API Starting Material Designation - Where Does cGMP Start? API starting material designation continues to be a troublesome issue.

1. API Starting Material Designation
Where Does cGMP Start?

2. • API starting material designation continues to be a
troublesome issue.
• Historically, API suppliers (DMF holders) have relied on the
1987Guideline for Submitting Supporting Documentation in
Drug Applications for the Manufacturers of Drug Substances,
• International Conference on Harmonization (ICH) Q7A (good
manufacturing practice starting material), and
recommendations from 2004 and 2006 working groups for help
in defining a starting material for the API manufacturing
process.
Background & History
CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http://www.ich.org/LOB/media/MEDIA433.pdf

3. • ICH Q11: Development and Manufacture of Drug
Substances provides recommendations for API process controls
and starting material considerations.
• The API supplier's decision of how far back in the synthesis to
go before designating the regulatory starting material is
impacted by the cost of current good manufacturing practice
(CGMP) compliance, publishing proprietary information, and the
necessity of reporting any future changes to the process.
• FDA uses a risk-based approach to determine where CGMPs
should commence and defines the regulatory starting material
accordingly.
Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances (1987)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070632.pdf
Current Approach

4. • Increasingly, DMF holders define a key intermediate as the
starting material and outsource the synthesis without due
consideration to quality.
• In some cases, multiple suppliers of the outsourced starting
material are provided, each with either a DMF or technical
dossier requiring review.
Considerations
Illing, GT, Timko, RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

5. • The starting material should be removed from the finished
product by multiple synthetic steps with intermediates
isolated and in-process controls specified.
• Salt interconversions, saponifications, esterifications,
recrystallization steps, resolution of racemates, and in-situ
reactions with no intermediate isolated do not count as
synthetic steps.
Considerations
Illing, GT, Timko, RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

6. • If a molecule is "well defined" in the literature, then the
literature should be cited along with appropriate detailed
comparative structural analysis from the DMF holder against
the literature values (e.g., published papers and patents).
• It is recommended that data from multiple lots using the
commercial process to demonstrate sameness be provided for
review.
Considerations
Illing, GT, Timko, RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

7. • Commercially available starting materials need not be
justified.
• In this context and per the draft ICH Q11, commercially
available means "a chemical that is sold as a commodity in
a pre-existing, non-pharmaceutical market.”
• In contrast, chemicals for which a contract manufacturer
custom synthesizes a predefined amount of material
specifically for the DMF holder are not considered
"commercially available."
Considerations
Illing, GT, Timko, RJ, and Billet, L, Drug Substance Starting Material Selection, Pharmaceutical Technology, Volume 32, Issue 12, pp. 52-57

8. ICH Q7 defined an API starting material as follows:
• “An “API starting material” is a raw material, intermediate, or
an API that is used in the production of an API and that is
incorporated as a significant structural fragment into the
structure of the API.
• An API starting material can be an article of commerce, a
material purchased from one or more suppliers under
contract or commercial agreement, or produced in-house.
• API starting materials normally have defined chemical
properties and structure.”
History – ICH Q7 Guidelines
CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http://www.ich.org/LOB/media/MEDIA433.pdf

9. Ambiguous?
• This definition of API starting material does not
talk about multiple synthetically relevant steps
that should separate the starting material and
the final API.
• Based on this definition of API starting material,
a downstream intermediate (even the crude API),
manufactured under non-cGMP conditions,
purchased from custom manufacturers around
the world meets the ICH Q7 criteria.
CH Q7A Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000). http://www.ich.org/LOB/media/MEDIA433.pdf

10. • ICH Q11, Development And Manufacture Of Drug Substances
(Chemical Entities And Biotechnological/Biological Entities)
• Sections 5.1 and 5.2 of ICH Q11 talks about the selection of
starting materials and source materials for APIs.
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf

11. The information in ICH Q11 regarding starting materials can be
summarized as follows:
 For API manufacturing process, cGMP applies from starting
material onwards
 Starting material should be a substance of defined chemical
properties and structure – not a non-isolated intermediate.
 Starting material should contain a distinct structural fragment
of the API – differentiates it from common agents for
esterification, salt formation etc.
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf

12. • Commercially available chemicals, with pre-existing non-
pharmaceutical market need not be justified as starting
material
• Enough of API manufacturing process must be disclosed in
the dossier so that the impurity fate/purge can be
understood
• Manufacturing steps which impact the impurity profile of the
API should be part of the process description
• It needs to be established that the changes in material
attributes/process conditions upstream (starting material
manufacturing steps) may have lower potential to affect the
API quality.
https://www.fda.gov/downloads/drugs/guidances/ucm261078.pdf
Clearing Up Ambiguity

