Article

pubs.acs.org/OPRD

Part 2: Designation and Justication of API Starting Materials:

Current Practices across Member Companies of the IQ Consortium
Margaret M. Faul,,* Carl A. Busacca, Magnus C. Eriksson, Fred Hicks, William F. Kiesman,
Maciej Smulkowski, John D. Orr,# and Steven Pfeier

Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320, United States
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Ridgeeld, Connecticut 06877, United States

Takeda Pharmaceuticals International Company, Cambridge, Massachusetts 02139, United States

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

Chicago Pharmaceutical Science Group, Takeda Development Center Americas, Inc., Deereld, Illinois 60015, United States
#
US API Process Research and Development, Pharm. Sci. & Tech., Eisai Inc., Andover, Massachusetts 01810, United States

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

S Supporting Information
*

ABSTRACT: Designation and justication of active pharmaceutical ingredient starting material (API SM) is a standard part of
the drug development and commercialization process. However, knowledge of current practices used within the industry varies,
depending on the individual company interpretation of regulatory guidelines. In 2011, the API and Analytical Leadership Groups
within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ),
established a Working Group on API SMs to determine current practices within the pharmaceutical industry on this topic. A
survey composed of four key areas, representing (1) drug substance (DS) attributes, (2) API SM attributes, (3) control strategy,
and (4) regulatory practices and strategy, was developed and distributed to IQ member companies. Data representing a total of
50 API SMs (used to prepare 24 late stage clinical or marketed DSs) were obtained. This data was used to gain a better
understanding of approaches utilized by pharmaceutical companies to dene API SMs. The data gathered was anonymous, and
the key information obtained is summarized in this manuscript. While no single approach to justifying API SMs emerged from
the survey data, key trends were evident that will provide valuable insight for the reader on this important topic.

1. INTRODUCTION
The material in this manuscript was developed with the support
of the International Consortium for Innovation and Quality in
Pharmaceutical Development (IQ Consortium or IQ). The IQ
Consortium is a not-for-prot organization composed 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 37 pharmaceutical and
biotechnology companies. Please visit www.iqconsortium.org
for more information.
A major deliverable during drug development is the selection,
designation and justication of the active pharmaceutical
ingredient starting material (API SM), the point in the
synthesis of the drug substance (DS) where GMP processing
begins. However, selection of the API SMs for DS manufacture
continues to be a much debated topic and industry practices for
their selection vary based upon company experience and
interpretation of regulatory guidances. In 2011, the API and
Analytical Leadership Groups, within the IQ Consortium,
established an API SM Working Group (WG), to assess how
IQ member companies make important decisions around how
to designate and justify API SMs and their associated regulatory
practices. The API SM WG chose to dene this area by posing
three fundamental questions:
2014 American Chemical Society

(1) How has the regulatory perspective on API SM

designation developed?
(2) How are peer companies approaching API SM
designation and justication?
(3) What should the industry do, if anything, to improve the
current process?
Part 1 of this series answers question 1 and has been
published as an introduction to the current manuscript.1 This
manuscript, Part 2, examines question 2 and will outline the
current practices used by the IQ member companies to support
their API SM designation with the regulatory agencies. These
practices are summarized on the basis of the results of a survey
that comprised case studies of 50 API SMs [that were used to
prepare 24 late stage clinical or marketed DSs].2 Part 3 of this
series is expected to be published in the future and will outline
opportunities to improve the process in alignment with ICH
Q11.

2. RESULTS AND DISCUSSION

2.1. Survey Composition. The survey focused on four
main areas: (i) DS attributes; (ii) API SM attributes; (iii)
Received: February 17, 2014
Published: April 10, 2014
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Table 1. Overview of API SM survey focus areasa

DS attributes

API SM attributes

synthesis
complexity
lot history
chiral impurities
impurities

complexity
manufacturing and validation
sourcing
propinquity
impurities

control strategy

regulatory strategy

process control
manufacturing
propinquity

regulatory status
ling structure
information shared for justications
timing of nal API SM strategy communication
regulatory communications with US, Canada, and EU

Analytical Control
Impurities Controlb
acceptance criteria
analytical methods
characterization
fate and purge
GTIs and pGTIs

All the raw data for the API SM survey is included in the Supporting Information. bExpanded list of the impurity control.

