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Deriving HEALTH-BASED
EXPOSURE LIMITS in the
PHARMACEUTICAL I N DUSTRY
A WORKSHOP I'YAS CONVENED TO ADVANCE HARMONIZATION AND BEST
PRACTICES IN ADVPDE DERIVATION AND APPLIGATION
fn pharmaceutical development and manufacturing health-
I based expoflre limits are established to protect against poten-
Itiul adverse health effects. For many years, the most cornmon
application of health-based exposure limits has been for occupa-
tional exposwe limits (OELs) used to protect workers who manu-
facture or process pharmaceuticals. OELs can be viewed as deriva-
tives of acceptable daily exposures (ADEs), and a transition to the
use of ADEs and permitted daily exposures @DEs) to protect prod-
uct quality has gained industry and regulatory interest.
Although there are many different types of manufacturing-
related impurities, recent regulatory scrutiny and intemational
guidances have foeused attention on prevention of cross-con-
tamination in equipment or facilities, induding residues of active
pharmaceutical ingredients (APIs) that may be present in other
medicinal products produced subsequentlyin the same equipment
or facility. This interest stems ftom 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 m.mage such cross-contamination issues and good
manufacturing procedures (GMPs). In general these empirical ap-
proaches have not been data-&iven methodologies. For example,
one approach has induded requirements for dedicated facilities
for"certain"types of compounds (e.9., certain antibiotics, certain
hormones, certain cytotoxics, and other high$ active compounds)
0C1I,2001; ENIL2014a; FDA" 1978).
However, this left to interpretation which compounds rcquired
dedicated facilities, and in turru even the definition of "dedicated".
Other early approadres used to derive product quality Iimits for shared
facilities did not use risk assessrnent methodologies for health-based
limit setting. For instance, limits were proposed based on analyical
74 Contract Pharma contractpharma.com September 2015
ADE OYERVIEW
detection levels (e.g., 10 ppm), organoleptic ievels (such as
visiblydean), a predefined traction of the median leihal dose
(LD50) or therapeutic dose (ID), or 1/1,000th of minimum
therapeutic dose or lowest clinical dose (l"CD) (e.9., Foumran
and Mullert 1993). Such approaches are contrasted to those
with a scientific basis for the determination of safety (SPE,
2010) as discussed below.
SETTING LIMITS FOR APIS
To address the issue of how to set health-based exposure
limits forAPIs in multiproduct facilities, two recent guidance
documents have been published: the lntemational Society
of Pharmaceutical Engineers (ISPE) Risk-MaPP Baseline
Guide (2010) and the European Medicines Agenry fiMA)
Guideline (2014a) on the manufacture of medicinal prod-
ucts in shared facilities. Both of these guidances advocate
the use of rystematig scientifically defensible, and health-
based approaches for deriving acceptable exposure limiis.
These guidances build on the approach for derivation of a
PDE as outlined in the Intemational Conference on Har-
monisation (IC$ guidances for the controi of impurities
(residual solvents and elements) and degradants in drug
product manufacturing QG1, 1997, 2006a, 20A6b, 2011; and
reviewed in Dolan et a1.,2005; Sargent et a1.,2013).
Although the EMA and Risk-MaPP guidances dif-
fer in terminology (EMA uses PDE, similar to ICH, and
Risk-MaPP uses ADE; EMA defines ADE as'allowable' daily ex-
posure instead of'acceptable'daily exposure), both approaches
aim to define the "eslimated 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 s)monyrnous by multiple
parties and agencies (Sargent et ai., 2013; EMA, 2014a).
Even though there are some differences between these guidances
related to deriving the exposure limit, both approaches indude the
fbllowing steps: 1) review of relevant human, animal in vitrq and in
silico data for hazard characterization; 2) identification of critical (i.e.,
the most sensitive or releyant) effect(s); 3) selection of the point of de-
partwe @oD) zuch as a no- (or lowest-) obsewed-adverse-effect level
(e.g., NOAEL or LOAEL); 4) calculation of the ADEIPDE by applica-
tion of adjustment factors (also called uncertainty factors, assessment
factors, safety factors, etc.), dose adjustments based on pharmacoki-
netic consideration for dosing regirnent and human body weigfr!
and 5) transparent documentation of the supporting rationale for de-
cisions made at each step (Sargent et al., 2013).
