ICH Q5a R1 vs R2: Revised guideline on Viral safety evaluation on biotechnology-derived products from Cell lines of Human or Animal origin

Introduction:

In this blog, we will explore the ICH Q5a R1 vs R2: (revised guideline on viral safety evaluation evaluation on biotechnology-derived products from cell Lines of human or animal origin.

The International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use is an organization dedicated to fostering global alignment in creating and endorsing safe, efficient, and high-caliber medicines. By uniting regulatory bodies and industry specialists from Europe, Japan, and the United States, it aims to streamline the global development process for new medicines, minimizing unnecessary delays and resource expenditure. ICH formulates guidelines and technical standards about medicine development, approval, and safety surveillance, which regulatory bodies adopt. The European Medicines Agency (EMA) plays a pivotal role in facilitating the European Commission’s involvement in ICH and enforcing ICH guidelines within the European Union. While ICH guidelines are not legally binding, regulatory bodies enforce them through national and regional governance mechanisms.

Q5 A Guidelines:

The latest iteration of the guideline was labeled as “ICH Q5A(R2) on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin.” It introduced several enhancements and advancements. It now encompasses products generated through in vitro cell culture utilizing recombinant DNA technologies. Products, such as interferons, monoclonal antibodies, and recombinant subunit vaccines. Additionally, it addresses products derived from hybridoma cells cultivated in vivo as ascites, specific genetically engineered viral vectors, and products derived from viral vectors. A notable update in the latest version involves guidance on utilizing next-generation sequencing (NGS) to replace in vivo assays, aligning with the European 3R strategy. Furthermore, this version provides specific guidance on genetically engineered viral vectors, viral vector-derived products, and inactivated and live attenuated viral vaccines containing self-replicating agents.

NGS is a contemporary parallel technology. It enabls DNA splicing to detect mutations or variations, typically within 100 to 300 base pairs. DNA fragmentation is achieved through mechanical means, enzymatic digestion, sonication, and other methodologies.

The ICH Q5A guidelines establish various standards for testing and analyzing viral and microorganism contaminations in diverse biological products at various biotechnology medical product production stages. The guideline’s scope now encompasses in vitro products like interferons, monoclonal antibodies, and recombinant DNA products from hybridoma cells grown in vivo as ascites.

Three Primary Control Guidelines:

This document outlines three primary control outlines:

• Selecting and testing the raw cell lines derived from biotechnological sources can end up being pathogenic to Humans and dangerous too.
• Assessing the production capacity of the process to clear infectious viruses.
• Testing the product at appropriate production steps for the absence of contamination of the infectious viruses..

What are the highlights of the guideline:

The guidelines suggest the following updates:

1. Stability Testing

The guidelines suggest conducting stability tests in varying environmental conditions to gauge the product’s stability. Conditions, such as temperature, humidity, and light exposure. These tests should be conducted regularly. Also, the data obtained should be utilized to determine a retest period or shelf life. Furthermore, the guidelines propose conducting these tests on at least three product batches and statistically analyzing the data to establish a confidence interval for the retest period or shelf life.

2. Viral Safety Evaluation

The previous iteration of the guideline was known as “ICH Q5A (R1) Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.” It has been in effect since 1997. This version primarily focuses on assessing the viral safety of biotechnological products. Particularly those derived from characterized human or animal cell lines.

3. New sections and new product types

A significant update in ICH Q5A R2 includes adding new sections reflecting advancements in scientific knowledge and covering new product types susceptible to viral clearance. These encompass products derived from viral vectors, both with and without helper viruses, and virus-like particles (VLPs) and protein subunits produced using baculovirus, herpes simplex virus, or adenovirus production systems. Moreover, ICH Q5A R2 introduces considerations for continuous manufacturing and utilizing prior knowledge (PrK) for modular validation and resin-reuse studies. It discusses novel molecular analytical techniques, notably next-generation sequencing (NGS). The main purpose was minimizing the necessity for product-specific validation efforts and offering flexibility in testing established rodent cell substrates.

4. Viral Safety Controls for Viral-Vector Platforms

For products manufactured utilizing viral-vector platforms, the revised ICH Q5A R2 advocates a risk-based approach to ensuring viral safety.  This approach addresses raw material sourcing, viral testing options at appropriate manufacturing stages, and removal/inactivation of adventitious and helper viruses during downstream processing. The updated guideline also acknowledges the technical differences in viral safety control between continuous manufacturing (CM) and batch processing. This emphasizes the need to design viral safety controls considering system dynamics, monitoring frequency, and system start-up and shutdown procedures.

Conclusions:

In summary, the latest version of the ICH Q5A guidelines incorporates numerous updates and innovations. These updates reflect progress in the biotechnology sector and viral safety assessment. It offers detailed guidance on testing and evaluating viral safety for a broader range of biotechnology products. The range of these products include those employing recombinant DNA technologies and genetically engineered viral vectors. Notable sources of contamination include viruses that may arise in the Master cell bank and adventitious viruses generated during product production.

ICH References:

• Committee for Medicinal Products for Human Use ICH Q5A(R2) Guideline on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin Step 5. (2023). https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q5ar2-guideline-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin-step-5_en.pdf
• ICH Topic Q 5 A (R1) Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Step 5 NOTE FOR GUIDANCE ON QUALITY OF BIOTECHNOLOGICAL PRODUCTS: VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN. (1997). https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r1-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin-step-5-first-version_en.pdf
• International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Step 2 document -to be released for comment. (2022b). https://database.ich.org/sites/default/files/ICH%20Q5A%28R2%29_Step2_Presentation_2022_1005.pdf
• ICH Q5 A (R1) Revision: Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin – ECA Academy. https://www.gmp-compliance.org/gmp-news/ich-q5-a-r1-revision-viral-safety-evaluation-of-biotechnology-products-derived-from-cell-lines-of-human-or-animal-origin
• Viral Safety With ICH Q5A Revision 2 – BioProcess International. https://bioprocessintl.com/downstream-processing/viral-clearance/viral-safety-for-biotechnology-products-including-viral-vectors-ich-q5a-revision-2-brings-updated-and-more-comprehensive-guidance/

General References:

• Qin, D. (2019). Next-generation sequencing and its clinical application. Cancer Biology and Medicine, 16(1), 4–10. https://doi.org/10.20892/j.issn.2095-3941.2018.0055
• Pharmaceutical Regulatory Round-up November 2022 I RSSL. https://www.rssl.com/insights/life-science-pharmaceuticals/november-regulatory-update/

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