Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning

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Issues and approaches for ensuring effective communication on Acceptable Daily Exposure (ADE) values applied to pharmaceutical cleaning Michael Olson a, *, Ellen C. Faria b, Eileen P. Hayes c, Robert A. Jolly d, Barle Ester Lovsin e, Lance R. Molnar f, Bruce D. Naumann g, Alison M. Pecquet h, Bryan K. Shipp i, Robert G. Sussman a, Patricia A. Weideman j a

SafeBridge Consultants, Inc., USA Janssen Pharmaceutical Company, An Affiliate of Johnson & Johnson, Belgium c EPHayes Toxicology Services, USA d Eli Lilly and Company, USA e Novartis, Switzerland f Mylan, USA g Merck & Co., Inc., USA h University of Cincinnati, USA i Pfizer Inc., USA j Genentech, Inc., USA b

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a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 May 2016 Accepted 19 May 2016 Available online xxx

This manuscript centers on communication with key stakeholders of the concepts and program goals involved in the application of health-based pharmaceutical cleaning limits. Implementation of healthbased cleaning limits, as distinct from other standards such as 1/1000th of the lowest clinical dose, is a concept recently introduced into regulatory domains. While there is a great deal of technical detail in the written framework underpinning the use of Acceptable Daily Exposures (ADEs) in cleaning (for example ISPE, 2010; Sargent et al., 2013), little is available to explain how to practically create a program which meets regulatory needs while also fulfilling good manufacturing practice (GMP) and other expectations. The lack of a harmonized approach for program implementation and communication across stakeholders can ultimately foster inappropriate application of these concepts. Thus, this period in time (2014e2017) could be considered transitional with respect to influencing best practice related to establishing health-based cleaning limits. Suggestions offered in this manuscript are intended to encourage full and accurate communication regarding both scientific and administrative elements of health-based ADE values used in pharmaceutical cleaning practice. This is a large and complex effort that requires: 1) clearly explaining key terms and definitions, 2) identification of stakeholders, 3) assessment of stakeholders' subject matter knowledge, 4) formulation of key messages fit to stakeholder needs, 5) identification of effective and timely means for communication, and 6) allocation of time, energy, and motivation for initiating and carrying through with communications. © 2016 Elsevier Inc. All rights reserved.

Keywords: Acceptable Daily Exposure (ADE) Permitted Daily Exposure (PDE) Stakeholder Contract manufacturer Regulatory agencies Pharmaceutical manufacturing Monograph Communication

* Corresponding author. SafeBridge Consultants, Inc./Trinity Consultants, One Copley Parkway, Suite 310, Morrisville, NC 27560, USA. E-mail address: [email protected] (M. Olson). http://dx.doi.org/10.1016/j.yrtph.2016.05.024 0273-2300/© 2016 Elsevier Inc. All rights reserved.

Please cite this article in press as: Olson, M., et al., Issues and approaches for ensuring effective communication on Acceptable Daily Exposure (ADE) values applied to pharmaceutical cleaning, Regulatory Toxicology and Pharmacology (2016), http://dx.doi.org/10.1016/ j.yrtph.2016.05.024

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1. Introduction: ADE values and communication goals This manuscript focuses on communication regarding Acceptable Daily Exposures (ADEs) and Permitted Daily Exposures1 (PDEs) applied to pharmaceutical cleaning with internal and external stakeholders. It is intended to be read in conjunction with the related paper on company-internal operations related to ADE programs (Hayes et al., 2016, this issue). While there is a great deal of technical detail in the written framework underpinning the use of ADEs in cleaning (for example, ISPE, 2010; Sargent et al., 2013), little is available to explain how to practically create a program which meets regulatory needs while also fulfilling good manufacturing practice (GMP) and other expectations. The lack of a harmonized approach for program implementation and communication across stakeholders can ultimately foster inappropriate application of these concepts. An example of how lack of harmonization in stakeholder communication can impede appropriate application of ADEs is in the writing style of the ADE document itself. Most ADE documents are written by scientists and as such are not always understandable or accessible to non-scientific stakeholders. This can have several consequences, including lack of confidence in the ADE derived, reduced support in implementing the ADE, or inappropriate implementation. Harmonization efforts on how to succinctly and consistently communicate key information in the ADE document (such as the rationale for the limit derived, any areas of uncertainty or assumptions made, and the applicability domain of the limit derived) to scientists and non-scientific audiences alike will help to ensure that these documents are widely understood, and that true collaborative partnerships between those who write ADEs and those who consume them can take place. Another example of how lack of harmonization can adversely impact communication is inconsistency in the use and definitions of key technical terms used in ADE preparation and implementation. The terms ADE and PDE are essentially synonymous; yet different groups have historically preferred the use of one term over the other, leading to confusion. Clearly defining and consistently using these terms will assist in more effective and more efficient conversations between stakeholders (see Sussman et al., 2016a, this issue). Thus, the period in time for the initial growth of ADE implementation (2014e2017) could be considered transitional with respect to establishing best practices related to ADEs, including creation of communication mechanisms that clearly articulate ADE program structure within a company and across companies, and regulatory expectations resulting from implemented practice. There is no universally identified stakeholder group in the ADE process, especially when considering stakeholders external to an individual business enterprise. Certainly, regulatory bodies charged with the oversight of pharmaceutical safety and efficacy and individual inspectors representing regulatory bodies are key stakeholder groups. Outside of the regulatory community, the inventory of enterprise partners performing contract or toll manufacture have a need to understand and correctly apply ADE concepts and specific values. Understanding key regulatory arenas is critical to tailoring ADE documentation and communication plans for the endstakeholder uses and for their regulatory needs.

