api starting material wg: a strategy for …api starting material wg: a strategy for justification...
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API Starting Material WG:
A Strategy for Justification of
API SM
9 October 2014
IQ Symposium 2014 – “Pre-competitive Collaboration for Innovation”
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Core Team• Mark Argentine, Eli Lilly
• Carl Busacca , Boehringer-Ingelheim
• Marjorie Egan, Infinity
• Magnus Eriksson, Boehringer-Ingelheim
• Margaret Faul, Amgen
• Zhihong Ge, Merck
• Frederick Hicks, Takeda
• William Kiesman, Biogenidec
• Ingrid Mergelsberg, Merck
• John Orr, Eisai
• Steven Pfeiffer, Kythera Biopharma
• Maciej Smulkowski, Takeda
• Gerald Waechter, Boehringer-Ingelheim
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3
Problem Statement & Opportunities
• Lack of consistent and clear guidance from regulators on
API SM selection
• Industry practices vary based on experience and
interpretation of the guidelines by different agencies
• Lack of harmonized interpretation of ICH Q11 by
different regulatory bodies (i.e. FDA, EMA etc.)
• API Starting Material WG established in 2011 to address
these challenges
• Topic is a strong Precompetitive Opportunity that can
provide value to the Industry
Sponsorship and Support by the API and Analytical LGs
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Generic Chemical Process and
the Advantage of API SMs
API SMIsolated GMP Intermediate(s)
A
B
C API
$
$
Raw Materials
Non-GMP Manufacture GMP Manufacture
Release of
API SM’s
Release
of API
Controlled by
GMP regulations
Controled by release
of API SM
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Value for Appropriate
Designation of API SMs
• API SMs relieve manufacturers, agency reviewers and
inspectors of a potentially significant burden in terms of
managing early-step technical information that provides
little value to overall DS quality,
• Selecting appropriate API SMs with analytical control will
provide appropriate quality assurance and process
control for the DS
• Rigorous adherence to GMPs should not be required
before the API SM is designated in the NDA/DMF.5
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API SM WG Progress
• Three fundamental questions are addressed in three different
manuscripts:
- How has the regulatory perspective on API SM designation
developed? – Manuscript 1
- What are peer companies doing currently? – Manuscript 2
- What should the industry do, if anything, to improve the current
process? – Manuscript 3
Manuscript 1 & 2 have been published; Manuscript 3 will be
published in Org. Process R&D 2015.
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Manuscript 1:
Regulatory & Industry Perspective
• First comprehensive review of all literature / perspectives
published on this topic during the last 25 years
- Summarizes current regulatory guidance's
- Provides a perspective from industry and regulators on the most
important elements regarding the justification of the API SMs
→ No alignment on application of control strategies (propinquity
vs. process knowledge / process control) to support the API SM
justification
Faul, M. M.; Kiesman, W. F.; Smulkowski, M.; Pfeiffer, S.; Busacca, C. A.;
Eriksson, M. C.; Hicks, F.; Orr, J. D.
Org. Process Res. Dev., 2014, 18 (5), pp 587–593
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Manuscript 2: Assessment of API SM
Selection by IQ Member Companies
DS AttributesAPI SM
AttributesControl Strategy
Regulatory
Strategy
• synthesis
• complexity
• historical data
• chiral
impurities
• stability data
• impurities
• complexity
• manufacturing
and validation
• sourcing
• propinquity
• impurities
• process control
• manufacturing
• propinquity
Analytical Control
• Control of impurities
• acceptance criteria
• analytical methods
• characterization
• fate and purge
• GTIs and pGTIs
• regulatory status
• filing structure
• information shared
for justifications
• timing of final
API SM strategy
communication
• regulatory
communications
with US, Canada,
and EU
Comprehensive Survey across IQ Companies:
Evaluated 50 API SM & 24 Drug Substances
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Part 1 & 2: DS & API SM Attributes
• Survey sought to determine if complexity of DS or API SMs
was an important factor in API SM designation
• Correlations between Steps from RM to DS, Rings, and Stereocenters
• Little or No correlation with MW
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Correlation between API SM
Sourcing and Attributes
• Correlations noted between API SM Source and API SM attributes as with
API SM Complexity
• 92% of all High & Medium complexity API SMs are custom manufactured
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Part 3: API SM Control Strategy
Survey indicated common trends in how the API SM quality is
controlled:
• Use of batch history data (minimum of 3 batches)
• Specifications based on use test data and resultant DS quality
• Control strategy: impurity fate and purge
• Use of Stability data
• Quality agreements (including change controls) with vendors
• Manufacturing of “high risk” API SMs under GMP
• Use of validated API SM processes
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API SM Analytical Methods
• API SM methods were adequately specific and sensitive to
actual and potential impurities from API SM manufacturing
process (eg., process intermediates, reagents , etc.).
