New China CDE guidance on platform validation of viral clearance aligns with FDA and EMA

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

In January, China’s Center for Drug Evaluation (CDE) within the National Medical Products Administration (NMPA) issued the new "Guideline on Platform Validation of Viral Clearance in Clinical Trial Applications of Recombinant Proteins (Trial)" (No. 2, 2024).¹ This follows the associated ICH guideline, with China-specific considerations which are outlined in this blog. 

Control of potential viral contamination is a key component of ensuring safety during the development and manufacture of biologics, including monoclonal antibodies and other biopharmaceuticals. It also affects development time and associated costs during development. Viral safety and in particular the capacity of the production process to clear viruses is a key focus issue and a common deficiency issue during Agency review. 

In China, typically study data for viral clearance is submitted in early-stage clinical trial applications. This data usually includes validation studies conducted in representative batches of the specific product (one GMP batch) and scaled-down models (two viruses, two repeats); validation results should demonstrate a viral reduction factor of ≥ 4 logs for each of the two operation units (typically low-pH viral inactivation and viral filtration).² 

Now, according to the recently issued CDE guideline, early-phase clinical trial applications utilizing “platform validation” for viral clearance will be accepted when the following conditions are met: 

• The process module is established based on sufficient cases or multi-factor orthogonal analysis. For example, for monoclonal antibodies, a process module can be established based on the validation study results of 3-5 other related products with similar characteristics and attributes and produced by similar processes. 
• Assay methods with the same principles (such as cell-based assays or nucleic acid-based assays) are used to evaluate viral clearance in the same process module. 
• The important process parameters that are planned to affect the virus removal performance in a specific process step should not exceed the worst-case operating conditions of the corresponding process module. In addition, these parameters should be compared with other process parameters to ensure the applicability of the scaled-down model. 
• When platform validation is applied to virus filtration, at least one product-specific validation study should be conducted using parvovirus as an indicator virus. 

Global alignment  

The approach described in the CDE guideline is consistent with the global regulatory principles on in-house/platform validation prior knowledge outlined in the recently updated ICH Q5A(R2) guideline³ which states, in brief: 

• For the unit operation concerned, there should be a comprehensive understanding of the mechanisms underlying viral clearance, to apply a platform validation approach. In addition, the process parameters impacting viral clearance should be well understood. Health authorities encourage the use of multi-factor orthogonal methods to conduct comprehensive research and analyze relevant factors.  
• The composition of the products (or process intermediates) should be compared (including potentially interfering impurities) and any potential interaction with the test virus and subsequent impact on viral clearance should be assessed based on risk. 
• The general limitations of viral clearance studies as outlined in the ICH guideline, should be considered. 

The new CDE guideline also aligns with EMA guidance (EMEA/CHMP/BWP/398498/2005)⁴ which outlines the viral safety requirements applicable to all stages of clinical development, therefore including first in human studies. While the EMA guideline states that validation of virus reduction should be performed before the start of a clinical trial, it also details circumstances where a reduction in virus validation studies may be acceptable. In brief, EMA guidance states that:    

• Virus reduction studies should include both an enveloped virus and a small non-enveloped virus, preferably a parvovirus.  
• The contribution of more than one unit operation unit for virus reduction and at least two orthogonal steps should be assessed. 
• The reproducibility of an effective virus reduction step should be demonstrated by at least two independent experiments. 

The EMA’s general principles for reducing the requirements for product-specific viral clearance validation are as follows: 

• Prior experience of the manufacturer with a specific downstream processing step. If a manufacturer is developing similar types of products by established and well-characterized procedures, virus reduction data derived for these other products might apply to the new product for an equivalent processing step. 
• In such circumstances, the manufacturer should provide rationale for why in-house data can be applied such as a comparison of the biochemical properties of the products/intermediates and a critical analysis of process parameters for the manufacturing step that affect virus reduction. 

EMA advises that in general, to make use of in-house data, the process steps should be carefully evaluated:  

• If in-house data are available for more than one product for a specific viral reduction step, the effectiveness of virus reduction should be comparable for the product. In addition, when this in-house prior knowledge is being applied, regulatory agencies typically expect the worst-case data, i.e., the product demonstrating the lowest reduction value, to be used. 
• Processing of the new and the established product(s) upstream to the step in question should follow a similar strategy. The product/intermediate should have comparable biochemical properties and be purified by identical methods. As each new product might have components not present in previous products the potential influence of product-specific components should be considered.   
• The manufacturer should provide a critical analysis of the manufacturing step for which in-house data will be applied and on the composition of the respective product intermediate. This should include, for example, the type of filter, load per filter area, flow rates, pressure for virus retention filters, or column bed height, load and linear flow rates for chromatographic methods.  
• The analysis should provide complete confidence that the process step is similar in its capacity to inactivate/remove potential virus contaminants for both products.  

These principles align with those on platform validation of virus reduction that are described in the CDE guideline. An important distinction within the EMA guidance compared to the CDE guidance is that if the manufacturer’s rationale for applying a platform validation approach is not entirely convincing, at least a single run with an appropriate virus is needed to confirm that the step is performing as expected. Otherwise, if the process performance is different, e.g., chromatographic profiles differ, then the process step should be validated according to the principles of the ICH Q5A(R2) guideline.  The CDE guidance requires the single run with the appropriate virus, even if the platform validation approach is entirely convincing.  

Regarding FDA requirements, the agency will generally require that IND applications include validation data from:   

• One batch 
• At least a murine retrovirus but now moving to inclusion of a parvovirus 
• All relevant operation units which may add up to four overall  
• Duplicate virus assays.  

Since the FDA has also adopted the ICH Q5A(R2) guideline, using platform validation for viral clearance in early-phase clinical trial applications may also be acceptable in the US. In this way, the new CDE guideline also aligns with FDA requirements. 

In summary 

The latest CDE guideline offers advice on platform validation for viral clearance. It recommends using platform validation data from 3-5 similar products and validation data from a single run of virus filtration using parvovirus for the bio-product undergoing platform validation. 

This approach is consistent with the requirements of the ICH guideline Q5A(R2) and the region-specific guidance from the EMA and FDA. Consequently, manufacturers pursuing global development programs – whether companies in China that follow the CDE guideline, or companies outside of China that follow the EMA, FDA, or ICH guidelines – are likely to have their methods considered acceptable by each of the respective agencies.   

Ready to discuss your platform validation approach? Our ex-FDA, EMA and NMPA/CDE regulators are always available for a conversation.

References 

¹ CDE. Guideline on Platform Validation of Viral Clearance in Clinical Trial Applications of Recombinant Proteins (Trial) (CDE No. 2, 2024). January 12, 2024. https://www.cde.org.cn/main/news/viewInfoCommon/52daa6be5e529f9e3b1f5c89fc5607ce 

² CDE. General Principles for Technical Review of Virus Safety Evaluation of Biological Tissue Extraction Products and Eukaryotic Cell Expression Products. August 23, 2007. https://www.cde.org.cn/zdyz/domesticinfopage?zdyzIdCODE=91a6a33747c86c4a153593079a96e965 

³ ICH Q5A(R2) Viral Safety Evaluation of Biotechnology products derived from cell lines of human or animal origin. November 1, 2023.  
https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf 

⁴ EMA. Guideline on virus safety evaluation of biotechnological investigational medicinal products (EMEA/CHMP/BWP/398498/2005). Feb 1, 2009. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-virus-safety-evaluation-biotechnological-investigational-medicinal-products_en.pdf 

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