Abstract
As a result of advances in technology and technique, and in response to unacceptable, tragic, and widely publicized violations of proper compounding procedure and practice, clear standards and requirements for both sterile conditions and careful procedures for compounding intrathecal medications have emerged. These standards and requirements differ from, and in some ways are far more stringent than, those for other compounded medicines. The standards and requirements include the nature of the physical space where compounding takes place, environmental monitoring of that space, personnel training, and regular testing to ensure that adherence to proper procedure is followed at every step of the compounding process. This chapter reviews the current status of these critical aspects of compounding intrathecal pharmaceuticals.
Keywords
Analgesia, Compounding, Intrathecal, Liability, Pharmaceuticals, Requirements, Standards
Outline
Introduction 879
What Is Compounding? 879
Standards for Compounding 880
Regulatory Considerations 880
Avoidable Errors and Their Tragic Consequences 881
Standards 881
Facility Standards 881
Equipment Standards 882
Cleaning and Disinfection of the Sterile Compounding Facility 883
Personnel Training and Testing 883
Gowning 883
Fingertip Assessments 884
Environmental Monitoring 884
Surface Sampling 885
The Compounding Process 885
Filtration 885
Endotoxins 886
Stability Considerations 886
Provider Liability 887
Conclusion 888
References 888
Introduction
From a historical standpoint, pharmaceutical compounding dates back 5000 years. The practice of apothecary is mentioned in the Bible as a trade. Apothecaries or physicians would compound oils, powders, aromatics, and elixirs to treat various medical conditions. Many compounds were extracted from animals and plants, such as opium. Throughout the 19th and 20th centuries pharmacists and physicians provided numerous compounded preparations to treat their patients. Many drugs currently on the market today often required a compounding pharmacist to prepare the medicine prior to approval by the United States Food and Drug Administration (FDA) and market launch ( ).
What Is Compounding?
Compounding involves a process by which a pharmacist or physician combines, mixes, or alters ingredients to create a customized medication for an individual patient. A compounded preparation consists of two or more elements whose composition is altered but which remain stable in the new state. A drug compounded by a pharmacist on order of a licensed practitioner is not subject to FDA regulations and does not receive a national drug code (NDC); such compounding of drugs is considered to be part of the practice of “pharmacy/medicine.” This chapter emphasizes the standards for compounding intrathecal (IT) medications, and is less concerned about the actual process.
Standards for Compounding
All sterile compounding follows general principles and guidelines. The conditions and procedures for compounding sterile medications have certain requirements to ensure that quality and accuracy are attained.
Nearly two centuries ago, on January 1, 1820, 11 physicians met at the US Capital Senate to create a pharmacopeia for the United States. The clinicians sought to develop a compendium of the best and successful medicines and provide recipes for their preparation. That first pharmacopeia was published in December, 1820. Over time the United States Pharmacopeia (USP) changed from being a text of recipes to becoming a compendium of recipes and standards for aspects related to pharmaceuticals.
The current standards for sterile compounding have evolved significantly over the past 16 years. In the early 2000s the American Society of Health System Pharmacists produced a set of standards guiding individuals and organizations to enhance the practice of sterile compounding ( ). In 2004 the USP released Chapter 797, the most comprehensive set of enforceable guidelines for sterile compounding. This chapter was revised and published again in 2008, with many changes aimed to enhance previous guidelines. The USP 797 standards have become integrated into pharmacy regulations across the United States. The institution of the USP guidelines has significantly improved the quality of sterile compounding ( ).
The compounding of IT medications requires a much higher standard than traditional sterile preparations for compounding medicines due to the nature of the subarachnoid space. Specifically, the IT space contains no antibodies to destroy bacteria. Many compounding pharmacists consider the compounding of IT medications to be a high-risk activity. This risk is very relevant due to the close proximity of neurons affected by opioids.