1 For this discussion the terms Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) are treated as synonymous, but with recognition that specific terms have been chosen by different regulatory bodies (ISPE, 2010; Sargent et al., 2013; EMA, 2014a). In this paper, use of the term ADE implies application to PDE derivation as well. In general, these terms describe calculated values intended to safeguard human (patient) health from unintended exposure to pharmaceutical substances.

Effective stakeholder communication and ultimately stakeholder engagement regarding ADE programs requires careful planning and acceptance by all stakeholders; internal and external to a company. This is a large and complex effort that requires: 1) clearly explaining key terms and definitions, 2) identification of stakeholders, 3) assessment of stakeholders' subject matter knowledge, 4) formulation of key messages fit to stakeholder needs, 5) identification of effective and timely means and venues for communication, and 6) allocation of time, energy, and positive motivation for initiating and completing communications. Ultimately, sharing suggestions for best practices to initiate and sustain a program supporting product quality activities could help guide companies and regulators to engage in a dialog that will lead to a more complete understanding of the merits and complexities of the ADE paradigm. 1.1. Identification of key terms and definitions A communication strategy for actively engaging stakeholders begins with clarity about what is implied by ADE values, as well as why the concept of health-based risk assessment is an important addition to existing methods supporting product contact surface cleaning. As defined by the International Society for Pharmaceutical Engineering (ISPE), an ADE is “a dose that is unlikely to cause an adverse effect in an individual if exposed, by any route, at or below this dose every day for a lifetime” (ISPE, 2010). ISPE further expands this definition to incorporate qualifiers regarding the scope of application of an ADE value e “By definition the ADE is protective of all populations by all routes of administration”. The European Medicines Agency (EMA) defines the PDE as “a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime” (EMA, 2014a). Recent updates to the European Union (EU) guidance on GMP Chapters 3 and 5 indicate that risk assessment for the control of cross-contamination and cleaning should rely on a toxicological evaluation to yield threshold, or ADE values (EMA, 2014b,c; EU, 2008). Risk assessors use many specific technical terms when developing ADEs, but there has been lack of consistency in the use of terms, as well as a lack of clarity as to what these terms mean (Bercu et al., 2016; Faria et al., 2016; Gould et al., 2016; Hayes et al., 2016; Reichard et al., 2016; Sargent et al., 2016; Sussman et al., 2016a, 2016b; all in this issue). An important first step in harmonizing ADEs is to ensure that these often used terms are defined unambiguously, precisely and in a manner that is easily understood by all parties. Table 1 reports definitions of several of these key terms used in ADE derivation and implementation, including multiple definitions for the same term when they are not aligned. It is hoped that use of these definitions will improve communication, increase consistency across ADE documents and ultimately facilitate sharing of information. 2. ADEs and program management ADE values are derived through an organized program led by technical experts who have a thorough understanding of the product portfolio and access to applicable datasets. While different assessment programs may follow similar underlying principles, specific methodologies and conventions will vary from program to program and consequently result in some differences in the final assessments (discussed below). This is considered acceptable because it has been established that different programs can produce varying values that are equally scientifically sound while using slightly different methodologies, defensible, and protective of human health. In addition, the flexibility to use program specific

Please cite this article in press as: Olson, M., et al., Issues and approaches for ensuring effective communication on Acceptable Daily Exposure (ADE) values applied to pharmaceutical cleaning, Regulatory Toxicology and Pharmacology (2016), http://dx.doi.org/10.1016/ j.yrtph.2016.05.024

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Table 1 Key terminology. Term

Definition

Reference

(Minimal/Lowest) Therapeutic Dose Acceptable Daily Exposure (ADE) Active Pharmaceutical Ingredients (APIs)

