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Expert Q&A - Dr Stephen Rumbelow: Why the industry needs better excipients

Dr. Stephen Rumbelow, Life Sciences Research Fellow, Croda Inc.Formulating a drug for parenteral delivery comes with its fair set of challenges. Aside from a high level of sensitivity to external factors like light and heat exposure for parenteral biologics, these large and complex drugs are prone to degradation when exposed to various chemical species. For this reason, these applications typically require extremely pure and highly functional excipients to stabilize the drug and aid in its delivery. Croda Pharma’s range of Super Refined™ excipients is designed with this in mind. We offer a wide variety of chemistries with exceptionally low impurity profiles, yielding improved oxidative stability for both the excipient and any solubilized drug. Dr. Stephen Rumbelow, Life Sciences Research Fellow at Croda Pharma sat down with Drug Development & Delivery to discuss polysorbates, a key excipient used for stabilising drug molecules in injectable dosage forms. Here’s a look at the interview they conducted:

Hi Stephen, can you tell us a little bit about your background and experience working with customers formulating with biologics?

I am the Life Sciences Research Fellow for Croda Inc, with responsibility for developing external partnerships with companies, universities and research institutes.  Previously, I was the Research and Technology Manager for the Innovation Support and Pharma teams for Croda Inc, where I managed a Pharma team responsible for generating new high purity excipients for the pharmaceutical industry.  This includes products for all major delivery routes and applications, ranging from emulsifiers and dispersants through to solvents and permeation enhancers. Additionally, the team is also very active in generating accompanying performance and application data for such applications, with a particular emphasis on the impact of excipient purity on drug delivery and performance.  Our Innovation Support team closely assists in these activities, along with supporting other businesses within Croda. In my current and more recent roles, I actively work on a number of collaborative projects with major companies in the pharmaceutical industry, covering many aspects of the use of polysorbates in injectable formulations. Customer collaborations focus on areas such as the impact of excipient purity on formulation stability and more recently, benchmarking the performance of these excipients against similar materials in this application. It’s worth noting that Croda also supplies a number of other materials for use in injectable formulations, including those for oncological treatments, and we have been involved in numerous studies demonstrating the importance of excipient purity on the stability of active pharmaceutical ingredients (APIs) for oncology.  Furthermore, with the purchase of Avanti Polar Lipids, our portfolio and expertise has expanded considerably in the field of lipid-mediated delivery, which addresses the needs of a widely diverse range of APIs, from small molecules to peptides and gene therapy agents.

Croda is known for making polysorbates; how are polysorbates used in parenteral applications?

Polysorbates 20 and 80 have a long track record of safe use and are listed on the FDA’s Inactive Ingredient Database (IID) list for injectable applications, typically being used in biotherapeutic formulations at concentrations ranging from 0.001-0.1%.  In the case of biologics, which are typically administered via injection, these excipients have been well recognized by the industry as important and highly effective stabilizers for proteins against interfacial stresses, even at these very low concentrations. These stresses can occur from a variety of sources, including air/liquid interfaces (particularly with shaking), surface interactions (with the internal surfaces of processing equipment and the vials themselves) and even ice/liquid interfaces (as might be encountered in freeze/thawing processes), all of which can cause surface adsorption, protein aggregation or precipitation. Polysorbates are very effective, not only in mitigating against these problems, but in their ability to stabilize therapeutic proteins and prevent aggregation. Similarly, the surfactant properties of these excipients can be very effective in facilitating the re-dissolving of freeze-dried formulations, too, in terms of both wetting and prevention of clumping and aggregation.

Can you speak to the implications of excipient grade on formulation stability?

