APIC POSITION PAPER

API STARTING MATERIALS

Contents

1. Summary
2. Introduction
3. Definition of the API starting material (SM)
4. Manufacture of the API SM
5. Pre-SM information
6. Conclusion
7. References
8. Abbreviations

1. Summary

The following principles should be applied when considering API SMs:

 Definition of the SM should be based on scientific knowledge.
 Risk management principles should be applied.
 Manufacture of the API from the SM is covered by GMP, which should include appropriate
supplier qualification.
 Manufacture of the SM is not necessarily covered by GMP but should be covered by an
appropriate quality management system.
 Any information provided on how the SM is manufactured in order to justify the SM
definition (“pre-SM information”) should not be subject to post-approval change
requirements.

These principles should be applied globally. They should be applied to new submissions1 that have
not previously been assessed in support of a product licence application2. They should not be
applied retrospectively.

Within Europe, the API SM should be assessed only once, at the first submission of the API
documentation. Thereafter the agreed SM should be accepted for subsequent applications, i.e.:
 If first included in an Active Substance Master File (ASMF), new marketing authorisation
applications (MAAs), in any member state, referring to the same ASMF, should not trigger
re-assessment of the SM.
 When a CEP application is submitted, if an ASMF has been submitted previously and the SM
accepted, this decision should be upheld by EDQM.
 If a company includes the API documentation in the MAA and then decides to submit an
ASMF or CEP application at a later date, or another MAA including the same API
documentation, the same should apply.

1
Includes DMFs, ASMFs, CEP applications and API documentation integrated in the product licence application dossier.
2
Includes MAA, NDA, ANDA, NADA, ANADA and related applications to health authorities.

Page 1 of 6
 Similarly, outside Europe, the health authority should assess the API SM when the DMF / API
documentation is first submitted. Once the proposed SM has been accepted, this should be upheld
for all subsequent applications referencing that DMF / API documentation.

2. Introduction

Health authorities have noted:

 A trend to describing shorter synthetic routes starting from complex SMs.
 A general lack of information when the SM manufacture is outsourced.
 Insufficient discussion regarding the carry-over of potential impurities.

This has often resulted in assessors challenging the proposed SM and, in the last few years, the
definition of API SM has been one of the top deficiencies in CEP applications.

One of the reasons given by assessors for requesting the re-definition of SMs further back in the
synthetic route is the management of the lifecycle of the dossier. Originally a company may
manufacture a SM in-house with full information and adequate control but later this material may
be purchased with less information and control. Another reason why short synthetic routes are
usually rejected by assessors is the implementation of GMP. Manufacture of SMs is not covered by
GMP and often inspectors face poor supplier qualification.

Industry, in turn, is faced with inconsistencies in evaluations and a lack of clear and unambiguous
guidance.

Requests from the authorities to re-define a SM further back in the synthetic route can have a
major impact on the API manufacturer. When the SM is re-defined, this re-classifies the SM
manufacturer as an intermediate manufacturer. This means that:

 Full information on the manufacture of the intermediate is required.

A common problem faced by API manufacturers is the reluctance of some suppliers to
disclose proprietary information on their syntheses to the API manufacturer, due to the
lack of a system to protect their confidentiality.

 The material must be manufactured under GMP.

This is not required for SMs therefore the manufacturer may not be in a position to comply.
In addition, the manufacturer of the originally defined SM may not produce the re-defined
SM himself so his systems must now cover qualification of the SM supplier.

 New quality agreements / contracts need to be drawn up.

In the case that the originally defined SM was not produced in-house, the API manufacturer
may no longer have direct contact with the re-defined SM manufacturer; yet he must
ensure that he is notified of changes in the manufacture of the SM to enable him to assess
potential impact on the API. The SM may have other, larger, non-pharmaceutical uses in
which case the supplier may be unwilling / unable to comply with the API manufacturer’s
requirements.

Page 2 of 6
  Existing customers of the API must submit variations / change applications.
If the API is already on the market, companies referencing the ASMF / DMF must submit
variations / change applications when the dossier is updated. The increase in workload for
both industry and the health authorities can lead to difficult situations when multiple
stakeholders – customers and health authorities – are involved.

Clearly, it is in the interest of all concerned parties that requests for re-definition of the SM further
back in the synthetic route are avoided. A common policy and harmonised approach is needed,
with transparency between the API manufacturer and the health authorities. Once an authority
has accepted a SM in a new API submission1, this decision should be upheld in all subsequent
applications involving that submission. Requests to re-define the SM should be rare and result only
from a serious concern for patient safety. The reasons for the request should be fully explained to
the API manufacturer.

3. Definition of the API SM

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.

