Many pharmaceutical companies spend considerable time, resources and energy to ensure that their facilities are in top shape, wary of the potential for US regulators to issue a Form-483 identifying deficiencies at a manufacturing facility and the costs associated with correction or remediation.

But if the prospect of just one Form-483 is enough to keep some regulatory affairs professionals awake at night, it's hard not to wonder how much sleep the compliance officials at Central Admixture Pharmacy Services (CAPS), a pharmaceutical compounder recently in receipt of six separate Form-483s, are getting.

Background

The US Food and Drug Administration (FDA) recently began a massive crackdown against compounding pharmacies after the products of one pharmacy, the New England Compounding Center, were associated with a massive outbreak of fungal meningitis that left dozens dead and hundreds injured.

In the wake of that outbreak and considerable congressional pressure, regulators set out to inspect or re-inspect compounding facilities deemed to be of the highest risk: those manufacturing sterile products.

The results haven't been favorable for those inspected, and nearly all have received some sort of notice of deficiency, while several others have received warnings letters or issued recalls citing sterility issues. And while other pharmaceutical compounders haven't exactly had stellar records-PharMEDium Service has received at least four Form-483s, and several others have received at least two-CAPS currently has the unenviable record of the most compounding 483s by at least half.

A Barrage of 483s

FDA's inspection reports to the company reference six separate inspections over the course of about seven weeks (29 January 2013 through 7 March 2013) at facilities in Massachusetts, Connecticut, Michigan, Missouri, Alabama and Illinois.

While the inspection reports may reference facilities separated by state lines, the problems alleged and cited by FDA are very much similar in many respects.

The chief complaint in all six 483s is one common to most other compounding inspections: Failure to assure sterility.

At CAPS' facility in Illinois, FDA investigators found that the company does not continuously monitor air pressure differentials, clothing worn by processing personnel was not suited to sterile manufacturing, components were not stored appropriately at all times to prevent contamination, sterility testing was not conducted on a daily basis and expiration testing was not conducted in some products.

Critically, FDA alleged that the company did not "thoroughly review the failure of a batch or any of its components to meet any of its specifications," and that the company had been aware of "recurring leaks" in a sterile parenteral nutrition bag product at "all of its facilities" but did not investigate the leaks for more than two years.

In Alabama, FDA investigators found that at least 18 orders of a Cardioplegia drug had already been released and distributed before test results confirmed they were contaminated with "objectionable microorganisms." The Alabama inspection also noted the company's failure to investigate the root cause of unexplained discrepancies, failure to test some products for identity and strength, failure to design procedures to prevent microbial contamination, and a lack of written procedures.

Similar Allegations Elsewhere

Similar alleged violations were seen at the other four facilities in Missouri, Michigan, Connecticut and Massachusetts.

In a statement on its website, CAPS said it is taking FDA's concerns into account as part of its "continuous improvement process," and otherwise sought to downplay the importance of the 483s.

"To those unaccustomed to reading FDA inspectional observations they can seem dramatic and concerning," the company wrote. "CAPS is open to reviewing these observations with our customers to provide the context and perspective that is otherwise missing from the overall observation."

The company noted that it continued to deliver the parenteral nutrition product that the 483s alleged were the subject of recurring, uninvestigated leaks.

CAPS is a subsidiary of B. Braun Medical.