On June 21, 2017, Barry J. Cadden, the owner and head pharmacist at the New England Compounding Center (NECC) will face sentencing for a conviction on more than 50 counts of mail fraud and racketeering. The accusation is hardly indicative of the accusations levied against Mr. Cadden, who has long been considered primarily responsible for a fungal meningitis outbreak in 2012 that sickened 753 people and left 64 dead.
The fungal infection was spread through contaminated vials of methylprednisolone acetate (MPA), an injectable pain medicine that was distributed to some of the country’s most prestigious medical facilities, including affiliates of Harvard, Yale, and the Mayo Clinic.
Fungal meningitis is an extremely rare form of the disease that normally afflicts people already suffering from a weakened immune system. As fungal meningitis spreads through the blood stream and spinal chord, it causes a range of complications from hearing loss to seizures, paralysis, brain damage, and death. In a cruel twist of fate for the patients who were infected by the contaminated pain medication, those who survived the outbreak have spoken of being sentenced to living with a lifetime of pain.
The 2012 meningitis outbreak is an extreme case that nonetheless demonstrates the necessity of quality assurance and quality control in the production and distribution of pharmaceutical products.
PUBLIC SAFETY and LEGISTATIVE CHANGE
When Mr. Cadden was subpoenaed to appear before the House Energy and Commerce committee, the scope of the outbreak was not yet known. It had begun, like most outbreaks, with two deaths that were linked to steroid injections in the patients’ spinal cords. When Dr. April Pettit, an infectious disease specialist at Vanderbilt University, identified the “index case” associated with the growing outbreak, 14 infected patients was considered frightening. When the outbreak was fully understood, a total of 817 people had been infected across 20 states. The Center for Disease Control issued recalls to 76 facilities for the NECC’s vials of MPA. It was estimated that 13,000 people could have been injected with the contaminated drug.
Two days before the House Committee on Energy and Commerce was scheduled to hold a hearing on the 2012 meningitis outbreak, the FDA released a report detailing similar quality assurance concerns at Ameridose, a pharmaceutical drug supplier and the sister company of the NECC. Spokesperson Sarah Clark-Lynn, speaking for the FDA, related that “inspectors observed conditions and practices at Ameridose which demonstrated that the firm could not consistently assure their injectable products were sterile and safe for use by patients.” Though the FDA could not link safety practices at Ameridose with the NECC, the report nonetheless raised the specter of concern for a public already terrified by a national outbreak caused by product contamination.
The NECC has since surrendered its pharmacy license and Ameridose shut its doors not soon after, but the outbreak galvanized a nation-wide conversation about compounding pharmacies, regulations, and federal oversight. The federal government pressed for new legislation in response to the outbreak and as a result of testimony to the House Committee on Energy and Commerce suggesting that the FDA’s limited power was crippling their efforts to enforce safety standards. Conflicting court decisions and a lack of consensus over the definition of compounding had crippled the FDA’s authority. Then Governor of Massachusetts Deval Patrick directed pharmacies in the state to submit annual reports on production, volume, and distribution. He also directed the state pharmacy board to ramp up unannounced inspections.
Inspection reports of the facility linked the outbreak to the compounding pharmacy’s own practices. The government contended that the NECC produced pharmaceutical products in unsanitary conditions and sold them to patients while fully aware of the risks. While the Food and Drug Administration (FDA) report did not amount to a formal indictment of the company, it cited air circulation and equipment sterility as the likely causes of the outbreak.
Speculation abounded in the wake of the meningitis outbreak. Multiple investigations were conducted by the FDA, the Justice Department, and the House Committee on Energy and Commerce. Congress heard testimony from experts, victims, and those purportedly responsible for the outbreak. No one appeared to disagree with the fact that the NECC with primarily culpable for the unsterile conditions that lead to the distribution of fungal-tainted MPA, but the agencies and experts involved also identified varied systemic causes.
The limited authority of the FDA to enforce safety standards and the lack of quality assurance and quality controls at the NECC were the two most frequently cited reasons for the outbreak. The rapid growth in compounding pharmacies since the 1990s meant that regulations and oversight had not kept pace with large-scale changes in the industry, creating confusion over the precise definition of compounding and how that differed from pharmaceutical manufacturing.
Key pieces of federal legislation had governed drug manufacturing up to the moment of the outbreak, but they did not anticipate that local pharmacies would position themselves to become all but manufacturers in name. This meant that the state pharmacy board—the entity primarily responsible for enforcing safety standards on local pharmacies—was placed in a position of policing one of its own. Mr. Cadden was, at the time, a member of the board and also on the committee tasked with rewriting rules governing compounding safety standards for the state.
