In recent years health scientists have voices their concerns about the adaptation of bacteria and fungi to environments that include hospitals, food processing facilities, industrial buildings and homes. More environmental diseases are creeping into the supply system due to changing conditions of environment, spread associated with product shipping patterns (ocean vessels, domestic trucking) and procurement and import of products from non domestic sources with long lead times. Much of our food supply arrives in the USA on pallets after having been stored in conditions of shipping that foster the spread of insects, fungi, and bacteria. Upon arrival into the domestic market place, these critters adapt.
In much the same way, the US chemical industry produces with materials sourced overseas from markets of foreign origin that may have transited thousands of miles with continuous rehandling and reconfiguration. Most of the chemicals we rely on for manufacturing of medicines is derived from foreign sources and arrives on our shores packaged in paper, plastic, cardboard, and wooden pallets that provide harborage for active bacteria, fungi and insects. Add to this, the growth of a compounding marketplace that relies on imported supplies to manufacture a wide range of compounded food, drug and biologic products and we have the makings of a supply chain that contributes to the spread of bacteria and fungi associated with the production of unsafe supplies.
Such was the case with New England Compounding Company (NECC), which routinely purchased supplies from nondomestic sources, stored pallets and packaging in a salvage yard next to their production facilities, and then transmitted contaminants into production through air handling duct work, bird droppings from birds that lived in the salvage yard, and through the movement of product from outside environs to inside environs. Their failure to recognize or address sanitary practices associated with reducing opportunities for environmental contamination led to the 2012 recall of 2,700 pharmaceutical line items in a variety of packaging, the exposure of 13,500 individuals in 21 states to contaminated steroids used for joint and spinal injections, the documented sickening of nearly 800, and the deaths of more than 70 from fungal and bacterial infections.
Since then, Congress passed the Drug Quality Safety Act (DQSA, 2013) which allows FDA to inspect compounding manufacturers who build products for sale and delivery across state lines. State Boards of Pharmacy are required to develop inspection systems for compounding manufacturers who produce for sale to individuals from mom and pop pharmacies, hospital pharmacies, or compounders that limit their sales to in-state marketplaces. But problems remain as the law does not afford FDA the ability to shut down violaters without state regulator assistance. While some states have built systems of inspection, others have been lax in meeting their obligations. As of this date, FDA has registered 72 outsourcing compounding manufacturers nationwide under the 503B requirements. Of this number, 61 firms have been issued Fm483 WARN letters for safety and sanitation violations but continue to produce compounded drugs fror sale across state lines to unsuspecting purchasers in the health care system. And, of the 61 firms that have received warnings, 53 have open warn letters with unresolved issues or have been involved in regulatory discussions. Four firms were shut down through the use of court injunctions.
Clear guidance for and regulatory oversight of sterile product preparation improves patient safety and protects public health. United States Pharmacopeial Convention (USP) standards in chapter 797 2 (USP 797) provide strict requirements for preparing sterile products, including those related to the preparation area, equipment certification, and aseptic technique. The DQSA covers all private and public hospital entities. Increasingly, both private and public hospitals have undertaken to install compounding systems with various degrees of success or scale as some drugs have become increasingly hard to obtain from the manufacturing sector.
Since October 2012 there have been over 100 recall events involving compounded drugs, many due to conditions and practices resulting in a lack of drug sterility assurance. Some recalls have been verseen by FDA, others overseen by the states ( FY 2013 – 30 recall events; FY 2014– 29 recall events; FY 2015 – 41 recall events). Since October 2012 FDA has issued 3 letters formally asking firms to recall compounded drugs after they refused informal requests
In 2015, the National Institute of Health (NIH) was inspected by FDA only to be cited for irregularities of production under DQSA. The FDA visited the laboratory on May 19 – 21 and May 26 and 29 and issued multiple citations (https://www.cc.nih.gov/phar/pdfs/483.pdf) for violations that led to six patients receiving vials of medication contaminated with fungal contaminants. NIH suspended compounding operations, stopped making and distributing products, and began testing for contamination. The shutdown affected 46 studies and human subjects enrolled in treatment protocols. An external group of experts in microbiology and sterile manufacturing practices was appointed to conduct a thorough review and assessment of all standard operating procedures, policies, staffing, and training, and make recommendations to the NIH director on the corrective actions required.
The Veterans Administration hospitals routinely purchase compounded products and in 25 locations, make some compounded drugs for distribution in their pharmacies. An examination of a recent procurement document VA249-15-Q-0485 issued in 2015 out of the Tennessee Valley VA system for a base year with four option years (2015-2020) indicates that “…all prospective bidders must have accreditation through the Pharmacy Compounding Accreditation Board (PCAB) and submit documentation indicating such. All quotes received without this documentation will not be considered. The offeror shall provide sufficient evidence that they possess adequate resources, capability, experience, responsibility and integrity to meet the technical capabilities to comply with the requirements of the resulting contract.” Among the many requirements for bidders, it is clearly stated that –
- The outsourcer shall have a state pharmacy license available where the compounding center resides.