Table 2. Comparison of DS complexity to attributes

survey sumsa for DS MW

DS complexity

survey averages

self rated complexity

no. survey cases

<400

400650

>650

steps from RMs to DSb

DS rings

DS stereocenters

DS synthesis typesc

High
Medium
Low

8
9
6

3
2
3

2
7
3

3
0
0

12.6
9.3
4.7

5.0
3.6
2.2

4.5
1.1
0.8

4C, 4L
5C, 4L
2C, 4L

a
Number of DSs of self-rated complexity and MW (molecular weight, in amu) value shown. bAverage number of steps from raw materials (RMs) to
DS. The number of steps for each case study is the sum of the steps to make each API SM and the steps from the (rst) API SM to the DS. cC =
convergent, L = linear.

While there was no route type trend for medium and high
complexity DSs, linear routes were used twice as much as
convergent routes to prepare low complexity DSs.
The number of rings correlated well to the self-rated
complexity, with average ring counts of 5.0 for the high
category, and 3.6 and 2.2 for the medium and low categories,
respectively.
The number of stereogenic centers provided a weaker
correlation to complexity. Two DSs with zero or one
stereogenic center were rated as highly complex, showing the
importance of multiple factors in assessing DS complexity.
Increased stereochemical richness did, however, track with
complexity in a more general way. The average stereocenter
counts were 4.5 for the high category and 1.1 and 0.8
respectively for the medium and low complexity DSs. The
survey showed that DS complexity correlated with the number
of DS stereocenters, rings, functional groups, and the degree of
justication required to demonstrate adequate control of the
DS Critical Quality Attributes.
2.3. API SM Attributes.4 In analyzing the data collected for
API SM attributes, three major categories emerged where
signicant correlations could be drawn to a number of
attributes: complexity, sourcing, and propinquity. Each of
these concepts have been recurrent themes in the evolving
regulatory guidances with respect to appropriate denition of
API SMs. In terms of complexity, nding the balance between
having an API SM represent a signicant structural fragment of
the DS per ICH guidance and having an API SM which is
deemed too similar in complexity to the DS is a component of
API SM designation. Propinquity was communicated in ICH
Q115 as the relationship between potential impact of material
attributes or operating conditions to their proximity to the DS.
This survey sought to understand if companies were making
decisions or arguments for their API SMs based upon the idea of
propinquity or independent of it. The dierence between the
justication burden for commercial or commodity vs custom

control strategy and (iv) regulatory practices and strategy. The

primary focus in each of these areas is summarized in Table 1.
For the rst time, data for each of these key areas was
collected and is shared through this manuscript to give an
unprecedented look at current industry practices in API SM
designation. Additionally, we sought to analyze the data not
only for simple trends between case studies but also to probe
for connections between seemingly unrelated focus areas of the
survey. The key objectives of the survey were to learn how
companies developed their control strategies to justify the
designation of their API SMs, how the information is led with
regulatory agencies, and the resulting outcome of their
proposals.
2.2. DS Attributes.3 In terms of understanding API SM
designation practices, it was rst important to understand the
nature of DSs. We collected information on a number of DS
attributes, and one was (survey respondent) self-rated
complexity. No standard denition was provided to the survey
respondents; rather, they were asked to provide an assessment,
based upon their companies perspectives, to facilitate the
development of a complexity denition.
Correlation of DS complexity to its key attributes, indicated
that MW provided some correlation to complexity. Each DS in
the highest MW category (>650 amu) was rated as highly
complex; however, three DSs self-rated to be highly complex,
had MWs in the lowest category (<400 amu) (Table 2).
The total number of steps, dened throughout this
manuscript to mean chemical transformations, excluding nal
salt formation or purication of DS, provided the strongest
correlation to complexity (see Supporting Information). The
average number of steps was 12.6 for high, 9.3 steps for
medium, and 4.7 steps for low complexity DSs. The survey
revealed a mild correlation between DS complexity and
synthetic route type (linear or convergent). The ratios of
linear/convergent routes used in low, medium, and high
complexity DS syntheses were 2/1, 1/1, and 1/1, respectively.
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Table 3. Comparison of API SM complexity to attributes