Traditional compounding is limited in scope. In a report to Congress following the meningitis outbreak, the Congressional Research Service (CRS) defined compounding as “a process where a pharmacist or a physician combines, mixes, or alters ingredients to create a medication tailored to the needs of an individual patient.” What’s important to note about traditional compounding is that it is highly individualized and typically serves the specific needs of particular patients. A patient who has trouble swallowing pills may need a liquid version of a prescribed medicine. The role of a compounding pharmacy is to fill the prescription according to that specific patient’s needs.
In the 1990s, however, compounding expanded to include large-scale production, arguably as a response to drug shortages and as a result of hospital outsourcing. The NECC was one of the compounding pharmacies that became a veritable drug manufacturer during this time, producing drugs without individual prescriptions for mass distribution. They also made copies of commercially manufactured drugs to supply the nation-wide shortage.
The FDA began to scrutinize the growth in pharmacy compounding almost from the moment it recognized the trend. David Kessler, FDA commissioner during the early 1990s, issued prophetic warnings about the growth in pharmaceutical compounding. He worried that they would produce a “shadow industry” that could cause “serious adverse effects, even death.” Kessler’s concerns proved to be sound as a spate of patients took ill or died after consuming compounded drugs.
PHARMACEUTICAL PRODUCTION and QUALITY ASSURANCE
Citing Kessler’s concerns over the growth of pharmaceutical compounding is not meant to imply that quality assurance and quality control do not exist in the pharmaceutical compounding. In fact, compliance with federal guidelines was reported at 73.9% in 2011—just a year before the outbreak—which then increased to 81.3% in 2014. Though an overwhelming majority of pharmacies abide by the federal statutes embodied in USP Chapter <797> standards, at the time of the outbreak the federal government argued that a lack of information on and authority over pharmaceutical compounding had lead to the tragedy.
Governing bodies at the state and federal level thus refocused their attention on sterile compounding. States have written new regulations and conducted more rigorous inspections. In conjunction with the federal government’s expansion of USP <797> to include the more rigorous standards of USP <800>, states have also updated their standards to assure patients and health care providers of quality pharmaceutical production at the local compounding level.
Any assurance offered to the public with concern to pharmaceutical production primarily deals with quality, safety, and efficacy. Pharmaceutical drugs should effectively treat diseases with as few complications as possible, and they should be free from contamination so as not to harm patients. In the shifting sands of compounding, quality assurance demands self-policing which begins with a full knowledge of how to safely produce pharmaceutical drugs. For instance, USP <797> requires hazardous drugs to be stored under negative pressure, but only 55% of hospital pharmacies reported abiding by this standard. Over 1/5 of those same respondents cited a lack of competency, training, and resistance to change as the main reasons for failing to abide by industry standards.
In light of the FDA’s report on the NECC, which cited air filtration and equipment sterilization as causes for the contamination that resulted in the meningitis outbreak, we may argue that even though the NECC knew the probability of potential contamination that there is also a possibility that an understanding on proper handling could have prevented the outbreak. Because of the FDA’s limited authority, it them becomes the responsibility of industry experts to inform and train the public.
PARTNERING for PRODUCT ASSURANCE
Product assurance and quality control of compounded pharmaceutical drugs begins when raw APIs enter the laboratory and covers their storage, the act of compounding, drug administration, and ultimately drug disposal. Flow Science, Inc. has worked directly with compounding pharmacies to address these points of potential contamination in order to design laboratory solutions that meet industry wide quality assurance standards.
Flow Sciences’ team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with toxic substances and uncertain risks. All of our products are engineered and manufactured at out corporate headquarters in Leland, NC and are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. In addition to compounding pharmacies, we have worked with pharmaceutical companies, research and development laboratories, manufacturing, and production facilities for 30 years. Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.
Flow Sciences was one of the first companies in the U.S. to use computational fluid dynamics (CFD) in drafting our enclosures to ensure optimum airflow. Our engineers use CFD algorithms to simulate fluid flows and interactions within contained spaces. This enables us to predict and control airflow through design, which we then test in our state-of-the-art laboratory. Working closely with our clients to mimic real-world applications, we develop testing protocols based on the intended use of our enclosures and measure them against industry-accepted standards to ensure proper containment. We have designed, manufactured, and tested over 13,000 enclosures, generating a wealth of data on situational flow dynamics, which allows us to control for consistency, safety, efficacy, and overall quality.
Because all of our hoods and enclosures are manufactured at our corporate headquarters in Leland, NC, we are able to control the entire production process, from sourcing raw materials to the installation of our containment solutions in your laboratory.
Ensuring safe pharmaceutical compounding and manufacturing requires a range of containment options for the entire scope of development from weighing and handling active pharmaceutical ingredients (APIs) to creating tailored solutions for patients without sacrificing quality. Flow Sciences offers bulk powder solutions, isolators, and gloveboxes for processing highly potent pharmaceutical drugs. Our systems are designed to protect against both product contamination and personnel exposure.
