The API Regulatory Starting Materials

an industry perspective

Vienna, November 2014

Marieke van Dalen

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The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

This presentation will focus on ICH regions, chemical

substances

2
The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

3
The issue
• In recent years there has been an increase in
the amount of questions on the Regulatory
Starting Materials (RSMs) (started in EDQM,
spread to EU).
• Also for generic APIs this trend is observed.
• Top 10 deficiency at EDQM.

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The issue
• EDQM was the first “authority” to raise
questions on the RSM.
• For CEPs for “generic” API’s the RSM was
challenged, even though the same RSM was
approved in the corresponding ASMF.
• No way for the applicant to prove what was in
the ASMF.

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The issue
• In the EU a trend to discuss the choice of the
RSM was also observed. Not only for new
applications/ASMFs, but also for generic use of
an already approved ASMF.
• Few questions from US.
• No questions from Japan.
• The authorities interpretation that the RSM is
shifting towards the API is “to avoid GMP” is
incorrect; the real reason is the enormous
regulatory change control burden.
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The issue
• Authorities seem to have no confidence in
industry’s selection / control of SM.
• Consequences of re-definition for industry are
potentially huge.
• Request to re-define is perceived as highly
dependent on individual assessors.
• Need for a common policy and harmonised
approach to ensure consistency of evaluations.

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The issue
• Consequences of re-definition for industry are
potentially huge.
• Request to re-define is perceived as highly
dependent on individual assessors.
• Need for a common policy and harmonised
approach to ensure consistency of evaluations.
• Authorities have no confidence in industry’s
selection / control of SM.

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The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

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Global guidelines
• ICH Q11: Development and manufacture of
Drug Substances.
• ICH Q7: Good manufacturing practice for Active
Pharmaceutical Ingredients.

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Global guidelines
ICH Q11: lists some criteria:
- A description of multiple chemical steps
- Steps that impact the impurity profile of the
drug substance should normally be included
- A starting material should be a substance of
defined chemical properties and structure
- A starting material is incorporated as a
significant structural fragment into the
structure of the drug substance.

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Global guidelines
ICH Q7: lists some criteria:
- Incorporated as a significant structural
fragment into the structure of the API.
- Can be an article of commerce.
- Must have defined chemical properties and
structure.

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Regional guidelines - Europe

• Guideline on the Chemistry of new Active

Substances CPMP/QWP/130/96 Rev 1 (2003)
• Guideline on Active Substance Master File
Procedure, dated May 2013
• Top Ten Deficiencies in New CEP Applications
(2011), dated June 2012
• Content of the dossier for chemical purity and
microbiological quality PA/PH/ CEP (04) 1 4R,
dated February 2007.

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Regional guidelines - Europe
• Reflection paper on the requirements for
selection and justification of starting materials
for the manufcature of chemical active
substances (published October 2014)

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Regional guidelines - Europe
• Mostly “old” guidelines, not reflecting current
situation/authorities’ position; Focus on origin,
fate and purge of impurities, GMP not
mentioned as an aspect to consider.
• “pre-RSM-information” required to evaluate the
suitability of the specifications /analytical
methods (flow chart only).
• Only the EDQM document Top Ten
Deficiencies provides detailed requirements.

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Regional guidelines - Europe
Top Ten Deficiencies
- The RSM should generally not have a structure
that is very close to that of the final substance in
relative size and complexity
- Multiple synthesis steps should separate the
starting material(s) and the active substance.
- The full description of the process should cover
all synthetic steps critical for safety (impurities)
and/or efficacy (genotox, stereochemistry,
biocatalytic transformations).
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Regional guidelines - Europe
Top Ten Deficiencies
- It is the combination of the number of chemical
synthetic transformation steps carried out under
GMP and the control strategy.
- The name and address of manufacturers of
starting materials should be listed.
- A flow diagram outlining enough steps of the
synthesis.
- An appropriate control strategy should be
proposed to ensure the robustness and
consistency of the manufacturing process.
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Regional guidelines - Europe

EMA Reflection paper

- Gives an overview of the current way of thinking
in EMA, as just explained in the former session.
- It is quite detailed as to what the expectations are:
unfortunately also here it is not clear what
happens to “old” ASMFS when referenced by a
new MAA.

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Regional guidelines - US
• Guideline for Drug Master Files (1989) – does
not contain detailed information.
• In 2004 a draft Guidance for Industry - Drug
Substance - Chemistry, Manufacturing, and
Controls Information was published with a clear
list of requirements. This draft was however
withdrawn by the FDA.