Regulatory Considerations
The profession of pharmacies and pharmacists is regulated by each State Board of Pharmacy, or a similar licensing board related to health. Each state has established specific regulations governing the profession and the facilities in which it is practiced. From a legal perspective, the regulations governing the profession of pharmacists and pharmacies are developed by each State Board of Pharmacy. Individual state regulations have gradually developed new and stronger regulatory language affecting sterile compounding. A closer look at the nature of state and federal regulations is instructive, and in the case of federal regulations raises issues with which every compounding pharmacist should be familiar.
Regulatory Issues—State
State agencies issue permits and licenses to pharmacists, pharmacies, and nonresident pharmacies outside the state. The agencies have the capacity to investigate and fine pharmacists or pharmacies for violation of state pharmacy laws. States have newly implemented or reexamined laws affecting sterile compounding since the New England Compounding Center (NECC) accident, described below. Some state regulations regarding sterile compounding are very detailed, while others are very brief. State Boards of Pharmacy also have the authority to inspect pharmacies for compliance with state regulations; inspection frequencies range from periodic or annual to only upon a filed complaint against a licensee. Hence some pharmacies may practice with little oversight.
Regulatory Issues—Federal
The US FDA has been aware of compounding pharmacies for over three decades. The FDA regulates manufacturers and certain large-scale compounding pharmacies under the conditions of employing current good manufacturing practice (cGMP) in the Code of Federal Records. In some areas the FDA looks at compounding pharmacies as small manufacturers, and in consequence applies higher standards. Additionally, FDA reports are not reflective of a pharmacy’s compliance with its state’s rules and regulations. Thus the FDA may cast, in some ways inadvertently, a shadow on a good pharmacy. For example, the FDA requires compounding pharmacies to perform smoke studies evaluating airflow patterns, which are not required by a State Board of Pharmacy Regulations. Such tests are helpful and informative, but not required by the state. Yet the federal requirement means that the additional investment for smoke studies must be made. Having made that investment, whether one agrees with the requirement or not, the pharmacist should look at the smoke test and its results as another component in ensuring that the highest standards are maintained throughout the compounding facility and the process which take place there.
Since the NECC tragedy the FDA has paid greater attention to compounding pharmacies across the United States. It began inspecting sterile compounding pharmacies and applying cGMP guidelines, which are far beyond the scope of state pharmacy regulations. Under the Food and Drug Modernization Act of 1997, pharmacies and physicians are exempt from cGMP requirements for compounding medications for humans. However, early on during the inspections many sterile compounding pharmacies were subjected to cGMP requirements by the FDA.
In November 2013 President Obama signed into law the Drug Quality and Security Act. This act gave the FDA more power and authority to enforce sections 503A and 503B of the Food, Drug and Cosmetic Act (21 U.S.C. 353a). With this change, the FDA classified compounding pharmacies as either 503A or 503B. According to the FDA, a pharmacy categorized as 503A can provide sterile compounded preparations pursuant to a patient-specific prescription. Under section 503B, an entity which may or may not be licensed as a pharmacy can provide sterile compounded medications without a patient-specific prescription. The 503B pharmacy must register with the FDA, be inspected, and practice under cGMP guidelines ( ).
Lastly, when a sterile compounding pharmacy has an inspection by the FDA it will receive an FDA Form 483, Inspectional Observations. This form lists points the FDA inspectors observed during their visit. In many cases Form 483 reflects observations based upon cGMP guidelines and not pharmacy laws or regulations. In some cases the FDA will issue warning letters regarding Federal law violations as they pertain to the Food, Drug and Cosmetic Act. FDA reports can be seen at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/ucm482754.htm .
Both regulatory and professional reviews have been heightened by recent tragic and wholly avoidable compounding errors. A brief description of two of these incidents serves as a reminder of the absolutely critical requirement for proper procedure and practice throughout the compounding process.
