Buffers, the compounds or compound mixtures used to control pH in drug manufacturing, are a vital component to maintain the stability of both small molecule and biologic drugs during production and in their final form. Today, with rising interest in cell and gene therapies (CGTs) for diseases ranging from cancer to inherited diseases, and the growing need for the manufacturing of vaccines, biopharmaceutical companies are increasingly looking to outsource the development and production of buffers for both their drug development programs and therapeutics manufacturing.

Whether constrained by physical space, requirements for higher titers, lack of resources, or a preference for lean operations, the economics of make-v-buy when it comes to buffers is leaning to buy. Growth in CGT, as well as changes in the small molecule market, have made the production and use of buffers more specialized and more challenging. As a result, large and small biopharmaceutical companies alike are increasingly relying on third parties to source their buffers.

Leveraging expertise

Buffers are an important element in the production of therapeutics, but keeping production in-house comes with associated capital and labor costs. These tasks are often better managed by a trusted outsourcing partner capable of producing GMP-grade buffers to meet both upstream and downstream needs.

While buffer production may seem like a straightforward process, increasingly it is one best managed by experts in this specialized field. As production techniques shift and new therapeutic classes like CGTs become more common, having a trusted partner to guide development and testing of all the buffers needed for each unique drug formulation can provide a more efficient manufacturing process.

As an example, over the past few years, many biopharmaceutical companies are producing higher titers of their therapeutics, which can create potential problems downstream in the purification process and require more buffers. This increasing volume demand can create a bottleneck for in-house production of buffers, a problem easily solved by on outsourcing partner. Further, CGTs are an even greater challenge, often requiring a balance of 25 to 30 different buffers incorporated into a single process.

For companies whose focus is on developing high-value protein-based drugs, turning their attention to the production of an optimized set of a couple dozen different buffer solutions is far from their core expertise and very likely a diversion from their company’s mission.

An outsourcing partner with deep experience creating customized bio buffers can help ensure that not only does a biopharma partner get the development expertise for the best combination and formulations of the buffers themselves, but also assures that it is getting just-in-time, GMP-grade buffers with all the validation and documentation required for downstream production.

Maximizing capital, minimizing facility footprints

A key consideration for many companies when deciding to outsource buffer production is the physical space required for the mixing tanks needed to produce buffers as well as the storage of the raw materials needed to make them, and then storage of the finished buffers before use. For many biopharma companies, especially startup companies, floorspace in their facility is at a premium and is likely better devoted for lab space or other core functions. Keeping buffer production in-house can easily add 20% or more to a company’s physical footprint depending on the number of buffers needed and their warehousing requirements.

In-house buffer production can also bottleneck a facility. Producing 1000 kg of bulk drug substance per year requires 1.5m liters of buffer for purification, which slows production. In addition, devoting manpower to manage the logistics of raw material sourcing and coordinating production of a broad array of buffers is complex and requires capital to keep all these materials in stock. A custom buffer supplier-partner can work with a biopharma’s internal production team to understand their production schedules, determine buffer consumption levels, and manage just-in-time deliveries of the needed supplies, which reduces both storage space and preserves capital. 

Outsourcing for CGTs

While biopharmas large and small can find solid reasons to outsource buffer production to either operate leaner, or because bringing a newly approved therapeutic into production will stretch their existing in-house capabilities, the case for developers of CGTs to outsource these functions is particularly strong.

A 2020 McKinsey & Company market report showed increasing clinical and preclinical development activities of CGTs, but it also noted that development activity in this area by the largest 20 biopharma companies was slow and measured. Only 15% of launched CGTs were from these companies. Further upstream, the numbers were even lower with only 13% of clinical programs and 4% of preclinical CGT assets held by big pharma.

The reason for this is simple, the report stated: large biopharma companies tend to focus on developing therapies in specific disease areas like cancer, and not on developing the new technology platforms needed to create new CGTs. Most technology platform work is performed in academic settings and, once proven, are spun out as small biotech startups.

By their very nature, these venture-fund-backed new companies need to operate leaner, with a laser focus on continuing to optimize their technology or potential drug candidates. Outsourcing for these CGT upstarts across needed, non-core, activities is commonplace.

When it comes to outsourcing the supply of buffers, there are unique challenges related to CGTs. Cell therapies have challenges based on the instability of living cells. This requires manufacturing to occur before the living cells expire and, since living cells can’t be sterilized, manufacturing must occur in an aseptic environment. Gene therapies also frequently require an aseptic manufacturing environment as they cannot be sterile-filtered, and the proteins in gene therapies tend to be sticky requiring segregation of the materials and frequent cleaning of the manufacturing lines to prevent cross contamination.

For these therapies, the need for GMP-grade buffers is essential for their production. Buffers in the upstream process need to maintain a very tight pH window for the culture material in order to preserve the therapeutic characteristics of the therapy. In these instances, the use of buffers such as TRIS, MES, and Guanidine Hydrochloride can ensure the efficacy of upstream processes while also complying with global regulatory requirements.

Buffers for the downstream processes need to provide for the very specific conditions under which CGTs will remain stable. In these instances, GMP-grade buffers including phosphate, citrate, and acetate that can maintain pre-defined purification conditions, provide stability for the therapeutic biologics, and protect them from co-precipitants.

While the development of CGTs is a new and highly specialized field, so too is the understanding and expertise required to optimize the buffers needed to shepherd these products to approval. Working with an experienced custom buffer supplier can help protect and optimize the assets of CGT startups to give them the best chance for clinical success.

Choosing the right supplier

Since the beginning of the pandemic more than two years ago, supply chain issues have come into sharp focus. When it comes to choosing a custom buffer supplier, the due diligence of biopharma companies should include understanding how robust its supply chain is and the company’s ability to maintain a steady on-time/in-full stream of the needed buffers. In addition, it’s essential to discern the company’s capabilities for warehousing the required buffer and whether the company meets all the quality requirements and provides the documentation needed for the project.

A facility visit is a good step to see first-hand how a buffer manufacture and supply company operates, the quality systems it has in place, and its ability to serve each of its client’s specific needs. Equally important is introducing the teams of each company that would be assigned to the project to allow for a better understanding of how each works, to outline the requirements of the project, and share information that can improve the design of the custom buffers.

A buffer supplier that shows it has the capacity, the manpower, the ability provide documentation quickly, and a dedicated team assigned to a client’s project can help assure a successful partnership. 

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Kate Buggle joined Actylis, formerly Aceto, in February 2022 as strategic business development director in the expanding company’s buffers and process solutions manufacturing group (formerly A&C Bio Buffers). A biochemist educated at University College Dublin (BSc) and National University of Ireland, Galway (MSc), she has spent 20+ years in specialty chemicals and biopharmaceutical buffer sales, marketing, and customer support roles, including six years at Merck KGaA, Darmstadt, and 16 at SAFC.

Actylis is a leading global manufacturer and supplier of differentiated specialty ingredients to life sciences and advanced technology end markets. With business operations in 10 countries, Actylis manufactures and supplies over 4,000 chemical compounds used principally by the pharmaceutical, biopharmaceutical, nutritional, agricultural and specialty chemical industries. Building on a series of strategic acquisitions by predecessor company Aceto, Actylis integrates 11 industry specialists including A&C, A&C Buffer, Biotron Laboratories, Cascade Chemistry, Finar, Inter-Actifs, IsleChem, Pharma Waldhof, Syntor Fine Chemicals, and Talus. Combining expertise and strengths of all these firms, Actylis provides a hybrid model for manufacturing and sourcing critical raw ingredients, including buffers, and stands as a worldwide supplier with a robust manufacturing footprint.