounding units in British hospitals. Section 10 of the UK Medicines Act enables a pharmacist to supervise preparation of products against a prescription without needing a specials license from the Medicines and Healthcare Products Regulatory Agency (MHRA). The MHRA is currently reviewing the regulation of unlicensed medicines. There will undoubtedly be greater control over what may be manufactured, testing requirements, enhanced requirements for stability information, and pharmacovigilance.
Sterility testing of sterile compounded preparations
US sterile compounding pharmacies that comply with USP <797> subject high-risk compounded sterile preparation, that is, non-sterile active pharmaceutical ingredient (API) to sterile preparation, to the USP <71> Sterility Tests. By conducting sterility tests on low- and medium-risk preparations they can extend the beyond use dating improving inventory control and drug availability. The USP <71> Sterility Tests is harmonised with its European Pharmacopeia equivalent (Ph. Eur. 2.6.1 Sterility Testing). The quantity of products per unit and the number of units tested is specified in Tables 2 and 3 of the compendial test. Both pharmacopeia allow for the use of alternate test method provided they can be shown as comparable to the compendial test during method validation.
Bacterial endotoxin testing of sterile compounded preparations
Another critical quality attribute of sterile compounded preparation is the bacterial endotoxin level within the preparation. Sterile buffered saline, which is a common vehicle, has a bacterial endotoxin limit of 0.25EU/ml. The limit for a specific CSP is determined by the route of IV administration, weight of the patient, the maximum human dosage, the rate of administration and the volume administered. The test methods, that is, gel clot, turbidimetric and colorimetric are described in USP <85> Bacterial Endotoxin Tests and is harmonised with the European Pharmacopeia chapter 2.6.14 Bacterial Endotoxins.
Conclusions
Pharmacy sterile compounding makes a significant and invaluable contribution to the healthcare by providing customised medications for patient care. Microbial contamination risks are higher than with industrial pharmaceutical manufacturing. However, with proper facilities, well-managed compounding operations and good aseptic handling techniques, these risks can be largely mitigated.
About Fresenius Kabi
Fresenius Kabi is a global health care company that specialises in lifesaving medicines and technologies for infusion, transfusion, and clinical nutrition.
Fresenius Kabi is committed to being a full-service partner, with not only its broad expertise but also a full-range and most comprehensive product portfolio for core therapeutic areas including enteral and parenteral nutrition products, IV generic drugs, infusion therapies and standard solutions, as well as automated compounders and the medical devices for administering these products.
In virtue of its corporate philosophy “caring for life”, Fresenius Kabi employs more than 37,000 people worldwide committed to putting essential medicines and technologies in the hands of people who help patients and finding the best answers to the challenges they face.
Aiming to shape the future of health care in providing products and services to help and to improve quality of life to chronically and critically ill patients in hospitals and outpatient care all around the globe, Fresenius Kabi also offers a comprehensive compounding competence to those who seek compounding excellence. Its extensive global experience is backed up by the highest commitment to product quality and safety: from assistance with facility design, to jointly funded and managed facilities on a client’s site, or to fully outsourced compounding services providing patient- specific ready-to-use medications. Fresenius Kabi compounding centres, designed and operated to comply with full good manufacturing practice standards across four continents, provide every year several millions of IV and PN compounded sterile preparations. Maintaining industry-level standards in all Fresenius Kabi compounding facilities worldwide requires obviously high levels of quality, strong expertise of qualified and experienced personnel, premium facilities and equipment, and state-of-the-art production processes. Fresenius Kabi holds itself to the highest standards of responsibility and competence: to ensure that compounded preparations are manufactured or compounded both safely and accurately first time, every time.
About bioMérieux
A global leader in in vitro diagnostics for more than 50 years, bioMérieux has always been driven by a pioneering spirit and unrelenting commitment to improving public health worldwide. Today, in more than 150 countries through 43 subsidiaries and a large network of distributors, bioMérieux provides diagnostic solutions that improve patient health and consumer safety.
bioMérieux industrial microbiology solutions enable faster, more precise diagnostic results, designed to optimise customers’ productivity and profitability by streamlining workflows. With expert consultation and consistent, accurate testing solutions, bioMérieux helps customers protect their brand reputation among business partners and end consumers alike.
Speed and quality are paramount in compounding pharmacy. Knowing your product is free of contamination allows for faster releases – giving you greater flexibility to respond to changes in demand and a competitive advantage in the market. With a comprehensive range of diagnostic solutions, bioMérieux delivers the rapid, accurate results that help you protect your consumers, your brand reputation – and ultimately, your bottom line.