There has been an evolution of GMP guidance for use in expo-
sure limit setting and the management of cross-contamination since
this issue was fust addressed by regulatory agencies over 50 years ago
(FDAy 1955).Amendments to drugregulations for current GMPs were
pubiished for the conkol of cross-contamination by penicillin frDA,
1965).Various guidances and regulatory requirements have been ad-
opted and adapted over the years $.-multiple organizations, enabling
notable differences amongregional authorities.ICH has made sigrrifi-
cant attempts at global harmonization of risk assessment methodolo-
gies in the areas of safety, quality, efficary testing impurities in gpneral,
and n'tutagenic impurities in particular [CL], 1997, 2W0, 2001, 2005,
2006a,b,2011,2014; as reviewed in Dolan et a1.,2005; Snodin and Mc-
Key Areas for Workshop Discussion
Crossen, 2012; Sargent et a.1., 2013).
Global harmonDation will help to specifically address consistenry
across companies and agencieg i" light of the intemational char-
acter of the manufactr:re 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 hm, expand on
earlier methodologies for setting OELs or PDEs, first-in-hurnan dos-
es for pharmaceuticalt acceptable or tolerable daily intakes (ADIs or
TDIs) for additives and./or contaminants in food andlor drinkingwa-
teq, and reference doses and concentrations (RfDs, Rircs) for chemicals
of environmental concem [able 1). A clear need for alignment and
consistenqy is readily apparent and recent attempts at harmonization
have been conducted for a number of key areas @olan et d..,2005;
Dourson and ltrker, 200[ Naumann et al., 2009; Wa]str, 201La" 2011b;
Snodin and McCrossen,2012; Bercu et a1.,2013).
\.Ahile progress has been made on using scientifically defen-
sible, health-based methods for setting exposure limits, significant
work remains. Existing guidances leave many areas ambiguoug
which may ultimately lead io variability in the limits derived, even
for the same d*g by risk assessors and/or implemented among
companies (Walsh et a1.,2013; Walsh, 2011a, 2011b; Snodin and
McCrossery 2012).This has several implications including the ero-
sion of confidence in the limits derived increased cost of manufac-
turing or, at worst, risk to human health.
Howwer, it is important for al1 to understand that just as there is
no single"correct"OEL, there is no single"correci"ADE value. Some
variation in ADE/PDE values may be expected based on different pa-
rameterg such as PoDs (e.9., based on a pharmacologic NOAEL iden-
tified in a proprietaqy, Phase 1 study, by the inno\,ator companyversus
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76 Contract Pharma .ontractphaflna, crJm September 2015
an estimated NOAEL based on a low dinical dose by a generic manu-
facturer), a{'ustrnent factors, and estimation methods (e.g., NOAEL
approach vs. benchmark dose approach) by quaJified toxicologists.
For examplg an innovator company may have a largerADE r,ralue
as its more comprehensive dinical and nonclinical testing data may
permit a more accurate estimate of a PoD and the use of smaller ad-
justrnent factors. On the other hand, generic or contract manuftctr:r-
ers 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 adjustrnent
factors and consequently lower ADEs. Howeveq, regardless of dataset
ADEvalues must be developedby qualified toxicologists or equivalent
experts in the ADE assessment process from either innova[ors'or ge-
neric manufacturers'to be prctective of patient health.
THE WORKSHOP
A workshop was convened in October 2014 to identi$r and ad-
dress further opporhrnities for advancing harmonization and best
practices nr ADE/PDE derivation and application. This workshop
brought together toicologists and other risk assessment scientists
from pharmaceutical industries, consulting groupt and academia.
The objectives of the workshop were to: 1) provide an open and
neutral forum for ihe discussion of current approaches to deriving
ADE/PDEs; 2) evaluate inconsistencies across guidances; 3) identify
kev areas for harmonization; and 4) document best practices for risk
ADE OVERVIEW
assessment of pharmaceuticals.
