Dr Anthony Ridgway, Canada
There is concern about biocomparability when a biological product is manufactured by two different processes, or possibly the same process at two different sites. The application of a comprehensive manufacturing control strategy is essential for any product but particularly for biologicals. Compliance with GMP, the application of process validation, a thorough characterization of the product and the setting of specifications are the main pillars of a control strategy that addresses the quality of the product by establishing and maintaining identity, purity, and potency. In concert with this inprocess control strategy, the characterization of the material derived from the new manufacturing process conducted in parallel with a recharacterization of the original material, and comparative data on release specifications are the two main pillars in establishing comparability.
The extent of studies required will depend on factors such as the stage and extent of the changes being made, the impact of those changes on the product, the analytical capability available to evaluate the possible outcome of changes, and the link between quality criteria and safety and efficacy. Changes associated primarily with the drug substances include those involving changes in cell banks, the fermentation process, downstream purification or the location of the manufacturing site. For the drug product, the changes might relate to the formulation or dosage form, the container, or the filling site.
For manufacturing changes that affect the drug substance, the comparative data should be generated from analytical testing, i.e., function testing, from the drug substance specifications and possibly from pharmacological studies. For the drug product, comparative data should focus on the specifications, stability and pharmacokinetics.
The ICH guidelines provide valuable guidance on addressing the quality and safety of the products and are therefore relevant to the issue of comparability. For a change in the production of the drug substances, the ICH Q6B document on specifications is the most relevant. Other documents, such as Q5A, Q5B, and Q5D, are also important references. In the case of the drug product, Q6B is again useful, to be supplemented with Q5C and S6.
Biocomparability can be assessed by controlling product quality with regard to the characterization of the product conducted in parallel with a recharacterization of the earlier version of the product, a demonstration that all specifications are met, and validation of the process changes.
The purpose of process validation is to establish, with a high degree of assurance, that a specific process will consistently produce a product conforming to the predetermined specifications and quality characteristics. Compliance with the specifications can ensure that the process is consistent, that product quality is maintained, and that the product is safe and effective.
In the characterization of biological products it is important to provide a comprehensive picture of the chemical structure,where known, physical and biological properties, impurity profile and degradation pathways of the drug substance.
The ICH Q6B provides important guidance on the characterization of biological products. There are provisions on the control of the chemical structure, physiochemical properties, biological activity, purity and impurity profiles, and protein quantity. The structural confirmation should involve looking at, for example, the amino acid sequence and composition, while typical physicochemical properties include relative molecular mass, isoform pattern, etc. Biological activity can be determined in a variety of ways, including animalbased, cell-culture-based and biochemical assays. It is also important to look at product-related and process-related impurities and potential contaminants.
Furthermore, one should also consider including additional tests that are specifically directed at evaluating the impact of the change on the products and process assays at the manufacturing steps most likely to be affected. In some circumstances a clinical trial may be required.
The globalization of the pharmaceutical industry and the modern regulatory environment present considerable challenges to industry.
The increasing number of manufacturing processes and facilities lead to an expanding inventory of biotechnology products, more new facilities, facility changes, etc. There are also direct and indirect costs associated with making manufacturing changes in a global marketplace, for example, the cost to keeping up to date with national and regional requirements.
There are wider consequences of delays in implementing manufacturing changes, since patients may have to wait longer for access to improved quality or less expensive products. Manufacturers may be discouraged by such delays from implementing improvements to a process.
The new ICH Q5E guidelines address the issue of industry costs and delays associated with meeting region-specific requirements. They propose harmonization of data packages to support manufacturing changes or variations.
It is agreed that there are no generic biological products, and subsequent-entry products will be examined on a case-by-case basis. New clinical data are required in some circumstances, but the extent of the data required should be agreed between the manufacturer and the National Regulatory Authority on a case by case basis.