US Pharm. 2023;48(5):HS8-HS12.
ABSTRACT: Contamination problems in the U.S. compounding industry led the FDA to develop new regulations and enhance its oversight to prevent further life-threatening occurrences. Compounding pharmacy firms that produce large inventories of sterile products and are voluntarily registered with the FDA as section 503B outsourcing facilities regularly undergo Good Manufacturing Practice inspections. The FDA has provided guidance for these compounders to help improve their understanding of contamination concerns, with some direction on how to mitigate them. Best practices can improve the efficiency of cleaning and disinfection, gowning, material transfer, and operator training, all of which are critical parameters of contamination control.
Just over 10 years ago, a contamination situation occurred in the U.S. compounding industry (the New England Compounding Center in 2012) that caused more than 50 deaths and in excess of 700 infected patients. This was not the first time that concerns were raised regarding compounding practices on a large scale. Problems have arisen since then, leading the FDA to develop new regulations and enhance its oversight to protect the public from further life-threatening incidents.1-4
Many pharmacies that compounded specific patient prescriptions were under the oversight of state pharmacy regulations, which often follow compendia guidance (e.g., U.S. Pharmacopeia), not federal regulations. Some compounding facilities produced drugs in large batches and for distribution across the country, similar to a manufacturing operation but not regulated by the federal government. Many compounded sterile and nonsterile drugs are produced without FDA approval and without following Good Manufacturing Practice (GMP), yet are under prescription auspices to supply physicians needing immediate or emergency drugs for their patients. The FDA revised some policies and regulations to allow compounders that manufacture larger-inventory products not by prescription but for larger “office stock” use by pharmacies and physicians to voluntarily register with the FDA as section 503B outsourcing facilities. Registered firms meeting section 503B conditions can qualify for exemptions from FDA approval requirements, the requirement to include usage instructions on labeling, and supply-chain security requirements.5
Upon registration, the FDA inspects such facilities on a risk basis and requires them to meet current GMP (cGMP) requirements appropriate for and relevant to compounding operations, as stated in Code of Federal Regulations Title 21, parts 210 and 211. Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act (Draft Guidance; January 2020) is a second revision of the original guidance document.5 Subsequently, the FDA published another guidance document, Insanitary Conditions at Compounding Facilities (Insanitary Conditions; November 2020), to describe observed insanitary conditions that could cause a drug product to become contaminated or injurious to health.6 Insanitary Conditions provides examples intended to help compounding facilities prevent the occurrence of these and other insanitary conditions as well as identify and remediate insanitary conditions already in existence.6 (Some of these examples will be discussed in this article.) The information in Insanitary Conditions is relevant both to 503B registered firms and to those facilities that are not registered, especially in the category of sterile products, wherein patients’ lives are at stake and the risk is greatest.
The Draft Guidance is consistent with GMP for compounding outsourcing operations, and it states principles for oversight and appropriate controls throughout the manufacturing process for sterile drugs. A risk-based approach to cGMP indicates areas considered high-risk and lower-risk.5
This article will discuss how to apply contamination control to a compounding outsourcing operation for sterile drugs, using pragmatic thinking and an approach that improves efficiency of cleaning and disinfection/decontamination. Some of the conditions mentioned in Insanitary Conditions will be presented, and methods for preventing these conditions so as to comply with cGMP will be provided.6
Visible Insanitary Conditions in Production
These conditions include6:
• Visible microbial contamination (e.g., bacteria, mold) in the production area or adjacent areas
• Standing water or evidence of water leakage in the production area or adjacent areas
• Production of drugs while construction is underway in a nearby area without adequate controls to prevent contamination of the production areas or product
• Cleanroom areas that have unsealed or loose ceiling tiles
The GMP for compounding facilities (III.B) clearly states that “processing and controlled areas must be clean and sanitary.”5 This is a broad requirement, but it is easily met with good design, proper planning, education, and continuous oversight. Contamination control is holistic, so every person in an operating facility (e.g., operators, engineers, cleaners, quality control scientists) can take note of conditions that are inappropriate for manufacturing pharmaceuticals, whether it is degradation or damage in the internal facility (i.e., building materials such as ceiling tiles) or systems (i.e., utilities) that are not working properly (e.g., leaks). High-efficiency particulate air (i.e., HEPA) filters are sealed into a ceiling with specific adhesives that can degrade over time. Cleanrooms are built in many sizes and with many different classification/activity intents, and the activities can change over time. The quality control unit is responsible for being aware of any changes (structural or activity) that impact the classified areas and communicating throughout the organizational structure to ensure that changes are documented and assessed and that problems are proactively mitigated, even if implementation is performed by another department.6
Examples of visible microbial contamination on surfaces include biofilm and molds. The presence of these types of contaminants indicates that the cleaning frequency is inadequate and/or the disinfecting agents used are not effective against these microorganisms. Another reason for visible contamination is that a surface is porous or damaged, resulting in hard-to-reach areas (e.g., scratches, dents, bends) for disinfectants. Periodic inspection of all surfaces in controlled areas should be routine, along with communication of any discovered issues to the cleaning team so that procedures can be adjusted to improve cleaning and disinfection of those areas, and to the engineering team so that problem areas can be repaired or replaced to improve conditions.