This specfic language was important because"harmonization"
refers to a shared understanding of methods, applications, and
their uncertainties. Harmonization in the context of the workshop
was not aimed at developing standardized or simplistic prescrip-
tive schemes, or to restrict groups from using methods that best
utilize the science and meet their organizational needs.
The workshop originated with a critical anallsis of available risk
assessment methods used forADE/PDE setting and the implementa-
tion of zuch limits for pharmaceutical deaning validation and other
related assessments. In this effort, three main topic areas were identi-
fied that were in need of harmonization: 1) regulatory guidance and
application; 2) operations and process manaplemenf and 3) ADEPDE
derivation methodologz Sigure 1). However, it should be noted that
several individual elements were featured in more than one rnanr top-
ic area of the workshop discussiory underscoring the cross-functional
and interdependent nature of ADE/PDE assessment and implemen-
tation processes. Each topic area is discussed below.
REGULATORY GUIDANCE AND APPLICATION
Cross-contamination of pharmaceutical products in shared facilities
has been the subject of global regulations and guidances in recent
years (SPE,2010; EMA 2014a).The current regulations have evolved
over time and reflect differences among regulatory authorities with
respect to approaches to deaning lalidation. Dfferences in default
September 201 5 Twitter: @ContractPharma Contract Pharma 77
ADE OVERVIEW
versr$ chemical-specitic risk-based approaches across regulations can
be identified b-v elaluating gudances over time and by organization.
Historica[y, several defau]t approaches have been used (such as
analytical detection lwels, vizual deanliness, a predefined fraction of
the LD50 or 1/1,000th of the minimum therapeutic dose or LCD)
to setADE/PDEs in pharmaceutical settinp, but there was a lad< of
guidance on how to move away from these defaults (//alsh, 2011a).
These gr-ridances aiso require dedicated facilities for"certain"types of
compounds. In more recent years, when data are insufficient to con*
duct a chemical-specific assessment, altemative science-based ap-
proaches have been ufilized, induding the threshold of tofcological
concem [tTQ approach polan et a1.,2005).
There are a number of vetted and acceptedTTC-s availabie for dif-
ferent toxicologicai endpoints and specific compounds in the current
literature (Kroes et a1.,20W; Dolan et al., 2005; Bemauer et aI., 2008;
Van Ravenanraay, 2011,,2012; Laufersweiler et a1-, 2012; Muller et a1.,
2005; Munro eta1.,1996; Stanard et a1.,2015).
Howeveq there has been a lag in the regulatory acceptance of
the use of these science-based approaches, specifically as it applies
to deaning validation and the cross-contamination of pharmaceu-
ticai products. Inconsistent interpretatiory la& of clarity, and lack
of harmonization also exist among regulatory guidances and can
be seen in a simple er,aluation of terminology across organizations
(ADL TDI, ADE PDE etc.). This confusing landscape of guidances
led individual companies to adapt these approaches for their needs
and in the process made it more difficult for regulators to use clear
acceptance criteria related to pharmaceutical risk assessments. Key
conclusions from the workshop included:
DEFAULT VS. HEALTH-BASED APPROACHES
rTiaditionai defaults (e.9.,1/1000th dinical dose, 10 ppnu etc.) that
take minimal or no account of available data on a compound:
-Can result in overly stringent limits, or
-Can result in limits that are not stringent enough.
r Acute orai LD50 testing has not been routinely conducted
for many years for APIs or other substances and, in any event,
should not be used when other options are available;
. Preference and priority should be given to methods that take
into account toxicological or mechanistic data that are avail-
able for a compound;
. An appropriate TTC approach provides cautionary guidance
that will provide a protective value for most adverse effects
and drug classes;
. Occupational exposure bands (OEBs) may be used as a basis
for assigning'heaith-based' limits for early- to mid-develop -
ment phase APIs or for prioritization of risk assessments;
r A systematic'tiered'approach should be considered for se-
lection of approaches when faced with limited data.
DIFFERENCES IN REGULATORY APPROACHES
. GMP reg;ulations are not globally harmonized and some rely
on outdated guidances for cleaning validation;
o Lack of harmonization and lack of clariiy in approaches re-
suits in inconsistent interpretation and application of GMP re-
quirements by pharmaceutical companies and regulators.