The pharmacologically active dose from which human patients will receive a beneficial effect such as treatment of a disease. A daily dose of a substance below which no adverse effects are expected by any route, even if exposure occurs for a lifetime. Active substance e The substance responsible for the activity of a medicine. Active ingredient is any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect. Active ingredient is any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals. Active ingredient (active substance, compound, active pharmaceutical ingredient) e Ingredient that alone or in combination with one or more other ingredients is considered to fulfil the intended activity of a medicine. Numerical adjustment used to extrapolate from experimentally determined (doseeresponse) relationships to estimate the agent exposure below which an adverse effect is not likely to occur. (Also referred to as assessment factor, safety factor, and uncertainty factor). An adverse effect may be considered to be a change (biochemical, functional, or structural) that may impair performance and generally have a detrimental effect on growth, development or life span of a non-clinical toxicology model. Change in the morphology, physiology, growth, development, reproduction, or life span of an organism, system, or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences. An undesirable and unintended, although not necessarily unexpected, result of therapy or other intervention (e.g., headache following spinal tap or intestinal bleeding associated with aspirin therapy). A biochemical, morphological, or physiological change (in response to a stimulus) that either singly or in combination adversely affects the performance of the whole organism or reduces the organism's ability to respond to an additional environmental challenge. A therapeutic agent derived from living things; any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of humans. A therapeutic product created through the genetic manipulation of living things, including (but not limited to) proteins and monoclonal antibodies, peptides, and other molecules that are not chemically synthesized, along with gene therapies, cell therapies, and engineered tissues. Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources d human, animal, or microorganism d and may be produced by biotechnology methods and other cutting-edge technologies. For deterministic effects, the first adverse effect which appears when the threshold (critical) concentration or dose is reached in the critical organ: adverse effects with no defined threshold concentration are regarded as critical. The first clinically significant pharmacological effect. The first adverse effect, or its known precursor, that occurs to the most sensitive species as the dose rate of an agent increases. The measureable residue of a material or product with another material or product. Causing damage to cell structure or function. Proposed: Cytotoxic compounds possess the ability to interact directly with DNA or DNA-associated macromolecules, resulting in cell death. In addition, a cytotoxic agent causes such damage in an indiscriminate manner, affecting healthy cells in addition to abnormal (i.e., tumor) cells, and causing serious systemic toxicity and in most cases genotoxicity. Cytotoxicity: the ability of a substance or a compound to cause a cytotoxic effect. A constituent of a medicine other than the active substance. An ingredient added intentionally to the drug substance, which should not have pharmacological properties in the quantity used. A code of standards concerning the manufacture, processing, packing, release and holding of a medicine. Regulations of the US FDA and comparable non-US agencies that describe the minimum standards for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packaging, or holding a drug, to assure that such drugs meet the requirements of the Act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. Part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. Refers to a shared understanding of methods, applications, and their uncertainties. Harmonization in the context of this manuscript series is not aimed at developing standardized or simplistic prescriptive schemes, or to restrict groups from using methods that best utilize the science and meet their organizational needs. Any component of the new drug product that is not the drug substance or an excipient in the drug product. Any entity of the drug substance (API) or drug product (final container product) that is not the chemical entity defined as the drug substance, an excipient, or other additives to the drug product.

ISPE (2001)

Adjustment factors

Adversity (adverse effect/ adverse agent)

Biotherapeutics/biologic/ biopharmaceutical

Critical effect

Cross-contamination Cytotoxic/cytotoxicity Excipient

Good manufacturing practice (GMP)

Harmonization

Impurities (cleaning agents, residual solvents, metals, intermediates, reactionby-products, etc.)

ISPE (2010) EMA (2014a) ISPE (2001)

US FDA (2012)

WHO (2013) IPCS (2004)

Dorato and Engelhardt (2005) IPCS (2004)

ISPE (2001) Lewis et al. (2002)

ISPE (2010)

US FDA (2012)

NIH (2014)

ISPE (2010) US EPA (2015) ISPE (2001) NIH, 2015 Sussman et al. (2016a), this issue

ISPE (2001) EMA (2015) ICH (1999) EMA (2015) ISPE (2001)

WHO (2013) Weideman et al. (2015)

ICH (2006) ISPE (2001)

(continued on next page)

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Table 1 (continued ) Term

Definition

Reference

Intermediate

A material produced during steps of the synthesis of a new drug substance that undergoes further chemical transformation before it becomes a new drug substance (ICH Q3A (R2)). A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated (ICH Q7). For biotechnological/biological products, a material produced during a manufacturing process which is not the drug substance or the drug product but whose manufacture is critical to the successful production of the drug substance or the drug product (ICH Q5C). Lowest-observed-adverse-effect level: the lowest dose or exposure level of a chemical in a study at which there is a statistically or biologically significant increase in the frequency or severity of an adverse effect in the exposed population as compared with an appropriate unexposed control group. Lowest-observed-effect level (analogous to LOAEL in the context of pharmaceutical risk assessment); in a study, the lowest dose or exposure level of a chemical at which a statistically or biologically significant effect is observed in the exposed population compared with an appropriate unexposed control group. The effect is generally considered not to have an adverse effect on the health and survival of the animal. The maximum dose received on any given day during a period of exposure generally expressed in mg/kg body weight/day. (see Hayes et al., 2016, this issue) No-observed-adverse-effect level: The highest experimental dose at which there are not statistically or biologically significant increases in frequency or severity of adverse health effects, as seen in the exposed population compared with an appropriate, unexposed population. Effects may be produced at this level, but they are not considered to be adverse. No-observed-effect level (analogous to NOAEL in the context of pharmaceutical risk assessment): The highest experimental dose at which there is not a statistically or biologically significant increase in the frequency or severity of effects seen in the exposed compared with an appropriate unexposed population or control group. A substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. Effectively synonymous with ADE. The dose-response point that marks the beginning of a low-dose extrapolation. This point can be the lower bound on dose for an estimated effect incidence or a change in response level from a dose-response model (BMD) or a NOAEL or LOAEL. A comparative expression of chemical or drug activity measured in terms of the relationship between the incidence or intensity of a particular effect and the associated dose of a chemical, to a given or implied standard of reference. The measure of the biological activity using a suitably quantitative biological assay (also called potency assay or bioassay), based on the attribute of the product, which is linked to the relevant biological properties. All phases in the life of the product from the initial development through marketing until the product's discontinuation. Individual with specific education and training in toxicology/pharmacology and risk assessment methods that can apply the principles of toxicology to deriving an ADE (or PDE or other safety values) for APIs, cleaning agents, degradants, intermediates, etc. A measure of the relative desirability of a drug for the attaining of a particular medical end that is usually expressed as the ratio of the largest dose producing no toxic symptoms to the smallest dose routinely producing cures A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. A measure of the relative desirability of a drug for the attaining of a particular medical end that is usually expressed as the ratio of the largest dose producing no toxic symptoms to the smallest dose routinely producing cures. Dose or exposure concentration of an agent below which a stated effect is not observed or expected to occur. The dose or exposure below which no deleterious effect is expected to occur. A concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures.

