Download API Starting Materials

API Starting Materials
Co-Leaders: Nina Cauchon (Amgen); Megan McMahon (Pfizer)
Co-Speakers/Moderators: John Lepore (Merck); Barbara Scott
(FDA); Kasturi Srinivasachar (FDA); Tim Watson (Pfizer)
Speaker comments and provided slides are not intended to represent the official
views of the speakers’ organizations or AAPS
API Starting Materials
• Represent the start of full GMP manufacturing controls
• Represent the start of the manufacturing process
description for the API process
• Defined properties and quality
– Well-understood impurity profile and impact on overall control
strategy
– The sponsor is accountable for SM quality
• Differentiated from other reagents/solvents (significant
structural fragment of API)
• Custom vs. Commercial
Regulatory Guidance and Papers
• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• ICH Q11: Development and Manufacture of Drug
Substances
• EMA Reflection paper on the Requirements for
Selection and Justification of Starting Materials for the
Manufacture of Chemical Active Substances – Sept
2014
• *ICH Q11 IWG Q&A Document – in progress
Issues for Starting Material Selection
• Transparency
– Clarity of selection rationale, justification and connections to
control strategy in marketing application
• Impurity profile and purge
– How do stereochemistry, mutagenic impurities, metals
impact?
• Significant structural fragment
Issues for Starting Material Selection
• Proximity (number of chemical transformations (CTs)
from drug substance)
– CTs should be sufficient to robustly control impurities and
stereochemistry
– Salt formation steps and deprotection steps are not
considered chemical transformations, though these often
offer significant purification opportunities and reduce risk.
– Critical steps for safety and efficacy should be included in
the regulatory synthesis
• Role of GMP
Issues for Starting Material Selection
• Lifecycle change management
– Changes in SMs synthesis/ suppliers may impact API
quality
– Supplier availability and dependability
– Multiple supplier impact on API quality
• Stability and storage requirements
What’s next?
• ICH Q11 Implementation Working Group (IWG) is
preparing a Q&A document on the Selection and
Justification of Starting Materials for the Manufacture
of Drug Substances
• Tentative Timing for Q&A Document:
–
–
–
–
Approval of Topic/Rapporteur & IWG Defined (complete)
First IWG Meeting (complete)
Step 2 Sign-off November 2015
Step 4 Sign-off TBD
Discussion Groups
Case Study #1 (Linear Synthesis)*
R1
Step 1
A
Step 2
R2
R3
C
Step 3
D
(B)
Step 4
R1
R3
R1
Purification
R4
Final Drug
Substance
R3
Step 6
R4
Step 5
F
E
“Crude”
Drug Substance
*Example taken from ICH Q11
Case Study 1, Scenario 1
• Assume a significant structural fragment is
introduced in Step 5. It is a commercially available
chemical.
– How is this represented in the dossier (raw material or
starting material)?
– How does the company manage quality of a significant
structural fragment that is not custom made?
• Unknown route of synthesis?
• Unknown impurities?
• Variable impurity profiles?
Case Study 1, Scenario 2
• Why might a reviewer challenge the proposal to use
compound D as an API starting material?
– Stereochemistry control (reactions setting or purifications)
• What discussion/data could be provided in the dossier to
support the stereochemistry being set prior to the regulatory
commitment?
– Assume a known mutagenic impurity is generated in Step 2.
• What data/discussion/commitments might support having this
step outside of the regulatory synthesis?
• Lifecycle management for changes to starting material
manufacturing processes or suppliers?
Case Study #2 (Convergent Synthesis)
A
Chiral center introduction
Step 1
[B]
Step 3
Non-isolated intermediates
E
Step 2
C
D
Step 4
Non-isolated intermediates
Step 5
Final Drug Substance
[F]
Case Study 2, General Considerations
• Which are the appropriate starting materials?
Always A and D?
• How to determine the number of steps? If “step 4” is
comprised of three separate chemical
transformations how does this change the SM
designation?
• Options for purification?
• Other discussion?
Case Study 2, Scenario 1
• Starting material D is sourced from 2 companies and
is prepared using two routes of synthesis.
– How is this presented in the dossier?
– Is material from the two suppliers managed under a
common specification, even if impurity profile is different?
– How are companies managing vendor change control in
general?
– Other considerations?
More Topics for Discussion
• Is isolation of intermediates the only way to reduce
impurities?
• How are companies managing risk of non-acceptance of
proposed starting materials?
– Are any risk mitigation steps implemented prior to filing (such as
Agency consultation, process validation of steps prior to the
proposed regulatory synthesis)
• Are companies observing inconsistent feedback from
different regulatory agencies? Please provide examples.
• Can reviewers point to/discuss any common deficiencies
observed in starting material justification?
– Examples from generic perspective and innovator perspective?
More Topics for Discussion
• What are the current company practices for the
following:
– Level of detail provided for API SM synthesis?
– Level of detail for impurity fate and purge studies?
• Differences for standard organic PRIs vs. mutagenic impurities?
– Specifications for raw materials or intermediates used in API
SM synthesis?
– Use of validated methods for API SM testing/in-process
testing?
Summary/Output
Change Control
• Supplier management
– Q10
– Qualification of new routes, new vendors
– Complex supply chain
– Risk assessment
– Quality agreements
• Drivers for change:
– Site changes, scale change, cost, new technology
Global Acceptability
• Inconsistent feedback/expectations from different
regulatory agencies.
– Management of different regulatory commitments
• Manufacture to tightest regulatory commitments
• Lifecycle management manages separately for different
regulatory commitments
– Managing risk of regulatory rejection to launch
Pre-Registration Regulatory Advice
• Timing
– Driven by availability of supportive data for justification and
not phase of development
– Challenging for accelerated programs (break-through
therapies)
• Who to receive feedback from?
– All major markets or most conservative?
• Communication of diverging opinions between
agencies
Risk Mitigation
• Ensuring use of launch supplies
– Full GMPs for pre-starting material steps
– Validation of pre-starting material steps
• Transparency around company change control
within dossier
• Seeking regulatory feedback prior to submission
• Detailed knowledge/understanding of starting
material synthesis
Convergent vs. Linear Synthesis
• Number of steps
– Isolated intermediates vs. bond forming steps
– Opportunities for purification (other than isolation)
• Not preferred to have all purification at API isolation
and purification
• ICH Q11 on drug substance CQAs
• More justification and dialogue may be needed for
convergent synthesis
Managing Unknown Impurities
• Risk based assessments
• Purge of structurally dis-similar impurities vs.
structurally similar impurities
• Understanding potential impurities
Q11 Principles
• All principles should be considered, not one
or two principles in isolation
• Significant structural fragment (clarification of
what this means)
• Science based justifications
Critical Steps
• Criticality of steps that introduce chirality or
mutagenic impurities
– Introduction of stereocenter or mutagenic impurity
may occur prior to designated starting materials
with appropriate control strategy
• Critical steps are those that impact drug
substance CQAs