OPERATIONS AND PROCESS MANAGEMENT
Operations and process management refers to approaches for
ensuring that the personnel responsible for developing ADE/
PDEs and related product quality acceptance iimits (e.9., swab
or rinse limits) are qualified to perform this function, as weli as
addressing approaches for implementing and communicating
these limits within and across organizations.
There is a clear need for increased communication (within
companies, between companies, and between companies and reg-
ulators). Specifically, the sharing of data across companies is critical
when contamination arises from the use of shared facilities. Whiie
compound-specific operational procedures are available for some
ciasses of compounds in some organizations (e.g., intermediates,
degradants, impuritiel iarge rnolecules, small molecules, etc.),
more guidance and harmonization are needed.
A decision process or framework to approach setting ADE/PDEs
for different compounds that covers the question of when derir,ation is
or is not necessarywould be usefi;l. However, this framework should
be flexible enough to conform to individuai company management
practices, identiSr robust and fransparent documentation of decision
points, meet regulatory e>gectaiions, and be adaptable to the chang-
ing state of the science. Key condusions from the workshop induded:
OPEBATIONAL CONSIDERATIONS
. Apart from the difference in route of exposure, another diflerence
between the ADE/PDE and OEL is the intended target poprilation,
(.e., patient population vs. assumed healthy adult populations in
workplaces). Howeveq, subtle differences eist among companies in
assumptions reiated to default body weight and adjustment or un-
certainty factors that lead to increased variabiiity;
r Converting an OEB or OEL to an ADE/PDE can give a good es-
timate to determine substances which may pose higher risks for
patients and can be used as a priority-setting method together
wiih severity of heaith hazards;
. There are some important differences that impact the production
of small vs. large molecule therapeutics, and also that may impact
the production of small moleculeAPlvs. formulated products;
. The availability of documentation forADEs/PDEs/OELs is criti-
cal for several reasons, and it could be beneficial to the industry
to establish a minimum description of the data which should be
included in this documentation.
STAKEHOLDER COMMUNICATION
r The basic concept is that the ADE/PDE approach employs a
rigorous methodology to accurately determine a safe/acceptable
dose for a given substance and a solid implementation plan to
ensure the consistent application of practices is employed bv
cross-functional users in complex organizational systems;
. The ADE/PDE must be technically sound accounting for and
resolving all the data to inform the evaluator or end user, use the
most appropriate methodologies, and be scientificaily defensible;
r The dataset used to derive the ADE/PDE must be sufficiently
robust and any data gaps and resulting potential uncertainties
must be appropriately accounted for by other means, such as ad-
justment factors;
. The methodology used to derive the ADE/PDE must be cur-
rent, using industry-accepted best practices;
78 Contract Pharma contractpharma. com September 201 5
r Donrmentation of the basis for the ADE/PDE r,alue should be ro-
bust, concise, ancl transparent for the end-ttser, ancl should be peer-
reviewed for cor-rcurrence by an equally qual.ified individual(s);
. Determination/setting of the ADE/PDE value should be per-
tbrmed by a qualified toxicologist or other equivalent experi
with appropriate credentials and experie'nce in this llpe of as-
sessrnent and slrould be reviewed appropriately such that any
pertinent ne,,r' information obtained is incorporated into ihe
value and its justitication/documentation on a timelv basis.
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ADE/PDE derivahon methodologv refers to ihe achral step-bv-step
process used by risk assessors to dewe safe exposure iimlts. This
generally indudes: literature rcvlew, seiectiou of ke1,5tudig's, determi-
nation of the"criiical effect(s)", seleciion of the PoD dosimeky and
pharmacokinetic (I']$ correchons, and application of adjustment fac-
tors. The ADE/PDE deriration process also considers the hazard as-
s€ssment context by incorporating methods specific to toxicological
endpoh! route of exposure, and product-specific considerations.
While the dataset for pharmaceuticals varies with the phase
of product developmeni, even early-phase development datasets
can include studies (e.g., in silico assessments, repeat-dose toxic
ity studies ir rnore tlran one species, pharmacologv/PK studies,
genotoxicity assays, and pharmacod\rramic (PD) characteriza-
tions) that, with application of appropriate adjustment factors,
can infonn the derivation of an ADE/PDE value.
