Lovsin Barle, Ester, Weideman, Patricia, Bercu, Joel, Dolan, Dave, Faria, Ellen, Flueckiger, Andreas, Gould, Janet, Luo, Wendy, Molnar, Lance, Morinello, Eric, Naumann, Bruce, Olson, Mike, Pfister, Thomas, Sandhu, Reena, Sargent, Edward, Seaman, Chris, Sehner, Claudia, Shipp, Brian, Stanard, Brad, Streeter, Anthony, Sussnam, Robert, Walsh, Andy, Willis, Alison and Maier, Andy (2015) A Harmonization Effort for Deriving Health-Based Exposure Limits in the Pharmaceutical Industry: Report of a Workshop. A Harmonization Effort for Deriving Health-Based Exposure Limits in the Pharmaceutical Industry: Report of a Workshop.

Abstract

Introduction and Background
In pharmaceutical development and manufacturing, health-based exposure limits are established to protect against potential adverse health effects. For many years, the most common application of health-based exposure limits has been for occupational exposure limits (OELs) used to protect workers who manufacture or process pharmaceuticals. OELs can be viewed as derivatives of acceptable daily exposures (ADEs), and a transition to the use of ADEs and permitted daily exposures (PDEs) to protect product quality has gained industry and regulatory interest. Although there are many different types of manufacturing-related impurities, recent regulatory scrutiny and international guidances have focused attention on prevention of cross-contamination in equipment or facilities, including residues of active pharmaceutical ingredients (APIs) that may be present in other medicinal products produced subsequently in the same equipment or facility. This interest stems from the fact that APIs by definition have biological activity, and in some cases, at very low doses.
There is a variety of empirical approaches that have been used historically to manage such cross-contamination issues and good manufacturing procedures (GMP). In general these empirical approaches have not been data-driven methodologies. For example, one approach has included requirements for dedicated facilities for “certain” types of compounds (e.g., certain antibiotics, certain hormones, certain cytotoxics, and other highly active compounds) (ICH, 2001; EMA, 2014a; FDA, 1978). However, this left to interpretation which compounds required dedicated facilities, and in turn, even the definition of “dedicated”. Other early approaches used to derive product quality limits for shared facilities did not use risk assessment methodologies for health-based limit setting. For instance, limits were proposed based on analytical detection levels (e.g., 10 ppm), organoleptic levels (such as visibly clean), a predefined fraction of the median lethal dose (LD50) or therapeutic dose (TD), or 1/1,000th of minimum therapeutic dose (MTD) or lowest clinical dose (LCD) (e.g., Fourman and Mullen, 1993). Such approaches are contrasted to those with a scientific basis for the determination of safety (ISPE, 2010) as discussed below.
To address the issue of how to set health-based exposure limits for APIs in multiproduct facilities, two recent guidance documents have been published: the International Society of Pharmaceutical Engineers (ISPE) Risk-MaPP Baseline Guide (2010) and the European Medicines Agency (EMA) Guideline (2014a) on the manufacture of medicinal products in shared facilities. Both of these guidances advocate the use of systematic, scientifically defensible, and health-based approaches for deriving acceptable exposure limits. These guidances build on the approach for derivation of a PDE as outlined in the International Conference on Harmonisation (ICH) guidances for the control of impurities (residual solvents and elements) and degradants in drug product manufacturing (ICH, 1997, 2006a, 2006b, 2011; and reviewed in Dolan et al., 2005; Sargent et al., 2013). Although the EMA and Risk-MaPP guidances differ in terminology (EMA uses PDE, similar to ICH, and Risk-MaPP uses ADE; EMA defines ADE as ‘allowable’ daily exposure instead of ‘acceptable’ daily exposure), both approaches aim to define the “estimated dose that is unlikely to cause an adverse effect if an individual is exposed to the API at or below this dose every day for a lifetime” (ISPE, 2010). The terms ADE and PDE are considered effectively synonymous by multiple parties and agencies (Sargent et al., 2013; EMA, 2014a). Even though there are some differences between these guidances related to deriving the exposure limit, both approaches include the following steps: 1) review of relevant human, animal, in vitro, and in silico data for hazard characterization; 2) identification of critical (i.e., the most sensitive) effect(s); 3) selection of the point of departure (PoD) such as a no- (or lowest-) observed-adverse-effect level (e.g., NOAEL or LOAEL); 4) calculation of the ADE/PDE by application of adjustment factors (also called uncertainty factors, assessment factors, safety factors, etc.), dose adjustments based on pharmacokinetic consideration for dosing regimens, and human body weight; and 5) transparent documentation of the supporting rationale for decisions made at each step (Sargent et al., 2013).