survey sumsa for API
SM MW

survey averages
steps to

API SM attributes

API SM complexity selfrated

no. survey
cases

<200

200
400

>400

API
SMb

DSc

rings

stereo
centers

high
medium
low

11
13
26

1
1
12

3
9
13

7
3
1

5.7
3.8
1.8

3.4 (2.2)
3.1 (2.5)
2.7 (2.4)

2.9
2.1
1.0

3.0
0.4
0.4

process devel. int.d% sourced from EMse%

73
100
50

36
15
62

a
Number of API SMs of self-rated complexity and MW (molecular weight, in amu) value shown. bAverage number of steps from raw materials to
API SM. cAverage number of steps from API SMs to DS (isolated intermediates between API SM and DS are shown in parentheses). dPercentage of
API SM processes developed internally, as opposed to externally at a third party manufacturer. ePercentage of API SMs sourced from emerging
market (EM) countries.

Table 4. Comparison of API SM source to attributes

survey sumsa for API
SM MW

survey averages
API SM attributes

API SM
source

no. survey
cases

custom
commercial
commodity

33
10
7

<200

200
400

4
4
6

9
5
1

>400

steps to API
SMb

steps to
DSc

10
1
0

3.9
1.9
1

3.17 (2.4)
2.4 (2.4)
2.7 (2.6)

rings

stereo
centers

process devel.
int.d %

sourced from
EMse %

2.0
1.3
0.4

1.0f
0.4
0.7

88
40
14

33
60
71

a
Number of API SMs of self-rated complexity and MW (molecular weight, in amu) value shown. bSteps from raw materials to API SM. cSteps from
API SMs to DS; isolated intermediates between API SM and DS in parentheses. dPercentage of API SM processes developed internally, as opposed
to externally at a third party manufacturer. ePercentage of API SMs sourced from EM countries. fThree API SMs, with a high stereocenter count,
associated with the atypically long synthetic sequence were excluded from this calculation. If included the value would be 1.4.

Interestingly, API SM attributes correlated similarly with

complexity (Table 3) and source (Table 4).
API SMs that are characterized as commodity chemicals are
sourced primarily from emerging markets (EM, 71%), while
only 33% of custom API SMs are sourced from EMs. This
potential geographical sourcing bias could be the result of how
both the applicant and regulatory agencies assess supply chain
risks and material controls (see discussion in section 2.4.1,
Process Control Strategy). As API SMs become more complex,
sponsors may place more stringent process and supplier change
controls and seem to prefer to contract with partners in North
America and Europe.
2.4. Control Strategy.6 The control strategy is a planned
set of controls, derived from current product and process
understanding, that assures process performance and product
quality (ICH Q10).7 For API SMs, control strategy includes
process control and analytical control.
2.4.1. Process Control Strategy. Control strategies for API
SM and DS rely upon a sound understanding of the
manufacturing processes employed. Our survey included
questions about API SM manufacturing details, including
where manufacturing processes were developed, the source of
the API SM (Table 4), the TPM quality agreements utilized,
and the extent to which the API SM syntheses were validated.
In general, the survey revealed that some common trends are
utilized to better demonstrate control of API SM quality:
API SM specications based on use test data and
resultant DS quality
knowledge of API SM lot histories ranging from a
minimum of three up to many more, depending on the
number of DS lots manufactured
impurity fate mapping generated to understand impurity
control strategies

