Sourcing reference products
For biosimilar products, the mode of action is the same as of the marketed product, thus minimizing the risk of failing in clinical trials. However, the regulatory expectations regarding the product quality and the biosimilarity assessment prior to entering into the clinical stage makes the development of a biosimilar product more difficult (and more expensive in the preclinical phase) compared to an NBE. Strict guidelines from the EMA and the FDA have been published that raise the bar very high for companies that develop biosimilars. Because most process information for the innovator is not available to the public, establishing biosimilarity to innovator (also called the reference product) is challenging.
Initially, a detailed analysis of innovator lots is required, in order to obtain information about the reference product (RP); then, an extensive physicochemical and biological characterisation needs to be performed, as so to demonstrate the analytical biosimilarity between the biosimilar and the RP. The implementation of an RP sourcing program at this very early stage of development is mandatory. Challenges are mainly related to identifying suppliers that have access to innovator lots from various regions (US, EU, and China) and getting enough lots at the right time. Additionally, the Certificate of Analysis (CoA) for the RP lots is informative, in order to understand what quality attributes have been tested, and can also help to set initial release specifications for the proposed biosimilar product.
RP-Testing: from young to old lots
The reference product sourcing strategy should be coupled with a storage and stability testing strategy. The goal of RP sourcing is to cover the RP life cycle and – when starting the development program – to have RP lots available for testing that represent “young,” “mid-aged,” and “old lots” (= end of shelf life, EoS).
Taking Mabthera, as an example, the shelf life is two years, thus, ideally to understand any changes of product quality over these two years, lots aged below three months (“young”), around one year (“mid-aged”), and close to two years (“old”) should be included in testing. It is not recommended to source many lots of RP from a short period of time, because they may come from the same drug substance (that can be stored frozen for many months) and, therefore, do not represent the diversity of the actual RP manufacturing process. In that case, the only variability that is revealed by testing such batches is related to the analytical method. This is an additional argument for sourcing more innovator lots, which requires implementing a strategic sourcing plan before starting the development.
Old RP lots are used to understand product changes manifesting at the end of shelf life – for example, the charge pattern might change and also the monomer peak might decrease. It should be noted that the procurement of RP lots that full-fill the criteria discussed above is difficult, because there are only a certain number of lots per year available in the market.
Testing in Humans
For clinical testing, the RP batch has to be selected very diligently, because it serves as the indicator for biosimilarity (a margin of 80 – 125% is allowed, where the biosimilar has to fall within for read-outs like PK or PD). From a sourcing perspective, it is important to source a large enough amount and to begin early enough in time to start the trial.
About ABF / GBA Group Pharma
ABF, a member of GBA Group Pharma, has an extensive global network and long lasting experience in sourcing RP for Biosimilar development. As a logistics service provider, we have supported the export of such material into non-EU countries located in Asia, the Middle East, and the US. GBA Group Pharma is one of the largest and most experienced service providers in the European pharmaceutical and biotechnology sector. www.gba-pharma.com
Dr Andreas Nechansky has worked for more than 25 years in the biopharmaceutical industry in leading positions and has also founded his own company.
This article was published in the European Biotechnology News Magazine Summer Edition 2020.