Part 1: A Review and Perspective of the Regulatory Guidance to

Support Designation and Justication of API Starting Material

Margaret M. Faul,*
,
William F. Kiesman,*
,
Maciej Smulkowski,

Steven Pfeier,

Carl A. Busacca,

Magnus C. Eriksson,

Fred Hicks,
#
and John D. Orr

Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320

Chemical Process Research and Development, Biogen Idec, Cambridge, Massachusetts 02142

Chicago Pharmaceutical Science Group, Takeda Development Center Americas, Inc., Deereld, Illinois 60015

Process Development and Manufacturing, Kythera Biopharmaceuticals, Calabasas, California 91301

Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Ridgeeld, Connecticut 06877

#
Takeda Pharmaceuticals International Company, Cambridge, Massachusetts 02139

U.S. API Process Research and Development, Pharmaceutical Science and Technology, Eisai Inc., Andover, Massachusetts 01810
ABSTRACT: Designation and justication of active pharmaceutical ingredient starting material (API SM) is a standard part of
the drug substance (DS) development and commercialization process. However, current industry practices are not well
understood and vary, depending on the individual companys interpretation of regulatory guidelines. In addition, regulators are
also applying varying interpretations to the designation of API SMs, further complicating progress in this arena. To increase the
understanding of the strategies employed in selection and justication of API SMs the authors, members of the API and
Analytical Leadership Groups of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ),
completed a broad industry survey of this topic among the 35 IQ Consortium member companies. To put the results of this
survey into context, an understanding of the historical development of API SM regulations and the industry perspective is
important and is summarized collectively for the rst time in this manuscript (Part 1). The detailed results of the survey are
summarized and published in a second manuscript (Part 2; Designation and Justication of API Starting Materials: Current
Practices across Member Companies of the IQ Consortium). Part 3 of this series is expected to be published in the future and
will outline opportunities to improve the process in alignment with Q11.

INTRODUCTION
The material in this manuscript was developed with the support
of the International Consortium for Innovation and Quality in
Pharmaceutical Development (IQ). IQ is a not-for-prot
organization of pharmaceutical and biotechnology companies
with a mission of advancing science-based and scientically
driven standards and regulations for pharmaceutical and
biotechnology products worldwide. Today, IQ represents 35
pharmaceutical and biotechnology companies. Please visit www.
iqconsortium.org for more information.
One of the major aspects of drug substance (DS)
development is the designation and justication of the Active
Pharmaceutical Ingredient Starting Material (API SM), the
point in the synthesis of the DS where GMP processing
begins.
1
However, designation of API SMs for DS manufacture
continues to be a much debated topic and industry practices for
their designation varies based upon company experience and
interpretation of regulatory guidances.
2
The target of regulators
is not aligned across regions and continuously reinterpreted. In
2011, the API and Analytical Leadership Groups (LGs), within
the IQ Consortium, established an API SM Working Group
(WG), to assess how IQ member companies designate and
justify API SMs. The API SM WG chose to dene this area by
posing three fundamental questions:
How has the regulatory perspective on API SM
designation developed?
What are peer companies doing now?
What should the industry do, if anything, to improve the
current process?
This manuscript, Part 1 of this series, answers question 1 and
will summarize the current regulatory guidances as well as
provide a perspective f rom industry and the regulators on the
most important elements that should be addressed in
justif ication of the API SMs. The accompanying manuscript,
Part 2 will answer question 2, and outline the current practices
used by the IQ member companies to support their API SM
justication with the regulatory agencies. Part 3 of this series is
expected to be published in the future and will outline
opportunities to improve the process in alignment with Q11.

