The final version of ICH's drug substance development and manufacturing guideline Q11 is nearing Step 4 clearance by the regulatory agencies in the three ICH regions following some significant changes the Expert Working Group (EWG) has made to the Step 2 draft based on the comments received.
Over 1,300 individual comments came in from the three regions during the comment period that ended in September. After removing duplicates, the EWG had about 200 comments to evaluate during the Step 3 review. That work was completed in Seville, Spain, in November, and the EWG has agreed on the content of a "pre-Step 4" document that will now go to regulatory agencies in the ICH regions for approval.
At the APIC/CEFIC meeting in Munich, Germany in mid-November, Q11 rapporteur Brian Withers (Abbott, UK), reported on the results of the EWG discussions that took place in Seville. He pointed out that there were "a lot of supportive comments" among those received, as well as others that prompted the EWG to make some "major" changes to the Step two draft.
In his presentation in Munich, Withers discussed Q11's history and scope, the general public comments on the Step 2 document, and changes made as a result of the comments received.
Modifications were made in the sections of the guideline addressing: - manufacturing process development - manufacturing description - commercially available chemicals - starting materials and their submission - control strategy - process validation - CTD submissions, and - lifecycle management.
Five Years in the Making
The EWG did its initial work on the scope and content of Q11 in late 2006 through 2007, and a concept paper was approved by the ICH steering committee in 2008. Six meetings were held over the following three years resulting in a Step 2 document that was released for public comment in May 2011.
"It is very hard to make progress across three regions when you are not all in the same room and you only meet twice a year," the rapporteur commented.
Recognizing the importance of completing Q11 in a timely manner, the EWG released the Step 2 document with a short comment period - five months in the US and Europe, and only three months in Japan due to the time needed to translate the document.
The EWG, Withers explained, digested the comments and made amendments to the draft where it felt they were needed. "It is a question now of going back and getting that confirmed by the different regions," he said.
The EWG tried to look out over the next ten years to anticipate what may develop and incorporate those projections into the guideline. This foresight, the EWG member commented, was "particularly difficult" for biotech products, where regulator experience with enhanced approach applications is limited.
"These guidelines have to be future-proof," Withers emphasized. "It is no good writing a guideline and then trying to revise it, because it takes five years to revise."
The scope and general organization of the pre-Step four Q11 document did not change from the previous version.
The scope remains drug and biotech substances, with an emphasis on ICH Q6A, Q6B, and the Common Technical Document (CTD) sections 2.2 to 2.6.
Withers explained that the organization of the document follows the general business process for industry, beginning with process development and moving into lifecycle management. "It does not necessarily follow the structure of CTD," he noted, which has caused some challenges for the EWG.
The ICH rapporteur stressed the holistic nature of the guideline.
"You have to be careful to read this document as a whole," he cautioned. "If you think you can go in and just read the section on control strategy and you will be okay - you won't. You have to look at the document in a holistic manner, because there are elements that are important in the development section to the control strategy, and within the examples there are elements that are important. You have to take the time to read the whole document."
Changes Address Impurities and Their Detectability
The definition in Q11 for critical quality attributes (CQAs) remains the same as that found in Q8R, as do general statements about those attributes. Also unchanged is the application of the CQA approach to the drug substance but not to raw materials, starting materials or intermediates.
"Q11 does not specifically say that only the drug substance itself has CQAs, although there is a strong hint of that," Withers commented. He added that there is flexibility for a firm to label "something downstream from the drug substance" as the CQA.
A paragraph on the "formation, fate and purge" of impurities was moved from the design space
section into the general section on API manufacturing process development to clarify that it applies regardless of the development approach taken.
Comments on the Step 2 document indicated that including the impurities discussion in the design space section gave the impression that impurities were only important if an enhanced approach was followed and the firm was proposing a design space.
Also added was a section on inherent limitations in the detectability of a CQA in the drug substance itself. An example is provided relating to a biotech product where testing for a virus cannot be conducted on the drug substance. Included is a recommendation that virus levels should be controlled at some point upstream.
"The examples are an important element of this guideline," Withers explained. "They are relatively simple examples, but when you read them in the context of the guideline they do help to exemplify what is meant. The focus is about how that information is used."
Design Space Section Adjusted
The Abbott official explained that there were "lots of clarifying edits" around terms and language used in the Step 2 draft in response to comments received. "The expert working group understood it" he said, but from the comments received "it was clear" that other readers did not and that some changes were needed in the language.
The section on design space in the pre-Step 4 document "has changed considerably," including the location of the design space definition and guidance on movement within the design space.
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Source: This article is taken from the IPQ (International Pharmaceutical Quality Journal).
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