- If located outside the state of Tennessee, the outsourcer shall be licensed to ship to Tennessee.
- If the outsourcer prepares a significant number of non-patient-specific preparations (>5% of the outsourcer’s volume, the outsourcer shall be registered as a drug manufacturer with the Food and Drug Administration (FDA).
On May 10, 2017, the Inspector General for the Veterans Administration issued a summary report for the inspection of laboratory compounding pharmacies throughout the VA hospital system. They noted “ high compliance in several areas , including that facilities had adequate policies and provided safe conditions for CSP preparation; that staff documented sampling for contamination in required areas and took actions when they identified positive cultures; and that when facilities used non-VA sources for CSPs, the sources were appropriately registered [p 2].” Nevertheless, there is clear evidence from procurement documents and purchase awards for the Tennessee Valley region, that among the more than 50 bidders who registered to provide supplies for distribution to veterans under this solicitation, a significant number of potential suppliers had been accepted as offerers despite open warn letters for violations of safety and sanitary production of compounded supplies. Some of these offerers with open warn letters for safety and sanitation violations actually delivered supplies to TN –TV region in spite of these violations.
Despite these requirements, at the time of the VA’s investigation, there were several reports of patient deaths and harm related to unsafe CSP preparation within their hospital systems. In fiscal year 2011, OIG had completed a review of chemotherapy drug handling at 44 facilities that identified multiple opportunities for improvement. System weaknesses were identified in three main areas in the May 2017 report. First, facilities’ competency assessment requirements and checklists and employees’ completed competency assessments did not include all required competency assessment elements. Additionally, sterile chemotherapy-type gloves were not available in all areas where hazardous CSP were prepared. Finally, facilities did not provide evidence of consistent cleaning of sterile compounding area floors and storage shelving. These findings align with violations of safety and sanitation on the Fm 483 issued to NECC by FDA in 2012.
So, as consumers why should we be concerned? What should we be concerned about?
Persons with complex illness and chronic pain consume significant amounts of compounded drugs through topicals and ‘sterile injectables,’ intravenous infusions, and surgical processes. Compounded drugs are less expensive, frequently purchased in bulk for rehydration, and may turn over slowly in hospital and clinical inventories. When produced by compounders, they are often produced without shelf-life extenders which means that they must be produced for specific individuals and for immediate use. Unfortunately, as we have seen, safeguards associated with production and inventory control may fail – either before they get to production conditions or after they are delivered to clinics for use by patients.
Fungi and bacteria adapt to new living conditions quickly. While we may be skeptical or ‘pooh pooh’ global warming, the fact remains that we can now track these organisms by their DNA profiles. Increasingly these profiles tell us that we have new and potent fungi and bacteria that are making their way into our food and drug supply chain from global locations and into the compounded drugs distributed to users. It is becoming clearer that these organisms are adapting, and may account for the post surgical, hospital and community acquired infections that are emerging and resistant to antibiotics and anti-fungals.
No hospital or clinic is exempt from the need to employ safety and sanitary and ‘track and trace’ practices that protect consumers. Because compounded drugs are experimental, and not FDA approved, consumers have no regulated protections from potential harms except to be informed and vigilant. Consumers who rely on compounded medications have the right to be informed about –
- The conditions under which compounded drugs might be recommended or used and the right to refuse their use in favor of drugs sourced from FDA registered manufacturers.
- The ingredients from which they are made and where they are purchased from
- The outsourcing manufacturer (hospital or outsourcing manufacturer)
- The date of production and expiration and lot number
- Laboratory analytics that reflect safety and soundness
Food and Drug Administration (n.d.). DA RegulatoryActions Involving Drug Compounding Office of Compliance, Intergovernmental Work Group, CDER/FDA. Retrieved from https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/UCM482521.pdf
Fulmer, B. (2015, June 9). NIH Drug-Making Laboratory Shut Down due to Fungus Fears. Retrieved from http://searcymasstort.com/recent-news/nih-drug-making-laboratory-shut-down-due-to-fungus-fears/
Department of Veterans Affairs, Office of the Inspector General (2010, May 7). Evaluation of Compounded Sterile Product Practices in Veterans Health Administration Facilities. Report No. 16-03807-223. Office of Healthcare Inspections. Retrieved from https://www.va.gov/oig/pubs/VAOIG-16-03807-223.pdf
A list of FDA registered manufacturing compounders is located at the link – https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm378645.htm).
A sample WARN letter which details violations can be found on the link https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm525103.htm)
NOTE. A “Closed” warning letter means the inspection has been closed without further action. An “Open” warning means that FDA has not made a determination as to whether further action will be taken – states may or may not be involved in followup. If an action has been taken, it will be listed. Possible FDA actions include – warning letter; seizure; or injunction.