 The SM should be appropriately characterised, 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.

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

1
Includes DMFs, ASMFs, CEP applications and API documentation integrated in the product licence application dossier.

Page 3 of 6
 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).

4. Manufacture of the API SM

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
programme, should be enforced during site inspection by the authorities.

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.

The name and address of the SM manufacturer and qualification documentation should be
available for review during site inspections. In APIC’s opinion, they should not be provided in the
dossier as they do not contribute to the science-based approach.

5. Pre-SM information

Many health authorities require the submission of information on how the SM is manufactured in
order to assess the suitability of the SM specifications. In their policy for defining API SM, EDQM
states that “this should include a flow diagram outlining enough steps of the synthesis [of the SM]
and information on the solvents, reagents and catalysts used during its synthesis”.

ICH Q11 states, in section 5.2.1, that “changes to the SM specification and to the synthetic route
from the SM to final drug substance are subject to regional, post-approval change requirements”.
EDQM’s policy is concordant with this, stating that “the approved SM is the starting point for GMP
and variations”.

While APIC recognises that it may be helpful to provide information on SM manufacture, it should
not be a prerequisite. In APIC’s opinion, if the information is provided, post-approval change
requirements should apply only from the SM onwards and any pre-SM information provided to
justify the SM definition should be exempt from these requirements.

Page 4 of 6
 APIC proposes that the submission of pre-SM information is handled as follows:
 The flow chart, including solvents, reagents and catalysts, showing the manufacture of the SM
may be provided if necessary.
 The definition of the SM is assessed only once therefore this pre-SM information is provided
with the initial submission only, as a stand-alone document ( i.e. separate from the dossier). It is
clearly marked as regulatory non-binding and it is understood and accepted that this
information will not be updated.
 During the lifecycle of the dossier, any change to the pre-SM information is assessed by the API
manufacturer.
 If the change to the pre-SM information impacts the dossier, i.e. if the SM specification or
subsequent control strategy has to change, a variation / change application is submitted in the
usual way to update the dossier.
 If the change to the pre-SM information does not impact the dossier, i.e. no change is required
to the SM specification and/or subsequent control strategy, no action is needed.

This avoids increased regulatory burden to both industry and health authorities by focusing only on
changes that potentially impact the final API.

6. Conclusion

APIC proposes a balanced approach to definition of the API SM, based on scientific knowledge and
risk management principles. Furthermore, a thoroughly documented and justified SM definition
should be acceptable globally as API manufacturers often supply their products for use in many
different drug products / markets.

In conclusion:
 A risk-based control strategy is key.
o The SM is not the only substance contributing to impurities in the API.
o The API is not the only substance contributing to impurities in the drug product.
 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.
 The provision of information on SM manufacture should not be a prerequisite.
 Post-approval change requirements should apply only from the SM onwards.

Page 5 of 6
7. References

Meeting minutes from the Working Group on API Starting Materials, EDQM, 21 June 2011.
Presentation by Dr Paul Marshall, MHRA, at 10th EGA Regulatory and Scientific Affairs Conference,
25-26 January 2010.
ICH Q11 Development and Manufacture of Drug Substances, Step 4, May 2012.
ICH Q7A GMP Guide for APIs, Step 4, November 2000.
Top Ten Deficiencies in New Applications for Certificates of Suitability (2011), PA/PH/CEP (12) 15,
June 2012.
Content of the Dossier for Chemical Purity and Microbiological Quality, PA/PH/CEP (04) 1 4R,
February 2007.
Guideline on the Chemistry of New Active Substances CPMP/QWP/130/96 Rev 1, December 2003.
Guidance on Frequent Changes to Applications for Certificates of Suitability, PA/PH/CEP (11) 76, July
2012.
Draft Guidance for Industry Initial Completeness Assessment for Type II API DMFs under GDUFA,
FDA, October 2012.
The API Starting Material and Other Materials in API Manufacture: Scientifically-Based Principles for
the Common Technical Dossier, Drug Information Journal, Vol 33, 755-761, 1999, Helga Möller and
Chris Oldenhof.

8. Abbreviations

ANADA Abbreviated New Animal Drug Application

ANDA Abbreviated New Drug Application
API Active Pharmaceutical Ingredient
APIC Active Pharmaceutical Ingredient Committee
ASMF Active Substance Master File
CEP Certificate of Suitability of the monograph of the European Pharmacopoeia
DMF Drug Master File
EDQM European Directorate for the Quality of Medicines
GMP Good Manufacturing Practice
ICH International Conference on Harmonisation
MAA Marketing Authorisation Application
NADA New Animal Drug Application
NDA New Drug Application
SM Starting Material

Version 1
16 January 2014

Page 6 of 6