ICH Q11 Q and A Document

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ICH Q11   Q and A Document

The topic of starting materials has been a vexed topic for some period. Indeed concerns relating to lack of clarity and issues pertaining to practical implementation led the EMA in Sept 2014 to publish a reflection paper—Reflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.(10) The paper sought to outline key issues as well as authority expectations; specific areas of interest identified included the following:


Variance in interpretation between applicant and reviewer.


The registration of short syntheses that employ complex custom-made starting materials.


Lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy.

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While the consensus was that overall this provided a useful perspective of at least the EMA’s interpretation of ICH Q11(2) and requirements for starting material selection, further discussion was required to address this subject to the satisfaction of both industry and regulators.
In November 2016 ICH released a Q&A document pertaining to ICH Q11, the purpose of which is to clarify the expectations regarding the selection and justification of starting materials for drug substance manufacture. This has reached Step 2,(11) a consensus document released for public comment, the deadline being March 2017.
The document comprises a series of sections, beginning with an introduction. This makes clear that the focus of the Q&A document is on chemical entity drug substances, excluding Biologics at least in the sense of definition of starting materials.
Another important proposal made within the introduction is that API starting materials that have already been accepted by regulatory authorities (e.g., for use in authorized medicinal products) would not need to be rejustified against the ICH Q11 general principles or the recommendations included in this Q&A document, unless significant changes are made to the manufacturing processes and controls.
This is important as a concern may have been that criteria defined in the document would be retrospectively applied. It is though caviated, stating that a starting material accepted for one manufacturer’s process may not be considered acceptable for a different manufacturer’s process.
It also states that designation of starting materials should be based on process knowledge for the intended commercial process. It emphasizes that all of the general principles in ICH Q11 Section 5 should always be considered holistically, together with the clarifications in this Q&A document, rather than applying a single general principle or Q&A clarification in isolation. This was a thread central to the argumentation within the earlier EMA guideline.

The questions and answers are aligned to specific sections within the guideline, although all questions are focused specifically on Section 5—Selection of starting material and source material. There are 16 questions in total covering the following aspects:

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Significant Structural Fragment: how should this be interpreted


Impact on Impurity profile of final product: this relates to the guidance within Q11 to include all stages that impact on impurity profile of the drug substance. This seeks to clarify what level would be defined as impactful.


Clarification of persistence


How an applicant should determine which steps impact the profile of mutagenic impurities in the drug substance.


Do all steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included in the process description?


Clarification of the stated need to describe “enough” of the drug substance manufacturing


Should all the ICH Q11 general principles be considered and met in selecting starting materials?


Application of Q11 principles to telescoped processes


Application of Q11 to linear and convergent syntheses


Starting material specifications: key attributes


Noncommercial starting materials


Differences: Commercially available vs Custom Synthesis


Requirements for justification of commercial availability


Scope: postapproval change–preregistered starting materials


Life cycle management


Starting material Q11 vs Q7 definition: clarification that this is effectively the same

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It is beyond the scope of this review to examine the specific text associated with all 16 questions. In general though the position articulated throughout is pragmatic and also, in general, answers are clear and relatively concise.

Key points of note include

  • “Significant structural fragment”: the document highlights the frequent misconception that this means that a proposed starting material should be structurally similar to the drug substance. It makes clear that in fact the intent is simply to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do.

  • Questions 5.2, 5.4, and 5.5 relate to mutagenic impurities. The answers provided should be useful in assisting an applicant in applying the risk based approach defined within ICH M7.(5)Prior to this there was a general misconception that a step that involved a mutagenic impurity needed to be part of the registered process. Such an assertion took no account of the highly reactive nature of such impurities and their propensity to be effectively purged.(12) The answer to question 5.2 makes clear the framework for defining the impact of an MI on the quality of the final drug substance, aligning this directly to M7 and the adoption of the widely applied 30% of the limit principle, i.e. prove levels in the final active drug substance are below 30% of the acceptable limit. The answer to question 5.4. provides a commentary of the actual practical steps involved in assessing the impact of an MI. Importantly within this it contextualizes the actual risk posed by low level MIs with the following important statement

    • “Such mutagenic impurities and by-products are usually present at much lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents, or intermediates from the same steps.”