manufactured materials has also been mentioned repeatedly in

the regulatory guidances. This survey found a strong relationship between complexity and sourcing, with 92% of all high and
medium complexity API SMs being custom manufactured. The
relationship between these two categories will be discussed rst,
followed by propinquity.
2.3.1. API SM Complexity and Source. Raw data for the API
SM attributes correlated well with self-rated complexity,
providing support for a denition of complexity, similar to
the DS, that is based upon the number of API SM
stereocenters, rings, functional groups, and the degree of
justication required to demonstrate adequate control of API
SM and API SM related impurity carryover in the DS
manufacturing process. The attributes of the API SM that are
correlated to complexity are dened below (Table 3).
The majority of high complexity API SMs have a MW
>400, while low complexity API SMs typically have a
MW <200.
Number of rings is most clearly dierentiated between
low complexity API SMs (1 ring, on average) vs medium
and high complexity API SMs (2.9 for both, on average).
Number of stereogenic centers shows a clear trend in
moving from high to medium and low complexity API
SMs (3.0 vs 0.4, on average).
Finally, the number of steps from raw materials (RMs) to
API SMs correlated with complexity. An average of 5.7,
3.8, or 1.8 steps were used to prepare API SMs with high,
medium, or low complexity, respectively. However, on
average, regardless of complexity, 2.22.5 isolated
intermediates separated the API SMs from DSs. Thus,
with respect to industry averages for propinquity, API
SMs are 23 steps from the DS, as noted below.
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Table 5. Strategies for manufacture of the API SM as a function of number of steps from the DS
steps from API SM
to DS

GMP mfga prior to DS

validation (%)

GMP mfg for DS

validation (%)

API SM mfg
included in MAb le (%)

sourced from
EM (%)

CCc agmtd in
place (%)

quality agmt in
place (%)

3
2
1

18
27
62

18
27
54

66
20
85

66
45
31

70
73
92

90
91
100

mfg = manufacturing. bMA = marketing authorization. cCC = change control. dagmt = agreement.

stability data for all custom and commercial and most

(80%) commodity API SMs
quality agreements (including change controls)
API SM manufactured under cGMP or near GMP until
approved
manufacturing of API SMs under GMP (review in
applicants quality systems)
use of validated API SM processes
dual sourcing of API SMs
The survey results indicated that for high to medium
complexity and custom API SMs, there was an increased
reliance on innovator company resources to develop the
syntheses. However, for low complexity, commercial, or
commodity API SMs there was a higher level of outsourcing
utilization, which increased perceived risk to the control
strategy (resulting from remote management of manufacturing
and controls). This risk increased further when API SMs were
sourced from EM. When EM sourcing was employed,
companies utilized similar risk mitigation strategies, as dened
above, regardless of API SM complexity or categorization. In an
attempt to further investigate the inuence of propinquity on
API SM designation practices, we sought to understand if there
was a dierence in strategy towards development, manufacture,
and ling for the API SM as a function of number of synthetic
steps from the DS. In total 55% of the API SMs were 2
synthetic steps from the DS. While these API SMs were
predominantly in the medium to low complexity range, a
number of strategies shown in the above list were used to
manage the risk of regulatory push back.
Use of Third Party Manufacturers (TPMs) in EMs for the
API SM synthesis changed as a function of the number of steps
from the API SM to the DS. For API SMs with one step from
the DS there is a reduced trend to source these materials from
EMs (Table 5, Figure 1). The source of the material custom,
commodity, or commercial and whether it was manufactured
internal to the company or at a TPM, did not appear to change,
depending on where the API SM was relative to the DS.

