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ICH Q11 Guideline Structure and Content Taking Shape

The structure and content of ICH Q11 on drug substance development and manufacturing is taking shape as the Expert Working Group (EWG) resolves the challenging issues around the guideline’s breadth and depth and its relationship to the other guidelines in the ICH quality family.

Under the current structure emerging out of the EWG discussions at its June meeting in Tallinn, Estonia, the guideline will contain sections on: ● manufacturing process development ● description of the manufacturing process ● starting materials ● control strategy ● process validation/evaluation ● process lifecycle management, and ● location of information in the CTD.

Each of the sections includes discussion of the applicable principles, identification of molecule-specific information (small vs. large, etc.) that may be needed, and what information should be provided to the regulator in filings relevant to the section topic.

At DIA’s annual meeting in Washington, D.C. in mid-June, ICH Q11 rapporteur Brian Withers (Abbott U.K.) provided an update on the discussions at the Tallinn EWG meeting the week before and the current status of the guideline’s structure and content.

Withers stressed the general importance of Q11 “both from making some of the principles in Q8 real for biotech” and in extending them from development into manufacturing.

Q11 is intended to be a high-level guidance clarifying and harmonizing the regulatory expectations relevant to manufacture as well as design and development. “That is important,” Withers commented, “because Q8 did not get into the manufacturing” of the drug product, whereas with Q11, “we are moving into that area.  And that has its own set of issues.”

The scope of Q11 stretches across small and large molecule drug substances as defined in Q6A and Q6B, which has involved the EWG in identifying the similarities and differences and how they should be addressed from a guidance point of view, the rapporteur explained.

In developing a structure for the guideline, the EWG decided that Q11 would reach beyond “just telling people what to submit” under the M4Q/CTD format to addressing “enhanced and systematic approaches” and science-based concepts for process development, manufacturing and validation.

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Filing on Non-critical Parameters Among Issues for EWG

In his presentation, Withers went through each of the designated chapters of the evolving guideline, highlighting the issues that have generated the most discussion and how the EWG is proceeding to address them.

The discussion on manufacturing process development in the current draft closely reflects the principles and approaches outlined in Q8(R), with some interpretation in the drug substance context, he said.

Some language has been included on development tools, quality risk management and prior knowledge.  Platform manufacturing is addressed in particular, reflecting its relative importance in the biotech context.

The Q8(R) definition of critical quality attributes (CQAs) was considered broad enough to be easily applicable to drug substances and has been retained, and impurities are used to exemplify this application in view of their importance in drug substance development and manufacture.

The rapporteur reported that the current version contains a detailed section “relative to the rest of the guide” addressing the submission of process development information. It requests a summary to be provided to give the regulator an overview. The summary should list the CQAs that have been defined and brief descriptions of the stages of evolution of the process and control strategy, a linkage to the identification of material attributes and process parameters that have an impact on the CQAs, and the development of any design space.

Along with the listing of CQAs, the guideline will ask that more detail be provided on the rationale for identifying particular attributes as critical.  Regarding the manufacturing process history, the information of interest includes what versions there were during development and how those link to what went into clinical studies.

A subsection on manufacturing development studies in the draft gives information about what to provide on risk assessments – “the basis for your experimentation, what you were trying to achieve,” Withers explained. The associated data should be presented “at a level that the regulator comes to the same conclusion that you did from the studies.”

The section on the description of the manufacturing process is currently very short, Withers reported – basically cross-referencing M4Q on where the information goes in the CTD structure and discussing elements of the design space.

Generating EWG debate has been the issue of how to address non-critical parameters – an issue that drew considerable attention among participants at the Q8-10 implementation workshop in Tallinn (see IPQ “In the News” July 3).

Pointing out that whether to file information on non-critical parameters or put numerical ranges around them continued to generate considerable discussion at a DIA session earlier in the day on biotech QbD, Withers noted that at one stage the EWG had put a statement in the guideline saying that the range was all that was needed to be provided for critical process parameters. However, the concept was not generally accepted by regulators and was removed.

“There is still a sense that somewhere the different parameters should be treated in a different way,” he said, adding his view that “we have to think about ways of doing that in the guidance.”

The elements that the guideline will define regarding the control strategy represent the applicant’s commitment for controlling quality and include input material, attribute control, procedural control and the drug substance specification itself.

The EWG has made the distinction between a traditional and QbD control strategy, the rapporteur said. “There is a discussion on what needs to be done if you wish to move controls upstream in a process.  It allows for a combination of approaches. So it recognizes that not all molecules will be controlled in the same way in all places or for all unit operations.”

In addressing manufacturing and validation, the Q11 EWG has affirmed that it would be mindful of not creating redundancy to the ICH drug substance GMP guideline Q7 (IPQ, May 2010, p. 5), and the discussion of validation in the draft has been kept at a high level. It is only about a page and a half compared to FDA’s 25 page draft guideline on the subject, Withers pointed out.

The section is one where balancing the needs for small and large molecules comes into play, he explained.

Small molecules don’t need to submit any validation apart from sterile products at the time of submission. Large molecules need to submit validation information at the time of submission.” Also, “validation has a slightly different meaning in biotech in terms of what it includes.   So there are elements of, for example, column lifecycle, column cleaning… considered to be validation that are included within the submission, where small molecule is very much focused on demonstrating the ability to manufacture the product by the process.”

In terms of principles, Q11 will incorporate the Q7 definition of validation as “documented evidence that the process can perform effectively,” and will recognize both the traditional approach  and continuous process verification as defined in Q8. “We have tried to put some color on what that means for drug substance,” Withers said.

Some biotech-specific validation issues are addressed in the emerging draft.  These include laboratory studies to support the validation of column lifecycles and emphasis on the removal of impurities and reference to viral clearance studies.  Also addressed is the use of platform or prior knowledge vs. the product-specific validation information needed.  In the biotech context, the issue of pooling and splitting comes into play, Withers noted. “Actually it becomes very difficult to understand what a batch is from a validation point of view, so there is some clarity there.”

The Q11 rapporteur described the section on product lifecycle management as “a work in progress.  We are not quite sure what to include on this.”

Monitoring of process performance and its link to the elements in Q10 is among the issues being considered – also the internal evaluation of post-approval changes.

Pointing out that “there are different regulatory processes available in the different regions that can help and hinder this section,” Withers commented that “there is still a good deal of work to do in this section before we have a consensus view.”

In addressing the last section on the location of information, the EWG has focused on the submission of items not specifically covered by the existing M4Q guideline.

The EWG’s current thinking is to place:

● for CQAs – the list and rationale in S.2.6
● for design space – the description in S.2.2, the supporting studies in S.2.6, and the relationship to the overall control strategy in the S.4.5 as per Q8(R)
● and for the control strategy – the summary in S.4.5, the related details in S.2.2, 2.3 and 2.4, and the evolution of the strategy during development in S.2.6.

In reviewing the progress of the EWG on Q11, Withers stressed the importance of industry’s involvement during the current stage in the guideline’s development process.

He urged the industry DIA meeting participants to take the opportunity to provide input “early and often” on Q11 and other guidelines before a Step 2 draft is settled on. “Once the expert working groups have made their mind up, it is going to be very difficult to change that at a later stage.  And so the guideline is better if you comment earlier.”

The EWG rapporteur projects that the Q11 guideline will not reach Step 2 until sometime after the November ICH meeting in Japan.

[See IPQ’s “In the News” companion story for the EWG’s consideration of starting materials and where Q11 is heading on this particular issue].

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