This is very important, particularly considering the risks (and financial implications) associated with potentially losing biological efficacy for biological APIs that are both expensive to develop and highly prone to degradation.  We always recommend using high purity variants of these products instead of the standard compendial grades, even if extra microbiological tests might have been performed on them. This is because the impurities in excipients can impact API and formulation stability in a number of ways. This is a topic which has been highlighted in numerous peer-reviewed scientific publications. The formulator should pay particular attention to such impurities as residual peroxides, which can lead to oxidative degradation, and metals, which can catalyze such reactions.  Residual aldehydes can also be of concern, since these, too, can react with various reactive groups on the amino acids, resulting in a loss of efficacy.  Finally, residual free fatty acid levels can also play a critical part in determining the likelihood of the onset of the formation of precipitates, which can, in turn, result in the appearance of cloudiness and, ultimately, the rejection of batches of formulations. It is well recognized that these excipient impurity issues can be successfully addressed using a combination of carefully selected high purity starting materials, in addition to well-controlled and mild processing conditions. In the case of Croda’s Super Refined™ range, this is further supplemented with a final proprietary purification stage that significantly decreases these impurity levels further. Super Refined™ excipients are well recognized and widely used in biotherapeutics, as well as in other application areas in the pharmaceutical industry where API stability is a chief concern.

Can you speak about the implications of polysorbate composition on formulation stability?

One of the reported concerns with biotherapeutic formulations has been the carryover of residual lipases from CHO cell-based cultures used to produce monoclonal antibodies, which can then, under certain circumstances, occasionally result in the hydrolytic degradation of polysorbates. Polysorbates are a complex mixture of chemical species by nature of their manufacture:  a multi-step process based around naturally derived sugars and fatty acids followed by ethoxylation. In the case of Polysorbate 20, if this hydrolysis proceeds to a significant extent, this can sometimes lead to the liberation of significantly high enough levels of higher molecular weight (>C14) fatty acids which, having poor water solubility, can precipitate out and lead to the appearance of cloudiness. However, there are clearly several ways to minimize the risk of such an issue, ranging from minimizing such carryover of lipases, through to selecting polysorbates of the appropriate grade and purity which have lower levels of residual-free fatty acids from the start. 

Despite their inherent complexity, it is quite possible to manufacture polysorbates with a high degree of reproducibility using the appropriate manufacturing controls and careful selection of raw materials of consistent quality. This can be readily verified, not just from the certificate of analyses for individual batches, but from more sophisticated chromatography and spectrometry techniques which show considerably more detail on their composition, down to the relative amounts of certain classes of compounds. Super Refined™ polysorbates are manufactured with these conditions in mind, which also helps considerably with batch-to-batch consistency, something formulators are actively looking for when selecting an ingredient supplier. Moreover, it is also possible to produce a custom variant of Polysorbates 20 and 80, in which the fatty acid levels distribution have been adjusted to further minimize this risk. Such products are now commercially available.

Are there any best practices for handling materials going into injectable formulations?

There are several best practices when handling polysorbates and, for that matter, any high purity excipient going into injectable formulations.  These products are typically supplied in sealed containers under nitrogen to ensure that they retain their high quality and protect them from degradation. Therefore, we prefer that end users select the appropriate package size so that they can ideally use all the material in a single use if possible. High purity, highly differentiated products are typically available in a range of pack sizes in order to accommodate this. Croda offers materials in a wide assortment of packaging, including as low as 250 gram bottles. For users that find themselves wishing to retain product containers that have been opened, we strongly recommend re-sparging with nitrogen and can supply detailed procedures on how to perform this effectively.  This is one of the most important considerations when handling these materials in this particular application area. Additionally, these products are typically supplied in metal containers in order to prevent light exposure, and we recommend that the customer stores them in their original containers. We would also discourage any practice of transferring high grade excipients that have been manufactured to meet high purity standards into secondary containers, as this can result in the quality of the excipient being compromised.

While polysorbates have a long history of use in the parenteral space, are there situations where they wouldn’t be used?

We are not aware of any situations where polysorbates cannot be used with biotherapeutic formulations and it should be noted that they have a long track record of safe and effective use.  There is some interest in the industry to consider alternative chemistries, but questions remain about their effectiveness and versatility and any such materials would need to go through the FDA approval process.

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