ICH (2006, 2001, 1995)

LOAEL

LOEL

Maximum Daily Dose (MDD) NOAEL

NOEL

Permitted Daily Exposure (PDE) Point of Departure (PoD) (see Bercu et al., 2016, this issue) Potency

Product lifecycle Qualified toxicologist or appropriate expert Therapeutic index

Threshold value Threshold of Toxicological Concern (TTC)

processes can be advantageous because variations in the process may foster evolution and advancement of the methodology. To achieve this, periodic review is a useful tool to ensure that the practices used by any single organization reflect the current best practice (Hayes et al., 2016, this issue). This is a key area where stakeholder engagement is critical so that best science and practices are shared in the field. Several desirable elements of an ADE program include steps to articulate objectives, standards, and recommended practice necessary to successfully achieve and maintain compliance. If ADE development is supported by a group within a company, then a charter for such a working team provides a vehicle to specify the participants, team purpose, scope, deliverables, and communication mechanisms used to engage various stakeholders. Standard operating procedures or recommended practice documents ensure

Derelanko and Auletta (2014) Derelanko and Auletta (2014)

Derelanko and Auletta (2014) Derelanko and Auletta (2014)

Derelanko and Auletta (2014)

EMA (2014a) US EPA (1993)

Derelanko and Auletta (2014) ICH (1999) ICH (2005) Eurotox (2012); Walsh (2015) Merriam-Webster (2015) NIH (2016)

IPCS (2004) US EPA (2011) Kroes et al. (2004)

consistency of processes and work products, capturing methodologies and conventions. These documents can also be used to provide transparency to stakeholders, clarify resource and information requirements, as well as inform expectations regarding the amount of time required to create documented ADE values. 2.1. Identification of stakeholders and assessment of expertise The responsibility of deriving, reviewing, and approving ADE values should be the remit of toxicologists or other qualified experts with risk assessment expertise and the resources to involve additional experts as needed (e.g., physicians, pharmacokineticists, etc.). While the toxicological assessment and limit (ADE) derivation should be prepared by toxicologists or other qualified experts, it is important that the process include stakeholders with appropriate

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complementary skills, experience, and representation to achieve overall program implementation goals and understanding throughout the organization. This includes ensuring the engagement of those individuals who are actively involved in communicating ADE values with external parties. In particular, several of the adjustment factors which are integral to the ADE/PDE calculation reflect pharmacokinetics (PK), pharmacodynamics (PD), and the relationship between PK and PD (see Reichard et al., 2016, this issue). [Note that pharmacokinetic and pharmacodynamics are essentially synonymous to toxicokinetic and toxicodynamic in the context of safe dose setting]. For this reason, a pharmacokinetic scientist is also a critical addition to the ADE team, at least on an ad hoc basis. Additional professionals from quality/analytical operations, industrial hygienists, health and safety professionals, drug safety toxicologists, veterinarian pathologists, and physicians, as well as the project team that is responsible for OELs may be part of the ADE effort either as part of committee structure or ad hoc advisors. Representatives from the engineering and manufacturing organizations could also provide valuable input to key operational decisions that may be affected by the use of ADEs. Depending on the organizational structure of the company, the ADE process may operate under the direction and sponsorship of a higher-level governance team, providing senior-level oversight to ensure continued vigilance (e.g., membership, resources, processes, and deliverables to ensure currency and fitness for purpose). The hazard identification, assessment, and characterization process and the subsequent development, peer-review, and approval of ADE values and supporting documentation should be conducted by qualified toxicologists, or other experts, who are proficient in risk assessment. While specific qualifications currently are not, and perhaps should not be, formally defined and controlled, it is reasonable to provide generalized expectations. For example, qualified toxicologists have been noted as individuals “with specific education and training in toxicology/pharmacology that can apply the principles of toxicology to deriving an Acceptable Daily Exposure value for APIs, cleaning agents, degradants, intermediates, etc.” (Walsh, 2015). Other toxicologist registries require an academic degree in a relevant subject, basic knowledge of the major areas of toxicology, at least 5 years of relevant toxicological experience, suitability for registration (e.g., by published works, reports or assessments), and current professional engagement in the practice of toxicology (Eurotox, 2012). In addition to industryaccepted toxicology credentials and certifications, membership and participation in professional toxicology societies may be considered advantageous. In a number of pharmaceutical companies, responsibility for originating ADE values is part of the remit of existing and robust Environmental Health and Safety (EHS) occupational toxicology programs, leveraging the synergy between the development of OELs and ADE values. Others enterprises draw expertise for ADE determinations from drug product safety toxicologists. In all cases experiential training in risk assessment practice and support of product quality concerns are also valuable skills for ADE originators. Referral to expert consultant toxicologists or other qualified experts should be considered by enterprises that need to supplement in-house resources for creation of ADE values. In such cases, care should be exercised that the selected consultants have appropriate experience and expertise. Likewise, programmatic considerations discussed in the following paragraphs may need to be modified in cases where in-house resource constraints limit the implementation of an ADE process. Regardless of the means of support for an ADE program, elements discussed in the following paragraphs which detail concerns for data acquisition, consistency in approach, development, and management of documentation should be carefully considered.