In essence, provided any MI associated with a starting material is demonstrably controlled it is not necessary to register stages that simply employ the use of mutagenic reagents.

  • Another important point addressed within the document is ‘persistency.’ It seeks to make clear that even where an impurity associated with a starting material does impact on the quality of the drug substance that control can be defined at the stage of the starting material. A classic example would be a stereoisomer. General downstream processing would have little impact on levels. In many cases this has led to a view that the step where such an impurity might arise must form part of the registered process, i.e. the stage of introduction of chirality. This now makes clear that, provided this is effectively controlled within the starting material, registration of earlier stages is not required.

Again, the key concerns raised by the EMA reflection paper(10) are reflected on, i.e. registration of short syntheses that employ complex custom-made starting materials and a lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy. Arguably in that context the answer provided to question 5.6 is the most critical in the Q&A document.
Question 5.6 ICH Q11 states that “enough of the drug substance manufacturing process should be described in the application···” What considerations should an applicant apply in the selection of the proposed starting materials to ensure that enough of the drugs substance manufacturing process will be described in the process description in Section 3.2.S.2.2 of the application?

The response highlights several key aspects

Of primary importance is that the applicant must first evaluate which chemical transformation steps in the manufacturing process impact the impurity profile of the drug substance. With the clarification now provided in respect to MIs and “persistency” this should be more straightforward than previously was the case.

Another key point made is the need for an applicant to examine steps immediately upstream of those identified as critical and within those upstream to consider if:

  • They include a unit operation that has been added to the manufacturing process to control specific impurities that would otherwise impact the impurity profile of the drug substance.

The key point made here is that you cannot simply add multiple purification steps prior to a proposed starting material.

  • Tight control (e.g., within narrow parameter ranges) is required to prevent generation of impurities that would otherwise impact the impurity profile of the drug substance.

If either are the case then these should be included within the registered synthesis.

Perhaps the most contentious aspect of the response though is the caveat that if having conducted the assessment described and if based on this the result is that only a small number of chemical transformation steps need to be registered, the Q&A document articulates a need to include one or more additional steps. The reasons stated for this needing to be considered are

  • Due to the risk of contamination arising from a late starting material and the impact this would have on drug substance quality and

  • The risk of changes made to the route/process for the starting material impacting again on drug substance quality.

Many organizations will I’m sure challenge this, as it seems to suggest little or no control around quality of starting materials; in reality that is far from the case.
Ultimately does the response to this question and the overall document adequately address regulatory concerns, in particular those outlined EMA? Only time will tell, but overall this is a welcome development.
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  1. 1.Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities EMA/CHMP/ CVMP/ SWP/169430/ 2012,http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf.

  2. 2.ICH Q11 – Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)Q11http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf.

  3. 3.TeasdaleA.Regulatory Highlights Org. Process Res. Dev. 201519 ( 4494– 498DOI: 10.1021/acs.oprd.5b00085

  4. 5.Assessment and Control of Dna Reactive (Mutagenic)Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1) March 2017,http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_Step_4_31Mar2017.pdf.

  5. 8.HarveyJ.TeasdaleA.FleetwoodA.Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development Regul. Toxicol. Pharmacol. 201784116– 123,DOI: 10.1016/j.yrtph.2016.12.011

  6. 9.Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/ 2012) .http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf.

  7. 10.Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substanceshttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500175228.pdf.

  8. 11.ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) – questions and answershttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Q_A_Step_2.pdf.

  9. 12.TeasdaleA.Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate Control Org. Process Res. Dev. 201317221– 230DOI: 10.1021/op300268u

  10. 13.EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Usehttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/chapter_5.pdf.

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