Scalability of single-use drug substance production

micheal-eder

Michael Eder

March 21, 2022

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It is common for early stage clinical products to produce small volumes of drug substance. Traditionally speaking, the use of single-use drug substance bulk freezing containers has been the norm for the 50mL – 1L range. However, while this size offers an acceptable operational fit for dispensing drug substance for smaller- volume pharmaceutical manufacturing processes, it is not ideal for larger-volume dispensing processes.

Most drug substances of interest are valuable, both in terms of their properties and price. It is not feasible to freeze large quantities just to determine the right freezing conditions.

Hence, scalability is important. The idea is to freeze small quantities in the range of 0.5L to 10L and determine optimal freezing conditions that can later be scaled up to larger systems (up to 100L).

The aim was to achieve a freezing process where the last point of freeze always happens at the same time throughout all scales. If successful, the generated freezing curves will look very similar. Temperature ramps have been used to slow down or accelerate the freezing process.

The results of the test, scaling up from 3L to 300L are illustrated in the figure below.

Scalability cold chain logistic single-use bag

What’s scalability?

  • Scalability around freezing means the ability to guarantee constant stress on proteins (biopharmaceutical molecules) in all scales, filling volumes and loading scenarios.
  • Single Use Support fulfils this requirement by standardizing the IFGS – ice front growth speed – for all possible scenarios regardless of the filling volume and type of bags but also regardless of the type of system, i.e. whether RoSS.pFTU Lab Scale or Large Scale.
Ice front growth speed in single-use bags

Batch size volume and load independent homogeneous freezing and thawing results:

(example of freeze/thawing curves of a fully scalable process)

3 liters / pre-clinical or Phase 1/2

small-scale-4-800ml

150 liters / Phase 2/3 or commercialized

pftu-16-8200ml1

300 liters / commercialized

lssp-6-50l
johannes-kirchmaier

Freezing kinetics must be practically identical no matter if you freeze 500mL or 200L.

Johannes Kirchmair, CEO

It is typical for commercial programs to generate several hundred liters of drug substance per batch.11 In general, the awareness and importance of the gap in bulk drug substance management (between downstream and fill and finish) is steadily increasing. Biopharmaceutical companies are willing to invest more in relevant technologies. This shows that securing the highest possible standard is not only important in terms of efficiency, but also in order to safeguard high-quality products as a responsibility towards patients.12

[Sources from the SUS_ebook_Rev. 1]

Scalability Guide RoSS.pFTU

Freeze & Thaw Scalability Guide

Scalability around freezing means the ability to guarantee constant stress on proteins (biopharmaceutical molecules) in all scales, filling volumes and loading scenarios.Single Use Support fulfils this requirement by standardizing the IFGS – icefront growth speed – for all possible scenarios regardless of the filling volume and type of bags but also regardless of the type of system, i.e. whether LabScale, MidScale or LargeScale
Whitepaper: Scalable Freezing & Thawing of Pharmaceutical Bulk

Whitepaper: Scalable Freezing & Thawing of Pharmaceutical Bulk

The process of freezing can lead to a denaturation of the protein. In fact, parts of the protein solution will always show less activity based on the stress the protein is exposed to during freezing and thawing. It is therefore important to optimize the freezing and thawing process in order to minimize activity loss. A key parameter for this process is the freezing or thawing rate.
eBook_Filling Gaps in Managing Large Volume of Biologics_Single Use Support

eBook: Filling Gaps in Managing Large Volumes of Biologics

Aseptic aliquotation and cryopreservation of drug substances are crucial process steps in bioprocessing. Even though they’re not in the spotlight of biomanufacturing. In drug development and drug delivery, biologics must be transferred at numerous occasions. Along the journey of monoclonal antibodies, vaccines and more, the drug substance passes lots of process steps where liquid transfer is required. This is relevant for the transitions between upstream processing, downstream processing and fill & finish, but also within these manufacturing milestones. The market of fluid & cold chain management has great growth potential and is on its way to professionalization and industrialization. To meet the challenges of manufacturing drug substances, Single Use Support helps manufacturers and CDMOs to advance their fluid & cold chain management process to achieve a secure and efficient process for liquids on the basis of single-use bags.
micheal-eder

Michael Eder

Senior Marketing Manager

Michael Eder, MA, is Senior Marketing Manager at Single Use Support. He is expert in pharma and health communication with his 8+ years experience in pharma. After completing his master's degree in International Healthcare Management at MCI The Entrepreneurial school in Innsbruck, he has gained experience in the pharmaceutical field. Michael creates articles about Freeze Thaw applications and Platform solutions from Single Use Support and is the author of current news with Single Use Support worldwide. 

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