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2.2. Formulation of key messages to fit stakeholder needs An important part of communicating ADE information is explaining how this method differs from other commonly used approaches, e.g., 1/1000th of the lowest clinical dose (LCD) or small fractions of LD50, e.g., LD50/50,000. Other authors of manuscripts in this series and elsewhere have described the value of health-based cleaning limits (Faria et al., 2016; Hayes et al., 2016; Sargent et al., 2016; all this issue). The definitions of key terms and context offered by the ISPE and EMA clearly imply the intent of derived ADE values e to protect consumers and patients from the potentially adverse effects of contaminants in drug products (EMA, 2014a; ISPE, 2010). Much of this guidance focuses on control of crosscontamination of one medicinal substance by another active pharmaceutical ingredient (API). The ADE is derived using the toxicological and clinical data available for APIs at the time that cleaning criteria are required (Sargent et al., 2016, this issue). This implies that ADE values must be periodically reexamined and updated as necessary to ensure the background dataset is fully considered if new information becomes available. The focus of the ADE on protection from possible contaminants in the intentionally consumed drug products highlights the importance of considering pharmacokinetic and pharmacodynamic effects, possible use of offtarget or non-therapeutic indicators of drug effect, and the origin, quality, and completeness of toxicological data (Bercu et al., 2016; Reichard et al., 2016; Sussman et al., 2016a; all this issue). In many cases, the ADE also integrates information on route, frequency and duration of exposure or the age or health status of potentially exposed individuals. Due to these nuances, the process for data acquisition should be clearly documented, including guidance for incomplete/developing data sets, and carefully followed to avoid data gaps or communication delays that could materially impact the timing for development of a new ADE value or revision of an existing value. Varying processes may be required for early-development-stage compounds and late- or commercial-stage compounds (see Hayes et al., 2016, this issue). It is important that processes are in place that either “push” new information being developed to the authors or enable them to “pull” from the most current source documents (e.g., clinical investigator's brochure). In addition, data availability can link to clear triggers and mechanisms for ADE value development within an organization. As data are developed or identified, criteria are typically set to gauge dataset robustness (e.g., considerations for data gaps and intra-species data extrapolations), studies or endpoints for inclusion in the analysis, and hierarchies for point of departure (PoD) selection (see Bercu et al., 2016, this issue). Conventions should be transparent and consistent regarding the application of adjustment factors to available datasets or default assumptions to account for gaps or uncertainties in earlystage or less robust datasets (Faria et al., 2016; Sussman et al., 2016a; all this issue). The availability of consistent and transparent data evaluation and assessment processes supports effective communication with stakeholders. Triggers and mechanisms for the reevaluation of an existing ADE value are also common to ensure that derived values reflect the latest scientific knowledge. The approaches to achieve this goal vary. Policies may call for review on a fixed, calendar-based review cycle, at drug development milestones [e.g., preclinical candidate approval, investigational new drug (IND) and new drug application (NDA) filings], or a reevaluation within reasonable time upon receipt of significant new hazard and health effects data. Processes or systems, including records and associated recordkeeping are used to track the development and revision history of ADE values and the practices used to set those values, including documentation of methodology revisions. No standardized format for ADE

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documentation across organizations has been developed; however, most organizations establish ADE value documentation formats as well as mechanisms for the communication of new or revised values.

3. Identification of effective and timely means and venues for communication Clear and definitive guidance regarding the communication of ADE values should be available for all who develop and use ADEs. This helps to avoid inappropriate distribution or interpretation of the information within a document. Circumstances that drive the need to share ADE values may include: 1. Transfer of APIs between operating entities within one company; 2. Work with contract research/manufacturing organization (CRO/ CMO) partners involved in handling and manufacturing of the API; 3. In-license/cross-license activities which result in APIs moving from a drug innovator to a partner pharmaceutical company (non-CMO); 4. Communication of ADE values to successor companies purchasing equipment previously used for API or formulated product manufacturing. 5. Addressing the requests of regulatory or oversight agencies. Effective communication with stakeholders must address a variety of aspects of the ADE process. As a matter of practical focus, the method underlying how a single-substance ADE is derived and applied will be of recurring interest and importance. A robust and transparent explanation of the risk assessment process for each drug substance should be available to all identified stakeholders. Defined qualifications for authors of these documents will assist in the ability of inspectors to trust that the ADE has been developed according to current scientific methodology. It is expected that inspectors representing drug approval agencies and other regulatory bodies may request a monograph or be provided with other documentation explaining the basis for the ADE value. Should an inspector lack sufficient background or expertise to review and comment on the scientific validity of the ADE value, it may be referred to a qualified individual who has been identified in another part of the agency. When working with drug innovators, CMOs do not always have access to sufficient proprietary information to develop a protective ADE that is not overly precautionary. This situation often arises since in the absence of the most relevant innovator's data, precautionary default assumptions are often adopted. If an ADE value is not provided by the drug innovator, the CMO may use consulting toxicologists or other qualified experts to perform the risk assessment. The difficulty here lies in the fact that each individual company utilizing the same CMO is responsible for the quality of their own product; including when contaminated with an API from a previous companies' product made in/on the same equipment and using an ADE value that was set based on proprietary and inaccessible data. Likewise, a situation could arise where two companies working with the same CMO could have access to different datasets resulting in different ADE values for the same compound. Although initial comments from regulatory agencies have discussed resolving these differences through negotiation, it is unlikely that these agencies will have the resources to harmonize differing ADE values. This reiterates the need for balancing all stakeholder ‘inputs’ and highlights where the communication and acceptance of methodologies is vitally important.