Because microbiological growth depends on access to water, the presence of standing water is a potential origin of microbial proliferation. Even in a cleanroom, microorganisms are present or enter via operators and materials and thus can grow. Standing water is usually visible and should be eliminated as soon as possible to prevent initiation of microbial growth.
Construction work in a facility that has a cleanroom has become common practice in these days of changing company strategies. Where robust isolation or relocation of adjacent production activities is possible, this could be the first action taken. The oversight of construction workers in a GMP facility is strongly recommended in any situation, and the prevention of contamination via any project occurring adjacent to or near a cleanroom is paramount. Given that most potential contaminants originate outside the cleanroom, any type of construction adds to the risk of contamination. Signage, restrictions on when and where to perform contaminating operations (e.g., welding, cutting), enhanced gowning practices, and limited/blocked access to external classified areas’ entry points are some controls for minimizing the possibility of cross-contamination. Also, increased daily cleaning and disinfection in key areas or periodic automated decontamination of the room (e.g., hydrogen peroxide vapor process during or post project) will help keep potential contaminants in check.
Inappropriate Gowning and Aseptic Practices
These practices include6:
• Failure to disinfect or change gloves frequently enough to prevent contamination, e.g., exiting and reentering the International Organization for Standardization (ISO) 5 area without changing or sanitizing gloves
• Failure to disinfect containers of sterile drug components or supplies immediately prior to opening for any use in operations
The changing of sterile gloves is a routine practice whether compounding is performed in an open cleanroom or biosafety cabinet or in a closed system or isolator. Yet the reasons that gloves are changed or when they should be changed often seem to be a choice of the company. When a key objective of training is an understanding of the potential for microbiological cross-contamination, operators will know that once a glove touches a nonsterile surface, this occurrence must always be followed by either an adequate sanitizing action using a disinfectant (e.g., 70% sterile isopropyl alcohol) or the removal and replacement of the gloves with a new sterile pair of gloves. This practice is a requirement—without modification—for GMP operations. Control of the disinfectant used for glove sanitizing is also important; that is, the glove disinfectant should be controlled to prevent contamination from entering the disinfectant solution/aerosol/foam during use or storage.
Material transfer is another area wherein a gap in procedures can lead to potential cross-contamination.6 The transfer of materials from a lower-grade classified area to a higher-grade area, using sterile materials/tools packaged in sterile or clean containers, consists of surface disinfection prior to entry of material into the higher-grade area. Also, when sterile drug components or supplies are being prepared inside containment systems (e.g., an isolator), the external surfaces should be sterile or disinfected prior to any manipulation. The use of a sporicidal disinfectant in the material-transfer process must be considered to control bacterial spore formers, and the use of an isolator that has an automated hydrogen peroxide vapor generator can reduce time and effort in the former step prior to any manipulations of a compounded drug.
Insanitary Conditions of Equipment/Facilities
These conditions include6:
• Equipment or production areas that are difficult to clean or contain porous, particle-generating, or visibly dirty equipment or surfaces (e.g., shelving, floors, walls, doors, ceilings)
Cleaning is the first step in preventing cross-contamination. Cleaning is important not because it is a compliance concern, but because decontamination/disinfection cannot be successful unless the surface is clean first. There are many possible residues, including prior disinfectants, that can influence a disinfectant’s effectiveness in removing/destroying microbial entities. Good cleaning removes residues and allows for the second step, disinfection, to be successfully performed. Good facility (cleanroom) design and awareness of problem cleaning areas are means to improve the ability to clean a surface well and consistently. Cleanrooms (any controlled or classified areas) should not have porous surfaces, and equipment brought into cleanrooms must be first cleaned and then disinfected prior to movement from a low-classified area to a higher-classified area.
Inappropriate Cleaning and Disinfecting
These practices include6:
• Use of nonsterile disinfecting agents in ISO-classified areas
• Failure to appropriately and regularly clean and disinfect (or sterilize) equipment located in the ISO 5 area
• Failure to disinfect equipment and/or supplies at each transition from areas of lower-quality air to areas of higher-quality air
• Use of disinfectant in a manner insufficient to achieve adequate levels of disinfection (e.g., contact time, concentration, or coverage)
• Use of sterile cleaning and disinfecting agents past their expiry or “discard after” date
• Lack of, improper, or infrequent use of a sporicidal agent in the facility’s ISO 5 and other classified areas
Cleaning and disinfection are key parameters of contamination control in every compounding outsourcing operation. Many parameters similar to quality control of drug ingredients and components apply to the cleaning and disinfection agents that are used in a cleanroom and the facility surrounding the cleanroom. Adequate cleaning and disinfection are a cGMP requirement for sterile product compounding. Supplier approval, control of chemical agents (e.g., separate storage, storage temperature, incoming inspection, proper labeling and tracking, expiry tracking), and control of tools utilized for the application of cleaners and disinfectants (e.g., mops, buckets) are all part of a good cleaning practices program.