There has been an evolution of GMP guidance for use in exposure limit setting and the management of cross-contamination since this issue was first addressed by regulatory agencies over 50 years ago (FDA, 1965). Amendments to drug regulations for current GMPs were published for the control of cross-contamination by penicillin (FDA, 1965). Various guidances and regulatory requirements have been adopted and adapted over the years by multiple organizations, enabling notable differences among regional authorities. ICH has made significant attempts at global harmonization of risk assessment methodologies in the areas of safety, quality, efficacy testing, impurities in general, and mutagenic impurities in particular (ICH, 1997, 2000, 2001, 2005, 2006a,b, 2011, 2014; as reviewed in Dolan et al., 2005; Snodin and McCrossen, 2012; Sargent et al., 2013). Global harmonization will help to specifically address consistency across companies and agencies, in light of the international character of the manufacture of pharmaceuticals. For example, both the Risk-MaPP and EMA Shared Facilities guidances build on the work of previously published pharmaceutical impurity guidances that also advocate for the use of chemical-specific health-based data for setting pharmaceutical impurity limits. These guidances, in turn, expand on earlier methodologies for setting OELs or PDEs, first-in-human doses for pharmaceuticals, acceptable or tolerable daily intakes (ADIs or TDIs) for additives and/or contaminants in food and/or drinking water, and reference doses and concentrations (RfDs, RfCs) for chemicals of environmental concern (Table 1). A clear need for alignment and consistency is readily apparent and recent attempts at harmonization have been conducted for a number of key areas (Dolan et al., 2005; Dourson and Parker, 2007; Naumann et al., 2009; Walsh, 2011a, 2011b; Snodin and McCrossen, 2012; Bercu et al., 2013).
While progress has been made on using scientifically defensible, health-based methods for setting exposure limits, significant work remains. Existing guidances leave many areas ambiguous, which may ultimately lead to variability in the limits derived, even for the same drug, by risk assessors and/or implemented among companies (Walsh et al., 2013; Walsh, 2011a, 2011b; Snodin and McCrossen, 2012). This has several implications including the erosion of confidence in the limits derived, increased cost of manufacturing, or, at worst, risk to human health.
However, it is important for all to understand that just as there is no single “correct” OEL, there is no single “correct” ADE value. Some variation in ADE/PDE values may be expected based on different parameters, such as PoDs (e.g., based on a pharmacologic NOAEL identified in a proprietary, Phase 1 study, by the innovator company versus an estimated NOAEL based on a low clinical dose by a generic manufacturer), adjustment factors, and estimation methods (e.g., NOAEL approach vs. benchmark dose approach) by qualified toxicologists. For example, an innovator company is likely to have a larger ADE value as its more comprehensive clinical and nonclinical testing data permit a more precise estimate of a PoD and the use of smaller adjustment factors. On the other hand, generic or contract manufacturers often need to estimate the PoD based on some limited testing data augmented with literature values. As a result, this greater uncertainty due to dataset completeness will drive the use of larger adjustment factors and consequently lower ADEs. However, regardless of dataset, ADE values must be developed by qualified toxicologists or equivalent experts in the ADE assessment process from either innovators’ or generic manufacturers’ to be protective of patient health.

Item Type:	Article
Date Deposited:	01 May 2016 23:45
Last Modified:	01 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25858