Pharma groups say ICH guideline on viral safety evaluation needs to incorporate continuous manufacturing

Regulatory NewsRegulatory News | 19 January 2023 |  By 

US pharmaceutical industry groups endorsed the major principles of the International Council for Harmonization’s (ICH) Q5A(R2) guideline on viral safety of biotechnology products but said it could be improved by incorporating continuous manufacturing principles and clarifying materials testing recommendations.
These comments were made in response to FDA’s release of the Q5A(R2) guideline for public comment in November 2022. The deadline for comments was 13 January.
The guideline sets harmonized scientific and technical requirements for evaluating the viral safety of biotechnology products. The document also encourages sponsors to use alternative tests, such as Next Generation Sequencing (NGS) and Polymerase Chain Reaction (PCR) which aligns with global initiatives and reduces the reliance on animal tests.
ICH released the Step 2 version of the Q5A(R2) guideline for public consultation in October 2022. (RELATED: ICH advances guidelines on selective reporting of safety data, viral safety, Regulatory Focus 11 October 2022)
FDA received six comments on the guideline, including submissions from the Pharmaceutical Research and Manufacturers of America (PhRMA), the Biotechnology Innovation Organization (BIO) and the Alliance for Regenerative Medicines (ARM).
BIO, PhRMA endorse guideline
Two large industry groups, PhRMA and BIO, expressed their overall support for the guideline. BIO said the document will “assist sponsors in designing and implementing a comprehensive program to test and evaluate the viral safety of biotechnology products. In particular, several changes to the guideline may reduce testing time and facilitate real-time decision-making.”
BIO said it supports the inclusion of NGS and other methods for detecting viruses in cell banks.
“The use of these molecular methods as replacements or supplements to existing tests represents a positive step towards reducing the use of animal-based testing and advancing new technologies with greater sensitivity … BIO appreciates the inclusion of NGS as this new method has been discussed in recent years and offers great benefit for testing time, especially for early-stage programs which require fast speed to first-in-human (FIH) studies. It facilitates real-time decision-making for virus test for unprocessed bulk or purified bulk as well,” the group wrote.
PhRMA echoed these sentiments, and stated that “the aggregation of definitions and viral safety testing guidance is critical to helping to bridge differences between compendia and documents of ICH member regulatory agencies.”
PhRMA, ARM want better alignment with ICH Q13
Yet PhRMA said the guideline could benefit from greater clarity on “several key concepts,” including better alignment with Q13 principles on continuous manufacturing.
“PhRMA recommends that the Q5A(R2) guideline ensure alignment with ICH Q13 concepts to further promote development, implementation, operation, and lifecycle management of continuous manufacturing (CM). We acknowledge that all principles used to ensure safety in batch manufacturing are also applicable to CM, but also want to highlight the aspects unique to CM, such as extended cell culture duration and continuous processing of harvested cell culture material to obtain drug substances. Viral safety testing and evaluation approaches should incorporate these unique aspects, and generally should be aligned with the CM paradigm,” PhRMA wrote.
ARM also recommended the guideline add more references to Q13 guideline, especially in the introduction.
Groups want more clarity on validation, tests for cell banks
ARM also requested more information on validating NGS methods. The group states that “no specific guidance on how to validate an NGS method is found” within the guideline. The group adds that “examples of suitable standards or reference materials for non-specific virus testing are missing.”
The guideline states that “for any NGS method used, a validation package should be provided to support its use for the application. This includes the method validation and assay or matrix-specific qualification, as suitable.”
PhRMA also wants more clarity regarding which tests are required or may be omitted for testing viruses in working cell banks (WCBs) and master cell banks (MCBs). The guideline’s Table 1 lists some of the recommended tests for these cell banks but does not specify which ones are recommended for each type of cell bank.
PHRMA: wants flexibility on viral clearance studies
PhRMA also suggests more flexibility on the number of viral clearance studies that should be conducted by sponsors.
The guidance suggests that “an effective virus removal step generally gives reproducible reduction of virus load in the order of 4 logs or more shown by at least two independent studies.”
PhRMA commented that “four logs may not be possible for a given step, particularly for non-enveloped viruses, which are generally more difficult to remove, and the requirements of four logs seems arbitrary.”
BIO wants reduced testing recommendations
In their comments, BIO suggested that the guidance should include more detail on testing materials for viral contaminants.
The group wrote that “additional detail should be provided on how to approach the testing of cell culture media components and raw materials for adventitious virus, as it is impractical to test every raw material and cell culture component. Instead, it would be useful if the guidance were more specific regarding how to apply risk assessments or other tools to determine which subset of components and raw materials should be tested.”
The draft guidance states that three principal and complementary approaches have evolved to control the potential viral contamination of biotechnology products: testing cell lines and other raw materials; assessing the capacity of the production processes to clear infectious viruses; and testing the product at appropriate steps of production for the absence of contaminating infectious viruses.
ICH comments


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