Draft ICH Q11 Q&A Guidance Would Clarify Starting Materials Selection

ICH regulatory members have agreed to request comment on draft Q11 Q&A guidance that is meant to clear up ambiguities on starting materials selection that have fueled debate between industry and regulators for years. The guidance also clarifies the difference between custom-manufactured and commercially available chemicals.

The regulatory members of the International Council on Harmonization have endorsed additional Q11 guidance that answers some questions on when industry must begin applying good manufacturing practice controls to active pharmaceutical ingredient manufacturing processes.

The US, the EU, Japan and other regulatory members will seek comment on the draft Q11 Q&A guidance in their respective regions using their respective notice-and-comment processes for regulatory guidance.

The guidance focuses mainly on how much information is enough for justifying selection of API starting materials, which is the point where GMP controls start to apply. It also clarifies the differences between custom-manufactured and commercially produced chemicals. Yet it stops short of specifying the number of manufacturing process steps it should take for a starting material to become an API.

The ICH regulatory members reached agreement Nov. 9 during an ICH meeting in Osaka, Japan, and the council posted the draft guidance documentonline Nov. 30.

ICH said that the guidance aims to clear up the current ambiguities associated with starting materials selection. The document says that “since ICH Q11 was finalized, worldwide experience with implementation of the recommendations on the development and manufacture of drug substance has given rise to requests for clarification relating to the selection and justification of starting materials.”

The document further states that API starting materials that have already been accepted by regulatory authorities would not need to be re-justified against ICH Q11 “unless significant changes are made to the manufacturing process and controls.”

Confusion over starting materials prompted the European Medicines Agency in October 2014 to publish a reflection paper to clarify the expectations of EU competent authorities arising from the ICH Q11 guidance. (Also see "Disagreement over how to justify starting materials selection prompts EMA action" - Pink Sheet, 16 Oct, 2014.)

How Much Information Is Enough?

The Q&A guidance was expected to answer the “how much information is enough” question, said Pfizer Global CMC Research Fellow Tim Watson at an industry meeting earlier this year. (Also see "Upcoming ICH Q11 Guide To Clarify What Constitutes Starting Materials" - Pink Sheet, 10 Jul, 2016.) Watson is serving as the industry rapporteur for the ICH Q11 Implementation Working Group (IWG).

ICH Q11 was vague in terms of what regulators expect to see in submissions to justify the selection of starting materials. The ICH Q11 guidance said that “regulatory authorities assess whether the controls on the drug substance and drug substance manufacturing process can be considered adequate, including whether there are appropriate controls for impurities. To conduct this assessment, enough of the drug substance manufacturing process should be described in the application.” Yet the ICH Q11 guidance did not address how much information was enough to support starting materials selection.

The Q&A said that in deciding whether enough of the drug substance manufacturing process is described in Section 3.2.S.2.2 of the Common Technical Document, or CTD, manufacturers should include the following information in submissions:

• The applicant should evaluate which chemical transformation steps in the manufacturing process impact the impurity profile of the drug substance.
• Then the applicant should examine the steps immediately upstream of those steps that impact the impurity profile of the drug substance. These can include a unit operation that has been added to the manufacturing process to control specific impurities. The guidance points out that “adding multiple purification steps prior to a proposed starting material would not be considered appropriate to support its justification.”
• After these two considerations if the evaluation results in only a small number of chemical transformation steps, then it is appropriate to include one or more additional transformation steps. The guidance states that “this is to ensure that enough steps are conducted under GMP and to mitigate risks associated with contamination and future changes to the synthetic route or supplier of the starting material.”

How Many Steps Are Enough?

Yet as expected, the guidance does not prescribe the number of steps for justifying starting materials. Watson said at the meeting that the ICH implementation team did not want to specify a certain number of steps as it would distract from the science of selecting starting materials. For example, he said that the number of synthesis steps needed for a robust process is different than the number of steps required for a less robust one.

The guidance states that “although ICH Q11 does not specify how many steps should be performed under GMP, ICH Q11 recommends the inclusion of ‘multiple chemical transformation steps’ in Section 3.2.S.2.2 in order to reduce the risk of contamination and support the effective implementation of the control strategy throughout the product lifecycle.”

What Constitutes Custom API?

The guidance also distinguishes between starting materials that are commercially available and those that are custom made. ICH Q11 did not define custom synthesized chemicals but it did define commercially available chemicals. Under ICH Q11 manufacturers do not have to define the synthetic steps for commercially made materials yet if a chemical is derived from a custom synthesis its use as a starting material should be justified.

There have been situations where manufacturers develop APIs in-house as a custom chemical, qualify three or four vendors to make the substance and then say it’s commercially available so they don’t have to document the synthesis steps to regulators.

The guidance said that “the availability of a chemical from multiple suppliers should not be the sole basis for the designation of a chemical as a commercially available starting material. This includes situations where a custom synthesized chemical has become available over time from multiple suppliers. Such chemicals should still be justified according to the ICH Q11 general principles for selection of starting materials.”

The Q&A also links the principles of lifecycle management of ICH Q11 into lifecycle management of starting materials. The guidance stated that “the lifecycle management section of ICH Q11 reinforces management’s responsibility described in ICH Q10, which is applicable to starting material lifecycle management.”

From the editors of Gold Sheet.