FDA cracks down on the unauthorised production of inhalation drugs
American national pharmacies for using the traditional practice of
compounding as a ruse in order to operate as drug manufacturers,
producing thousands of unapproved copies of commercially available
nebuliser medications that do not meet good manufacturing practice
(GMP) standards.
Warning letters have been sent to RoTech Healthcare, CCS Medical and Reliant Pharmacy Services, asking them to stop mass producing inhalation drugs or face injunctions and seizure of their products.
While the FDA will not reveal the exact number of doses these firms manufacture, the agency believes that by compounding mass amounts of drugs, a number of pharmacies go well beyond traditional compounding.
Compounding is a practice in which pharmacists manufacture prescription drugs by combining, mixing or altering bulk ingredients in response to a physician's prescription to create a medication tailored to the needs of an individual patient.
"Compounded inhalation drugs are not reviewed by the FDA for safety and effectiveness, often are not produced according to good drug manufacturing practice, and typically are not sterile," said Steven Galson, director of the FDA's Center for Drug Evaluation and Research.
"To avoid these risks, we encourage patients to use FDA-approved drugs whenever possible."
Yet the FDA has for years turned a blind eye to pharmacies that engage in compounding because they accommodate the specialised medical needs of some patients.
For example, a patient may be allergic to an ingredient in a mass produced drug or may require a liquid dosage form of tablets which is not commercially available.
But many pharmacies exploit this loophole to make large quantities of unapproved medicines that are commercial copies of approved drugs, particularly in the lucrative respiratory disease market, where their profit margins can exceed 75 per cent.
Thus, RoTech was found to produce budesonide inhalation powder in 0.4mg and 0.3mg vials, despite AstraZeneca's budesonide drug Pulmicort already being commercially available in strengths of 0.5mg and 0.25mg.
The FDA therefore decided there was no legitimate medical need for these insignificant differences in formulation and that RoTech was essentially manufacturing an unauthorised generic version of Pulmicort.
Moreover, the regulator deplored RoTech's production of albuterol 2.5 mg/ipratropium 0.5mg in 3ml vials, which is essentially a copy of the bronchodilator DuoNeb made by Merck KGaA, since the only noteworthy difference is that the new version contains the preservative benzalkonium chloride whereas DuoNeb contains edentate disodium, though no medical need is satisfied by this change.
Crucially, an FDA inspection in August 2005 revealed that RoTech's production of these products was problematic.
Among the deviations from GMP for finished pharmaceuticals the Florida-based pharmacy is accused of is the failure to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications.
There were also omissions in the process validation as well as validation of the aseptic filling operation for the inhaled products and inadequate separation of packaging and labelling, though the FDA's warning letter does not go into details.
In the case of CCS Medical, the firm manufactures several inhalation products that are the same strength as the commercially available products, including budesonide 0.25mg in 2ml vials and albuterol 2.5mg/ipratropium 0.5mg in 2.5ml vials.
Pharmacies argue that by combining several ingredients, they can cut the nebuliser time of inhalation products by more than 50 per cent, but patient advocacy groups protest that, apart from the safety concerns their manufacturing raises, some patients are fooled into accepting compounded drugs as legitimate generics.
"While we commend the FDA for sending out these warning letters, we need the agency to go one step further and force these companies to notify patients who are in receipt of unlawful and potentially unsafe medications," said Nancy Sander, president and founder of Allergy & Asthma Network Mothers of Asthmatics.
"Millions of doses have been manufactured and distributed, but patients and prescribers alike are often unaware that their prescriptions for FDA- approved medications were substituted with unapproved, unlawful medications made by RoTech, Reliant and CCS Medical."
Although compounded drugs are widely viewed as safe, this is hard to verify since states do not require pharmacies to report adverse events associated with their compounded products.
This latest development will intensify calls by drug manufacturers for tighter regulations for compounding pharmacies, however, the FDA claims it has to balance their arguments against the benefits many patients see from custom made medicines, since stricter rules may drive many pharmacies out of the legitimate compounding business.
