Blog 12 – Technology Transfer of Clinical trial manufacturing.
Firstly, what is Technology Transfer – I suppose putting simply it, includes everything that’s needed to move a technical process from one location to another. See my Blog #1 for more detailed definitions.
While most discussions are around the transfer to commercial scale manufacturing, it should be remembered that process and assay information (tech) transfer also occurs at all points through a products life cycle from development to production end of life, including through the clinical trial phases.
Based on: “Unraveling the Complexities of Technology Transfer” – Thomas Chattaway – September 2020 in Bioprocess International
However transferring products still at the clinical phase stages have specific problems and challenges:
The main one being that the manufacturing process has not yet been defined and can still be modified / developed (even at phase 3 stage) and is subject to change, and analytical tests may not have been fully developed, validated, or verified. Indeed these aren’t strictly necessary for early clinical manufacturing, filter validation for instance being one of these – although it should be performed as early as possible.
Some of the challenges can be:
- Product specification not yet defined.
- Analytical methods not yet finalised – or even been fully defined.
- Product may not yet have been characterised.
- Manufacturing process not developed – indeed in its current form it may not even be GMP compliant.
- Current manufacturing process may not be scalable.
Key documents and items of information traditionally relied on for technology transfer to commercial manufacturing scale may only be in draft form if at all.
Let’s take a look at some of the most crucial tech transfer points between these stages:
Preclinical to Phase 1
Challenges:
- Scalability of the process; whether it can be replicated at scale
- Needed materials, which may not comply with GMP requirements.
- Equipment between sites is likely to different
- R&D often based in another country with different cultures and time zone
- “Tribal” knowledge may be prevalent and not always be captured on paper – a prime task of technology transfer at this stage is to try and capture all of this knowledge. The problem is that a massive amount of data is needed to encompass all the different procedures, equipment setups, protocols and reports, methods, output, validation, parameters, and equipment guidelines.
- Remote workforce, which has become the new normal. Teams are now distributed across sites and even continents, making ad hoc meeting and document review often difficult.
At the preclinical phase, there is little or no process information. Product characterization, information, procedures, and early stability data may be present.
One of the key roles of the technology transfer at this stage is to ensure that the process being transferred is or at least capable of being GMP compliant (yes, I’ve heard R&D staff say “but GMP doesn’t apply to us” and in a sense they can be right) but failure to ensure that a product cannot be manufactured in a GMP compliant manner at this stage is planning for failure. Such an example could be the reliance of raw materials or excipients that were either not GMP grade or could not be sourced as GMP compliant materials and would waste time / money re-formulating the product.
Other examples could be:
- Equipment that could not be scaled up (e.g., rotary dryers)
- Processes that could not be performed easily or at all at manufacturing scales (e.g., fast heating or cooling rates required – O.K. at test tube scale, but unfeasible at 2,000L scale).
So, the main role of technology transfer at this stage is probably to ensure that as much data as possible is captured about the product and process (at this stage what is important or not is usually unknown) and to ensure that the process being transferred is at least potentially GMP compliant.
Perhaps a word of caution is appropriate at this time, you should be careful to protect your intellectual property, not only regarding the product, but also in respect of the analytical methods and process methods used as it would otherwise be possible for any entity performing further development work to be able to patent the methods themselves.
Early phase Clinical Phase transfers
This is where the development teams hard work starts, turning an R&D (possibly non-GMP compliant) into something that resembles a GMP / regulatory compliant process that can be scaled up through pilot plant to commercial scale, and produces a product that is safe for animal and human trials.
Technology transfer at these stages may require:
- A Quality Target Product Profile (QTPP) to have been created.
- Product characterisation data to be available.
- Critical Quality Attributes to have been determined.
- Preliminary Critical Process Parameters to have been developed (what they are even if numeric values are not yet available).
- A draft process description, although at early clinical phase stages this is expected to change significantly before a commercial scale process is defined.
- Details of development work and batch records of previous manufacturing especially at the pilot scale. – what went right, but also what went wrong), any process development reports.
- Scale up and regulatory strategies may also be developed at this stage.