Companies exercise increased oversight and change control at

TPMs that produce API SM with one step to the DS.
Across all case studies, greater than 90% of the companies
have change control agreements in place, and 100% companies
have quality agreements in place to control these materials.
As stated above, more important than propinquity of the API
SM, was control of the DS manufacturing process to
demonstrate that the API SMs do not aect the quality of
the DS, as required by ICH Q11. The majority of respondents
indicated that there were no API SM-related impurities (API
SMs, impurities in API SMs and related impurities) in the DS
above the identication limit.
2.4.2. Analytical Control Strategy. The API SM control
strategy is a critical component of the API SM justication. As
required by ICH Q115 information should be provided to the
regulatory agency(ies) on:
the ability of analytical procedures to detect impurities in
the API SM
the fate and purge of API SM impurities and their
derivatives in subsequent processing steps
information on how the proposed specication for each
API SM will contribute to the control strategy
the control strategy should include controls of genotoxic
impurities that can be introduced into the DS
manufacturing process from the API SM
the control strategy must include controls of impurities
not related to the DS or API SM structures, such as
residual solvents, metals and other substances used in the
process.8
The API SM controls therefore play a signicant role in the
overall DS control strategy. In the survey, 67% of respondents
indicated that there is a relationship between API SM
complexity and the amount of data needed for the control
strategy. This result is lower than one would anticipate, and it is
likely due to a conservative approach utilized by most
companies wherein the same high standards that are applied
to more complex API SMs are applied to less complex API
SMs. Nevertheless, greater API SM complexity necessitates that
more data be acquired in order to demonstrate fate and purge
of impurities.
2.4.2.1. API SM Analytical Methods and Impurities. The
survey data indicates that, to control the quality of the API SM,
companies developed API SM analytical methods which, in
addition to actual impurities, also separate potential impurities
(such as process intermediates and reagents used to make the
API SM). In all cases, API SM methods were either validated
(92%) or qualied (8%).
2.4.2.2. API SM Impurities. The average API SM impurity
reporting threshold was 0.10%, and the majority (93%) of
responses fell within the range of 0.05%0.20%. The average
API SM impurity identication threshold was 0.21%, and the
responses ranged from 0.05%0.50%.
To justify API SM impurity limits, the majority (85%) of
respondents used fate and purge data along with batch history

Figure 1. Strategies employed by companies correlated to the number

of steps from API SM to DS.
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level of this impurity in the DS is below the acceptable level

(ICH M7 Step 2 Guideline on genotoxic impurities).9 As the
survey demonstrates, the API SMs and their impurities, as
potential impurities in the DS, are included in this control
strategy.
Of the API SMs evaluated in the survey 72% did not contain
any GTIs, and 28% contained up to 5 GTIs. The majority of
respondents (64%) controlled actual API SM GTIs at the
Threshold of Toxicologic Concern (TTC)10 level in API SMs
or GMP process intermediates. Two respondents controlled
API SM GTIs above the TTC level prior to the DS. One of
them, in addition, controlled the GTIs in the DS at the TTC
level, and the second justifyied GTI specication limits in
process intermediates by using purging experiments to
demonstrate that GTIs are controlled at the TTC level in the
DS by the manufacturing process (as per option 3 of the ICH
M7 Step 2 Guidance).1 In addition, three API SMs were
genotoxic and contained genotoxic impurities. These API SMs
were controlled in the DS at the TTC level, and scientic
judgment was used to justify that their impurities were not
present in the DS.
In addition to control of actual GTIs in the API SM, the
majority of respondents (92%) assessed the API SM
manufacturing process for potential genotoxic impurities
(pGTIs) as usually required by EMA and Health Canada
(HC) and in some special cases by the FDA. Per the authors
experience, this assessment for API SM pGTIs may require
only evaluation of the impurity purge by the API SM and DS
manufacturing processes, and does not necessarily require
analytical testing.
2.5. Regulatory Practices and Strategy. Of the 24 case
studies received, 63% were either approved or in the licensure
review process, 29% were past the end of phase 2 (EOP2), and
8% were in phase 1. Thus, a clear majority of case studies
(92%) were at the later stages of development where
meaningful data for the justication of API SMs were available
to inform regulatory practices and strategies employed by the
IQ member companies.
Typically during product development, the API SM selection
strategy is shared with the regulatory agencies at or around the
end of phase 2 (EOP2). However, despite the potential for
signicant impacts on the strategy for development of the DS
and supply chain risks, roughly a third (30%) of the sponsors
still waited until the pre-NDA/MAA meeting or the time of the
NDA/MAA/NDS ling to discuss the API SM selection with
regulators (Figure 3).
The frequency and format of regulatory communications that
companies engaged in with agencies in North America and

data from one of the following materials or combination of

materials: API SM, GMP intermediate(s), or the DS.
Potential API SM impurities were identied via an evaluation
of the API SM manufacturing process for most of case studies
(96%).
2.4.2.3. Stereogenic Impurities. In total, 43% of the API
SMs contained stereogenic centers, and an interesting
correlation was found between the number of API SM
stereogenic centers and the percentage of possible API SM
stereogenic impurity standards that were prepared (Figure 2).