REVIEW OF CURRENT REGULATORY GUIDANCES

FOR API SM DESIGNATION AND JUSTIFICATION
Regulatory Position. In 1987 the Food and Drug
Administration (FDA) released the Guideline for Submitting
Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances
3
and indicated that while
Received: February 17, 2014
Published: April 10, 2014
Article
pubs.acs.org/OPRD
2014 American Chemical Society 587 dx.doi.org/10.1021/op500059k | Org. Process Res. Dev. 2014, 18, 587593
denition of an API SM applicable to all situations cannot be
given the following general criteria should be employed:
It is incorporated into the DS as an important structural
element.
It is commercially available.
It is a compound whose name, chemical structure,
chemical and physical properties, and impurity prole are
well-dened in the chemical literature.
This guidance indicated that the API SM needs to meet
several, but not all, of these criteria. For instance, an API SM
that is not commercially available could be acceptable as long as
it had well-dened properties in the chemical literature or if
additional analytical testing for impurities could be provided.
The requirements were clearly an attempt to require that the
complete DS synthesis be provided in Section S.2.2 f rom simple
commercially available API SMs (the commercially available
requirement was referred to as the Catalog requirement). The
major failure of this guidance was that it required evaluation and
control of too many steps not related to f inal DS quality, did not
provide f lexibility in changes to early steps in the synthesis that did
not af fect quality, and did not allow for outsourcing of early steps to
contract manufacturers without a Post Approval Supplement. In
addition, little clarity was provided to the industry on acceptable
def initions for the terms important structural element and
commercial availability. It also failed to recognize that most API
SMs are not well characterized in the literature, particularly with
respect to their impurity prof iles because the scientif ic and patent
literature may address purity (assays) of chemicals, but very seldom
presents their impurity prof iles, especially impurities at the level
required for control in DS manufacturing.
In 1999, Mo ller et al.
4
dened the elements of a scientically
based approach to the designation of API SMs. They believed
that the key issue concerned impurities that may be carried
through to the DS, introduced the concept that the number of
process steps that an API SM is removed from the DS was
important, and that f ull analytical control over substances used
in the manufacture of a DS should be judged during the
evaluation of an API SM.
Regulatory Position. In 2001 ICH Q7A provided a new
denition for API SMs as A raw material, intermediate or an
API that is used in the production of an API and that is
incorporated as a signicant structural fragment into the
structure of the API. It went on to describe that the API SM
can be an article of commerce, a material purchased from one
or more suppliers under contract or commercial agreement, or
produced in-house. In addition, API SMs are normally expected
to have dened chemical properties and structure. This
guidance indicated that companies should designate and document
the rationale for the selection of the API SMs, f rom which point
appropriate GMP, as def ined in ICH Q7A, should be applied to
the intermediate and/or DS manufacturing steps. However, while
this guidance improved upon the basic def inition of an API SM, it
did not provide information on how to construct the elements of a
rationale for the justif ication of the API SMs.
In 2003, a PhRMA working group, led by Mitchell, provided
a perspective on the challenges and opportunities of a science-
based approach to starting-material denition.
5
They recom-
mended that the 1987 guidance should be re-examined and
shift away from the traditional paradigm of commercial
availability and known in the literature to a new paradigm
whereby criteria for SMs would be based on scientically sound
and relevant controls. Risk-based approaches were proposed,
suggesting that more stringent guidelines should be put in place
as the synthesis progresses. Later steps are most likely to impact
DS quality; however, with the advancement of analytical
methods, selecting a process intermediate, in the GMP
sequence, as an API SM with an appropriate level of analytical
control can also provide appropriate quality assurance.
Decisions on the API SM should be based upon impact to
DS quality, and PhRMA recommended a decision tree
regarding the impact of the chosen API SM on the DS quality.
If the decision tree indicated that the intermediate is not a
suitable API SM candidate, since it did not provide sucient
control over the DS quality, then an intermediate earlier in the
synthesis should be evaluated. The article also mentioned that
changes in vendor or manufacturing site for that API SM
should have no regulatory (i.e., ling) impact. This approach
and decision tree was broadly leveraged as a framework by
industry in their approach to the designation of API SMs.
Regulatory Position. In order to provide a clearer path for
API SM designation, a 2004 draft Guidance was issued by the
FDA.
2a
It proposed a two tiered approach to the selection of
API SM with an exception being made for those API SMs that
have a signicant pre-existing nonpharmaceutical market. The
guidance proposed that the API SM should be selected and
controlled in a way that the risk from future changes in the
quality of the API SM aecting the identity, quality, purity, or
potency of the DS is minimized. To control these risks four
selection criteria for API SM without a signicant non-
pharmaceutical market were described:
Propinquity: the proposed API SM should be separated
from the nal intermediate by several reaction steps that
result in isolated and puried intermediates.
Isolated and puried: the proposed API SM should be an
isolated and puried intermediate.
Carryover of impurities: the proposed API SM should
not be the source of signicant levels of impurities in the
DS.
6
Complexity of structure: the API SM should be readily
distinguishable from potential isomers and analogues so
that adequate controls can be established.
This guidance also proposed that a robust API SM