4. Documentation for ADE monographs At the operations level, the availability of documentation for ADEs and other safe values is critical for several reasons. It demonstrates that the product owner has completed an appropriate hazard assessment that is protective of patients and/or employees. For contract manufacturing operations it provides a rationale that can be reviewed to determine appropriate patient and employee protection. Additionally, it can serve to inform and facilitate communication between different operational groups, e.g., a toxicology group that is establishing ADEs or OELs and an engineering/ manufacturing group that is charged with implementing quality risk management program elements, e.g., cleaning validation. These documents are the subject of audits and inspections, and marked differences in the level of detail may raise critical questions for inspectors and reduce the credibility of the company/industry. EMA (2014a) has proposed a short summary for the risk assessment report. It has check boxes to specify potentially genotoxic, carcinogenic, reproductive/developmental, and sensitizing substances, as well as the basis for the ADE (i.e., critical effect and dose), references related to the critical effect and dose, and the ADE calculation. A formal written document should summarize the scientific rationale for the recommended health-based limit (e.g., ADE). As suggested by the EMA, the document should include a summary to facilitate review by stakeholders and the basis for the ADE should be clearly described. The reader should be able to readily determine the health endpoint (critical effect) on which the ADE was established and understand the values chosen for adjustment factors and which sources of variability and uncertainty they address. Any further adjustments (e.g., bioavailability correction) must be clearly explained. The format of the documentation of the ADE does not necessarily need to be standardized; however, the body of the document often includes sections, regardless of designation, addressing the following: 1) chemical identity information, physico-chemical properties, and chemical structure, 2) intended use and mechanism of action, 3) pharmacokinetics and pharmacodynamics, 4) animal data including acute toxicity, local effects, repeat-dose toxicity, developmental and reproductive toxicity, genotoxicity, and carcinogenicity, 5) veterinary use if applicable, 6) human data including pharmacokinetics, clinical use, adverse reactions, susceptible sub-populations (e.g., pregnancy and nursing mothers), 7) identification of the critical effect, 8) adjustment factors, 9) references, and 10) appendices that provide further details, e.g., equations showing the calculation of the ADE, chemical-specific adjustment factors, etc. Many companies have developed standardized formats for ADE documentation, and this trend could be beneficial to the industry to establish a minimum description of the data that should be included in ADE documentation. Also of importance, it is noted that as the available dataset changes (typically expanding) as an API moves through development, uncertainties related to absent data should be described in the risk assessment report with a discussion of the adjustment factor (AF) for database completeness. Further, while an ADE can usually be derived for a substance administered by the intended clinical route of administration, it may be possible for that substance to become a contaminant in a product that would be used by a different route. This would more likely be a possibility during drug substance (API) synthesis operations vs. drug product formulation. Therefore, a consideration of factors (e.g., bioavailability correction factors) associated with route-to-route extrapolation would become especially important for these cases (Reichard et al., 2016; Sussman et al., 2016a; all this issue). Providing the qualifications of persons who derive and author the ADEs on the summary documents, as suggested by the EMA

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guidance, should lend assurance that the authors have of the appropriate educational background and experience needed to derive these values. CVs of authors of documentation should be available if requested by regulators or partners. 5. Dealing with variation in ADE values The methodology and calculations for derivation of ADE values have been described in several other manuscripts in this issue (Bercu et al., 2016; Sussman et al., 2016a; all this issue). The ADE values set by different companies for identical substances will often differ to some degree. This is unavoidable and to a certain extent normal. For most cases and compounds, significant professional judgment goes into determining the PoD and AFs [e.g., LOAEL versus NOAEL, expert determinations on the biological significance of the clinical effect, shape or steepness of a dose-response curve, statistical significance vs. biological importance (e.g., is a 10% change in a particular effect biologically relevant?)]. Moreover, different companies will have differing levels of detail and access to sources of data and information. An example is an ADE written by the originating pharmaceutical company or by an agency that might be based on a more complete toxicology dataset than an ADE independently derived by a generic pharmaceutical manufacturer. An ADE written as a review by a company other than the originating company may need to rely on public information, e.g., agency-approved product labels, review information available from online and subscription databases, etc., rather than on original preclinical and clinical study reports. When working from secondary sources, or when data are not available, the AF values selected can be higher, and resulting ADE values lower than when working from original documents as there is more uncertainty regarding the technical information in the former case. As more information becomes available, there is more certainty in the assessment and so AF values typically decrease; final ADE values may be higher (or lower) than those used when less information was available and default AF values were used. Furthermore, organizations may use different body weight assumptions (e.g., adult body weight could range between 50 and 80 kg, whereas that for a child could range between 11.4 kg and 20 kg). It is possible that the recent EMA guideline will focus prospective ADE development toward use of a standard 50 kg person that may aid in minimizing variation resulting from this specific issue. Given the many factors that go into deriving these values, a variation up to 10-fold between ADE values is not uncommon and should not be concerning. Like other health-based risk assessment values, ADEs are imprecise. This range of variation is typically accepted for OELs developed for and applied to pharmaceuticals. This is also true for drinking water limits where the data and methods used in calculating these values lead to some variability in the final numbers (Bercu et al., 2008; EC, 2011; Schwab et al., 2005; US EPA, 2000). In fact, the difference in such values is often implicit in their definition. For example, the US EPA's RfD value is considered to be a safe value “with uncertainty spanning perhaps an order of magnitude” (Barnes and Dourson, 1988; US EPA, 1999, 1993). Regulatory acceptance of this variation is essential to allow for manufacturing operations. Given that the composite adjustment factor covers the AFs employed in deriving an ADE, and that process capability and robust cleaning procedures are implemented, an adequate margin of safety (MOS) can still exist even in situations where an ADE is ten times higher than another value for the same compound. However, if the ADE values vary by more than 10-fold, it is recommended that a toxicological review be requested to verify there is an appropriate margin of safety. Effective means of communication between stakeholders is necessary to facilitate this review. The differences in ADEs are often due to company-specific

