How To Reduce Costs And Risk For Cell & Gene Therapy Facilities
By Moria Feighery-Ross, CQA, CMQ/OE, senior consultant, Pharmatech Associates
When it comes to cell and gene therapy (CGT) facilities, how will you save costs in construction, commissioning/qualification/validation (CQV), and ongoing operations? Compared to traditional pharmaceutical and biotech facilities, cell and gene therapy facilities are simpler, requiring fewer critical utilities and needing only a limited selection of specialized systems since many processes are small-scale and enclosed.
As with many topics in the biopharmaceutical world, this discussion begins and ends with risk: What are the risks of a particular course of action and whom do they impact? How do you mitigate these risks? Who bears the costs of reducing or accepting risk? And, in this particular article, why is considering risk the best way to reduce the costs of a CGT facility?
Most of the formalized risk assessments we do in the pharma and biopharma industry are centered on risks to the patient, as represented by risk to the quality of the products used by and for patients. Even when we are doing a supplier or vendor risk assessment, we are ultimately considering the impact of the supplied material on product quality. However, in consideration of the fact that this is an article about cost savings, we are going to center the discussion on the risk of poor fiscal decisions, without ever, ever forgetting that the true bottom line is patient safety.
Spending Or Not Spending
In general, there are two ways to save money. The first is simple: save by not spending. The second is to save by spending; that is, determine where money wisely spent will save it elsewhere. You can apply these principles when you are designing and building the facility, during commissioning, qualification and validation (CQV), and in ongoing operation. Your strategy for each of these will have a certain amount of impact on the others.
When designing and building a CGT facility, by far the easiest way to save money doing it is not to spend. Let’s consider the aspects of facility design and capital project construction where there’s money to be saved.
A Dedicated Capital Project Manager
There are two critical ways to save by spending during design/build and they are 1) hire a design partner with deep experience in (bio)pharma facilities, and 2) hire an experienced, full-time capital project manager. If you take no other advice, let it be these; they are the best way to mitigate the risk of avoidable delays. It is absolutely painful to watch a facility be designed, redesigned, construction begun, design changed again, reworked, etc., while knowing that two-thirds of that work could have been avoided if the plan had been right the first time. For example, there’s no amount of experience in commercial facility HVAC that would tell a designer where the sinks should be in your pressure cascade if you’re using adenovirus as a gene therapy vector vs. expanding and purifying stem cells to treat nerve damage. Likewise, even the best facilities director will struggle to manage the build while simultaneously selecting and receiving equipment, staffing up, and building their department’s procedures, likely to the detriment of each of the tasks and the director as well.
Timelines And Risk
Another consideration for the construction side is that managing expectations around timeline is key. Compared to five years ago, lead times for construction materials and utility system components have increased dramatically. Likewise, the lead times for certain kinds of production and lab equipment have increased as well. If your schedule is built based on 2018 timelines, you might have a lot of people waiting around, and that time doesn’t come cheap. You will want a plan B and maybe even a plan C for suppliers of things like controlled-temperature environments and centrifuges if you want to start operating when you said you would.
But didn’t we promise a discussion of risk? Let’s talk about how properly applied risk assessments can save you costs in facility design and construction. While it’s true that aseptic processes require a cleaner environment than, for example, oral solid dose (OSD) pharma production, CGT processing is on a micro scale in comparison. A good risk assessment will indicate that certain process steps should occur within Class 5 glovebox isolators, and the rest are closed processes that do not require a Class 5 cleanroom with Class 7 separate gown in and gown out rooms and Class 8 supply and return corridors. That is a whole lot of HVAC you are able to spend less on specifying and purchasing, not to mention the ongoing operational and environmental monitoring (EM) cost savings of fewer square feet of highly classified space. When you are developing your EM program, use risk assessments to determine the places to pay the most attention to while reducing sampling in lower risk areas.
Another great place to discuss risk is in cleaning, especially equipment cleaning since we touched on the facility itself just above. Going back to OSD, since that’s where we started, can we talk about single-use-technologies? Now there’s how to eliminate some risk! Let’s just take entire pages of our old risk assessments and throw them right out the window. No more worrying about liquid retained in supply lines after cleaning and in storage! No more cycle development in autoclaves! Because the risks we mitigated with all that steam sanitization and parts washers needing utility water for injection (WFI) are eliminated, we can now purchase process water in adorable little bottles in cases to supply what the process needs. We now require only a square meter of controlled room temperature storage and a somewhat more expensive bill from the waste management company where we used to need an entire 12-liter-per-minute WFI still and a hot recirculating-loop distribution system that took a year to qualify and required ongoing monitoring.