specication was required and that if a proposed advanced
intermediate met all four criteria it could be considered as an
API SM. Alternatively. if the API SM had a pre-existing
pharmaceutical market. it would be an acceptable API SM.
During a Hot Topics discussion at the 2004 DIA Annual
Meeting, Miller of the FDA reviewed the 2004 U.S. draft
guidance and provided an outline of a hypothetical synthesis
noting the following:
7
There was a tendency of the applicant to move API SM
towards DS.
The agencys tendency was to move the API SM away
from DS to control impurities, identity of the DS.
The agency wants to ensure that controls in the GMP
steps are appropriate to ensure the quality, and
ultimately, safety of the DS.
Miller subsequently went on to provide examples of
propinquity (proximity/nearness), clarifying that an API SM
should be separated from the nal intermediate by several
reaction steps that result in isolated and puried intermediates
while discussing how to dene a Commercial API SM
introduced late in the synthesis. Giralt later proposed that the
expectations for API SMs can be reduced to one statement
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The API SM should be selected and controlled so that the risk
from future changes in the quality of the API SM aecting the
identity, quality, purity, or potency of the DS is minimized.
8
These concepts introduced in the draf t FDA guidance were the
subject of much debate and there were ef forts in the regulatory
community to align around common principles. Af ter all of these
ef forts the guidance document was withdrawn in 2006, because the
FDA made the decision that all guidances should be harmonized
across regions through the ICH process and the FDA should not
have separate guidance. Unfortunately, by the time it was
withdrawn it had already signif icantly inf luenced how many
companies developed their API SM strategies and lef t a gap in
providing a path for companies to follow.
Interestingly, at this point in time, although the pathway for
API SM designation was murky, many pharmaceutical
companies were beginning to embrace the idea of outsourcing
their key raw materials and API SMs in order to focus their
eorts on more value-added, later-stage activities. This change
in business strategy added another layer of complexity to the
process. In response to this Gavin et al. published a quality
evaluation strategy for outsourced API SM.
9
They believed that
a signicant component of any commercialization and
registration of a DS was the establishment of appropriate
impurity specications for the API SM. As multiple sources and
routes of manufacture of the API SM became readily available,
understanding the capability of the DS synthetic process for
tolerating impurities introduced with the API SMs became a
priority. Risk assessments and prior knowledge of actual and
potential synthetic routes were used to predict potential
impurities in the intermediates and ultimately in the DS and
guide purity method development.
As the concept of design space began to grow, Illing
published a perspective that outlined three areas that should be
applied to API SM review: process control, analytical control,
and change control.
10
To demonstrate process control of the
DS process, the applicant must determine whether the
proposed API SM is made by custom synthesis or is a
commodity reagent, that the process is well understood, and
that further scale-up will not present a risk to a patient. Next,
the essence of a strong API SM justication is the
demonstration of adequate analytical control of the initial
characterization of the API SM, an overview of stability, batch
data from various suppliers, assessment of how process changes
impact impurities and their levels, and the understanding of
selectivity of analytical methods for actual and potential
impurities. Finally, evidence is needed that a robust change
control system is in place for both the applicants activities and
those of its suppliers, to ensure that improvements will not
undermine patient safety. The change control programs of both
the applicant and vendor are a vital part of the overall control of
DS quality. The starting point for the assessment of potential
process modications are the original operating conditions and
analytical methods. It is essential to conrm that the analytical
techniques are capable of detecting and controlling dierent
impurity proles that may result from a proposed change of
route or process to the API SM. The change control
mechanism should assess potential changes for their inuence
on critical quality attributes of the DS. Seevers sought to inform
the process for API SM designation and published a paper that
recommended a regulatory strategy for communication with
agencies at EOP2 meetings.
11
He acknowledged that regulators
seek to limit a sponsors choice of suppliers (sometimes to a
single supplier) and aim to limit the ability of sponsors to
switch suppliers of API SMs in order to ensure consistent
quality. In addition, to limit the risk of new impurities in the DS
regulators will want three things:
to have synthetic routes to the DS that are several steps
in length
to understand the API SM synthesis
to request the manufacturer to use just one synthetic
route.
While these approaches allow a thorough understanding of
the quality of the API SM, these limitations are in direct conict
with needs of sponsors to ensure uninterrupted supplies of API
SMs from multiple suppliers and to drive continuous
improvement in the manufacturing processes for API SMs.
Discussions with the FDA at the EOP2 meeting should include
the following:
analytical capability to detect impurities which may arise
from dierent synthetic routes to an API SM (or from
the reaction products of impurities in the API SM)
process purication capability to remove impurities
acceptance criteria for the API SM so that any impurities
which may arise from supplier or synthetic route changes
will be detected and controlled to appropriate levels in
the nal DS.
Regulatory Position. In 2011 the ICH Q11 Guidance on
Development and manufacture of drug substances (chemical
entities and biotechnological/biological entities) was pub-
lished which discussed some considerations for API SM