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science-policy decisions as illustrated by approaches for setting ADEs for vitamins. Some companies base their ADEs on the recommended daily allowance (RDA) while others use the tolerable upper intake (TUI) as their starting point. Having consistent approaches such as a rule-based framework for adjustment factors is one means of getting more consistent ADEs (Sussman et al., 2016b, this issue). However, such rules can also limit flexibility for subject matter experts and lead to precautionary assessments, and some flexibility in approach is accepted by the EMA guidance. 6. Structuring communication to foster ADE implementation The fact that stakeholders in the ADE process will have a variety of experiences and responsibilities strongly implies that while toxicologists and other qualified experts may derive ADE values, these values will likely be interpreted or put into action by staff with altogether different academic and experiential training. Therefore, in structuring an ADE program, careful consideration should be given to creating documentation that is easily accessible and explicit regarding conclusions and sources of information. In addition to creating robust ADE criteria documents, an ADE program should incorporate design elements aimed at ensuring that ADEs are communicated and curated in a manner implying their importance in corporate product quality practice. Program design should focus not only on company-internal stakeholders (e.g., those who use ADE values to direct cleaning validation) but also on any parties to whom careful design and implementation of an ADE program demonstrates compliance with regulatory expectations. The following list suggests program design elements that could provide transparency and credibility to an ADE program and serve as points of emphasis in external communications: 1. Accountabilities and responsibilities for managing various aspects of the ADE program; 2. Designation and credentials of responsible technical experts and authors for preparation of ADE documents; 3. The method aligned to business needs for scheduling preparation of specific ADE values and systematic approach to “push and pull” aspects of ADE considerations; 4. Information about routinely utilized channels for communication of newly established, as well as revised/updated ADE values and supporting documentation; 5. Specific mention of any restrictions on the use or application of ADE values; 6. Description of document management systems used to ensure maintenance of ADE documentation according to prevailing company Quality Assurance, GLP/GMP standards (including electronic information systems management).

7. Summary and conclusions e What is the fundamental message? The ADE concept is rooted in basic principles of toxicology. To paraphrase Paracelsus, the father of toxicology: all substances are harmful at or above some threshold dose/exposure level. Ideally, this dose level would be precisely defined and identifiable so it can be applied to the various exposure scenarios for each material. As an accurate and precise definition of this dose is not feasible, the next best alternative is to identify a dose that is reasonably certain to be somewhere below this true toxic threshold dose. Determining such a number can be quite simplistic and still provide a high degree of confidence or certainty in its safety. However, routinely getting close to or accurately approximating the true toxic

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threshold dose (without going over it) and having confidence in the validity of this number necessitates a rigorous methodology based on utilization and interpretation of all available data e clinical and non-clinical. This is the basic concept that the ADE approach employs e a rigorous methodology completed by a trained and knowledgeable individual(s) to accurately determine a safe/ acceptable exposure for a given substance and a solid implementation plan to ensure the consistent application of practices is employed by cross-functional users in complex quality risk management systems. In order for users or reviewers of an ADE value to have confidence in the validity of the value, several quality aspects are typically incorporated in the derivation and governance process. These items form a potential list of expectations for ADE stakeholders. Communication on ADE topics address these expectations:
The ADE, which is intended to be protective of patient health, must be scientifically sound; accounting for and resolving all the available data to inform the evaluator or end user, and be scientifically defensible.
The dataset used to derive the ADE must be sufficiently robust to account for any potential uncertainties or these potential uncertainties must be appropriately accounted for by other means, such as adjustment factors (e.g., safety/uncertainty/modifying factors) (see Sussman et al., 2016a, this issue).
The methodology used to derive the ADE must be current, using industry-accepted best practices (Faria et al., 2016, this issue). Striving to employ currently acceptable best practices serves as an “internal audit” that ensures acceptability of the approach used and leverages the collective experience and knowledge of the industry as a whole.
Documentation of the basis for the ADE value should be robust (adequately describing the available clinical and preclinical data, identifying data gaps/uncertainty, and detailing the derivation and reasoning underlying the derivation), concise, and transparent for the end-user. This documentation should adequately justify the ADE value derived, providing confidence (to any reviewer of the documentation) in the value, the rationale used to obtain the value, and the conditions necessary for the value to be valid.
Derivation of the ADE value should be performed by a qualified toxicologist or other relevant expert with appropriate credentials and experience.
The ADE value along with supporting documentation should be peer-reviewed for concurrence by an equally qualified individual(s).
The ADE value along with supporting documentation should be reviewed periodically such that any pertinent new information obtained is incorporated into the value and its justification/ documentation.
Appropriate and efficient systems should be in place to ensure availability to the pertinent end users, including guidance on the acceptable distribution of the information. Adhering to these basic guidelines of using all of the available data to derive a scientifically justifiable ADE value protective of patient health, as well as supplying justification through proper documentation processes and peer-review, ensures robust methodology. As such, when properly conducted, the documentation and derivation should provide both familiarity and confidence in the process and the derived values on behalf of both reviewers and those using these values for limit setting. The essence of useful and appropriate communication when presenting ADE concepts is to fully convey the program design elements that guide creation of robust ADE values within a business enterprise as well as to impart