Figure 2. Relationship between number of stereogenic centers in the

API SM and percentage of potential stereogenic impurity standards
prepared.

As the number of API SM stereogenic centers increased, the

percentage of potential API SM stereogenic impurity standards
prepared decreased. Respondents that prepared fewer than all
of the possible API SM stereogenic impurity standards
indicated that either their risk assessment showed a low risk
of stereogenic impurities carrying over into the DS (67%),
stereogenic impurities were suciently controlled by employing existing analytical methods (25%), or stereogenic impurities
were controlled in the API SMs (8%).
2.4.2.4. Carryover of API SM Impurities. The survey
indicated that 98% of respondents conducted fate and purge
studies of API SM specied impurities that could carry forward
in the DS manufacturing process. All respondents performed
assessments of potential API SM impurities in the API SM
synthesis. For example, some conducted studies that showed
that the API SM analytical methods were adequately specic
and sensitive enough to allow the detection of potential
impurities and had batch history data that showed a lack of
presence of certain potential API SM impurities.
2.4.2.5. Propinquity. We were interested in understanding
the level of analytical controls needed relative to the API SM
introduction point in the DS manufacturing process. When the
API SM introduction point was closer to the DS, 60% or
respondents indicated the analytical controls were increased,
due to limited impurity purging opportunities.
In general, tighter API SM impurity controls were
established, and extensive fate and purge studies were
conducted the closer the API SM was to the DS. With one
step, extensive fate and purge studies were conducted several
steps prior to the proposed API SM or more justication
discussion and spiking data were shared to show process
purging power. A number of respondents indicated that they
strived for high-purity API SM, manufactured it under GMP
until approval, and provided regulatory agencies with API SM
manufacturing vendor quality agreement details.
2.4.2.6. Genotoxic and Potential Genotoxic Impurities.
When an impurity has been characterized as mutagenic, it is
important to develop a control strategy that assures that the

Figure 3. Timing for communication of API SM designation strategy

with regulatory agencies.
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analysis across these three dierent but related areas can be

performed, and the survey provides interesting information on
how API SMs are handled across the pharmaceutical member
companies within IQ. For custom API SMs a clear majority of
respondents (77%) share the synthetic schemes in their
regulatory lings and those that did not instead provided a
short written description of the process. Some companies
provided additional data including fate and purge information,
specications, and abbreviated synthetic schemes as needed.
Interestingly, the responses shifted when the API SMs were
identied as readily commercially available. In those cases,
half of the companies did not provide a synthetic scheme and
fewer than 20% of sponsors supplied synthetic information for
commodity chemicals. Interestingly, the complexity of the API
SMs followed a similar trend, wherein custom API SMs
possessed the greatest structural complexity followed by
commercial and then commodity. This information taken
together suggests that as the complexity of an API SM increases
companies provide more information about their syntheses.
The next regulatory relationship examined was whether
structural complexity had any eect upon the inclusion of the
API SM synthetic process in the ling and if the GMP status
(production controls) was used as a risk mitigation strategy to
ensure the acceptability of their API SM as the regulatory
starting material. Of the API SMs rated as medium to high
complexity, around 90% were designated and led in the NDA/
MAA/NDS, and 7080% of these materials were manufactured
under GMP controls. There was some variability noted across
regions, as roughly 50% of API SMs designated in NDAs are
not manufactured under GMP controls, while the gure drops
to 30% in the other jurisdictions.
After viewing all of the regulatory data from the survey
responses it was evident that there is a wide variety of
approaches used by IQ member companies to design and
communicate the justication of API SMs. Some companies
make their cases at the very beginning of development, while
others increase the content as the programs move through
development, and there are even some that wait until the
review of the nal marketing applications. Regardless of the
timing of the regulatory interactions, IQ member companies
each have strategies for designating and justifying their API
SMs based on a multitude of factors ranging from the structural
complexity and source of the compounds to the availability of
characterization data for impurities and measures of process
robustness.

