BIO

When partnering with a contract development and manufacturing organisation (CDMO) for the production of virus-based therapies, therapeutic developers must ensure a successful technical transfer, avoiding disruption that could lead to delays impacting the success of the end product.

The handover of knowledge and technical capability from one stage in the drug development supply chain to another can take several forms, for example: 

  • The transfer from the research and development (R&D) stage to the current good manufacturing practice (cGMP) stage, including scale-up engineering 
  • The transfer of a project from one production site to another, within an organisation or between two partners

All technical transfer processes involve challenges that must be overcome to ensure success. These obstacles can multiply when it involves virotherapy manufacturing, due to the unique complexities of the field. 

In this article, Rebecca Powell, Director Tech Transfer explores the do’s and don’ts of navigating the technical transfer process for viral vector projects. 
 

Technical transfers from R&D to cGMP

Whether transferring between internal departments or to a viral production projects must follow the same steps and processes as other biopharmaceutical projects. 

It is crucial to follow quality by design (QbD) engineering processes from the beginning. This is vital to establish a successful technical transfer programme with the appropriate:

  • Critical quality attributes (CQAs)
  • Critical process parameters (CPPs)
  • Standard operating procedures (SOPs)

To achieve this, it’s important to establish the design space, considerations defined in risk assessments and settings mechanisms for control. 

The sooner this process takes place, the easier it will be to build a robust and effective cGMP manufacturing process. The more a process has been developed with QbD principles in mind, typically the more defined the process transfer will be, contributing to overall improved success of the transfer. 

Another critical step is to develop manufacturing processes utilising a scale-down model, where all equipment is a smaller-scale version of production equipment intended to simulate larger- or at-scale operations. This model allows for the performance of USP/DSP process characterisation, as well as defining robustness and creating opportunity to design and evaluate process optimisations translatable to the pilot plant or cGMP manufacturing setting. 

Unlike the model used in early research processes, the scaled-down approach is designed to simplify the characterisation, optimisation and standardisation processes needed to prepare for the scale-up to large-scale cGMP manufacturing. 

The scale-up should be relatively easy to execute if QbD principles have been considered and scaled-down steps have been carried out effectively. During scale-up process development, scientists will adjust scale-dependent operating parameters while keeping scale-independent parameters unchanged. When scaling up viral vector processes in particular, production unit operations and equipment need to be assessed and adjusted to create a scale-up model. The key machinery that must be reviewed as part of this includes: 

  • Bioreactors
  • Depth filters
  • Chromatography
  • Tangential flow filtration 

This is crucial to obtain an accurate assessment of large-scale manufacturing capability and to identify potential risks in advance, so they can be mitigated appropriately. 
 

Technical transfer between different sites 

When transferring viral vector projects between two geographical sites, such as between a development facility and a CDMO partner, it is important to begin with an assessment of the new facility and ensure it is fit for transfer. This process will help project leaders fully understand upstream and downstream processing equipment availability, the analytical instruments required and the quality systems in place. It will also help determine whether the supplier truly has the expertise to ensure security and reliability during transfer. 

For viral vector projects, it is particularly important to know the receiving facility’s cleanroom grade and biological-control level, as well as the total number, size and type of the critical process equipment in place. 

Thorough preparation prior to establishing technical transfer is vital to success. Above all, this preparation will benefit from considerations of QbD, established CQAs, CPPs, SOPs and risk assessments, as with any technical transfer from R&D to cGMP. Added to this, though, are other processes that need to be performed: 

  • Creation of manufacturing flow diagrams: identifying required equipment, processes, raw material movements and operator needs. 
  • Platform-based and validated assay lists: detailing incoming, in-process, drug substance/drug product (DS/DP) release and stability monitoring, highlighting platform-specific assays such as potency, identity and product impurity as well as considerations on a sampling plan. 
  • Process and test method characterisation summary reports: detailing processes and test methods. 
  • Lists of essential biological materials: describing the specifications of master or working cell banks, master viral seed stock/infection or helper virus banks, plasmids, cytokines, growth factors and lipid supplements.

A robust CDMO partner will evaluate these processes prior to or upon delivery of the technical transfer package, focusing on gap analyses to identify any insufficiencies in terms of equipment, instrumentation, expertise, capability and capacity.
 

Technical transfer with viral vector products 

In addition to the above requirements, viral vector manufacturing presents unique challenges compared with other biopharmaceutical projects that need to be overcome to ensure technical transfer success. 

Common virus and viral vector challenges that should be considered in the technical transfer process include: 

  • Infection or transfection efficiency 
  • Upstream titres 
  • Residuals and impurities such as residual plasmid, host-cell protein or DNA levels 
  • Capsid integrity 
  • Upstream impact on downstream considerations 

Additionally, the high variability of platform-specific processes in the viral vector space can make scale-down and scale-up modelling and other transfer processes highly complex. 
 

Benefiting from viral manufacturing expertise 

Few CDMOs have the skills and capabilities to support virotherapy companies in addressing these technical transfer challenges. Therefore, working with an experienced CDMO specialising in virotherapy products is very important. 

Whether taking on a project directly from the originator or from another supplier, CDMOs should have the expertise and experience to identify and overcome the challenges that frequently arise during technical transfer. A CDMO specialising in virotherapy development also has the dedicated technical insight to streamline process integration and incorporate key analytical method development goals for proper characterisation and QC release.