The selection of a starting material for the synthesis of an active substance and its justification is often one of the most crucial steps in the approval process. Assessors at regulatory agencies of the EU member states have to evaluate whether the data provided sufficiently justify the selection. The criteria for this are outlined in the 2012 ICH Q11 guideline – however, not in a sufficiently precise manner. This resulted in questions and additional demands by the agencies, thereby delaying the approval processes. In order to establish a common understanding in regards to the information on starting materials in module 3 (section 3.2.S.2.2) for assessors as well as applicants, the ICH published the final version (step 4) of its Q&A document for ICH Q11 on 6 September of this year.
Since reaching Step 4 in 2012, worldwide experience with implementation of the ICH Q11 Guideline and its recommendations on the development and manufacture of drug substances has given rise to requests for clarification relating to the selection and justification of starting materials.
The Q11 Implementation Working Group (IWG), established by ICH in 2014, developed a Questions and Answers (Q&A) document which reached Step 2b of the ICH Process in November 2016. These Q&As are intended to provide additional clarification and to promote convergence on the considerations for the selection and justification of starting materials and on the information that should be provided in marketing authorisation applications and/or Master Files. The focus of the Q&A document is on chemical entity drug substances.
In total, the document contains 16 questions and their corresponding answers, all of which refer specifically to the guideline ICH Q11, chapter 5 “Selection of Starting Materials and Source Materials“.
Below is a selection of questions/answers related to particular aspects of it:
Question: Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?
Answer: Yes, the terms are synonymous. However, the regulations in ICH Q7 relate to the GMP compliant manufacture of active substances, not the procedure of selecting and justifying starting materials. This is covered by ICH Q11.
Question: What is the difference between a commercially available chemical and a custom synthesised chemical?
Answer: According to ICH Q11, a “commercially available substance” is one that is offered and sold as a commodity in the non-pharmaceutical market in addition to its use as a starting material. The term “custom synthesised” is not defined in ICH Q11; it is generally understood to be a substance which has been synthesised specifically for pharmaceutical manufacture and in consideration of a customers’ requirements. The distinction between these two terms plays an important role in ICH Q11 insofar as that an applicant does not have to justify the use of a “commercially available” substance as a starting material in the dossier – on the contrary to “custom synthesised” compounds; those are subject to the regulations of ICH Q11. The same goes for intermediates that do not count as “commercially available” according to ICH Q11.
Question: ICH Q11 recommends that “manufacturing steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process described in Section 3.2.S.2.2 of the application.” At what level would a related substance or mutagenic impurity be considered to impact the impurity profile of the drug substance?
Answer: For non-mutagenic impurities, the limits in ICH Q3A apply. When related substances are at a level that exceeds those limits, an impact on the impurity profile is to be expected. In that case, the dossier has to describe a control strategy and justify the choice of starting material. For mutagenic compounds, the 30% threshold as described in ICH M7 is authoritative.
Question: What is meant by impurities that “persist” in ICH Q11 Example 4?
Answer: This means impurities which are not purged over multiple synthesis steps and possibly remain in the final product (e.g. enantiomers). If a persisting impurity appears at some point during a synthetic route, it may be acceptable to control this impurity through the specification of the starting material, even if the impurity profile of the active substance is changed. In cases such as this, a detailed description of all synthesis steps in which these impurities are formed may be forgone in the dossier (section 3.2.S.2.2), provided that the general principles of ICH Q11, section 5.1.1 are being followed.
Changes to the process
Question: Can the Lifecycle Management section of ICH Q11 (Section 9) apply to starting materials?
Answer: Yes. Changes in earlier synthesis steps (upstream) must be made in accordance with the quality assurance system of the applicant. Residual risks in regards to the drug substance quality are to be assessed. The corresponding regulations of ICH Q7 and ICH Q7 Q&A document (Chap. 7 and 13, respectively), Q9 and Q10 (Chap. 2.7) must thereby be applied to starting materials as well.
Question: Does ICH Q11 include specific guidance for post-approval changes to steps upstream of the starting material (e.g. changes in synthetic route, reagents, solvents, starting material, supplier)?
Answer: No. ICH Q11, section 9 describes basic scientific and risk-based concepts for the evaluation of post-approval changes to the starting material. These concepts should logically be applied to steps upstream of the starting material as well.
The idea behind the differentiated description of the facts in this question/answer-format is to mostly eliminate ambiguities from the interpretation of ICH Q11. Together with the recently published updated EMA reflection paper on API starting materials, the applicants as well as the assessors are now provided with sufficiently detailed documents, which lay the foundations for a more harmonised interpretation of ICH Q11. It remains to be seen whether this will speed up approval processes.