Europe varied signicantly. The FDA had the most overall

interaction with sponsors regarding API SM selection and had
3 times the frequency (number) of interactions than either the
EMA or HC. Generally the interactions with the FDA and
EMA were split evenly between face-to-face and written
interactions, while HC communications were three times
more likely to be conned to written answers to inquiries.
The top four categories of information that sponsors
disclosed to the health authorities to enable the selection of
the API SM were related to the control strategy to ensure the
quality of the DS and included proposed acceptance criteria,
analytical characterization data, synthetic schemes, and impurity
purging studies (Table 6). In all cases where genotoxic
impurities were present in the DS, API SM evaluation of
genotoxic impurities was provided in the Marketing Application
the ling.
Table 6. Types of information shared with the health
agencies during API SM selection discussionsa
API SM data package contents

% of respondents who provided the

following information

sponsor-proposed acceptance
criteria for API SM
analytical characterization datab
synthetic scheme
impurity purging studies
genotoxic impurity information
vendor identication
certicates of analysis

95
90
86
86
100
62
57

Other information included: stability data, batch history overview,

bioactivity study (5% each). bInformation in addition to the
summaries of data contained on certicates of analysis.

The majority of sponsors le their API SM acceptance

criteria, synthetic schemes, batch data, and vendor information
in the Control of Materials section of the Common Technical
Document (CTD) (3.2.S.2.3) and while this is true across all
regions (North America and EU), there is more consistency
between European and HC lings (Table 7). Information about
Table 7. CTD sections used to describe API SM strategy by
ling region
sections of le

FDA (%)

EMA (%)

HC (%)

S.2.2 - Description of Mfg Process

S.2.3 - Control of Materials
S.2.6 - Mfg Process Development
S.3.1 - Elucidation of Structure
did not include
Appendix

5
52
19
5
5
5

0
75
19
0
0
6

0
73
7
0
0
7

3. CONCLUSIONS
This paper reviewed the results of a survey of pharmaceutical
industry API SM practices. Globally there has been no
systematic risk-based decision framework designed to assess
the justications and control the quality of the regulatory
output for API SM selection. This gap creates an opportunity
for the industry and regulators to rethink the current
justication process, establish a common language and
denitions to enhance understanding of the key scientic
concepts and material attributes, and develop easy to use
decision trees that can create uniform justication packages for
future products that can be applied within each respective
company. This will be a framework for discussion in Part 3 of
this series. It will then be each companys decision as to what
stage of development a scientically driven justication process
will be implemented based on the therapeutic indication, API
class, and the individual regulatory objectives. The shared goal

API SMs is also sometimes included in the Manufacturing

Process Development section (3.2.S.2.6). Companies tend to
provide the names and addresses of their API SM suppliers in
the majority of EMA and HC regulatory lings (72% and 75%,
respectively); in contrast, this information is regularly shared in
only 55% of FDA lings.
Understanding the relationship between API SM complexity,
source, and how each of those attributes inuences the ling
strategy between multiple companies has previously been
dicult to ascertain because these types of data have never
been readily available for comparison. However, all of these
attributes were captured in this survey, so for the rst time an
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Organic Process Research & Development

