Aloka Srinivasan, Ph.D.Vice President, Regulatory Affairs

May 24, 2017

API – Selection of Starting Materials –Impact on First Cycle Approval

Presented by

Trends in Selection of Regulatory Starting Materials for API Manufacturing Process

• Questions related to choice of Regulatory Starting Materials (RSM) for Active Pharmaceutical Ingredients (APIs) has persisted for over a decade from FDA as well as other regulatory agencies in the world

• FDA has been requesting the industry to define the RSM more upstream in the API manufacturing process

• There is a tendency in the industry to shift the RSM more and more downstream, towards the API. 

• The inappropriate selection of RSM or lack of adequate information regarding the RSM has been and in GDUFA II, could be a major road block to first cycle approval of ANDAs

Some Highlights of the Regulatory Guidelines for API Starting Materials

ICH Q7 defined an API starting material as follows:

Drawbacks with this definition

• This definition of API starting material does not talk about multiple synthetically relevant steps that should separate the starting material and the final API, purging of impurities.

• 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 for being a Regulatory/Key Starting Material.

“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.”

Some Highlights of the Regulatory Guidelines for API Starting Materials

ICH Q11, Development And Manufacture Of Drug Substances (Chemical Entities And Biotechnological/Biological Entities) and ICH Q11 Questions and Answers

• ICH Q11 provides detailed discussion on the desirable Regulatory Starting Material (RSM)• Section 5.1 and 5.2 of ICH Q11 talks about the Selection of Starting Materials and Source

Materials for APIs.• ICH Q11 Q&A provides clarifications regarding some of the statements in ICH Q11

In spite of the clarifications in ICH Q11 Q&A guidance, the definition of what constitutes an appropriate “Regulatory Starting Material” in the API 

manufacturing process has still remained subjective.

Trying to fit the science of RSM selection into regulation is like hammering a “square peg in a round hole”

Some Highlights of the Regulatory Guidelines for API Starting Materials

Selected information in ICH Q11 and ICH Q11 Q&A regarding starting materials can be summarized as follows:

For API manufacturing process, cGMP applies from starting material onwards, based on ICH Q7

Starting Material should be a substance of defined chemical properties and structure – not a non-isolated intermediate.

Starting material should contain a significant structural fragment of the API – differentiates it from common agents for esterification, salt formation etc. Also, precludes defining starting materials very early in the synthetic process.

For a custom synthesized starting material appropriate controls (specification, method of synthesis, impurities, reagents, catalysts) should be provided in the dossier. Also, the Pharmaceutical Quality System of the API manufacturer should address the residual risk associated with future changes in the starting material – quality and process.

Some Highlights of the Regulatory Guidelines for API Starting Materials

Selected information in ICH Q11 and ICH Q11 Q&A regarding starting materials continued:

Commercially available chemicals, with pre-existing, non-pharmaceutical market need not be justified as starting material. However, if the starting material is custom made for the specific API, no matter how many sources are there, it will be considered custom synthesized and need justification.

Enough of API manufacturing process must be disclosed in the dossier so that the impurity fate/purge can be understood. API manufacturing process should include a few steps upstream from those which affect the impurity profile.

Manufacturing steps which impact the impurity profile of the API should be part of the process description. For a non-mutagenic impurities, if it is present in the API at a level above the ICH Q3A Identification Threshold, it is believed to have an impact on the impurity profile of the API. For a mutagenic impurity, if it is present at 30% of the ICH M7 acceptable intake in the final API, it is considered to have an impact on API quality.

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. If there is an impurity that persists from the starting material manufacturing process, it should be controlled adequately in the RSM and also fate/purge studies should be done to justify how it is controlled in the API.

An Example: Selecting the Appropriate RSM

• The following example is not part of any NDA/ANDA/DMF but adapted from the article in Journal of Organic Chemistry, “Total Synthesis of (+)-Lysergic Acid1

• The purpose of this example of multistep synthesis is to discuss the subjective nature of the process of selection of appropriate regulatory starting materials

Reference:1. Liu Quiang et. al., J.Org.Chem, 2013, 78, 10885-10893

An Example: Selecting the Appropriate RSM

(+) Lysergic Acid

Observations form the example

•However, FDA reviewer may not be agreeable considering the fact that there are too few steps to purge the impurities from Intermediate 5 and thus conversion of 5‐>6 is preferably done under very controlled conditions.

•Conversion of 3‐> 4 will generate significant amount HCN and cyanide and thus has an impact on the impurity profile. Based on ICH Q11 Q&A, Intermediate 1, which a few steps upstream from Intermediate 3 theoretically fits the ICH Q11 definition of RSM.

• Intermediates 1‐5, all  of which have similar backbones, can be designated as a RSM based on the based on the sponsor’s process controls and reviewer’s prerogative

• Intermediate 6 has the true significant structural fragment of the fused ring system 

of Lysergic Acid, but is too close to the final API to be the RSM

• Industry may prefer to have Intermediate 6 as the RSM as the conversion of Intermediate 5 ‐> 6 uses an expensive palladium catalyst and also has very low yield. Intermediate 5 may need significant purification.

Challenges to Industry and FDA related to choice of RSM

Challenges to industry if different sponsors are approved with different RSMs

• The variation in the cost of manufacturing of the API based on designated RSM may cause serious competitive disadvantage

• Increased load related to life cycle management, as most changes in the process downstream from RSM need to be reported to the FDA in supplements

• The increase in the number of cGMP steps have a potential to increase the cost of the process

Challenges to FDA related to choice of RSM

• For the same API and a comparable process of manufacturing, different RSM for different sponsors may cause inconsistencies in the review process and time needed to approve applications

• Requesting that an upstream intermediate, manufactured at an outsourced facility, as an RSM makes the tracking of quality very difficult (this can lead to significant increase in cGMP related workload)

• Increased post approval review load as the changes downstream from RSM will need to be submitted as amendments to DMFs and supplemental applications to the ANDAs in many cases.

For FDA: Some points to consider related to selection of regulatory starting material:

•Develop a pathway for providing advice related to the proposed RSM, pre‐submission of the dossier (DMF or ANDA) though a formal meeting request or controlled correspondence

•The DMF Webpage or a relevant guidance could have the information on how a meeting request/cc can be submitted and the key information needed from the sponsor regarding the RSM selection that can help FDA make a decision

•Provide response to the sponsor within a given time (30‐60 days)

•For the same process of manufacturing an API, attempt to assure consistency in the proposed RSM from sponsor to sponsor

•When requesting that the RSM is redefined upstream, clearly indicate the level of cGMP compliance that is being proposed:

•Is there going to be a FDA inspection of the manufacturer/s of the RSM?

•Is it adequate if the sufficient information regarding the RSM manufacturer is available to the inspector at the API manufacturing site?

For Industry: Some points to consider for selection of regulatory starting material:

•Avoid declaring a crude API, racemate of an optically active API, a salt or free base/acid of the API, an ester of a free acid or alcohol as the RSM; FDA will push back on such choices

•Review the vendor’s manufacturing process and find out the risks associated with impurities, potentially genotoxic intermediates, reagents etc. and include controls of these in the starting material: a well controlled RSM has a greater chance of acceptance. 

•Perform appropriate fate/purge studies to justify the starting material: this can be critical in demonstrating the low risk in your RSM selection

•Know the supplier of the Starting Material and evaluate if they will pass an FDA inspection, if requested by the review division.

Thank You

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