selection and aimed to harmonize the denition and criteria
for selection of API SMs.
2c
Two sections on the API SM were
provided: (i) general principles for choosing API SM derived
from custom synthesis, and (ii) information to be submitted in
the dossier. The following principles, paraphrased from Q11,
were proposed for selection and designation of API SMs and to
provide a common framework on the regulatory expectations
required by all three ICH regions:
Changes in material attributes or operating conditions
that occur at the beginning of the manufacturing process
have lower potential to impact DS quality. An increase in
number of steps and isolation points decreases carryover
risk of impurities from API SM into DS.
Enough of the DS manufacturing process should be
presented to demonstrate how impurities are formed and
removed in the process, and how changes in the process
could aect the formation, fate, and purge of impurities.
Manufacturing steps that impact the impurity prole of
the DS should be included in the manufacturing process
description.
Each branch of the manufacturing process should begin
with one or more API SMs.
Performing manufacturing steps starting from the API
SM under GMP, together with an appropriate control
strategy, provides assurance of quality of the DS.
An API SM should be a substance of dened chemical
properties, have adequate stability, and represent a
signicant structural fragment of the DS. Nonisolated
intermediates are usually not appropriate API SMs.
Quality agreements by suppliers committing to reporting
of changes
In addition, Q11 emphasized that an aggregate evaluation of
all six principles should be conducted and API SM justications
should strive for a balanced approach, such that if one of the six
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principles is pursued with an aggressive strategy, additional
strengthening of some of the other principles should be
considered. For specic information that should be included in
the dossiers, ICH Q11 proposed the following:
Identify all proposed API SMs or source materials.
Provide appropriate specications for both incoming and
puried API SMs.
Justify proposed API SMs in terms of how they each
comply with the general principles for the selection of
the API SMs. This is not necessarily needed for
commercially available chemicals.
The justication document can include the following
information related to the ability of the analytical methods to
detect impurities in the API SMs: the fate and purge of those
impurities and their derivatives in subsequent processing steps
and how the proposed specication for each API SM will
contribute to the control strategy
The applicant should also provide, as part of the justication,
a ow diagram outlining the current synthetic route(s) for the
manufacture of the DS, with the proposed API SMs clearly
indicated. Changes to the API SM specication and to the
synthetic route from the API SM to nal DS are subject to
regional, postapproval change requirements as are requirements
concerning API SM suppliers. In addition, where the API SM
information is contained in submissions (i.e., sections S.2.2 vs
S.2.3) it is also dependent upon the regional authority practices.
Regarding commercially available API SMs, it was indicated
that the applicant does not need to justify the use of a
commercially available chemical as an API SM. A commercially
available chemical is usually one that is sold as a commodity in
a pre-existing, nonpharmaceutical market in addition to its
proposed use as an API SM. Chemicals produced by custom
syntheses are not considered to be commercially available. If a
chemical from a custom synthesis is proposed as an API SM, it
should be justied in accordance with the general principles for
the selection of API SMs. While Q11 clearly embraced the science
driven risk-based assessment of the propensity for API SMs to
inf luence the quality of the f inal DS, overall it was too general and
lef t a few specif ic points open to broad interpretation. Its main
purpose was to provide a f ramework around the control strategies,
risk assessment, and QbD development of the DS synthesis with
selection of the API SM being represented as only a part of the
guidance. Important concepts for designation of API SMs are lef t to
Example 4 of the guidance which suggests a late-stage intermediate
DS, two steps removed f rom the f inal intermediate and af ter the
generation of the key chiral sites in the molecule can be successf ully
negotiated as an API SM. Propinquity was not specif ically named
in the guidance but elements of propinquity were described.
Unfortunately, no clear alternative was provided, leaving a concern
that the regulatory authorities will default to previous propinquity
practices and ignore the control strategy and risk assessment
details.
12
One of the key gaps not addressed in ICH Q11, is how to
address regulatory changes to the upstream synthesis to the
cGMP designated API SM. FDA has no guidance in this area.
Once the API SM is designated, the upstream synthesis may be
changed under cGMPs without any regulatory notication. One
of FDAs concerns is control of future changes and the
notication requirements for this type of information.
At the 2011 DIA meeting, Smith and Watson provided both
the regulatory and industry perspectives on aspects of the Q11
guidance.
13,14
Smiths expectations around the guidance
reiterated the shared general principles but also highlighted a
few renements including:
Each branch of a manufacturing process begins with one
or more API SM, GMP (ICH Q7) applies to each branch
beginning with the rst use of a API SM.
Commonly available chemicals used to create salts,
esters, or other simple derivatives should be considered
reagents.
He also suggested that information for Dossiers Submitted
on the API SM should include:
appropriate specications
justication of proposed API SMhow does each
comply with the general principles
insight into the scientic rationale and compelling data.
Watson focused not only on the examples of how an API SM
candidate can be evaluated against the Q11 general principles
but also on the emerging outsourcing and the supply chain
environment for API SMs with some case studies. He explained
that, with the growth of outsourcing, most vendors are global
