Guidance documents, as the US Food and Drug Administration (FDA) often reminds industry, are not legally binding entities. Rather, they represent insight into regulators' current best thinking on a particular subject, giving companies the opportunity to make compliant their operations and avoid any regulatory headaches.
But just because they're not legally enforceable on their own doesn't mean that FDA isn't interested in taking action in accordance with the regulations they interpret.
Background: Penicillin Guidance
Take for example an April 2013 guidance document released by FDA entitled Non-Penicillin Beta-Lactam Drugs: A Current Good Manufacturing Practice (CGMP) Framework for Preventing Cross-Contamination.
The guidance is aimed at manufacturers of non-penicillin drugs, which are characterized by a beta-lactam ring, a chemical structure common to many types of antibiotics including caphalosporins, monobactams, penems, carbapenems and penicillin.
One of the main problems associated with the manufacture of these drugs is their propensity to cross-contaminate one another if not properly separated. While problematic for its own sake, the contamination can create additional problems as well at the user level if not properly controlled, FDA explained. That's because some people are hypersensitive to penicillin and can have an "exaggerated allergic immune response" if exposed to the drug, potentially resulting in death.
In FDA's interpretation of its CGMP regulations, as explained in the guidance document, it is recommended that manufacturers take extreme care when manufacturing penicillin, and make sure the manufacture takes place in a separate facility or facilities.
But a June 2013 inspection by FDA investigators of Americare Compounding, a compounding pharmacy located in Garden City South, NY, found extensive violations of the very principles FDA established through that very guidance document.
The agency has been in the midst of an extensive crackdown on compounding pharmacies, the result of a massive outbreak of fungal meningitis in October 2012 that ultimately killed dozens and injured hundreds more. In the aftermath of the outbreak, congressional pressure prompted FDA to begin inspecting compounders, which it had previously been loath to do. The results of those inspections, many of which are featured on FDA's website, catalogue varied and extensive violations at many facilities, with the majority related to CGMP deficiencies.
Americare, for example, was found to be processing and packing penicillin incorrectly.
"The operations relating to the processing and packing of penicillin are not performed in facilities separate from those used for other drug products for human use," FDA explained. "Specifically, your firm is processing Penicillin, such as Penicillin Ophthalmic solution, in the same cleanroom with your non-penicillin products. The absence of a structurally isolated area creates the potential that accidental breakage of vials of penicillin powder could contaminate your other sterile drug products."
In addition, the company's air-handling systems were not separate from areas in which the company was compounding non-penicillin drugs, another violation of CGMP principles. FDA also noted that the company did not maintain separate facilities for processing penicillin products, increasing the potential for mix-ups. "These beta-Lactam powders are processed on the same work station as sterile non beta-Lactam drugs in the same clean room," FDA noted.
FDA's Form 483 detailing inspection deficiencies may be found here.
FDA Guidance on Penicillin Manufacturing
Form 483 to Americare Compounders