credibility to substance-specific ADE values. Uncited reference Dourson and Stara, 1983, Winkler et al., 2014.

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Acknowledgements The statements and conclusions in this paper reflect the opinions of the authors and do not necessarily represent official policies of the organizations as listed on the title page. The authors would like to acknowledge Patricia Weideman, Andrew Maier, and Alison Pecquet for organizing and facilitating the workshop that served as the basis for developing this manuscript. The authors would also like to thank all of the participants of the workshop for their contributions at the workshop and subsequent reviews of this manuscript, including: Joel Bercu, Courtney Callis, David Dolan, Andreas Flueckiger, Janet Gould, Wendy Luo, Andrew Maier, Eric Morinello, Thomas Pfister, Reena Sandhu, Edward Sargent, Christopher Seaman, Claudia Sehner, Bryan Shipp, Brad Stanard, Anthony Streeter, and Andrew Walsh. The manuscript was developed in part with funding from Genentech Inc. for organizational and editorial staff activities. Michael J. Olson was an employee of GlaxoSmithKline at the time of the workshop from which this publication is derived. Transparency document Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.yrtph.2016.05.024. References Barnes, D.G., Dourson, M., 1988. Reference dose (RfD): description and use in health risk assessments. Regul. Toxicol. Pharmacol. 8, 471e486. Bercu, J.P., Morinello, E., Sehner, C., Shipp, B., Weideman, P., 2016. Point of departure (PoD) selection for the derivation of acceptable daily exposure (ADE) values for active pharmaceutical ingredients (APIS). Manuscr. Accept. Regul. Toxicol. Pharmacol. Q5 Bercu, J.P., Parke, N.J., Fiori, J.M., Meyerhoff, R.D., 2008. Human health risk assessments for three neuropharmaceutical compounds in surface waters. Regul. Toxicol. Pharmacol. 50, 420e427. http://dx.doi.org/10.1016/j.yrtph.2008.01.014. Derelanko, M.J., Auletta, C.S. (Eds.), 2014. Handbook of Toxicology, third ed. CRC Press, Boca Raton, FL. Dorato, M.A., Engelhardt, J.A., 2005. The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s). Regul. Toxicol. Pharmacol. 42, 265e274. http://dx.doi.org/10.1016/j.yrtph.2005.05.004. Dourson, M.L., Stara, J.F., 1983. Regulatory history and experimental support of uncertainty (safety) factors. Regul. Toxicol. Pharmacol. 3, 224e238. EC, 2011. Common Implementation Strategy for the Water Framework Directive (2000/60/EC). Guidance Document No. 27: Technical Guidance For Deriving Environmental Quality Standards. Technical Report - 2011-055. European Commission (EC). http://dx.doi.org/10.2779/43816. Available at: https://circabc. europa.eu/sd/a/0cc3581b-5f65-4b6f-91c6-433a1e947838/TGD-EQS%20CISWFD%2027%20EC%202011.pdf. EMA, 2015. European Medicines Agency Glossary. European Medicine Agency (EMA), London. Available at: http://www.ema.europa.eu/ema/index.jsp? curl¼pages/document_library/landing/glossary.jsp&mid¼. EMA, 2014a. Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities. EMA/CHMP/CVMP/SWP/169430/2012. European Medicine Agency (EMA), London. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2014/11/WC500177735.pdf. EMA, 2014b. Part 1- Chapter 3: premises and equipment. In: The Rules Governing Medicinal Products in the European Union. European Medicine Agency (EMA), Brussels, Belgium. Available at: http://ec.europa.eu/health/files/eudralex/vol-4/ pdfs-en/cap3_en.pdf. EMA, 2014c. Part 1- Chapter 5: production. In: The Rules Governing Medicinal Products in the European Union. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, vol. 4. European Medicine Agency (EMA), Brussels, Belgium. Available at: http://ec.europa.eu/ health/files/eudralex/vol-4/pdfs-en/cap5en.pdf. EU, 2008. The Rules Governing Medicinal Products in the European Union. In: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, vol. 4. European Union (EU), Brussels, Belgium. Available at:

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