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Regional guidelines - US
• The draft guidance for Chemistry,
Manufacturing, and Controls listed four main
criteria:
- Propinquity
- Isolated and purified
- Carry-over of impurities
- Complexity of structure

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Regional guidelines - Japan
• Rules laid down in the Pharmaceutical Affairs
Law.
• In the (English) publication Drug Approval and
Licensing Procedures in Japan (2005) some
information is provided but not detailed.
• From experience it is known that in Japan two
chemical conversion steps are needed and
found sufficient.

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The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

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Recent examples - 1 - ASMF MRP
• ASMF for a steroid with 13 chemical conversion
steps described.
• For steroids the chemical backbone is always
the same.

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Recent examples - 1 - ASMF MRP
• It is thus difficult to fulfil the requirement that
“the RSM should generally not have a structure
that is very close to that of the final substance
in relative size and complexity” .

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Recent examples - 1 - ASMF MRP
• The ASMF was referenced for the originator’s
product. When the ASMF was first referenced
for generic applications, 8 countries asked for
name and address for every supplier of the
Starting Material and a description of the
synthesis for each supplier, starting from the
natural source. Moreover, it was asked to
provide details on origin (plants) and
method used for extraction.

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Recent examples - 1 - ASMF MRP
• It seems strange that the originator’s product
was safe for many years without this
information.
• 13 chemical conversion steps were described
and the impurities that are potentially present in
the API do not originate from the starting
material.
• What does the additionally required information
provide in terms of patient safety??

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Recent examples - 2 - CEP
• CEP for API X. For capacity constraints
(increasing demand) outsourcing of (part of) the
synthesis was considered. A supplier for the
final intermediate was found:
- This supplier also holds a CEP for API X
- This supplier uses the same chemistry (that is
structures of starting material and
intermediates are the same).

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Recent examples - 2 - CEP
• If the customer (the Drug Product
Manufacturer) would have obtained material
directly from this second CEP holding supplier
this would have been a 1AIN variation
• It was decided to keep the final chemical
conversion and the purification steps in house,
ensuring the proven purification power of these
steps and to avoid any potential polymorphic
issues.

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Recent examples - 2 - CEP
• Reference to the supplier’s CEP dossier (which
had been assessed by EDQM) was not
possible, therefore a flow chart with reagents,
solvents etc. was presented in the request for
revision of the CEP.
• This was found insufficient by EDQM and more
details were requested (including all process
parameters. Sources of starting materials etc
etc.)

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Recent examples - 2 - CEP
• The supplier did not want to provide that
information. Not so much for confidentiality
reasons, but “since all this information was not
provided in their own CEP dossier”. Their CEP
had been granted on basis of one chemical
conversion step…
• Providing all the required information would
thus mean that changes in the early steps at
the supplier could result in revisions of our
CEP, but not of the supplier’s CEP….
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Recent examples - 2 - CEP
• Now where is patients’ safety?
• Again: if the customer (the Drug Product
Manufacturer) would have obtained material
directly from this second (CEP holding) supplier
this would have been a 1AIN variation. No one
would have bothered that there is only
information on 1 manufacturing step.

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The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

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What does Industry want?
• What we do not want:
- Retrospective application of new RSM policies:
once a RSM has been accepted, it should be left
that way, unless there is a safety issue (also
when going from ASMF to CEP, originator to
generic)
- information on the manufacture of the RSM (“pre-
RSM information”) being regulatory binding. This
is in contradiction with Q11 that states that the
RSM is the starting point for change control.
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What does Industry want?
• What we do not want:
- Only if a change is made in the manufacture of
the RSM and it impacts the RSM specification or
downstream control strategy then a revision /
variation is required.
- If there is no impact on the specification or
downstream control strategy, a revision / variation
should not be necessary.

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What does Industry want?
• What we do want:
- Definition of the RSM should be based on
scientific knowledge.
- Risk management principles should be applied.
- Manufacture of the API from the RSM is covered
by GMP, which should include appropriate
supplier qualification.
- Manufacture of the RSM is not necessarily
covered by GMP but should be covered by an
appropriate quality management system.
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The API Regulatory Starting Materials

• The issue
• Global guidelines / regional guidelines
• Recent examples
• What does Industry want?
• Conclusion

36
Conclusion

• Retrospective application of “new” guidance leads

to (huge) differences between different players on
the same market for the same API.
• More discussion is needed between regulators and
Industry on how to solve the problem on both
sides.

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