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Biologics testing: The right time to move to new standards?

Biologics testing

Quality control (QC) testing is essential to ensure the efficacy and safety of therapeutic biologics. Even though state-of-the-art molecular methods are well established, laboratories still primarily rely on animal testing, using protocols developed in the 1970s. A recent guideline update encourages the biopharmaceutical industry to abandon the use of animals and move to new standards in biologics QC, including next-generation sequencing (NGS)-based assays.

Therapeutic biologics cover a wide range of modalities, including monoclonal antibodies, vaccines, recombinant proteins, viral vectors, and cell and gene therapies. Quality control procedures must be performed for every biologic and throughout the manufacturing process, from raw materials to intermediate and final products, to ensure patient safety and therapeutic efficacy. 

The biologics QC process covers three main areas. First, genetic identity (ID) testing confirms the identity of the active biologic. For example, it must be demonstrated that a therapeutic viral vector carries the correct sequence inserted in the proper position. Today, ID testing is mainly performed by PCR. 

Second, the potency of the biologic is evaluated using various methods specific to each therapeutic entity. Finally, all samples are tested for contamination with pathogens or other adventitious agents. This step is still primarily carried out by animal testing – injecting the sample into mice, rats, or hamsters and monitoring viral propagation.

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    What are the challenges with biologics testing?

    Despite the global agreement to minimize animal testing in drug development, as reflected in the 3R (replace, reduce, refine) principle and directives implemented in the EU and the US, animals are still widely used in biologics QC testing.

    Besides ethical issues, animal-based procedures are expensive and have long turnaround times of weeks or even months. In addition, not all human pathogens can replicate in rodents, limiting the bandwidth of the test portfolio.

    Last but not least, the inherent variability of animal cohorts prohibits validation. Strictly speaking, biologics safety testing has relied on an unvalidated method for the last 50 years. Still, the official regulations of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have recommended animal testing until 2023.

    Recently, PCR-based QC assays have been developed for safety testing; however, the need to add defined primers means that PCR fails to detect unknown viruses or new variants. In contrast to animal tests, PCR methods also cannot determine whether a virus is replicating, carrying a higher risk for patients.

    Are NGS assays suitable alternatives?

    The latest addition to the testing portfolio uses NGS-based assays. These assays have advantages in ID testing because they allow the determination of the entire sequence of a therapeutic, such as a recombinant viral vector or mRNA vaccine. 

    “NGS enables an accurate identity analysis, independent of, for example, the insertion site location, “ explained Sébastien Renouf, Chief Pharmaceutical Officer and Qualified Person at PathoQuest, a company dedicated to NGS-based assays for biologics QC.

    The unbiased nature of NGS-based assays also makes them valuable tools in safety testing. As the raw data cover all nucleic acid sequences present in the sample, both known and unknown pathogens can be detected. In addition, dedicated assays targeting the transcriptome can be applied to ensure that no virus is replicating in the sample.

    November 2023 marked a turning point in biologics QC when the ICH published the Q5A(R2) guideline update. For the first time, this guideline officially recommended methods based on NGS for safety testing.

    DSC4167 Jean Francois Brepson

    “The new ICH guideline is a milestone for biopharmaceutical companies developing or manufacturing therapeutic biologics. Having the option to move away from animal testing is a game-changer, not only for ethical reasons but also because of the shortcomings of current methods.”

    Jean-François Brepson, CEO at PathoQuest.

    Biologics safety testing: A case study

    In partnership with Charles River Laboratories, PathoQuest recently conducted the first head-to-head comparison of safety testing in animals with NGS methods for characterizing cell banks designed to produce monoclonal antibodies, recombinant proteins, and vaccines. 

    In a joint study published in Vaccine Journal, PathoQuest scientists inoculated nine virus-infected cell lines to assess the transcripts subsequently produced by the cells. PathoQuest’s proprietary NGS-based iDTECT® assays were shown to accelerate manufacturing timelines by several months compared to animal testing while demonstrating superior sensitivity and reliability. 

    “The assays were able to identify both known and unknown viruses and virus variants, including those that did not replicate in rodents and were, therefore, not detected in animal testing. The study clearly shows that our iDTECT® platform can overcome the challenges of biologics QC,” said Renouf.

    The study design and main data obtained were presented to the French National Agency for Drug and Health Product Safety (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and the Innovation Task Force of the European Medicine Agency (ITF EMA). Both organizations concluded that based on assay suitability and risk assessment, PathoQuest’s NGS assays could replace in vivo and in vitro tests for adventitious agents QC testing.

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    How can PathoQuest help you with your biologics quality testing needs?

    Current data demonstrate that the NGS technology is fit for purpose for biotech product development, easy to adopt and well recognized by regulatory bodies in Europe and the US. However, the implementation of NGS assays is still on a learning curve. 

    The scientific team at PathoQuest is aware of the potential issues associated with adopting innovation. To facilitate the move to new standards, the company has developed the iDTECT® platform, offering assays for viral safety and genetic characterization of biologics. iDTECT® assays are GMP compliant, fully validated, meet the requirements of leading regulatory authorities, and are suitable for Investigational New Drug (IND) and Biologics Licence Application (BLA) submissions.

    Typically, QC samples are sent to one of the sites in Wayne, PA, or Paris, France. The two GMP-validated laboratories are set up as mirrors, using identical procedures for nucleic acid isolation and NGS procedures. Clients can use the site closest to them or both in the case of multinational companies. The data obtained are analyzed using proprietary, validated tools to deliver unambiguous results.

     As an end-to-end service, study reports are regularly shared in a certificate of analysis format. For viral safety analyses, virologist NGS experts additionally provide virology reports. Clients can download actionable reports and certificates of analysis from an easily accessible on-premise data center or a digital cloud with unlimited data capacity. 

    “Our tools co-evolve with the complexity of products tested. Depending on the needs of our clients, we can flexibly adapt and customize QC assays. We also provide support in discussions with regulatory authorities, ensuring a smooth implementation of new standards,” Brepson stated.

    With the publication of the updated ICH guideline, the days of animal testing in biologics QC are finally over, opening the door to alternative methods such as the iDTECT® platform.

    CTA: Learn more about how your biologics QC can benefit from the iDTECT® assay platform

    Images Courtesy: PathoQuest

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