companies with diverse cultures and that the vendor-purchased
API SMs may or may not coincide with approved API SM in a
regulatory submission. Heightened concern over the past
decade on the potential for cross contamination due to
manufacturing in multipurpose facilities has become an added
risk that needs to be managed.
European Requirements. While ICH requirements apply
across regions within the EU, there is increasing concern with
the inconsistency of approaches from reviewers to support the
API SM submissions. From 2010 to 2011, about two out of
three CEP dossier applicants received a request to redene
their API SMs due to their failure to demonstrate an
appropriate control strategy from the API SM to the DS.
15
To address their concerns, the EDQM Certications Steering
Committee approved a new assessor guide, available only to
assessors, for API SMs in 2012. This guide provided an
overview of the current API SM guidances, described the
dierences between API SM and intermediates, provided a
denition of a synthetic step, described the information
required to support use of purchased API SMs and dened the
requirements to harmonize the assessment of applications
across reviewers. Specic prerequisites regarding the structure,
complexity, and source of the API SM, the analytical control
strategy documenting the fate and purge of impurities, and the
data required to justify the specications were discussed.
15
While in alignment with Q11, it argued that propinquity is not
an argument to support selection of the API SM; the number of
steps from API SM to DS may be related to the overall control
strategy. Thus, the closer the API SM is to the DS, the greater
the information on the control strategy that is required to
demonstrate that the sponsor has a full degree of process
understanding and that the quality of the DS can be controlled.
While not disclosing the questions to industry, their purpose is
to ensure consistency regarding expectations for the applicants
and reviewers.
16
Canadian Requirements:
17
The guidance contained in
ICH Q11 is intended to address API SM designation and
justication at the time of NDA. FDA and EMA have not set
out specic expectations regarding the disclosure of API SM
syntheses in regulatory lings for programs in late development
(Phases 2 and 3). In contrast the Canadian authorities have
communicated their expectations for sponsors as a regional
requirement. The Canadian guidance document stipulates that
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at phase 2 sponsors should provide details on the API SM
synthesis. The guidance sets forward the following expect-
ations:
18
The analytical control strategy on the API SM and GMP
steps should increase the closer the API SM is to the nal
DS.
For API SMs which are commercially purchased, the
source and a copy of the provisional specications is
typically considered acceptable.
For API SMs which are manufactured in-house, a copy of
the synthetic scheme and provisional specications
should be justied. Specications should include one or
more specic identity tests, an analytical method that
tests the potency of the API SM, including analytical
methods for specied and unspecied impurities in
addition to the total impurities.
In order to assess the presence of all potential impurities,
including regioisomeric and stereoisomeric impurities, toxic
impurities, residual solvents and residues of catalysts in the API
SM, a brief narrative description of the synthesis leading to the
API SM, from raw materials, with all the reagents, solvents, and
intermediates specied, and the owchart of the synthesis
should be provided. Potential for the presence of adventitious
agents, including viral and bacterial agents, residual proteins,
and transmissible spongiform encephalopathy (TSE) agents in
the API SM selected should be discussed.
Genotoxic Impurities. Introduction of regulatory guide-
lines on control of genotoxic impurities (GTIs) signicantly
increased requirements for control of DS manufacturing
processes, including control of API SMs. Assessment and
control of genotoxic impurities at sub-ICH Q3A/B thresholds
required identication of actual and potential impurities,
including those related to early stages of DS manufacturing
process (pre-API SM steps), evaluation of their genotoxic
potential, development of sensitive analytical methods with
detection limits in ppms, testing at that level intermediates or
DS for genotoxic impurities, and developing adequate control
strategy for these impurities to ensure control at the threshold
of toxicological concern (TTC) level.
19
Requirement for
evaluation of potential impurities in early stages of the DS
manufacturing process soon precipitated, as described below,
with increased requirements for control of the API SM
manufacturing process.
The rst guideline, published by the EMEA (now EMA) in
2006, followed the ICH Q3A in denition of potential
impurities which include impurities associated with raw
materials that could contribute to the impurity prole of the
DS. These impurities should be assessed for their genotoxic
potential, and if identied as genotoxic, controlled to acceptable
level based on the TTC. Following the Guideline, EMEA
Questions and Answers (Q&A) documents provided an
excellent clarication of the Guideline and introduced the
Staged TTC (higher than TTC) that could be applied during
development.
20
The FDA Step 1 Guidance from 2008, similar to the EMEA
Guideline, stated that the Guidance also applies to known API
SMs or anticipated reaction products. Neither document
provided any specics for evaluation and control of GTIs
related to API SMs. However, in the past few years EMA and
Health Canada usually required, in addition to the evaluation of
actual API SM impurities, an evaluation of API SM potential
impurities for their genotoxic potential and related risk to the
DS. The FDA asked for this evaluation usually only in special
cases, for example, when the API SM was introduced close to
the DS in the DS manufacturing process.
The new ICH M7 Step 2 document (published Feb/2013)
provides a more comprehensive approach to addressing GTIs,
including impurities related to API SMs. Key sections of the
Step 2 document that address this topic are outlined below.
