Dr Takao Hayakawa, Japan

The problem we are facing is how to develop and establish rational concepts and approaches for assesssing the comparability of protein products derived from different biopharmaceutical manufacturing processes. Such an assessment is needed when a manufacturer claims that a product of a new manufacturing process Y is comparable to an existing product of manufacturing process X in terms of quality, safety and efficacy. A rational step-by-step approach, taking into account both product and process, is needed.

The essential first step is to establish whether the new product is comparable to the existing one in terms of both molecular and quality attributes. The criteria for molecular and quality comparability will depend on the nature or type of the product, e.g. the initial cell clone in the case of monoclonal antibody preparations.

It is also necessary to examine whether the new manufacturing process can ensure the consistent production of the active protein product as well as the elimination of potential impurities andcontamination by infectious agents. The direct and indirect effects of any changes in the manufacturing process on the product should be considered and the modified process should be reevaluated or validated as needed. It is also necessary to consider the suitability of available analytical methods.

Further assessment of preclinical and clinical comparability may be necessary in some cases. The extent and nature of preclinical and clinical studies should be determined on a case-by-case basis, taking into consideration various factors. These might include: the nature and extent of changes in the manufacturing process; the results of evaluation or validation studies on the new process, including the results of relevant in-process tests; the capabilities and limitations of tests used for any comparability studies; the extent of comparability of the candidate product with any existing counterpart with respect to molecular and quality attributes, including impurities; the nature of the product; its intended clinical use; the availability of existing preclinical and clinical data; the extent of existing information and experiences pertaining to the product in question; and the stage of product development.

The types of documents to be submitted with a product application will depend on the nature of the case, including whether a product is at preapproval stage, postapproval stage, or coming from the same manufacturer or different manufacturers. At present, there is no specific international guidance on assessing the comparability of biotechnology products. However, the regulatory authorities of Canada, the European Union, Japan and the USA have recently started to develop an international harmonized document on technical requirements for establishing comparability of biotechnology products. A fruitful outcome is expected in the near future.