At BioPharmaSpec we often get asked what can we do to accelerate our client’s product development and help with early interactions with the regulators.
From our point of view the answer is all about creating a strong data package for the product. For any biopharmaceutical manufacturer, the process of obtaining such data can be accelerated through working with an experienced service provider with a strong knowledge base.
In our opinion this knowledge base needs to extend across:
Considered and meaningful data interpretation and, additionally, putting these data into context.
Below are some examples of where and why having a broad knowledge base from the very outset of product development is significantly helpful in plotting the most efficient route to gaining solid information about the product.
In terms of the product, prior knowledge about the cell line used for manufacture and the possible structural features that gain importance on this basis is significant. For example, biopharmaceutical products and biosimilars engineered in an E. coli cell line require in vitro re-folding through disulfide bridging and therefore the disulfide bridge pattern of such products gains particular importance.
Also important is knowing that that certain excipients can interfere with analytical methods. This can range from the obvious (e.g. amino acids in formulation buffers will need to be removed prior to amino acid analysis) to the less obvious (e.g. polysorbates and antifoams can interfere with chromatography-based analyses).
Knowledge regarding which methods can be applied to analysis of a particular product to gain the required information is also very helpful in providing data in an efficient manner. In practice, the list of applicable methods chosen for analysis of any product should be data-led rather than decided theoretically.
At BioPharmaSpec ,we generally apply a range of methods (i.e. all those required by ICH Topic Q6B) to a product during an initial Pilot Study and subsequently choose the most appropriate applicable methods for the product based on the data obtained. We know that there are knowledge-based generalities that apply and can help with efficiencies. For example, secondary and tertiary structure analyses generally require product in concentrations of >1mg/mL. Therefore, for products such as Erythropoietin where the Final Product is formulated at ~35µg/mL, it is not possible to get such data for the Final Product. Analyses of these molecules would have to be performed at the Drug Substance stage.
Once you have the data set, putting what you have into context is the most knowledge-based driven area of the whole process. It is essential that the scientists interpreting your data have sufficient experience to understand the derived data (in context) and also bring together the orthogonal aspects of the analysis. For example: “do the acidic peaks in the charge profile analysis compare well with the levels of deamidation being observed in the peptide mapping analyses?” This approach to interpretation gives a clear and understandable summary of the data and the provided product.
Furthermore, a sound knowledge of the analytical methods, their limitations and what they say (and do not say!) about the product means that data can be understood appropriately. Supportive or complimentary data from other relevant techniques can then be used to bolster or support conclusions.
Any issues with the product that the data may highlight need to be recognized as such, leading to further analytical work to investigate these issues in more detail. Once thoroughly understood, a manufacturing solution can be more easily identified. The need for significant knowledge continues when data from further batches of a novel product or a biosimilar/innovator comparability study become available, in terms of comparing the data sets and defining whether data are comparable i.e. within the expected experimental variation, or not.
It is imperative to either recruit or build up the necessary knowledge within your in-house analytical departments. This is no mean feat; appropriately skilled and experienced experts are in great demand and it can take considerable time to train and build-up the necessary level of experience of existing scientists. An efficient alternative is to work with a CRO that already has the required knowledge base. Their experts will have gained a wide-ranging knowledge base through working on diverse projects over a long time-frame. Indeed, senior scientists may have even been involved in the development of the instrumentation and methods which have become essential for modern day structural characterization. Together with an in-depth knowledge of each product’s individual requirements, they are well placed to help accelerate the development process.