Section 5 Drug Substance and Drug Product Impurity
Assessment. This Guideline states that potential impurities
which should be evaluated for their genotoxic potential could
include starting materials, identied impurities in starting
material, and reasonably expected reaction by-products. Knowl-
edge of the API SM synthesis, in particular the use of
mutagenic reagent, is an important factor in understanding the
potential impurities in the API SMs, especially when there is a
reasonable potential that such impurities may persist in the
DS. The last statement does not provide clear requirements
for evaluation and control of pGTIs related to the API SMs.
These requirements are still under discussion by the ICH
EWG. Industry experience in addressing GTIs since the rst
EMEA Guideline increased understanding that genotoxic
impurities, being very reactive, are generally converted and/or
purged within the DS manufacturing process; therefore, the risk
that GTIs from API SMs could be present in DS is low.
21
All identied actual and potential impurities in the DS should
be evaluated for mutagenic potential that includes literature and
database searches for carcinogenicity and bacterial mutagenic-
ity. Data can be obtained from a computational toxicology
assessment using two complementary prediction method-
ologies (for example the most popular platform, DEREK,
along with Leadscope or Mcase). Any structural alert may be
overruled by negative bacterial mutagenicity assay (Ames test).
In the absence of identication of a structural alert or if
bacterial mutagenicity assay is negative, an impurity can be
treated as an ordinary impurity per ICH Q3A guidance. A
structural alert, without a negative bacterial mutagenicity test
result and all positive test results, requires control of impurity as
GTI at or below the staged TTC.
22
Section 8, Control. The Guideline provides four options
for development of a control strategy for DS; these options may
be used to control pGTIs related to API SMs:
Options 1 and 2 include a test for the impurity in the
specications of DS, intermediates, and raw materials
with an acceptance criterion at or below the acceptable
limit using an appropriate analytical procedure. It is
possible to apply periodic testing for these options.
Option 3: Include a test for the impurity in the
specication for a raw material, API SM or intermediate,
or as an in-process control, with an acceptance criterion
above the acceptable limit using an appropriate analytical
procedure coupled with demonstrated understanding of
fate and purge and associated process controls that
ensure the level in the drug substance is below the
acceptable limit without the need for any additional
testing.
Option 4: Understanding of process parameters and
impact on residual impurity levels (including fate and
purge studies) with sucient condence that the level of
the impurity in the DS will be below the acceptable limit
such that no analytical testing is needed for this impurity.
Teasdale et al. introduced a simple method for calculation of
purge factors that could be used to demonstrate control of
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PGIs per options 3 and 4.
23
For option 3, the Guideline
provides an example of control of impurity from the API SM by
the API SM specication and the purge factor determined in
the laboratory-scale studies.
The guideline also states that for genotoxic impurities
introduced in the last synthetic step, the testing of the DS
(Option 1) would be expected unless otherwise justied. This
would include genotoxic API SMs and genotoxic impurities in
API SMs introduced in the last step of DS manufacturing.
From the industry perspective, options 3 and 4 are
particularly suitable for addressing GTIs from API SMs for
which, as stated above, risk of presence in the DS is low. If
based just on scientic principles, justication of the control
strategy per option 4 is not feasible; the common solution is
development of acceptance criteria for GTIs in API SMs and
justication of those criteria per option 3.
Section 9 Documentation. The Guideline provides
requirements for documentation of the control of pGTIs that
should be provided in dierent stages of the regulatory lings.
For these and other requirements of the ICH M7 Step 2
Guidance, refer to the guideline document.
24
In recent years, the pharmaceutical industry has observed
increased requirements from countries outside the ICH,
notably China and Korea, to include the evaluation and control
of pGTIs in the lings. Also, in 2012 Argentina issued
regulations on the control of genotoxic impurities.
25
Now, after
the ICH M7 Step 2 Guideline was published and with the
anticipation that the nal document will be nalized in June
2014, we can expect that more countries will follow suit.
Related Expectations on Starting Materials for
Generic Drugs. This new Q&A guidance from the EDQM
has also been taken up by the European Generics Medicines
Association (EGMA) who has also published a position paper
for the EU on the Active Substance Master Files (ASMFs) and
CEP Applications to ensure a consistent approach to dening
API SMs by ASMF holders, DP manufacturers, and competent
authorities to understand the supply chain and ensure patient
safety. Their goal was to gain a harmonized understanding of
API SMs and a consistent understanding of documentation
required. In addition to the expectations of the EDQM, the
EGMA put knowledge and understanding of the origin and fate
of impurities (including GTIs) as the most important aspect in
the denition and identication of API SMs. They support a
science and a risk-based approach (as opposed to a one size
ts all) accompanied by an appropriate change control strategy
as the best strategy.
26
A similar approach to demonstrate a control strategy for the
synthesis of the API SMs around stereogenic impurities and
GTIs/pGTIs in the ANDA ling was published by the Oce of
Generic Drugs in 2012.
27
This article highlighted general
principles for the selection of API SMs and also provided
examples of what would not be acceptable as an API SM. The
case studies in this article are interesting and provide insight
into the FDAs current thinking on API SM designation.
Although the topic was related to those of ANDA, in reality the
concepts apply to all DS.