Avoidable Errors and Their Tragic Consequences
Bad news makes good headlines—and invites greater scrutiny and regulation. In September 2012 an outbreak of fungal meningitis was reported in the United States. The outbreak killed 77 people and more than 750 fell sick. Three lots of methylprednisolone prepared by NECC were contaminated and shipped to facilities in 23 states. The states most affected were Indiana, Michigan, and Tennessee. Approximately half of those treated with the contaminated medication developed a rare fungal ( Exserohilum rostratum and Aspergillus fumigatus ) form of meningitis. Patients began reporting unusual symptoms in late August, but clinicians were slow to realize a common cause for the rare meningitis. The compounding facility responsible for the contaminated methylprednisolone was revealed to be practicing in all but unimaginable conditions. News and FDA reports indicated the environmental conditions of the sterile compounding room to be deplorable. The pharmacy’s environmental monitoring program obtained both bacteria and mold. The surface-sample results exceeded the firm’s alert and action limits, but no investigation was conducted to determine the root cause. In many cases the surface-sample results indicated “over growth” of mold in the aseptic compounding area. The sampling of personnel utilizing touch plates, taken upon the completion of sterile compounding, showed both mold and bacteria ( http://framingham.wickedlocal.com/news/20160625/co-founder-of-new-england-compounding-center-freed-from-home-detention ; http://www.newsweek.com/2015/04/24/inside-one-most-murderous-corporate-crimes-us-history-322665.html ).
Another case involved a compounding pharmacy located in Birmingham, Alabama, which prepared contaminated total parenteral nutrition (TPN) that was delivered to five local hospitals in 2011. A total of 19 patients were affected, resulting in 9 deaths. Health officials determined that bags of amino acids utilized in compounding TPN were contaminated with Serratia marcescens . The most likely cause of contamination was the failure to sterilize the final preparation properly ( ).
Standards
In consequence of both increased regulation and adherence to the highest standards of the profession, compounding pharmacies should follow a detailed and strict set of procedures and standards throughout the compounding process. These standards and procedures begin with the compounding facility itself.
Facility Standards
The compounding of sterile IT preparations should be performed in a dedicated and separate control area, which minimizes airborne contamination. The square footage shall enable staff to move freely about the room without distractions or interruptions. The environment should be comfortable and well lit. The facility should consist of at least two rooms, an anteroom and a buffer room, separated by hard walls, doors, and pass-through windows.
The anteroom area shall be utilized for storage of supplies, hand washing, and gowning of compounding staff. The ceiling should contain an appropriate number of high-efficiency air particle filters (HEPA) and low-particulate shedding panels. The air quality of the anteroom shall be International Organization for Standardization (ISO) 8. 1
1 The International Organization for Standardization ( ISO ) is an international standard -setting body composed of representatives from various national standards organizations. Founded on 23 February 1947, the organization promotes worldwide proprietary, industrial and commercial standards . Taken from the internet: https://www.google.com/#q=what+are+the+iso+standards .
The buffer room will contain similar features as the anteroom, including laminar airflow workbenches (LAFWs) where the actual compounding will take place. The LAFWs’ air velocity shall be sufficient to remove particulates or bacteria from the direct compounding area. The buffer room shall be constructed in such a manner that prevents turbulent airflow introducing microbes or particulates into sterile compounding area. The buffer room shall have ISO 7 air quality with a temperature of 20 Celsius or cooler and a relative humidity of 30%–55%. Fig. 71.1 shows a general compounding area layout.
The interior of the sterile preparation area shall consist of floors, walls, ceiling panels, fixtures, counters, and storage cabinets; all these surfaces must be smooth, impervious, nonporous, and sustain continuous cleaning and disinfection treatments. The anteroom shall contain a fixed sink with hot and cold running water. The sink cannot be located in the buffer room under any circumstances. This area will require a dedicated heating, ventilation, and air-conditioning system with advanced filtration devices to remove particulates and bacteria continuously. The buffer area must have a minimum of 30 air changes per hour. This significant feature continuously removes bacteria and dust particles from the compounding environment. Fig. 71.2 represents the concept of room air changes occurring.
The ISO provides specific nonviable particulate air quality standards for compounding sterile preparations. Table 71.1 indicates the maximum number of nonviable particulates obtained per cubic meter sample.
| ISO Class | Number of Particles/m 3 |
|---|---|
| 4 | 352 |
| 5 | 3520 |
| 6 | 35,200 |
| 7 | 352,000 |
| 8 | 3,520,000 |
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