By Trefor Jones, owner, Bluehatch Consultancy Ltd.
As the gene and cell therapy sector develops and its products start to move from development to commercial manufacture, the requirement for the technology transfer of these products will only increase. This technology will transfer from smaller or academic establishments and development laboratories, to larger facilities with greater capacity in-house, or to a partner company or CMO. It can occur at any phase of a product’s life cycle, from R&D preclinical stages to post-Phase 3 clinical trials to full commercial production.
What Is Technology Transfer?
ICH Q10 defines technology transfer as a stage of the product development life cycle:
“The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement.”1
In practice this means passing on all the information required for the receiving site to be able to replicate the manufacture of the product, at the required quality and scale in a safe manner, and in a way that complies with regulatory requirements. Specifically, this product knowledge transfer should include a detailed and robust process description and its experimentally derived critical quality attributes (CQAs) and critical process parameters (CPPs).
Differences/Risks Particular To Gene And Cell Therapy
The methodologies used in the technology transfer of pharmaceutical and biopharmaceutical products are well-documented.1-5 However, the technology transfer of gene and cell therapy products is different than traditional technology transfer methods in several fundamental aspects due to the unique nature of the products and their manufacturing methodologies. Some of the main issues/differences are as follows:
- Gene and cell therapy product manufacturing processes are complex.
- There is a lack of standardized operations (i.e., everyone does it differently, using different equipment, different methods, etc.). Ensuring alignment of the sending and receiving sites in terms of equipment and prior knowledge as in traditional technology transfer processes probably will not work in these cases.
Each manufacturing process is bespoke and requires skilled manual operations. In some cases, it’s more of an art than a science. This applies equally to the production and the analytical processes used.
- The starting materials are usually obtained from many individual patients and lack consistency and, in many cases, may come from patients in ill-health or who are receiving other drug therapies at the same time. Starting materials can vary dramatically from patient to patient depending on severity and/or type of illness, age, previous therapies administered, and other clinical factors.
- Some reagents may not be available in either the quantity or quality required for advanced development or GMP manufacture, such as uncharacterized animal-derived materials.
- The processes (e.g., apheresis and purification) may no longer be co-located (or even close to each other), requiring both extended time and transport conditions among the different locations to be assessed. The effect on the product’s critical quality attributes (CQAs) and characteristics should be investigated and fully understood.
- Scaled-out processes can become unmanageable once a larger number of time-dependent steps coupled with the real-time completion of documentation are required.
- Some analytical processes may not be suitable for the increased number of samples required for increased scaled-up or scaled-out processes.
- There may be a lack of basic GMP awareness in early stage development laboratories, which can lead to processes being developed or methodologies used that are not compatible with GMP requirements. CDMOs find the state and quality of the manufacturing processes being transferred to them can vary extremely among clients. This can “often correlate to clients’ understanding of good manufacturing practices (GMPs) and what is appropriate for each phase of a planned clinical trial.”6
- Some production processes may not be scalable (e.g., laboratory use of rotary evaporators or benchtop centrifuges not easily scaled up).
If these issues are not addressed at an early stage in the product development, the technology transfer may require significant changes to the process to make it economically viable. This incurs a significant risk with regard to comparability of products made by the original and new processes and may require a repeat of your clinical trials.
So, what do you need for successful technology transfer?
Step 1: Realization
The first step is to understand that technology transfer of gene and cell therapy products is not something to be embarked upon only when you need to transfer a process. Preparation is the key. Poor preparation inevitably leads to sub-optimal technology transfer, which in turn often leads to significant delays, the need to repeat work, and a negative financial impact. Technology transfer is a journey, not a destination.
Step 2: Risk Assessment Of The Current Process
- Does your process use GMP-grade materials (e.g., contains no material of animal origin)?
- Can your current or alternative suppliers continue to supply the materials for the next 20 years?
- Considering the grade and purity of the raw materials: Are you absolutely sure the effect you see is not due to impurities in the reagents and materials you are using?
- Are you developing an appropriate sample plan so as the product develops, you don’t use all the product for stability testing and analytical tests? This may be acceptable to some extent at early development stages but disastrous at commercial scale.
- Are you leaving potency and comparability studies to Phase 3 trials? It’s very tempting to save money during Phase 1, but by Phase 3 you might find you have to repeat development and clinical trials if you can’t demonstrate comparability.
- Do you have a rigorous understanding of the desired product quality profile?
- Have you reviewed the business goals for your product and identified areas (both process and analytical) that can be invested in immediately and areas where investment can be delayed? For example, ensuring a manual process that will suffice for the time being is readily scaled up or automated with low comparability risk later on?
Step 3: Risk Assessment Of Transferring, Scaling-Up, Or Scaling-Out A Process
- Changes in starting materials: Has product development been carried out using materials solely or predominantly from healthy individuals? This carries a risk of unanticipated effects (on both manufacturing processes and analytical methods), as that may not represent the material from affected patients who may also be receiving other drugs as part of their treatment.
- Changes in reagents: Changing from a laboratory “technical-grade” reagent to a “USP-grade” reagent can sometimes have a significant effect on manufacturing and analytical processes.
