EU official says ICH Q6B is outdated and needs revision

Regulatory NewsRegulatory News | 01 December 2021 |  By 

The International Council for Harmonization’s (ICH) Q6B guideline setting acceptance criteria for new biological products needs to be revised to incorporate a more patient-centric approach and to include the science and risk-based concepts embodied in other ICH guidelines, according to a regulator from the EU.
Mats Welin, a senior expert for vaccines and monoclonal antibodies (MAbs) for the Swedish Medical Products Agency, made this assertion at the 30 November webinar sponsored by the International Society for Pharmaceutical Engineering (ISPE) on patient-centric specifications. He said that the current practice of setting specifications based on a limited number of batches is contrary to the concept of setting specifications tailored to patients.
He added that “industry needs to better address why their proposed limits can be considered clinically justified.”
In June, the ICH assembly agreed to adopt ICH Q6A and ICH Q6B as a new area for harmonization. (RELATED:  ICH reports “significant milestones” reached on guidelines ranging from impurity testing to eCTD standards, Regulatory Focus, 14 June 2021).
Clinically relevant specifications, according to FDA’s “One Quality Voice” approach to pharmaceutical quality oversight, are “a set of criteria and acceptance ranges to which drug products should conform in order to deliver the therapeutic benefit indicated on the label.”
Still a good guideline
ICH Q6B, which was adopted in September 1999, is “still a good guideline and its general principles still apply, at least in most cases,” said Welin. The guideline acknowledges that the specification is only part of the overall control strategy and should work with in-process controls, good manufacturing practices (GMPs), and raw materials testing.
Also, a “considerable part” of the guideline covers what attributes should be considered for setting final specifications.
Guideline has “mixed messages”
Yet the guideline has some “mixed messages.” For example, it states that “acceptance criteria should be established and justified based on data obtained from lots used in preclinical and/or clinical studies, data from lots used for demonstration of manufacturing consistency and data from stability studies, and relevant development data.”
The guideline also states that “specifications should be based on data obtained for lots used in pre-clinical and clinical studies. The quality of the material made at commercial scale should be representative of the lots used in preclinical and clinical studies.”
Welin said this is a “very tricky” provision and that it is “not always possible to combine” the last two statements. As a consequence, the current guideline promotes the setting of specifications with limited batch data available.
“Normally, few batches are used in clinical studies and their variability may not be sufficient to assign acceptance criteria which will be acceptable for routine testing without a risk of having multiple future OOS [out of specification results] and rejections,” added Welin. “Setting specifications based on statistical calculations of routine batch results will not by itself guarantee that the levels can be considered clinically meaningful.”
Welin added that “the common use of tolerance intervals applied on a few batches will result in wide limits, often far from what has been used clinically.”
A lot has happened since 1999
Welin asserted that since the guideline came out in 1999, “a lot has happened.” When it was written, “we had four or five antibodies and expression systems were not very effective and you needed a lot of batches for your clinical studies.”
Since then, there has been “incredible development of biotech molecules” including MAbs, other recombinant proteins, antibody drug conjugates (ADCs) and advanced therapy medicinal products (ATMPs) as well as “considerably better understanding of product characteristics.”
There are also more testing methods, such as liquid chromatography-mass spectrometry (LCMS) and deep sequencing. These methods “will find much more than was ever detected with traditional methods.”
Since the guidelines came out, other ICH guidelines such as ICH Q8- Q12 have been issued, which all reflect the more modern principles of process and product understanding, including the concept of criticality and the real-time release of products.
Welin suggested that the guideline incorporate the science and risk-based concept of the ICH Q8-Q12 guidelines, which, he said, “all have an impact on setting specifications.” Yet he said that while the guideline should be revisited and modernized, “a lot is still applicable.”
In revising ICH Q6B, he cautioned that the ICH working group should “avoid a too high-level a document which may result in considerable regional differences in interpretations.”
ISPE webinar on patient-centered specifications


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Tags: ADCs, EU, ICH, MAbs, Q6B

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