Contained manufacturing is becoming increasingly important as a greater number of APIs in development have higher potency. Manufacturing systems must be designed to protect product quality and patient safety by preventing cross-contamination and to protect workers through environmental, health, and safety (EHS) controls. Containment addresses both patient and worker safety, but the challenge is finding the appropriate level of containment that manages risk at a reasonable cost.
The International Society of Pharmaceutical Engineering (ISPE) launched the Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross contamination to achieve and maintain an appropriate balance between product quality and operator safety (1). The guide was published in September 2010, and industry members are evaluating the concepts. A key concept in Risk-MaPP is controlling crosscontamination to the Acceptable Daily Exposure (ADE), which represents an acceptable amount of drug that may be contained in another product without causing harm to the patient. For worker safety, a similar value, the occupational exposure limit (OEL), is an acceptable airborne concentration that workers may inhale during an eight-hour work-shift. Companies can put a quality program in place using ADEs as the basis for acceptance—for materials with any level of potency—to show that they are managing risk to acceptable levels, explains Stephanie Wilkins, president of the consulting firm PharmaConsult US, which provides facilitation to firms implementing Risk-MaPP principles, and cochair of the ISPE Risk-MaPP Baseline Guide Task Team. In many cases, the approach is being used by large-scale generic-drug firms and by CMOs in response to actual or potential regulatory action.
Companies are increasingly asking for assistance in calculating ADEs, says Robert Sussmann, managing principal for Eastern operations at Safebridge Consultants, which provides EH&S consulting for the pharmaceutical industry. A robust and transparent ADE monograph is essential in properly documenting the risk assessment, Sussmann adds.
“Companies are anxious to see how the regulators treat the Risk-MaPP approach,” says Wilkins. She comments that a January 2011 FDA Warning Letter to Teva Pharmaceutical Industries regarding cross-contamination used similar wording to RiskMaPP, which some in the industry construed as FDA’s unofficial buy-in to the RiskMaPP approach (2). EMA’s concept paper, published in Oct. 2011, also suggests using “a more scientific approach…to establish threshold values” (3). A first draft of the guidance was to be discussed in February 2012, with draft guidance published in June 2012 and final guidance in March 2013. However, the methodologies developed by the EMA guidance for calculating ADE may be different than those outlined by Risk-MaPP, predicts Sussmann. Having an official direction from EMA would be a big step forward that the European industry would readily follow, says Richard Denk, director of the pharmaceutical department at Hecht Technologie.
Changes in industrial hygiene practices are moving slowly because of the costs involved, says Julian Wilkins, founder and vice-president of PharmaConsult US. In the last few years in the US, however, the Occupational Safety and Health Administration (OSHA) has become more involved in identifying problems for workers in the pharmaceutical industry and requiring corrective action. OSHA’s involvement will drive increased use of containment, predicts Wilkins, who notes that containment equipment must be practical, not costly or unwieldy.
One of the biggest trends in containment is toward flexible and disposable systems rather than hardwall isolators, says Sussmann. For highly hazardous substances produced in multipurpose facilities, traditional technologies are not easy to clean and the risk of material remaining on the surfaces is too high, says Denk. Disposables solve these problems, but have limitations with some solvents, he notes. New technologies with improved, cleanable surface qualities need to be developed, proposes Denk. The International Society of Pharmaceutical Engineering (ISPE) Germany/Austria/Switzerland section’s Containment Group is currently writing a containment manual, with a draft expected mid-2013. The manual will provide industry guidance on the basics of containment and will answer questions such as how to compare transfer systems, where the critical areas are located in a containment facility, how to validate a containment facility, and what is important to know when cleaning equipment or a facility, says Denk.
1. ISPE, Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP), (Tampa, FL, Sept. 2010)
2. FDA, “Letter to Teva Pharmaceutical Industries” (Rockville, MD), Jan. 31 2011.
3. EMA, Concept Paper on the Development of Toxicological Guidance for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, (London, Oct. 2011).