Health Systems Are Still Failing the Test for Safe Compounding

Health Systems Are Still Failing the Test for Safe Compounding

by Terri Lewis, PhD.
Dr. Terri Lewis is a rehabilitation educator, clinician and researcher who specializes in chronic pain and is a frequent contributor to the National Pain Report.

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 –

  1. The outsourcer shall have a state pharmacy license available where the compounding center resides.
  2. If located outside the state of Tennessee, the outsourcer shall be licensed to ship to Tennessee.
  3. 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

References

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.

Subscribe to our blog via email

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Authored by: Terri A Lewis, PhD.

There are 9 comments for this article
  1. Sarah at 12:25 pm

    Bacteria and fungi have kept to their evolutionary goals for survival of their species. Humans, not so much?
    Market forces and medicine are not mixing well if pre-1938, substandard drugs can be slipped into supply chains:
    –unnoticed by unassuming, trusting patients
    –during times of their greatest vulnerability
    –injected into their bodies in a compulsory manner, breaching immune defenses
    –without information regarding potential benefits and risks
    –without having been offered an alternative product, and
    –where that alternative product may be designated and warrantied sterile and apyrogenic

    The deadly NECC outbreak would have gone unnoticed had it not been for what Pasteur called the “prepared mind” of a lone epidemiologist in TN. it is extraordinarily difficult to identify and connect the epidemiological links in time and geographical space that connect multiple victims’ signs, symptoms and initial diagnoses of medical conditions with a rapidly evolving, invasive infectious process that ignites biologic system chaos and ultimate failure, graphically and tragically depicted in the necrotic brain of one of the first patients to die after being injected with the multi-pathogen containing, marketed sterile preparation. Outbreaks smaller magnitude, but larger in number are likely to be occurring today, without detection.

  2. Jean Price at 10:44 am

    Laura…I’m guessing many of us have had your same experience…both with some product or generics not being up to par in delivering the needed results…AND also being looked at as if we are crazy when we say so!! I KNOW I HAVE had to deal with both things, too!

    Recently two different medications I’v used long term were filled with generics which were “new” to me…and they just didn’t work! (One was a cardiac med to control rapid heart rate, the other was a low dose antidepressant for nerve pain caused when the nerve was damaged from an injection of mepavacaine prior to surgery on my foot.) The generics I had been taking helped so much I could easily tell the differences!

    My husband actually looked up the manufacturing company…in India, and found they had been cited several times and had several “hand slaps” for their drugs not meeting the standards of the other generics or the brand!! They were supposed to even reformulate some of them…and I wonder if they had even recalled those particular inferior ones!

    My mail in pharmacy service unfortunately could ONY supply this same kind of generic!! (Lots of contracts to save money come into the picture here, I’m sure!). So like, you…I requested brand on one, and paid the exorbitant difference in cost! And for the other I went back to my local pharmacy who WOULD order the generic I had previously used that had helped!

    There’s a world of difference even in Bayer aspirin and other brands! Especially in the rapid bioavailability! So why would we think this doesn’t happen with companies who are either innocently guiltily of contamination, or just guilty of cutting production cost by using substandard chemical ingredients and fillers?! The actual chemical of the drug is supposed to be exactly the same…yet all the inactive ingredients of the brand name drug are proprietary and that “recipe” is owned by the BRAND company and NOT released when the patent expires! So it’s up to the other companies to come up with an appropriate delivery recipe of their own. I think that’s where the main issues start up…and obviously also with contaminated ingredients. Sad…and scary! And it can mean higher costs for us, too, too to special order from the more reliable manufacturers.

  3. Jona Angst at 2:08 pm

    James Cangelosi, Terri Lewis knows more then you do! She has been instrumental in helping the victims of the 2012 fungal meningitis outbreak! If it wasn’t for her we wouldn’t know the vast amount of knowledge that we now know! Many people died and the survivors still suffer today after 5 years!

  4. James Cangelosi at 4:37 pm

    Terri Lewis, You really don’t have any idea what you’re talking about do you. Many inaccurate statements here.

  5. Bruce at 11:20 pm

    The entire food chain is contaminated with GMO’s because the seeds have been blown around and found a home in even “organic” farms. The whole thing goes much deeper than chain of custody and lax implementation of standards. That’s only the part we can SEE. Getting people sick is big money.
    My pain specialist threatened to discharge me if I didn’t continue to get lumbar block injections even after the ones I took didn’t work. Said I could fill out hardship papers to pay for them. We are just cash cows. I would rather use the compound I rub on my feet from the bizarre Chinese pharmacist who recommends taking fish oil every day for eternity to help my pain than have some militant director of a pain clinic threaten me with whatever injection in a sensitive area that can cause additional nerve damage if not properly placed would. Sure, I’ll just transfer to another pharmacist or compounding facility who doesn’t have a contract with my clinic. Good luck with that. They’ll put me in a state database and flag me for being a problem. You take what these monsters give you, or you go out to the street corner and score heroin. That’s the reality. There is no choice.

  6. Laura Robertson at 6:02 pm

    Since I was ten tears old, and given novo-rythro-stearate (which they no longer use because everyone complained about it) rather than erythromycin for chronic bronchitis, I have been arguing that the generics do NOT feel the same, and that some actually made me feel very sick. I was told that this was not possible, and was treated like i was crazy.

    As recently as last month I had this same argument about a muscle relaxant. The Mylan-Baclofen I was given worked extremely well, while the generic was as useless as popping smarties I had no idea that the Mylan brand was the original, and the other was a generic replacement, so I expected the same result.

    When I told this to my doctor and pharmacist, I was again treated like i was crazy. But I insisted on the name brand, and had to wait five days for it to come in.

    From carcinogenic dyes used to colour our medications, to non-regulated fillers that include bird droppings?

    Apparently, I am not crazy, my health care system is. Nice to know, and extremely disturbing.

    Thank you for this exposé.

    Now please tell it to our health care “professionals”, who have a duty if care to protect us and ensure our medical health and safety.

    Laura
    chronicpain@bell.net

  7. Bob Schubring at 4:54 pm

    Anyone dumb enough to mix bird droppings in with food or medicine, should not be trusted to manage a healthcare facility of any kind. Feces contain massive numbers of harmful bacteria.

    To not comprehend the danger of administering these harmful bacteria to patients, means that one is ignorant of every medical advance that took place since 1872, when Robert Koch and Louis Pasteur proved that infectious bacteria cause infections.

  8. wanita 1 at 3:43 pm

    Very informative article! Thanks for writing it.

  9. Sheryl M Donnell at 11:22 am

    Well, just one more thing to add to my list of legitimate fears. And I believe what he is saying is valid when I think about our food supply. 11 years ago I was extremely lucky to go on 2 trips. One to Italy with my daughter who has lots of food sensitivities and an Alaskan Cruise with my husband who also suffers from the same issues. Neither one had a single issue eating anything on these trips, even their biggest trigger foods but both trips had their food completely from other countries that have much stricter laws on Food Safety (our cruise had been stocked with food food flown in from Europe the same day). Both of them were in heaven until they returned to the mainland and tried anything they were sensitive to and were immediately sick. We have contaminated our own food, and why not our compounded drugs, and so many other things just to try to make corporations top executives richer. It is no wonder so many of us have autoimmune diseases and other illnesses. I miss the days when there were still local farms around in our area where we could buy bushels of vegetables (And they were only organic, what else would they be the farmer fed these to his family too) and I’d help my mom can everything for days on end so all winter we had healthy food…maybe I need to find a way to do it again. Maybe it will help counteract whatever they are filling my pain pump with every 3 months….