- Analytical methods to be used – these should be developed in parallel with the process to ensure that appropriate tests were defined and appropriate sensitivities for the developing process were possible. This may require some preliminary values for critical process parameters to ensure analytical requirements and capabilities are matched. it is not expected that all methods and specifications be defined for a Phase I biologic. For a Phase I biologic, analytical methods should be in place; however, at this early stage, they do not need to be validated.
Process validation at this stage of technology transfer can seem a long way off – something to be thought about later. However, it is worth emphasising that planning for eventual process validation is something that should be incorporated in the technology transfer at this stage of product development as decisions taken now can greatly affect the ability of the process to be validated without having to either repeat studies incorrectly performed or indeed not at all.
Late phase (phase 2 and 3) Clinical Phase transfers
At these stages the product should be characterised and the process should be being developed in a way that is GMP compliant, taking all the data that has been generated to date and then using it to replicate the early phase clinical process under GMP conditions, using GMP compliant materials.
Quite often the process changes during these phases and it is vital that bridging studies are performed to demonstrate that the product is still comparable with the product from earlier clinical stages.
The process description should be in late draft stage, and process Critical Quality Attributes and Critical Process Parameters should have been defined (even if their values are still to be confirmed), the Design Space should be in draft state.
Risk assessments should be performed during these phases and remaining studies (i.e. confirmation of formulation) that may still be required to “fill the gaps” in the process knowledge such as scale-up or scale down studies should be planned and performed. Analytical methods if not compendial need to be defined and any validation required planned.
If technology transfer is performed during these stages the main aim should be to transfer what is known, and what is yet to be defined / determined.
By the end of these clinical phases all studies, process parameters, process descriptions and analytical methods should be complete and validated as necessary, as this will be the process that is used for the Process Validation.
Commercial manufacturing stage
At the commercial stage the process validation studies will have been completed and product licences granted. Although the clinical stages have been completed. However Technology Transfer has not – contrary to popular belief – been completed. Demonstrating that the transferred process is controlled and stable must surely be the aim of a successful transfer, and this requires careful post Process Validation monitoring and analysis as part of the process Continued Process Validation (CPV). Of course, I’m not suggesting that like CPV technology transfer never actually ends, just that a statistically significant number of initial commercial batches be studied to demonstrate consistency and control. How many is “significant” is probably another topic for another blog.
Some of the references used are:
- Chattaway, T. (2020, September 22). Tech Transfer: Unraveling the Complexities. BioProcess International. bioprocessintl.com
- Fallentine, B. (2019, February 1). Mind the Gap: Tech Transfer from Early Stage Cell Culture to Phase I Clinical Manufacture. Pharmaceutical Technology. pharmatechassociates.com
- Jones, T. (2018, January 16). 4 Steps for Successful Tech Transfer of Gene and Cell Therapy Products. Bluehatch Consultancy Ltd. bioprocessonline.com
- Makowiecki, J. (2020). Best Practices for A Successful Bioprocess Technology Transfer. Cytiva Life Sciences. lifescienceleader.com
- O’Sullivan, C., Rutten, P., & Schatz, C. (2020, July 23). Why tech transfer may be critical to beating COVID-19. McKinsey & Company. mckinsey.com
- Witcher, M. (2020, September 23). Can We Eradicate Tech Transfer and Other 20th Century Pharma Manufacturing Practices? BioProcess Online. bioprocessonline.com
- Agrawal, M., Eloot, K., Mancini, M., & Patel, A. (2020, October 20). Industry 4.0: Reimagining manufacturing operations after COVID-19. McKinsey & Company. mckinsey.com
- Best Practices for Technology Transfer. (2011, June 1). BioPharm International. biopharminternational.com
- National Institutes of Health: National Cancer Institute. (2020). Technology Transfer Considerations. PREVENT Cancer Preclinical Drug Development Program. prevention.cancer.gov
- Steinmetz, K. L. (2009, June 12). The basics of preclinical drug development for neurodegenerative disease indications – BMC Neurology. BioMed Central. bmcneurol.biomedcentral.com
About The Author:
Trefor Jones is a technology transfer specialist with Bluehatch Consultancy Ltd. After spending over 30 years in the pharmaceutical / biopharmaceutical industry in engineering design, biopharmaceutical processes, and scale-up of new manufacturing processes, he now specializes in technology transfer especially of biotechnology and sterile products.
He can be reached at trefor ”at” bluehatchconsultancy.com.