The resuit is a plethora of endpoints for which dose-response
data may be available, some of which are common to all toxicity
studies (e.g., standard chnical chemistrv batteries, organ histo-
pathologli organ weights) and others that are uniqr.re tbr phar-
maceuticals such as PD effects and highlv sensitive measures of
adverse effects. Currently, no harmonized guidance is available
that describes u'hen and how to tuily leverage the data sets that
exist for pharmaceuticals for use in risk assessment.
Other areas in need of harmonization include PK adjustments re-
lated to dosing inten'a1s, the apprcpriate human body weight to use
tbr nomralizatiory and route-to-route extrapolation, particuiarly fbr
non-standard exposure routes (e.g., inkathecaf intraventricular, inka-
vikeal). Although there are a number of paper:; published on these
issr"res (llrstino et a1., 2003; Naumann et al.. 2005, 2009;1C11,2014a;
rcHRC, 2006), there is little regulatory consensus or accepted best
practices on these issues related to use in the pharmaceutical arena.
Other ham.roniz-ation needs reflect the use of special toxicological
endpoints: q.totoxiciry genotoxicilv, reproductive and developmental
kxicity, immunogenicitv, sensitization, and altemative approaches
for diffbrent tlpes of phamraceuticals (e.g., macromolecules/peptides
versus small molecules). Finally, a harmonization of adjustment fac-
tors to be applied under diftbrent data availability scenarjos is desired
because current gudances are conilicting and generally undear on
this issue. Key conclusions hom the norkshop rrciuded:
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. The PoD is the starting dose which is used to derive the ADE/PDE;
o Pharmaceuticals represent a unique class of compounds with
rich datasets, including studies in humans. Therefore, selection of
the PoD should be performed by a qualified toxicologist or other
equivalent expert with experience in both pham-raceutical datas-
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ADE OVERVIEW
ets and risk assessmen!
. The "critical effect" for a drug can be either pharmacologicai or
toxicologicaf and clinically significant pharmacological effects
are undesired or adverse in the context of anADE/PDE.This is in
contrast to drug development where pharmacoiogy is consldered
beneficial for the intended patient population;
r The PoD represents a dose for which data show a certain effect
ievel on the"critical effect"considered, optimally the highest dose
without a sigrrificant effect on the respective parameter;
. The FoD and"critical effect"determine what adjushnent factors are
needed. For examplg for some drugs, such as life-saving anticancer
drugs with higher risk tolerarrce given the benefit provided to the in-
tended patient populatioa higher adjustment factors may be required
to protect all patient populations potentially exposed to the drug as a
cross contaminant if the PoD is taken from a therapeutic dose.
PHARMACOKINETIC ISSUES AND DOSIMETRY
o PK data can be used to support the choice of dose mekic and in-
dudes free drug/toxicologically active metabolite concentration at the
critical receptor site, drug concenkations in the blood, plasm4 or other
fluids, area under the (time-concentration) cuwe (AUQ, peak plasma
concentration (Cmax) clearance rates, glomerular filtration ratet and
othermeasures reflective of the criticai target tissue concenEation. Se-
lection of the best dose metric is not always clear-cu! and it may not
be easy to define the most appropriate one to use;
. Accounting for eposures that are inconsistent with patient dosing
zuch as iess than dailyadministration orintermittent dosingin toxicity
studies, can be done using PK and PD data for duration adjustrnent of
the PoD instead of default time-weighted averaging
o There are a number of PK and PD considerations for use as
chemical-specific data to support repiacement of default adjust-
ment factors, inciuding whether the chemical itself or a metabo-
lite is the active species, the relevance of the PK or PD data to
the critical endpoint, and how representative the data are of the
patient population being protected;
o Several investigations and reviews have provided background
on the use of bioavailability correction factors and guidance on
when and how they should be applied for ADE/PDE develop-
ment (many specifically relate to OEL development, but these
approaches are relevant to setting ADE/PDEs as well);
o The maximum daily dose [MDD, or maximum recommended
human daily dose (MRHDD)I is used to derive product quality
limits and is a key component of product carD/o\,,er and cross-
contamination assessments, but there is currently little guidance
available on best practices for its use. In relation to PK issues,
the lack of guidance for dose-averaging for intermittent dosing
schedules is an area of concern related to the MDD.
