Revisiting the Unsanitary/Insanitary Conundrum of Custom Biopharmaceuticals

Compounding the Problem?

If we were called upon to characterize last year in just two words, we would undoubtedly select unprecedented and pandemic as the most obvious watchwords of 2020. And at this point in time their definition is abundantly clear. But, as we start 2021, a couple of terms have resurfaced that apparently remain somewhat opaque, among them insanitary, unsanitary, and the difference – in in respect of compounding pharmacy hygiene – between them. So, given the recent release by the U.S. Food and Drug Administration (FDA) of the updated ‘Insanitary Conditions at  Compounding Pharmacies. Guidance for Industry,’ we thought it might be time to take a look at what is meant by these terms, at what a ‘compounding pharmacy’ actually is, and at the new regulatory guidance itself. After all, transparency in terminology is especially critical when public health is at stake.

As we discussed in our 2016 article, Compounding Pharmacies: Exploring the Insanitary/Unsanitary Conundrum, there is a very real distinction between ‘insanitary’ and ‘unsanitary’ in relation to manufacture. The difference is more than mere semantics and also goes above the accepted use of the words in general parlance. In terms of the regulation of the bio-pharmaceutical industry the term unsanitary connotes ‘a state of unhealthiness, of dirt, one that is conducive to harboring or spreading disease. Conditions, places, buildings, physical environments may all be ‘unsanitary,’ as may practices, procedures, or operations. Insanitary […] simply implies a lack of sanitation. A slight but, for our purposes, significant difference – and one fully recognized by the FDA.’(1) Moreover, under federal law, a pharmaceutical product is considered ‘adulterated if it is prepared, packed or held under insanitary conditions that could cause the drug to become contaminated with filth or rendered injurious to health.’(2)

So what do we mean by compounding pharmacies?

It’s understandable if the term is unfamiliar, given that the American Pharmacists Association recognize only 7,500 of these specialized providers – a small fraction of the 56,000 ‘regular’ pharmacies in the US.(3) So, in the spirit of getting clear about definitions, what is a compounding pharmacy? The FDA defines the process of compounding as follows: ‘Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.’(3) And Single Care, which partners with major chain pharmacies such as Walgreens and CVS, describes a compounding pharmacy as one in which ‘the pharmacists actually customize medication for each individual patient and his or her unique needs, as long as that drug is not available from a drug manufacturer. The ingredients are kept on hand, and when a patient needs a particular treatment, a compounding pharmacist mixes it up from these ingredients […] Pills and tablets are not commonly compounded. But, liquids, creams, ointments, lozenges, suppositories, and often capsules are compounded.’(4)

Under what circumstances would a patient require this level of specialized service? In some cases an exact formulation needs to be tailored to create medications devoid of gelatin, dyes, lactose, and other allergens. Alternatively, the required dosage may be unavailable in the regularly manufactured drug, as Jesica Mills, Pharm.D. notes in the Single Care primer: ‘Naltrexone, a medication used to treat opioid and alcohol-use disorders that normally comes in a 50 mg tablet. “[Some studies show] that this medication at one to five milligrams [can] help with autoimmune issues [but since] there isn’t a way to split a 50 mg tablet to get a 3 mg dose, [compounding] pharmacies can order the Naltrexone powder, weigh out [the appropriate amount] and then place it in a capsule for a patient to take.”’(5) Of course, the other reason for using a compounding pharmacy is when a drug cocktail is not even available commercially – in that case, the niche problem demands a niche solution.

So given this specialist market can we assume the protocols followed by compounding pharmacies are regulated as strictly as those of their more broad-reaching counterparts? Actually, no: in reality, compound drugs are exempt from FDA approval and are ‘regulated by state boards of pharmacy based on standards set by the United States Pharmacopeial (USP) Convention.’(6) And how has that been working out? Let’s take a look…

In 2012, the New England Compounding Center (NECC) was the epicenter of a fungal meningitis outbreak that sickened more than 800 patients across the country. As we described in our earlier article ‘[t]he cause of this uncommon outbreak was traced back to supplies of an injectable steroid, methylprednisolone acetate, commonly used for pain management [which] was contaminated with fungal spores that found their way directly into unsuspecting patients. Of those who received treatment from this tainted batch of product, 64 died in 20 separate states.’(7) In the subsequent investigation of NECC, the FDA found a host of problems with the company’s cleanroom: a leaky boiler, stagnant water, uncleaned powder hoods, and an air intake vented close to a recycling plant. Within this shockingly unsanitary environment drugs were compounded that were destined for injection directly into a patient’s spine.

When the situation at NECC came to light, public outrage understandably exploded at the rank breach of trust on the part of the company, while authorities focused on bringing a raft of charges against top executives and pharmacy employees. Facing accusations that ranged from racketeering to fraud and conspiracy to murder, some individuals took extraordinary measures to evade justice, with one supervising pharmacist, Glenn Chin, arrested at Boston’s Logan Airport attempting to flee to Hong Kong, a country that had no clear-cut extradition policy with the US. Yet as dramatic and tragic as this episode was, unfortunately NECC would not be the last compounding pharmacy to play roulette with public health. According to Ian F. Deveau, Ph.D., an FDA lead compliance officer in the NECC case, ‘the NECC tragedy was not unique. It was by far the most prominent, the most wide-spread, and sadly, the most tragic in terms of deaths and injuries. However, prior to NECC there were others — and even more sadly, we continue to see harm to patients because of poor compounding procedures.’(8) Indeed, since 2012, myriad cases have come to light of pharmaceuticals contaminated with bacterial, fungal, or microbial pathogens or tainted with environmental contaminants such as human hair. The FDA’s website maintains an alphabetized list of inspections, recalls and other regulatory actions, and it is currently unnecessary to read beyond the ‘A’s for a plethora of examples. A Chem Rx, LLC, (dba Cortez Drugs), of Brooksville, FL, is one such example…

