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EMEA gives EU six months to respond to highly technical draft guidance on viral safety of biotech meds.
In high summer, the European Union delivered a new assignment to the clinical trials community, for completion by midwinter. What, it inquired, are the correct controls for ensuring that clinical trials on biotechnology-derived medicines do not pose unacceptable viral safety risks.
In addition to the delicacy of this calculation, the significance of the challenge is all the greater because of the rapidly growing volume and scope of biotech medicines themselves. So now that the European Medicines Agency has released its draft "Guideline on Virus Safety Evaluation of Biotechnological Investigational Medicinal Products" [http://www.emea.eu.int/pdfs/human/bwp/39849805en.pdf], reflection is starting in earnest across many sectors of the clinical trials community. Many organizations are already getting to work on their comments, to be able to submit them by the deadline of the end of December 2006.
The Agency admits that to date, transmission of a virus through the use of an approved biotechnological medicine product has never been reported. In some cases, a viral contaminant has been detected during manufacture—generally as an adventitious contaminant deriving from biological material used during fermentation, such as serum.
Content Requested for Clinical Trial Authorization
The declared purpose of the document is to provide scientific guidance on viral safety of biotechnological medicines used in clinical trials, so as to allow a harmonized approach throughout the EU for both sponsors and regulators. "Assuring the viral safety of biotechnological medicinal products is a complex process, and a reliable assessment of the viral safety of an investigational medicinal product (IMP) is critical," it states, rather obviously. But the carrot for the clinical trials community is that agreement on the nature of the assessment will be particularly valuable for multicenter studies that involve several different member states.
The draft sets out proposed criteria for viral safety evaluation studies, especially validation studies, required before and during clinical development. It also suggests the extent to which manufacturers should be able to refer to in-house experience concerning virus safety evaluation, and outlines the nature of the risk assessment, which should form part of the safety evaluation. What it amounts to is advice on the viral safety data and documentation that should be submitted in a clinical trial authorization request, over and above the standard data requirements for marketing authorization applications.
The guideline will apply to investigational products prepared from cells cultivated in vitro from characterized cell banks of human or animal origin—an open-ended commitment. As the text recognizes, although many products are derived from well-known and well-characterized rodent cell lines, "a variety of cell lines are in use or under development." In addition, the replacement of in vivo tests by in vitro testing for the exclusion of specific adventitious agents (for instance, by validated cell-based assays) is being investigated by several manufacturers. Such approaches ultimately will require full validation of these alternative tests and a general acceptance of them by regulatory agencies, the guideline points out.
In concrete terms, the scope will include monoclonal antibodies and recombinant DNA derived products including recombinant subunit vaccines. But it does not apply to products that contain recombinant viruses such as vaccines or gene therapy products using viral vectors, nor does it cover products derived from hybridoma cells grown in vivo. Material to be used solely for nonclinical testing is also excluded.
Three complementary approaches lie at the heart of the guidance: thorough testing of the cell line and of all raw materials for viral contaminants; assessment of the capacity of downstream processing to clear infectious viruses; and testing the product at appropriate steps for contaminating viruses.
Testing of the master cell bank for viral contaminants should be performed prior to the initiation of a Phase I trial, the draft indicates. A working cell bank—which might only be set up at a later stage during clinical development—should be tested as soon as it is established. Cells at their limit of in vitro cell age should be derived from the scale used for the intended clinical batch and similarly tested. Any change in the production process that results in an extension of the in vitro cell age will require reassessment of end-of-production cells. Consequently, it may be useful for manufacturers, at their first assessment, to examine cells taken beyond their in vitro cell age, in order to allow expansion of the cells during development.
Since endogenous retroviral viruses or particles are present in most cell lines currently in use, and there is a probability that they will be present in a novel cell line, particular attention should be paid to investigating the cell line for their presence.
Where a validated in-house cell bank is used by a manufacturer to derive individual cell lines expressing different biopharmaceuticals, viral safety information for that cell bank (e.g., data on susceptibility to a wide range of viruses) can contribute to the overall virus safety evaluation.
Independent of the stage of development, the unprocessed bulk should be tested, including via quantification of retroviral particles, where applicable. The source and viral safety of the raw materials used during fermentation should be taken into account when devising the unprocessed bulk testing.
Validation is required to characterize and evaluate process steps that can be considered effective in inactivating/removing viruses and to estimate quantitatively the overall level of reduction of any virus/viral particle, such as endogenous retroviral particles, that are known to be present.
For IMPs, it enjoins a case-by-case approach taking into account the characterization of the cell line and the viral safety of raw materials, as well as the nature of the process steps. Even when no raw materials of biological origin have been used and the cell line is fully tested, viral validation studies will be required, it states firmly, as extensive testing cannot guarantee the viral safety, due to limitations in viral detection assays. Full viral validation should be initiated as soon as the final production and purification process has been established and should be completed prior to use of the investigational medicinal product in Phase III studies, unless otherwise justified.
The relevant steps in product purification that contribute to virus clearance should be described and their capacity to inactivate/remove potential virus contaminants should take into consideration the viral safety of the production cell line—for example, the type and level of endogenous retroviral contamination or the use of human or animal derived materials during manufacture and possible levels of contamination.
There is no ambiguity in the instruction that prior to Phase I studies it must be demonstrated that any virus or viral particle known to be present in the bulk harvest has been effectively inactivated or removed during downstream processing. A retrovirus should be used in validating the inactivation/removal of viruses to demonstrate full clearance of particles present in the bulk harvest.
Regardless of the extent of direct virus testing of the production cell line, there remains a potential for unknown contamination of the cells with a virus originally present in the cells or arising from materials of biological origin that have been or are being used during cultivation of the production cells. Potential contaminants may be enveloped and nonenveloped viruses. Consequently, prior to Phase I studies, the process should normally be evaluated for the inactivation/removal of enveloped viruses or retroviruses and small nonenveloped viruses.
For Phase I/II clinical trials, the suitability of the analytical methods applied for viral testing should be demonstrated. A tabulated summary of the results of the validation should be provided (such as results of values found for specificity, linearity, range, accuracy, precision, quantification, and detection limit), but it is not necessary to provide a full validation report. Viral tests performed in accordance with the European Pharmacopeia are normally not revalidated by the company.
Full viral validation should be initiated as soon as the final production and purification process has been established and should be completed prior to use of the product in Phase III studies, unless otherwise justified. For Phase III studies, a full report of the validation of analytical procedures should be held available and should be submitted upon request.
Reevaluation of viral safety is urged during development to take account of the impact of changes in the cell culture system, cell generation level or the manufacturing process. In light of the virus safety risk assessment, additional virus studies and new validation studies may be required.
The draft was compiled by the Agency's biotechnology working party over the course of 2005 and 2006, and was given the green light as a consultation document at the end of June. This allows just six months for review and comment by interested parties.
But more than with other draft guidelines released by the Agency, this one is intensely technical, firmly admonitory, and couched in very definite terms. The margin for modification—the nature of the text suggests—is not wide. So anyone who finds it not to their taste better get their arguments together cogently and early if they want to influence the outcome.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.