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By Margaret Speed Ricci and Hanns-Christian Mahler

Margaret RicciHanns-Christian MahlerProtein biopharmaceuticals are frequently prepared aseptically in a hospital pharmacy or manufactured in advance in a compounding facility or center, and the ready-to-administer preparations are likely subjected to a holding time before use. Aseptic preparation (or “traditional” compounding) of ready-to-administer parenteral preparations by dilution, reconstitution, or infusion preparation can be done for individual patients within a hospital pharmacy, whereas bulk production (or “nontraditional” compounding) of ready-to-administer preparations at compounding centers is considered manufacturing. Because of the scale of production and potentially significant holding times of the compounded products, general good practice (GxP) manufacturing considerations should be required.

How the product is handled by the health care professional and patient is extremely important in ensuring stability, efficacy, and safety. The fungal meningitis outbreak associated with compounded products from the New England Compounding Center can be considered an example for how lack of quality considerations during manufacturing can impact patient safety.

Physicochemical and microbiological stability and recovery of the active drug upon dilution and/or reconstitution are typically evaluated during drug development in order to provide the healthcare professionals with the necessary information about in-use stability.

Figure 1: Factors that affect physicochemical and microbiological quality of compounded parenteral products (t=time; T=temperature).

Figure 1: Factors that affect physicochemical and microbiological quality of compounded parenteral products (t=time; T=temperature).

Assurance of the physicochemical and microbiological quality of biological products by the user is a function of the aseptic preparation process, conditions of interim storage, and administration procedures (figure). Key factors for aseptic quality assurance within the aseptic compounding process include the environment (e.g., ISO class 5, or laminar airflow hood, versus an uncontrolled environment) and the complexity of the process, such as number of drug product units and/or entries into the IV infusion bag (USP<797>). Within the interim storage and administration period, both physicochemical and microbiological stability are a function of the time, temperature, and physicochemical conditions (pH, buffer, excipients) within the reconstituted/diluted solution or within the disposable syringe/IV infusion bag.

In-use stability considerations are provided by pharmaceutical manufacturers on the package insert (PI), but many users actually use the product beyond the PI/manufacturer recommendations, e.g. using diluents or materials not recommended or not listed in the PI or applying longer holding times than recommended by the pharmaceutical manufacturer. In many cases, users perform their own physicochemical stability studies after opening or rely on third-party published studies, which may lack adequate and product-specific method panels and assessment criteria. Thus, some scientific publications in the field may provide conflicting recommendations based on incomplete analysis. In addition, there is no clear guidance on in-use stability, specifically with respect to appropriate analytical testing and acceptance criteria.

When compounding and preparing sterile, unpreserved ready-to-administer parenteral products, care must be taken to avoid microbial contamination. Considering the number of cases of product contamination and/or lack of aseptic assurance that surfaced after the 2012 meningitis outbreak, it became obvious that compounding centers in many cases do not have appropriate measures in place to ensure sterility. The compounded product may often be subjected to extended holding times due to the fact that medication is often compounded in bulk form rather than per individual patient prescription, which again puts microbiological quality at risk. Many of these facilities considered themselves as compounders rather than manufacturers that should follow GMP principles.

The pharmaceutical industry can support understanding of the microbiological integrity after accidental contamination, e.g. by microbial growth studies. But these studies may provide limited information under specific defined experimental conditions, such that the data cannot predict nor simulate possible microbiological contamination (in type or quantity) and thus may have limited value to de-risk actual occurrence of compounded non-sterile units. Sterility of the preparation is required, but aseptic assurance is in the hand of the users. Microbiological growth data should not be viewed by users effectively to allow or even promote compounding under non-sterile conditions.

We welcome an open dialog with the regulatory agencies and across the industry to ensure product quality (and sterility) of compounded single-use parenteral products. The session Microbiological Stability of Sterile Drug Products after Opening: Considerations for Product Design, Regulatory Filings and Compounding and Clinical Pharmacy Practices at the upcoming AAPS Annual Meeting will be dedicated to discuss this topic further and will include John Metcalfe (FDA) and Irene Krämer (University Hospital, Mainz, Germany).


  1. Ricci, M.S., Frazier, M., Moore, J., Cromwell, M., Galush, W.J., Patel, A.R., Adler, M., Altenburger, U., Grauschopf, U., Goldbach, P., Fast, J.L., Krämer, I., Mahler, H.-C. (2014) In-use stability of biological parenteral products: Aspects of physicochemical and microbiological stability after container penetration, reconstitution, dilution and holding time, AJHP (in print)
Margaret 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).