The agency recently took a critical look at our surveillance and enforcement approach to pharmacies that produce sterile drug products. The agency’s objective was to determine whether certain pharmacies that were known to have produced high-risk sterile drug products in the past posed a significant threat to public health from poor sterile drug production practices.
Using a risk-based model, FDA identified 29 firms for priority inspections that focused on their sterile drug production practices. During these 29 inspections, in two instances, FDA identified secondary firms associated with the initial priority inspections, which it then inspected, for a total of 31 firms. Criteria for FDA’s risk-based model included serious adverse event reports, historical inspection data, and reports of product quality problems. Facilities that met at least two criteria or had a reported death were identified for the priority inspections. The inspections took place over a seven week period from February to April 2013. The Agency inspected these firms according to federal standards regarding aseptic practices.
The majority of the inspections (28/31; 90%) were completed in coordination with applicable state boards of pharmacy or other state officials. Each inspection evaluated the firm’s sterile drug processes to identify firms that may pose a higher risk of producing unsafe or poor quality sterile drugs.
To conduct the inspections, FDA mobilized highly-skilled, certified drug investigators who have specialized experience and specific training to evaluate pharmaceutical production and determine a firm’s compliance with sterile production standards. These investigators performed the targeted inspections in 18 states.
During each inspection, the investigators visually examined the firm’s practices and procedures by observing the production environment, equipment used to make the drugs, the design of the facility, and personnel practices and behavior. In addition, FDA interviewed the firm’s technicians and collected information on the firm’s operations, standard operating procedures, and products to learn more about the effectiveness of the firm’s sterilization methods and drug stability program. Finally, the investigators looked into the firm’s potency, sterility and endotoxin failures, as well as the firm’s air flow studies (if present). If warranted, investigators collected samples when they observed an abnormality, such as drug product residues, particulates or discoloration within the production environment or the actual sterile drug product.
As of April 11, 2013, the agency had completed 29 of the 31 priority inspections, and FDA had issued a list of inspectional observations, called an FDA Form 483, to 28 of 29 firms. The one firm not receiving a FDA Form 483 was not producing sterile drugs. FDA has subsequently posted the FDA Form 483s on its website. Select FDA observations during the inspections include: incomplete and/or inadequate drug product batch failure investigations, inappropriate and/or inadequate clothing for sterile processing, lack of appropriate air filtration systems, insufficient microbiological testing, and other practices that create risk of contamination.
At one firm, Lowlite Investments, d/b/a Olympia Compounding Pharmacy in Orlando, FL, FDA’s inspection was delayed because investigators had to obtain an administrative warrant to gain access to, and make copies of, that firm’s records. Once the warrant was obtained, U.S. Marshals accompanied FDA investigators to the firm to collect records and conclude the inspection. In January 2013, FDA also had to obtain an administrative warrant to get access to records and complete a for-cause inspection of Wedgewood Pharmacy in Swedesboro, NJ.
In addition, 4 out of the 31 firms initially refused to permit FDA investigators access to records or to allow observation of their sterile processing activities. After some initial delay, and in some instances, discussion with the firms’ legal counsel, these firms eventually provided the investigators the necessary access to inspect their facilities.
The agency is currently evaluating the information obtained during the inspections and where applicable, will apply its existing legal authority to protect the public health. For the firms that are operating outside the bounds of traditional pharmacy compounding and who had significant sterile production issues, FDA plans to take aggressive action, including through enforcement actions, as appropriate. Under the current regulatory framework, FDA may not be able to take enforcement action against firms that meet certain criteria and are operating within the bounds of traditional pharmacy compounding unless certain provisions of the law are violated, such as producing or distributing a contaminated drug product. However, FDA is coordinating closely with the state boards of pharmacy and referring the appropriate cases to them.