Risk-MaPP

ISPE launched Risk-MaPP in Brussels on Sept. 20–21, 2010. The North American launch is planned for Oct. 4–5, 2010. A Japanese launch is planned on Oct. 21–22, and a Singapore launch on Oct. 25–26. ISPE is also offering a half-day session on Risk-MaPP at the ISPE Annual Meeting in Orlando, Florida on Nov. 10, 2010, and is planning two-day training courses for 2011.

The principles of Risk-MaPP can be applied to large and small molecules, preclinical and clinical materials, and commercially manufactured products in all operations. Wilkins says it is also important to note that the principles of Risk-MaPP are beneficial for all classes of compounds, not just high hazardous compounds. In considering Risk-MaPP, Wilkins says there are three important underlying elements: the relationship between risk, hazard, and exposure; the use of health-based limits; and how the modes of exposure are different for cross-contamination and operator safety.

Health-based limits. Wilkins explains that Risk-MaPP suggests the use of acceptable daily exposure (ADE), which is the daily dose of a substance below which no adverse effects are expected by a route, even if exposure occurs for a lifetime. The ADE is scientifically derived, based on health effects, and set by toxicologists from data from clinical studies, drug filings, package inserts, or other sources, which rely on the same data used to develop occupational exposure limits (OELs). "So the premise is that a safe level of a compound is below the ADE," says Wilkins. "Some of the more traditional limit-setting methods such as the use of 1/1000th of the low clinical dose or 10 ppm are not health-based and may be overprotective or underprotective of patient health." She points out that when a limit is underprotective, the implications are understood as to the related concerns, but there are also issues when the limit is overprotective. "When we look more closely using a limit that is lower than the safe limit (i.e., the ADE), the product is not any safer, but a manufacturer may spend more time in cleaning, or may dedicate equipment because the lower limits cannot be met, which all leads to an increase in the cost of manufacturing the product. To be clear, the cleaning processes should be controlled based on process capability and below the safe limit. The distance between the data and the safe limit is considered the margin of safety for the process.

Modes of exposure . Modes of operator exposure may be inhalation, dermal, ingestion, ocular, and mechanical. "Industrial hygienists have many tools and methods for both assessing and controlling occupational exposure," explains Wilkins. "Risk-MaPP borrowed these concepts from industrial hygiene and adapted them for cross-contamination issues." The exposure modes for contamination are mix-up, retention, mechanical, and airborne transfer. "Of these modes, mix-up and retention are the areas that could cause the highest risk while mechanical and airborne transfers tend to be lower risk issues," she says. Mechanical and airborne transfers require product on non-product contact surfaces to find a path into the process in amounts that would be above safe levels. "Many times this is not feasible as the quantities would not be large enough for the human eye to see," she adds.

Looking forward

As of press time, an ISPE meeting launching Risk-MaPP on a global basis was being held in Brussels. One item that will be watched is EMA's stance on the Risk-Mapp launch. EMA is currently revising the wording in its GMPs, which discuss the need to control issues of cross-contamination and dedicated facilities. In December 2009, EMA provided on update on its revision of Chapters 3 and 5 of its GMP Guide for dedicated facilities and outlined the agency's recent consideration of the matter. In February 2005, EMA published a concept paper that highlighted a lack of clarity in the existing GMP guide (Section 6, Chapter 3, Sections 18, 19, Chapter 5) with respect to when a medicinal product should be manufactured in dedicated, self-contained facilities. The concept paper proposed that any guidance in this field should take into consideration the principles and concepts of quality risk management as described in ICH Q9. EMA published its progress in January 2008. In its December 2009 communication, EMA said, "the drafting group has continued to look into the different aspects of this issue; it has been researching and evaluating all the scientific information related to this topic, including input from toxicological/pharmaceutical experts."

Although open to risk-based approaches for most compounds and classes of compounds, EMA stated in its December 2009 communication that dedicated facilities should normally be required when beta-lactam antibiotics are produced and live pathogenic organisms are handled. EMA further said in its December 2009 communication: "In the meantime for other products, manufacturers introducing a product into shared facilities should carry out an assessment of all relevant product and process characteristics to evaluate whether it is suitable for production in shared facilities. This assessment should include input from a toxicologist. Where the product has known sensitizing potential, or is highly potent or toxic, the Supervisory Authority should be consulted to discuss the manufacturer's risk-management measures." The ISPE conference in Brussels in late September will serve as an opportunity to gain an update on EMA's progress. Risk-based approaches will also be discussed at the ISPE conference in early October.

As for Risk-MaPP, Wilkins points out the value in incorporating a risk- and science-based approach to cross-contamination through quality risk-management plans. "Importantly, companies that have applied Risk-MaPP to their operations are better prepared for regulatory inspections and more knowledgeable about their products, processes, and facilities."