Nature/history of production cell line key to justify virus detection assay omissions.

RESTON, VA -- A number of general factors should be considered in justifying the omission of any of the virus detection assays listed in ICH Q5A and a reduction of product specific validation studies, noted Hannelore Willkommen, Ph.D., Regulatory Affairs & Biological Safety Consulting Biopharmaceuticals, Blood Products and Tissues, New Lab BioQuality AG, in Germany.

Addressing the IBC conference on well-characterized biologicals Nov. 12 on the European draft guideline on Virus Safety Evaluation of Products in Development, he said these factors include:

* The nature of the production cell line;

* The history of the cell line and its use;

* The extent of characterization of the cell line;

* Use of non-use of raw material of human or animal origin during manufacture;

* Potential exposure to adventitious contamination;

* The stage of development of the product;

* Experience of the company with the cell line involved;

* Experience of the company with specific inactivation/removal procedures used; and

* Published data.

Willkommen said that "such in-house experience also be applicable to the data requirements of an MAA [market authorization applications]; however, the guideline does not address this point."

He noted that the scope of the guideline includes products covered by ICH Q5A, Case A and Case B (cell derived products). It covers Phase I and II materials, and is not applicable to MAAs.

Regarding cell line qualification, the guideline recommends that where a validated, in-house cell bank is used by a manufacturer to derive in-house cell lines expressing different biopharmaceuticals, viral safety information for that cell bank can contribute to the overall virus safety evaluation.

The speaker said that "replacement of in vivo tests such as MAP/HAP/RAP tests by in vitro testing for the exclusion of specific adventitious agents is being investigated by several manufacturers. Such approaches will require full validation of these alterative tests and a general acceptance of them by regulatory agencies."

For validation of materials for Phase I and II studies, Willkommen noted that any virus or virus particles known to be present in the bulk harvest has been effectively inactivated or removed during downstream processing.

"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 material of biological origin. Potential contaminants may be enveloped and non-enveloped viruses."

Also, for both Case A and B cells, the process should be evaluated for the inactivation/removal of an enveloped virus and a small non-enveloped virus, unless otherwise justified.

A reduced program for virus validation can be justified under the following circumstances:

* Extent and use/non-use human-animal derived raw materials;

* Published data;

* Prior experience of manufacturer with specific downstream processing; and validation data from one product might be applicable to a new product for an equivalent process step.

For validation of materials in Phase III studies, "full validation according to Q5A 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," according to Willkommen.

He concluded by noting that this new guideline provides the chance to use in-house data for demonstrating virus safety of investigation medical products.

Some modification of the current draft requirements for products in develop seems to be justified:

* Cell line characterization--no testing of EOP cells;

* Virus clearance studies in full compliance to ICH Q5A required for MAA but not for Phase III material; and

* Use of in-house data to demonstrate virus safety extended to phase II material.

Willkommen stressed that full validation according to ICH Q5 should be conducted as soon as the commercial process is established and will be provided in the MAA.

By Joseph Pickett

Managing Editor