- Changes in equipment size and process scale: It will not be possible to maintain the same dynamic process parameters in larger-scale equipment as in bench-scale equipment, especially in equipment such as bioreactors where several CPPs have to be controlled simultaneously or in mixing systems where parameters such as mixing speeds cannot be linearly scaled. Quite often, even small changes in the scale of cell culture processes can have a significant effect on the process or product quality.
- Changes in equipment type: During technology transfer there can be many reasons for changing the processing equipment used — perhaps better or more efficient systems are available such as for washing or isolating cells, or to take advantage of improvements in monitoring and control, or simply because scaling-up laboratory systems such as culture plates is not feasible. Even slight changes to equipment can change the processing environment.
- Changes in process timing: Extra time needed for real-time documentation of the process as well as the requirement for real-time activity verification (and documentation of) by a second, independent observer can add significant times to each process activity.
- Changes in product storage and shipment: It is probable that small-scale processes that are currently co-located will have to be separated as the scale of manufacturing increases or to meet GMP requirements. Cell therapy products may be manufactured in a central location (such as Novartis’ Morris Plains facility in New Jersey) with raw materials and finished products shipped either frozen or under controlled conditions to and from clinical locations. Such issues as risk to product quality from freezing and thawing processes or shelf life if not frozen need to be established, together with supply chain risks. Transportation and freeze/thaw cycle studies not typically performed during product development have to be performed before technology transfer can be successfully performed. For patient-specific products, sub-batch processing (splitting a lot to compare processes at transfer and receiving sites) might not be feasible.
Step 4: Start Planning Now
Understand, validate, and document the process.
Document each step of the current process in as much detail as you can. This should include all equipment and materials used and step-by-step instructions. This document is usually referred to as a process definition.
- Do not assume that just because you use a “standard operation everyone knows how to perform,” that everybody does indeed know how to perform it.
- Do not assume that because a process is detailed in an SOP that you do not need to document it — it is unlikely your CMO has the same SOPs!
- Specify each material used, including the vendor and grade of material.
- Document the process parameters and the variation allowed (when, for instance, you specify pH7, do you mean pH 7.0000 or pH 7.0 +/- 0.1). Specify which parameters are critical to the process and product quality. Define the CQAs and CPPs for your process.
- Document the timeline for the process. Which time intervals or operations are critical to the process?
- Review development reports and document the process and product consistency (variability), robustness, and failure rates.
- Document the product release specifications.
Understand your analytical methods.
- Ensure you have developed suitable analytical assays to define and monitor the consistency of a therapy’s functional attributes for product release after manufacture.
- Appropriate analytics are especially needed for autologous therapies to assess potency and to be used for comparability across batches for a single patient or across multiple patients.
- It is essential that these analytical techniques be non-destructive or at least do not use up too much of the product.
- Ensure the required analysis methods are available at the right time and available at the CMO. Some CMOs outsource/sub-contract their analytics.
- Keep in mind that the analytics are a GMP process in their own right. And being so, if new methodologies have to be developed, who has the IP on the analytical method?
Create a technology transfer pack.
A technology transfer pack should contain all the information necessary for the GMP manufacture of the product. However, a properly structured technology transfer pack will also contain the results of the risk assessment processes. Part 2 of this article will examine the contents of the technology transfer pack.
- World Health Organization. Annex 7: WHO guidelines on transfer of technology in pharmaceutical manufacturing. WHO Technical Report Series, No. 961, 2011.
- ISPE. Good Practice Guide: Technology Transfer. 2014.
- Schmidt, W., Uydess, I. “Keys to Executing a Successful Technology Transfer”. Pharmaceutical Technology, Volume 2011, Supplement, Issue 2, Feb. 1, 2011.
- Perry, S. “Tech Transfer: Do It Right the First Time”. Pharmaceutical Manufacturing, Jan. 6, 2010.
- Schniepp, S., Harrison, A. “Requirements for Product Technology Transfer”. Pharmaceutical Technology, Volume 40, Issue 4, Apr. 2, 2016.
- Mcintyre, C., Sumen, C. “Are You Ready for a Tech Transfer? Part 2: Challenges and Critical Factors for Success in Cell Therapy Development”. BioProcess International , Jun. 16, 2015.
About The Author:
Trefor Jones is a technology transfer specialist with Bluehatch Consultancy Ltd. After spending over 30 years in the pharmaceutical and biopharmaceutical industry in facility engineering design, biopharmaceutical processes, and scale-up of new manufacturing processes, he now specializes in the technology transfer of biotechnology and cell therapy products, working with many major companies (e.g., Biogen and Lonza) and contributing to the Parenteral Drug Association (PDA) outsourcing guide and the International Society of Pharmaceutical Engineers (ISPE) baseline guides.
A chartered chemist and scientist, Jones is a member of the Royal Society of Chemistry, ISPE, and the Institute of Chemical Engineers (IChemE). He gained his B.Sc. degree in biochemistry and genetics from the University of Liverpool. He can be reached at firstname.lastname@example.org.