The next thing we should talk about in facility design and qualification is economies of scale. The risk of a product not making it through clinical trials is very real. In addition, it’s not exactly a risk and sometimes it’s a goal, but many Phase 2 companies are acquired outright or their products are bought by a larger company. What, then, will happen to this shiny new facility? One potential solution to this challenge is a phased approach to facility completion and qualification – consider completing one clean suite and putting it into production so you can get to your next funding round while the next is finished and qualified or consider completing two but using one for non-GMP R&D, which has a lower operating cost. Or consider a large open warehouse-type space into which you can drop modular cleanrooms when and as needed. You have much lower utility and cleaning costs then, and qualification of a modular cleanroom is easier than a stick-built facility, if only because you’re less likely to find issues.
Commissioning, Qualification, Validation
Let’s talk specifically about CQV, although nearly everything we talked about above has implications in this area. Use risk assessment when determining what parts of your facility and utility systems can be commissioned and what parts need to be qualified. One example is that if you draw the system boundary of the HVAC right before the supply HEPA filters and consider those as part of the facility room, you can commission the HVAC and stop there, as long as you have robust EMS monitoring, a solid risk-based EM program, and continuous particle counts in-process. The risk of the HVAC system failing to filter particles is well mitigated by those detection systems and, anyway, you’re doing your open processes in isolators, right? You will, of course, have documented this rationale in a formal risk assessment.
When selecting equipment, you can reduce personnel costs by automating portions of the process, which also tends to reduce the risk of contamination by performing multiple steps within one system and reducing human contact. And when selecting automated equipment, you can also consider the types of systems that will enable you to scale out rather than up, meaning you buy more of the same unit and avoid the process of increasing the volume of materials in a unit operation, which is rarely as simple as we’d hope.
When qualifying GMP production and laboratory equipment, consider buying vendor protocols and perhaps execution as well. There are several good reasons for this, starting with the fact that some systems require someone who is very experienced with the equipment to even write a test script for it, and some systems must be tested by someone with an external laptop and proprietary test software. Frankly, it would take even a highly experienced validation person long enough to become familiar with the equipment to generate a good test script that it’s simply more cost-effective to let the vendor do it. You need only to review the testing carefully to be sure it covers all your user requirements and company procedural requirements.
Phase-Appropriate Approach
When it comes to purchasing benchtop equipment for an early clinical operation, you are frequently tasking your R&D personnel to develop the clinical process. Now, this approach can be a big step for an experienced QA person to make, but right here you can apply phase-appropriate qualification and life cycle documentation. Try thinking about it this way: The only requirement my user can articulate is that they want this make and model. Lean into this, allow the vendor specification to become the URS, and test the equipment against it using the vendor’s own test scripts. This is exactly backward from the traditional expectation, which is to write the requirements then select the equipment that best meets them, but the only real risks to the approach are that Part 11 and data integrity requirements are not always explicitly covered in vendor documentation and qualifications. You would discover this while you are reviewing the vendor protocols and working with the vendor to get tests added or generate a wraparound protocol to cover those items to your satisfaction. When implementing this solution and phase-appropriate CQV in general, a key point is to remember is this: There is no “phase-appropriate” for data integrity; every record should be assumed to end up in your regulatory submissions.
There are many ways to reduce costs in designing, building, and qualifying a CGT facility, and the most important thing to consider is this: You can adopt any number of interesting solutions as long as you have a thorough, documented risk assessment and rationale for the risks you are accepting. Be honest with yourself, QA, and your company about what the risks might be and the mitigations and justifications for your course of action. We would wish you good luck, but if you do your risk assessment right you won’t need it. Go forth and succeed!
About The Author:
Moria Feighery-Ross, CQA, is a senior validation engineer for Pharmatech Associates, working in the regulated life sciences industry for more than 10 years. With technical expertise in validation and quality management systems, she provides end-to-end support for pharma, biopharma, and medical device companies of all sizes, with emphasis on development, remediation, new facility startup, and validation. Feighery-Ross holds a B.S. in biology from the University of California, San Diego.