Although not all ISO-classified areas require the use of sterile disinfectants, awareness of the risk posed by using nonsterile disinfectants in areas adjacent to ISO 5–7 areas makes clear the importance of learning about and assessing the risk prior to making a selection. If disinfectants are prepared internally, procedural controls must be in place to ensure consistency and proper expiration.
Equipment dedicated to an ISO 5 area (e.g., stainless pump) should be routinely sterilized between uses—first intent if possible—or should be cleaned and disinfected between uses. Performance of cleaning and disinfecting should be documented to ensure that it took place before each compounding activity.
As mentioned earlier, the disinfection of materials/equipment that are transferred from lower-quality air/grade to higher-quality air/grade areas must be routine. It is not always possible to use sterile supplies, tools, and equipment dedicated to each classified area; therefore, robust training in transfer-disinfection practices can lead to better contamination control and ensure that proper equipment and supplies are available in compounding-critical areas.
Developing a successful cleaning and disinfection program is dependent on good training of cleaning operators, selection of appropriate chemical agents, equipment being in good condition, and consistent and adequate application of the cleaning and disinfection agents. The importance of consistent application of these agents cannot be overstressed. For each application, there should be a documented procedure identifying the room surface, the appropriate agent, the appropriate concentration to use (based on either label claim or disinfectant-efficacy testing relevant to actual in-use conditions), the expected contact time (wet contact time on the surface, also based on either label claim or disinfectant-efficacy testing), and coverage. “Coverage” means how well the agents are applied to the intended surfaces in terms of consistency and knowledge of how mops or wipes work best.6
Similar to the GMP approach for control of handling and storage of excipients, active ingredients, and components, chemical disinfectants have expiry dates for stability prior to the first opening of a container. A compounding facility should have procedures and validation studies in place for determining (from supplier information) expiry dating of a prepared solution. One common approach in industry has been to prepare a disinfectant solution and use it not more than 24 hours post preparation; however, best practice would recommend using the solution immediately after preparation. Any use-by dating should be supported by analytical data for the active ingredient.
The cGMP states that a sporicidal disinfectant should be used in the ISO 5 and other classified areas on a “regular basis.”5 Cleaning teams should be aware of both the negative and the positive outcomes of using a sporicide. Sporicides are oxidizers and can corrode stainless steel if not rinsed routinely after use. They are highly effective disinfectants for vegetative bacteria, fungi, and bacterial endospores. Sporicides are also chemicals that are hazardous to humans, which can be a concern for application without proper personal protective equipment, when so stated on the label. Sporicide use should be based on environmental monitoring and identification of species recovered; these agents should mainly be used if bacterial spores are expected or are recovered, especially in an ISO 5 environment. Rotation of disinfectants in large areas has commonly been interpreted as using a broad-spectrum disinfectant routinely and a sporicide less frequently. The GMP for compounding outsourcing facilities (III.C) states, “A system for cleaning and disinfecting all critical areas to produce aseptic conditions includes sporicidal and other sterile disinfectants.”5
The rotation balance of disinfectants for ISO 5 and other classified areas must be justified for each area based on the risk of the activity being performed and environmental monitoring recoveries identified in these areas.
Taking a practical view of cleaning and disinfection practices and developing a contamination-control strategy are important aspects of cGMP compliance. The compounding of sterile drugs is a high-risk operation; consequently, expectations for quality and compliance are high. Making appropriate selections for cleaning and disinfecting agents, training cleaning personnel in good application practices and GMPs, and being constantly aware of infrastructure deviations and how they may impact the cleaning and disinfection program will all support contamination control of a compounding outsourcing operation.
1. Sutton S. GMP and compounding pharmacies. Am Pharm Rev. 2013;16(3):48-59.
2. Cundell T. Mold monitoring and control in pharmaceutical manufacturing areas. Am Pharm Rev. 2016;19(5):10-19.
3. Gottlieb S. Statement from FDA Commissioner on agency’s efforts relating to compounded drugs. Am Pharm Rev News. July 3, 2018. www.americanpharmaceuticalreview.com/1315-News/351581-Statement-from-FDA-Commissioner-on-Agency-s-Efforts-Relating-to-Compounded-Drugs. Accessed April 3, 2023.
4. Gottlieb S. FDA statement on new efforts to assure the quality of compounded drugs. Am Pharm Rev News. December 11, 2018. www.americanpharmaceuticalreview.com/1315-News/356549-FDA-Statement-on-New-Efforts-to-Assure-the-Quality-of-Compounded-Drugs. Accessed April 3, 2023.
5. Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act: Guidance for Industry. Draft Guidance. Silver Spring, MD: U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research; January 2020.
6. Insanitary Conditions at Compounding Facilities: Guidance for Industry. Silver Spring, MD: U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research; November 2020. [The source of this document is: FDA Code of Federal Regulations, Title 21, Sec. 211.56 Sanitation.]
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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