ENDPOINT. AND PRODUCT.SPECIFIG GONSIDERATIONS
. Pharmaceuticals can cause a wide-range of totci$r The approach
for risk assessment and determination of the ADE should be adjust-
ed dependingon characteristics of the molecule beingassessed. One
must consider dose-response, pharmacokinetics, physical/chemical
properties, and amount of available information on a compound and
current techniques to determine safe ADE/PDEs;
o Additional consideration should be given for special end-
points including: rytotoxicity, genotoxicity, reproductive and
developmental toxicity, sensitization, immunogenicity, and
immunosuppression;
r There are often limited datasets for some APIs and synthetic
intermediates; however, approaches exist to assess the haz-
ards and manage risks in the absence of critical data;
o Product-specific considerations are used to evaluate special
moiecules such as: antibody drug conjugates (ADCs), large
molecules/peptides vs. small molecules, and solvents and
metals versus other impurities-
ADJUSTMENT FACTORS
. Depending on the PoD used, adjustment factors for interspecies
extrapolation, inter-individual variabiiiry exposure duration, and
extrapolation to a NOAEL or No-Observed-Effect Level (trlOEL)
may be applied. Further factors (e.g., tbr severe tofcity or data-
base completeness) may be applied on a case-by-case basis;
. Although organizations may use slightly different adjust-
ment (safety/uncertainty) factors, the overall uncertainty and
need for other adjustments are generally accounted for;
. Although adjustment factors should be considered individuaily, it
should be noted that they are not independent of each other.
GONCLUSIONS AND NEXT STEPS
A harmonized core set of recognized scientilic principles is need-
ed to inform individual efforts in calculafing interpreting and
implementing pharmaceutical risk assessments. Ultimately, this
harmonization effort should foster closer alignment of methods
among risk assessors and increase the ability of outside parties,
including reguiatory bodies and project managers, to understand
and accept the ADE/PDE values derived.
Detailed outcomes and conclusions for each workshop topic will
be published as a series of publically accessible reports. It is hoped
that these reports will shed llght on inconsistencies and data needs,
lead to further research of the knowiedge gap+ and contribute to
informing decision making among risk assessors in the pharmaceu-
tical industry by providing a"guide to best practices"that further the
value of and builds on current intemational guidelines.
It is also hoped that this effort will serve to slimulate discus,
sion among industry partners and govemment agencies, so that
the interests of all parties in achieving practical, science-base{
and health-protective exposure limits can be best served. CP
"For a list ofreferences please oisit the online oersion of this
arficle at con tr actp h arm a. com.
WEIDEMAN P., Genentech; Bercu J.P, Gilead Sciences; Callis C., Eli Lilly;
Dolan D.G., Amgen; Faria E., J&J; Flueckiger A., Roche; Gould J,, Bristol-
Myers Squibb; Hayes E.P, EP Hayes Toxicology Services; Jolly R., EIi Lilly;
Lovsin Barle E., Novartis; Luo W., Bristol-Myers Squibb; Molnar 1.8,, Mylan;
Morinello E., Genentech; Naumann 8.D., Merck & Co.; formerly 12, cuneniiy
130lson M., formerly GlaxoSmithKline, currently SafeBridge Consultants;
Pfister T., Roche; Sandhu R., SafeDose; lSargent E,V, Rutgers University;
Seaman C., GlaxoSmithKline; Sehner C,, Boehringer lngelheim; Shipp B K.
Pfizer; Sianard 8., Medlmmune; Skeeter A.J., J&J; Sussman R., SafeBridge
Consultants; Walsh A,, PharmaClean Group; 20, 2lWillis A M., Toxicology
Excellence for Risk Assessment (TERA) University of Cincinnati; Maier A.,
Universiiy of Cincinnati
80 Contract Pharma contractpharma, com September 2015