• API SM methods were either validated (92%) or qualified (8%)
• To justify API SM impurity limits, fate and purge data along
with batch history data from one of the following materials or
combination of materials were used: API SM, GMP
intermediate(s), or the DS.
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Stereogenic Impurities
• 43% of API SMs contained stereogenic centers
• As number of API SM stereo genic centers increased, the
percentage of potential stereogenic impurity standards
prepared decreased
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9
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Number of Stereogenic Centers in each API SM
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Control of Genotoxic Impurities
• Actual API SM GTIs controlled at TTC levels in API SMs or
GMP process intermediates
• Some API SMs were genotoxic and were controlled to the
TTC level in the DS
• Scientific judgment used to justify that API SM pGTIs were
not present in the DS
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Propinquity
• For one step GMP processes:
- Extensive fate & purge studies conducted several steps
prior to the proposed API SM
- Tighter API SM impurity controls were implemented
• For short GMP processes:
- Respondents strived for high purity API SM
- Manufactured API SM under GMP until approval
- Provided regulatory agencies with API SM manufacturing vendor
quality agreement details
A 2-3 step GMP synthesis appears to be a “default standard”
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Part 4: Case Studies Phase of
Development
16IQ Consortium Confidential
• 92% of Case Studies were post-EOP2 to inform regulatory
practices and strategies employed by the IQ member companies
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Data Sharing in Filings
• % Synthetic Scheme / information shared by
respondents with regulatory agencies:
• Custom API SMs 77%
• Commercially available API SMs 50%
• Commodity chemicals < 20%
Summary: As the complexity of an API SM increases companies
provide more information to regulators about their syntheses.
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Manuscript 2: Summary
• Globally there is no systematic risk-based decision framework
to assess the justification and quality control for API SM
selection
18IQ Consortium Confidential
Faul, M. M.; Kiesman, W. F.; Smulkowski, M.; Pfeiffer, S.; Busacca, C. A.;
Eriksson, M. C.; Hicks, F.; Orr, J. D.
Org. Process Res. Dev., 2014, 18 (5), pp 594–600
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Manuscript 3: The Framework
• Manuscript will:
- provide a framework on approaches to the API SM justification process
- establish a common language and definitions to enhance
understanding of the key scientific concepts & material attributes
- outline a proposal to create uniform API SM justification packages for
future products to the regulatory agencies in compliance with ICH Q11
- specific case study examples demonstrating how process understanding
is used to justify the control strategy
Faul, M. M.; Kiesman, W. F.; Smulkowski, M.; Eriksson, M. C.; Hicks, F.; Orr, J.
D.; Egan, M.; Mergelsberg, I.; Ge, Z.; Waechter, G.; Argentine, M.
Org. Process Res. Dev., 2015, Issue related to ICH Q11
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The Team Dynamics…..
What worked well…..
• Clear set of goals and deliverables defined
• Team passionate SMEs, driven to learn and publish data of
value to the community
• Diverse group with different experiences (API, Analytical,
regulatory, EU, FDA)
• Clear accountability within team to deliver
• Team developed trust and supportive in collaboration
Challenges…..
• Significantly complex topic with multiple aspects
• Survey had to be run twice and required months to compress
into meaningful data
• Defining the right tools to assess the data
• Keeping the output simple….
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Value and impact of the precompetitive
Collaboration on API SMs
• Manuscript 1 & 2 were within the most cited / read
articles in OPR&D in 2014
• First comprehensive review of literature on API SMs
• Significant body of data on current practices across IQ
member companies
• Significant reference materials
• Strong positive feedback from community 21
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