The Glovebox Workstation provides negative-pressure containment for toxic applications using highly potent active pharmaceutical ingredients (HPAPIs) that meets or exceeds ISO 5 clean processing. The Glovebox Workstation comes standard with a HEPA inlet that creates a clean environment ensuring product protection; it also uses horizontal laminar flow to reduce turbulent airflow and reproduce consistent, performance-based results. Laminar, or unidirectional airflow systems direct filtered air in a constant stream, reducing turbulence. Consistent airflow is necessary for reducing exposure and ensuring reproducilibity.
- HEPA INLET exceeds ISO 5 requirements for cleanroom classification,
- BAG-IN/BAG-OUT HEPA exhaust ensures safe recirculation of air in the room
- LAMINAR AIRFLOW reduces turbulence and allows for consistent, performance-based results, and
- BALANCE STABILITY to the 7th decimal place makes the Glovebox Workstation ideal for weighing and working with HPAPIs.
HEPA filtration, laminar airflow, and negative pressure containment are integral to creating a controlled environment for pharmaceutical drug manufacturing purposes. In order to demonstrate the superiority of these engineering controls, we have submitted the Glovebox Workstation for evaluation by third-party testing facilities that have confirmed containment levels at or below 50 ng/m3 with balance stability to the 7th decimal place. This ensures that while you are working within one of our containment devices, your products will be protected and your results will be reproducible.
MATERIALS of CONTROL
We have also begun manufacturing many of our standard units in stainless steel in order to respond to the industry’s increasing demand for cleaner processing. High-polished stainless steel is non-reactive, non-additive, non-absorptive, and non-corrosive. Low-carbon stainless steel also has a proven resistance to most “hostile” chemical compounds, and is used when products require maximum levels of containment against contamination, as in drug development or compounding.
The advantage of using stainless steel for pharmaceutical compounding is its inherent resistance to contamination, which is generalized as “corrosion” in the metals industry. Stainless steel is also a preferred material of construction because it can be easily cleaned and disinfected. Its smooth surface—which is a result of polishing—does not encourage bacterial growth. Coupled with proper ventilation and air circulation systems, a stainless steel unit will also prevent mold growth.
Stainless steel is also versatile because it is an alloyed metal. There are over 200 different grades of stainless steel with a range of properties to suit various manufacturing needs and product protection requirements. For pharmaceutical hygiene products, grades 304 and 316L are chosen for their corrosion-resistant properties.
The 300 series of austenitic stainless steel is most appropriate for pharmaceutical use. It is an iron-based, low-carbon alloy that is non-magnetic and owes its high-corrosive resistance to chromium. The basic structure of 300-series austenitic stainless steel is 18% chromium, 8% nickel alloy, and 0.10% carbon; it is commonly known as 18/8 steel.
Within the 300 series, 304 stainless steel is known as “surgical stainless steel.” It is used primarily in brewery, dairy, and pharmaceutical production equipment applications. 316 stainless steel contains molybdenum and a higher nickel content (10%) than 304. In conjunction with chromium, molybdenum provides superior resistance to attack by most chemicals and an increased resistance to chloride corrosion as compared to 304 stainless steel. 316 L is the most common type of stainless steel used in the pharmaceutical industry. Corrosion resistance is the same as standards 316, but the low carbon content is used to avoid possible sensitization corrosion in welding. 316 L stainless is also frequently specified in pharmaceutical installations in order to prevent excessive metallic contamination of pharmaceutical products.
Table 1: What’s in Stainless Steel
|Carbon||Iron is alloyed with carbon to make steel, which increases the hardness and strength of iron.|
|Manganese||2% manganese improves the working strength of stainless steel at high temperatures, more than 20% manganese improves tensile strength.|
|Silicon||When added to steel alloys, Silicon increases strength and resistance against strong acids like sulfuric acid.|
|Phosphorus||Added with sulfur, phosphorus improves machinability.|
|Sulfur||In small amounts, Sulfur improves machinability much like Phosphorus.|
|Chromium||At precise ratios, chromium makes steel’s surface resistant to corrosion and oxidation; it also adds tensile strength to the metal.|
|Nickel||Improves resistance to hot and humid environmental conditions.|
|Molybdenum||Improves resistance to pitting and crevice corrosion, especially in environments where chlorides and sufur are prevalent.|
|Nitrogen||Yield strength is greatly improved when Nitrogen is added to steel as is resistance to pitting corrosion.|
Grade 304 is an excellent general-purpose stainless steel option that is used in many domestic applications, but 316L is preferable, particularly within the pharmaceutical industry. With lower carbon and higher inclusion of molybdenum, 316L stainless has greater corrosive resistance. While grade 304 is used for “non-product” applications within the industry, 316L is used wherever pharmaceutical products are directly handled or manufactured. No matter what grade, sanitary, pharmaceutical grade stainless steel must exhibit good corrosion resistance and maintain its structural integrity so that it is not affected by heat or corrosive elements, like strong acids or bases.