Following an inspection in February 2020, A Chem Rx, LLC, a manufacturer of non-sterile drug products, was issued a FMD-145 Letter and Form FDA 483, the Establishment Inspection Report (EIR). Although redacted to protect confidential corporate information (marked as a (b)(4) redaction), the document indicates that the pharmacy was out of compliance with regulatory guidelines due to observed contamination within the immediate compounding area. According to inspector Jessica L. Pressley, a drug specialist, a vent positioned directly over a working surface was characterized as ‘un-clean, shedding and [observed] to contain an unknown brown residue.’(9) In addition to the environmental contamination, the handling of some drug ingredients was exposed as highly questionable: ‘Hazardous drugs were produced without providing adequate containment, segregation, and/or cleaning of work surfaces, utensils, and/or personnel to prevent cross-contamination.’(10)

At the time A Chem Rx, LLC, manufactured three very significant medications. The first, Estradiol 0.1mg/g Cream is an estrogen steroid hormone that is critical to the female reproductive cycle, as well as well as being both neuro-protective and beneficial to the coronary arteries. A second product manufactured at the compounding pharmacy was a prescription Testosterone 1mg/mL Cream, used primarily to treat non-age related hypogonadism. And thirdly, there was the matter of the Naltrexone 4mg Capsules. In higher doses, Naltrexone is used in medication-assisted treatment (MAT) of opioid or alcohol addiction, but in Low Dose Naltrexone (LDN) therapy – such as these 4mg capsules – the drug is hypothesized as an ‘off-label’ treatment for conditions such as Crohn’s disease, multiple sclerosis, and as beneficial in reducing symptom severity in behavioral disorders such as compulsive gambling or kleptomania. In short, contamination of the three medications had implications for a very broad range of patients of differing healthcare challenges.

So given that A Chem Rx, LLC, is only one of the companies on the FDA’s extensive list of actions relating to compounding facilities and given that the problem of sanitation compliance seems to be more extensive than we’d have hoped, it was a surprise to see how little fanfare accompanied the release of the FDA’s updated guidance for insanitary conditions. But perhaps this comparative lack of excitement could be because the update arguably falls short of expectation. According to Regulatory Focus, the document outline contains only minor ‘clarifications’ regarding protocols for handling radiopharmaceuticals, some physician compounding processes, and repackaging. Indeed, the article also notes that ‘[t]he most significant change in the final guidance is a shift a risk management approach to prevent the occurrence of insanitary conditions. Now, instead of focusing primarily on corrective actions compounders can take to address insanitary conditions, the guidance provides recommendations for prevention.’(11) So, in essence, what we are looking at here is a document eight years in the making that offers minimal new information above minor ‘clarifications,’ and throws the responsibility for protecting public health back onto the compounders themselves: ‘It is critical that all compounding facilities prevent the occurrence of any insanitary conditions within their facility […] Prevention of insanitary conditions begins with the identification of risks associated with a process, procedure, or facility. Risk management tools offer a way to evaluate risk and to develop controls designed to prevent the occurrence of insanitary conditions within a compounding facility.’(12)

But is this really sufficient? In an industry where some less scrupulous pharmacies cut corners to maximize profit or where others have simply not instituted the correct protocols to ensure product safety, is it really enough to offer recommendations for compliance without bringing the processes under the same umbrella as the rest of the (non-compounding) industry? When we see examples of companies using sanitation products incorrectly or using the wrong products altogether, skimping on personal protective equipment (PPE), or ignoring protocols such as current Good Manufacturing Processes (cGMPs) and Hazard Analysis and Critical Control Points protocols we have to wonder whether the regulatory agencies are allowed a sufficiently strong role. In its article, the agency’s own divisional director Deveau does highlight the fact that ‘there are now many compounding facilities that appear to appropriately prepare compounded medicines. We have come a long way in our efforts to forge improvements. But we’ve seen multiple times over the years, all it takes are a few bad operators to make compounding a riskier practice than it needs to be.’(13) And let’s not forget that the working failures of those ‘few bad operators’ can ultimately be the difference between life or death for patients. So after waiting eight years for the release of the FDA’s industry guidance documentation following the NECC affair, the question still remains: for a vulnerable patient demographic, is it acceptable to allow amounts to industry self-regulation? Is this indeed a risk we should continue to allow?

What are your thoughts? Should the FDA take a stronger role in regulating compounding pharmacies? We’d love to read your comments!

References:

1. https://berkshire.com/insanitary-unsanitary-conundrum/
2. https://www.fda.gov/news-events/press-announcements/fda-takes-efforts-protect-patients-potentially-harmful-compounded-drugs-through-finalizing
3. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding
4. https://www.singlecare.com/blog/compounding-pharmacy/
5. ibid
6. ibid
7. https://berkshire.com/insanitary-unsanitary-conundrum/
8. https://www.fda.gov/drugs/news-events-human-drugs/cders-efforts-help-improve-quality-drug-compounding-include-ongoing-focus-insanitary-conditions
9. https://www.fda.gov/media/135410/download
10. ibid