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Margaret RicciHans-Christian MahlerMargaret Speed Ricci is director of drug product development at Amgen, Inc., in Thousand Oaks, Calif.
Hanns-Christian Mahler, P.D., Ph.D., is head of pharmaceutical development and supplies, PTD Biologics EU, F.Hoffmann-LaRoche Ltd (Basel, Switzerland).

The fungal meningitis outbreak associated with tainted steroid injections from the New England Compounding Center has highlighted questions about the product needs of hospitals and clinics, as well as the quality assurance of pharmacies that produce compounded sterile products. Virtually all single-use parenteral biologic therapeutic solutions for IV infusion or freeze-dried powders for injection require sterile compounding steps, such as reconstitution, dilution, or preparation of an IV bag for patient administration.

In-use studies must demonstrate chemical and physical stability to justify the acceptability of interim holding conditions of the prepared solution for a given recommended storage temperature and time duration. Per the European Medicines Agency (EMA) guidance, the product should be used immediately to minimize microbial growth, and it is the responsibility of the end user or clinical facility to ensure appropriate aseptic practices and suitable in-use storage prior to administration. The assurance of quality aseptic manufacturing steps such as dilution and reconstitution are tightly regulated in Europe; drug laws and clinical pharmacist guidances require operator training, aseptic media fills, and good documentation practices, just to name a few.

To ensure patient safety, the pharmaceutical industry relies on regulatory guidance documents to ensure the quality of compounding in clinical pharmacies or compounding centers. Product-specific risk assessments in conjunction with the EMA guidance and USP 797 may help to create a decision tree that accounts for the sterile compounding environment (e.g., ISO class 5) and number of drug product units and/or entries into the IV bag. Such assessment provides defined storage guidance based on the risk level, along with product-quality data. In addition to utilizing best practices and appropriate facilities for the sterile compounding, regulatory agencies have recently requested microbial challenge studies be performed by pharmaceutical manufacturers to assess the microbial growth potential of the compounded product. The utilization of aseptic process verification and microbial challenge studies in conjunction with USP 797 guidance is being explored by the industry as a means to ensure sterile compounded product quality.

A hot topic session at the AAPS National Biotechnology Conference in San Diego will discuss sterile drug product distribution issues from the clinical perspective, including sterile product challenges facing patient care organizations and the biopharmaceutical industry. This session will also discuss technical issues of sterile product fabrication, with an emphasis on an approach to qualify pharmacies to produce compounded sterile products.

An open dialog among regulatory agencies and industry is needed to ensure product quality—and sterility—of compounded single-use parenteral products. It is imperative to evolve the associated legislation to provide guidance and set standards on microbiological product quality assurance.