Article

(6) Denitions are provided based upon the ICH Q3A denitions of
impurity and potential impurities. Similar denitions can be used for
both DS and API SM. Impurity: Any component of the DS that is not
the chemical entity dened as the DS. Potential impurity: Any impurity
that theoretically can arise during manufacture or storage. It may or
may not actually appear in the DS. Method validation: The process of
proving, through scientic studies, that an analytical method is
acceptable for its intended use. A method validation protocol is
prepared, experiments are executed, and method performance relevant
to predened validation acceptance criteria is documented. Method
qualif ication: Although similar to method validation, a protocol is not
prepared and acceptance criteria are not set before the method
verication studies. Per analogy, genotoxic impurity (GTI) (or actual
genotoxic impurity) and potential genotoxic impurity (pGTI) of the
DS, for the purpose of this survey, are dened as follows: Genotoxic
impurity (actual genotoxic impurity), GTI: Any impurity of the DS
identied as potentially genotoxic or genotoxic by the mutagenicity
assessment. The mutagenicity assessment may be based on
mutagenicity test(s) (most often Ames test) or on in silico analysis,
if results of the mutagenicity tests are not available. Potential genotoxic
impurity (pGTI): Any potential impurity of the DS identied as
potentially genotoxic or genotoxic by mutagenicity assessment (see
above).
(7) ICH 10: Guidance for the Industry. Pharmaceutical Quality
Systems. April 2009.
(8) Questions on the control of these substances were not included
in the survey since the focus was more on API SM and DS related
impurity controls.
(9) ICH M7: Assessment and control of DNA reactive (mutagenic)
impurities in pharmaceuticals to limit potential carcinogenic risk.
Current Step 2 version, February 2013. http://www.ich.org/products/
guidelines/multidisciplinary/article/multidisciplinary-guidelines.html.
(10) The Threshold of Toxicological Concern (TTC) is a concept
that refers to the establishment of a level of exposure for all chemicals,
whether or not there are chemical-specic toxicity data, below which
there would be no appreciable risk to human health. The concept
proposes that a low level of exposure with a negligible risk can be
identied for many chemicals, including those of unknown toxicity,
based on knowledge of their chemical structures.

of regulators and industry is to deliver high-quality, lifesustaining products to patients in a timely manner. All we have
to do is agree on how to get there together because our
patients/customers are waiting.

ASSOCIATED CONTENT

S Supporting Information
*

Raw Data from the 50 API SMs and 24 DS Case Studies

obtained from the IQ member companies as a Microsft Excel
Spreadsheet; analysis of the 24 case study responses and a
framework for evaluaton of complexity metrics based upon the
following descriptors of the API SM and DS (i) molecular
weight (MW), (ii) number of stereogenic centers, (iii) number
of rings, and (iv) number of synthetic steps to the target
molecule (DS or API SM), and a detailed overview of these
complexity metrics and correlation with the self-rated complexity, assigned by the individual authors. This material is available
free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*Telephone: 805-447-0599. E-mail: mfaul@amgen.com.

Notes

The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
The authors thank Maja-Leah Marshall from Drinker Biddle &
Reath LLP for her support in formatting, distributing and
compiling the survey results. We also 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.

REFERENCES

(1) See preceding manuscript for Part 1, DOI: 10.1021/op500059k.

(2) The following IQ Consortium member companies are acknowledged for providing comprehensive Case Study Data to the survey:
Abbvie, Amgen, AstraZeneca, Biogen Idec, Boehringer Ingelheim,
Bristol-Myers Squibb, Celgene, Eisai, Eli Lilly & Company, Kythera,
Merck, Millennium, Takeda, Vertex, Sunovion and Teva. Company
responses on the API SM Case Studies were submitted electronically
to the law rm of Drinker, Biddle and Reath (DBR), the umbrella
organization that administers the IQ Consortium. Company aliations
were removed from survey responses, and the blinded survey results
were compiled and analyzed by the API SM working group to generate
the data presented in this manuscript.
(3) Denitions used in this manuscript: Propinquity: The proposed
API SM should be similar in structure to the DS and separated from
(or nearness to) the nal DS by several reaction steps that result in
isolated and puried intermediates. Number of Chemical Steps:
Represents steps from the API SM to DS without salt and/or
purication steps included per Regulatory guidance. Convergent
synthesis: A synthesis route where two separate synthesis paths
converge, ultimately leading to the DS. Number of isolated
intermediates: Represents how many intermediates were isolated in
the GMP sequence from the API SM to the DS.
(4) Denitions used in this manuscript: Commodity API SM has a
signicant pre-existing, nonpharmaceutical market in addition to its
proposed use as an API SM. Commercially available API SM is available
from multiple vendors via Third Party Manufacturer (TPM)
technology. Custom API SM is available through limited number of
TPMs using company technology.
(5) ICH, Q11: Development and Manufacture of Drug Substances
(ICH, May 2011).
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