Stainless steel does not release contaminants because the chromium content of the steel combines with oxygen in the atmosphere to form an invisible film of chrome-containing oxide, called the passive layer. The chromium oxide layer protects stainless steel when it encounters potential damage by machining or chemicals. If the metal is scratched and the passive film is disrupted, more oxide will form and recover the exposed surface, protecting it from oxidation corrosion. Though the protective layer is too thin to be visible, it is responsible for the glossy look of stainless steel.
Common types of corrosion in stainless steel:
- Pitting corrosion happens when the passive layer on stainless steel is attacked by strong chemicals. Chloride ions are the most common cause of pitting corrosion and can be found in everyday materials, like salt and bleach. The probability of pitting corrosion can be calculated based on alloy content. (Pitting Resistance Equivalent Number)
- Crevice corrosion happens when not enough oxygen reaches welded corners. Stainless steel requires oxygen to make sure that a passive layer of protective chromium oxide forms on the surface. Crevices do not always allow for chromium to interact with oxygen, which makes the steel vulnerable to corrosion. (mention coved corners)
- General corrosion can occur with the use of concentrated chemicals—most notably with hydrochloric and sulfuric acids—which corrode stainless steel uniformly and distribute metal loss across the entire surface.
- Stress corrosion cracking is a rare form of damage that is the result of low tensile strength, extreme temperature, and the presence of a concentrated corrosive chemical, often with chloride ions.
- Intergranualar corrosion is another rare form of corrosion that occurs when the carbon level in steel is too high. Chromium can combine with carbon to create chromium carbide between 450–850° This type of corrosion is called sensitization and typically occurs during welding operations when the passive layer of chromium is reduced to the point where corrosion can occur. Intergranular corrosion can be avoided by choosing low-grade carbons or by using steel with titanium or niobium.
The addition of chromium is what adds to steel the properties most sought by the pharmaceutical industry, namely its excellent resistance to corrosion and strength at high temperatures and pressures. There are three main classes of stainless steel depending on the metallurgic structure, but not all of them are appropriate for pharmaceutical use.
|16–20% chromium||10.5–27% chromium||11.5–18% chromium|
|Up to 35% nickel||Nickel free||1.2% carbon with nickel sometimes added|
|Highest corrosion resistance||Less critical anticorrosion||Modest corrosion resistance|
|Aircraft and dairy/food processing||Architectural and auto manufacturing||Cutlery, surgical instruments, wrenches, and turbines|
If the meningitis outbreak of 2012 has taught us anything about industry safety, it is akin to the ancient Greek lesson that guards against limiting perspectives. We must constantly look to the broad and the specific in order to balance our actions. The growth of compounding pharmacies in the 1990s was a direct response to overall industry shortages of necessary drugs, but the inability of regulatory agencies to keep pace with these changes resulted in production oversight that cost people their lives. These tragedies, like the production and distribution of MPA by the NECC could have been prevented with access to proper information about airflow requirements and appropriate equipment for processing pharmaceutical drugs.
While states and federal government agencies eventually interceded, it was not without the cruel recognition that the technologies needed to prevent these kinds of tragedies are well within our reach. It is wise for companies to understand the options that they have when it comes to designing laboratories for production purposes. Stainless steel is not merely shiny; its high gloss is, rather, a sign of its resilience and its ability to resist corrosion, which means that you can produce more safe and effective drugs for patients in need.
Though it is resilient enough on its own, not even stainless steel can guard against all types of contamination, which is why it is also imperative that drug manufacturers use appropriate air filtration systems to guard against the type of mold that infected the vials of MPA that eventually caused the outbreak of 2012. Partnering with experts like the engineers at Flow Sciences is an assured way to guarantee the integrity of your production process. For over 30 years, we have specialized in helping compounding pharmacies design containment systems to establish and improve their quality assurance.
The FLOW SCIENCES ADVANTAGE
As a manufacturer of safety products, we are also intimately familiar with quality as a standard of production. We know how important it is to certify raw materials and establish chains of command and consistent quality controls across the entire production chain. We know how important details are to the ultimate function of safety systems, just like how the smallest differences in stainless steel are critical to its function. It is our job to know these details, and we also consider it our duty to share them with our customers in hopes that, together, we can build a safer pharmaceutical industry.