CONCLUSION
Today, 27 years after the rst Guidance (1987), the following
statements from the Guidance are still valid: What constitutes
the starting material may not always be obvious and
generally the decision about what is the starting material has
been reached by agreement between the applicant and the FDA
chemist (i.e. reviewer) before submission of the NDA.
However, with the evolution of the regulatory guidances
there is a clear understanding that what the regulators deem
most important is for the applicant to demonstrate a control
strategy to ensure the quality of the DS. While today there is
alignment on the intent of Q11 which is to demonstrate a
control strategy, there is not alignment on the application of
control strategies (whether it is more appropriate to control
through propinquity alone or via enhanced process knowledge)
to support the API SM justication. Moving forward, to align
the focus of applicants and regulators on the critical factors in
the justication, it will be important to have a unied,
international, common denition, and approach across all
jurisdictions (i.e., not a regionalized approach) to both the
denition and documentation for API SMs. Despite the
continued debate on this topic, limited work has been
published in this area to add clarication, and there are few
concrete case studies where applicants have published the
information submitted to justify their API SM in the regulatory
le. With the regulatory background and understanding
outlined in this manuscript (Part 1), the API and Analytical
LGs of the IQ Consortium sought to build an understanding of
the current practices within the IQ member companies on this
important topic, and this will be outlined in the accompanying
manuscript representing Part 2 of this series.

AUTHOR INFORMATION
Corresponding Authors
*Telephone: 805-447-0599.
*E-mail: mfaul@amgen.com.
Notes
The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
The authors would like to thank the following individuals and
companies for their review of this manuscript: Ingrid
Mergelsberg (Merck, Inc.), John Pavey (Astra Zeneca), Oliver
Thiel (Amgen), William Leong (Celgene), Daiichi Sankyo,
Gilead Sciences Inc., Kythera Biopharmaceuticals.

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