13. API Starting Material – Best Practice
• The criteria used to define the API SM should be scientifically
justified.
• A risk-based control strategy should be developed that includes
not only SM specifications but also downstream GMP controls, in-
process tests, operating conditions and validation of the API
manufacturing process.
• The API manufacturer should demonstrate a thorough knowledge
of the quality of the SM and its impact on the quality and safety
of the final API.
• The SM specifications and overall control strategy should be
based on this knowledge.
https://www.fda.gov/downloads/drugs/guidances/ucm261078.pdf

14.  The SM should be appropriately characterized, with a well-
defined impurity profile.
 The fate of potential impurities (related substances, solvents,
metals, potential genotoxic impurities) in the downstream
manufacturing process should be well understood and
documented.
 The capability of the downstream process to remove impurities
and/or their derivatives should be established.
 Potential impurities that are critical to the quality and safety of
the API should be appropriately controlled, using suitable
analytical methods, depending on whether they are carried
through to the API or reliably removed during processing.
API Starting Material – Best Practice
https://www.fda.gov/downloads/drugs/guidances/ucm261078.pdf

15. In some cases, a late stage intermediate may be appropriate
as SM; in other cases it may be necessary to go further back
in the synthetic route.
The focus should be on the level of understanding and
control.
Non-science-based criteria should not be applied in the
definition of the SM.
These include:
 Number of synthetic steps
 Structural complexity
 Commercial availability
 Significant structural fragment
API Starting Material – Best Practice
https://www.fda.gov/downloads/drugs/guidances/ucm261078.pdf

16. • The term “significant structural fragment” should be used as
stated in ICH Q11, i.e. to distinguish SMs from reagents, solvents
and other raw materials.
• It should not trigger a search for the earliest possible substance
that is a structural fragment.
• A commercially available material may be classified as a SM but
only if it meets the scientific criteria.
• Regarding the introduction of stereochemistry into the synthesis,
this may occur before the designated SM if justified (as in
example 4 in section 10.4 of ICH Q11).
API Starting Material – Best Practice
https://www.fda.gov/downloads/drugs/guidances/ucm261078.pdf

18. Production of API Starting Materials
• In accordance with ICH Q7 and Q11, GMP begins with the first
use of an API SM.
• Manufacture of the SM itself is not subject to GMP
requirements.
• Under GMP, the API manufacturer is required to have systems in
place to cover supplier qualification.
• GMP compliance of the API manufacturer, including their
supplier qualification program, should be enforced during site
inspection by the authorities.
Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of
Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TGX-
4JRVDX0-

19. • Industry’s quality management of the SM manufacture should
incorporate risk assessment.
• The qualification process should include a quality agreement /
contract between the API manufacturer and SM manufacturer
to ensure that the impact of changes in the manufacture of the
SM can be adequately assessed by the API manufacturer.
• The SM manufacturer should have an appropriate quality
system in place and on-going monitoring / evaluation should be
performed by the API manufacturer.
Production of API Starting Materials
Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of
Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TGX-
4JRVDX0-

20. The name and address of the SM manufacturer and
qualification documentation should be available for review
during site inspections.
A risk-based control strategy is key.
• The SM is not the only substance contributing to
impurities in the API.
• The API is not the only substance contributing to
impurities in the drug product.
Production of API Starting Materials
Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of
Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TGX-
4JRVDX0-

21. • There should be an appropriate balance between
assessment of the SM and other process risks, e.g. other
raw materials, design of the manufacturing process.
• Manufacture of APIs under GMP is a critical part of the
control strategy and this includes supplier qualification.
• Adequate supplier qualification is a GMP requirement that
must be managed by the API manufacturer and verified by
inspection.
• More paper work is not a solution.
• Describing an excessive number of steps in the dossier is no
guarantee of a safe API.
Production of API Starting Materials
Gavin, PF, Olsen, BA, Wirth, DD, and Lorenz KT, A quality evaluation strategy for multi-sourced active pharmaceutical ingredient (API) starting materials, Journal of
Pharmaceutical and Biomedical Analysis, Volume 41, Issue 4, 16 June 2006, Pages 1251-1259 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TGX-
4JRVDX0-

22. The goal of working with regulators in the area of starting
material selection, then, should be to provide a solid, data-driven
case that the choice of starting material is backed up by
sufficiently discriminating analytical methodology, appropriately
set starting material acceptance criteria, and effective purification
processes that we are certain that we know what is in the
medicine we will be giving to patients.

23. Stuart Silverman
CEO & Founder
RyMat Incorporated
(803) 397-8087
stu@rymatinc.com
RyMat Incorporated