We have a story that we tell to new employees who need to understand the challenges of supplying and using equipment in the bioprocessing industry. It is about one of our favorite customers who has used our products for years. One day, years ago, they called us to their facility. They took us to a conference room, and then they dumped a pile of failed Silicone diaphragms on the table and said, “We have been using your diaphragms for years and this has never happened before. What did you change?” We responded with, “Nothing! What did you change?” They, of course, responded with, “Nothing!” The issue is that we were both telling the truth, well almost.
For years, this customer made a batch of their product every 30 days. They never had a diaphragm fail, but could start to see the signs of wear after a year. So they replaced their diaphragms like clockwork every year.
As business got better for them, they refined and improved their process, which allowed them to increase their batch frequency from 30 days to every three days. Yes, three days. Instead of making 12 batches a year, they were making over 100 batches a year. So, although they didn’t change their process at all, they were now exposing their Silicone diaphragms to harsh CIP and SIP processes every three days instead of every 30. As a result, they were experiencing diaphragm failure at the end of several months.
As we discussed the issue with them, it was clear that what they really wanted was the same thing anyone who has to go through a stringent validation process would want when solving a problem: they wanted the existing Silicone diaphragms to last longer—by decree. Of course, at the time, as we said to the customer, “There are only two options. The first option is to change your diaphragms more frequently. The other option is to change to another diaphragm material, like EPDM, which will last significantly longer in your processing environment and allow you to increase your preventive maintenance schedule.”
As you can imagine, the customer’s reaction was, “Changing diaphragms as often as we are, isn’t viable. It adds way too much downtime and cost to our process. Changing materials would also be problematic, because we would have to revalidate our process, which would be a huge cost in time and money. Isn’t there any way to improve the Silicone diaphragm so that it will last longer and we won’t have to revalidate?”
Figure 1. ASEPCO’s family of diaphragms
The Art of Pharmaceutical Plant/Process Validation
Most of our customers would have switched their diaphragm material, if the material worked with their process, and returned to business as usual. Why not this customer? Part of it has to do with the art of process definition and validation. We actually have customers who anticipate the need to evolve their processes and plants over time. Instead of specifying only one material (like Silicone), they validate their processes with multiple materials to give themselves the flexibility to change materials in their process, if necessary. That way, if they need to change a material, they can do so quickly and efficiently.
Unfortunately, there are a lot of processes running right now that can’t be changed—even a small amount—without revalidation, which is time consuming and costly, especially when you factor in the production losses.
We are hoping that the FDA’s new Quality by Design (QbD) process validation guidelines enable and encourage companies to make minor changes without revalidation. The FDA wants to require that all companies have a solid process-development program that can help expedite the product approval process. In theory, this type of program will allow companies to develop and validate a “design space” for the product development process. The “normal operating range” of the process will be within the design space, but changes in materials, the plant, or the process that are still within the design space won’t need to be revalidated. In essence, there are potentially many valid alternative operating ranges that do not require approval (see Figure 2).
Figure 2. Quality By Design (QbD) illustration
The hope is that companies will be able to continuously improve their process as new technology and materials are available that they want to integrate. Although we think that defining and validating the “design space” is likely going to be an art form, this approach definitely has the potential to encourage innovation within the industry.
Some of our customers would tell you that asking them to anticipate process/plant evolution is just too much. But let’s look at another industry that has to deal with this issue at a ridiculous level. The electronics industry is used to having to deal with Moore’s Law. Every couple of years, they are forced to increase the power of CPUs and the amount of memory in devices by an order of magnitude. In addition, the size of electronics continues to decrease. A computer that would be the size of a 20 ft x 20 ft room in 1980 now fits in a wrist watch. In addition, the cost of the same compute power has gone from 10 million dollars to 200 dollars.
Figure 3. Illustration of Moore’s Law
The only way that the electronics industry has been able to make this happen is by continuously updating their processes and plants. They are constantly looking for ways to make things smaller, cheaper, faster, and more powerful.
Ah, you say that the comparison is not a good one. The electronics industry doesn’t have the myriad of governmental regulations or safety issues that they are required to comply with. That’s true. However, we are often struck with how little effort and resources biopharm companies put into process/plant innovation. Yes, they do put a huge amount of resources into looking for and developing new products, but not for adopting new manufacturing processes on an industry-wide basis.
Going back to our earlier story, we had a customer who clearly wanted better results than they were getting, but were reluctant to make any changes, because of how onerous making a change was in their environment. Embracing change, especially new technology, is one of the biggest (and most ironic) challenges for the bioprocessing industry. Here is an industry dedicated to discovering and creating cutting-edge drugs to improve the life and health of their customers. On the other hand, there is typically a strong impetus to prevent change in processing equipment, because there is risk and cost associated with those changes.
A great example of quick embracing innovation is the introduction of disposables. Since its introduction to the market, disposable technology has grown quickly and is used throughout the industry today, from sampling to production. While this technology has its advantages and disadvantages, it has largely been accepted by the industry to improve processing in applications for which it is best suited.
Conversely, you can find examples of great technology that was never fully adopted by the industry. For instance, there was a fitting developed more than a decade ago that solved the problem of gasket intrusion for the industry, but has never been fully accepted or widely adopted.
There are many reasons technologies are not adopted, including high implementation costs, too many competing technologies, and industry regulations, among others. As the industry matures, we need to develop ways to find, investigate, and quickly adopt the best solutions available.
Supporting Plant/Process Evolution
So, how do we encourage more innovation? Even though most biopharm companies have pilot plants that they use to carefully evaluate their processes, equipment changes, and new technologies, we think they often abandon ideas prematurely if it is not clear that the benefits of the change will be greater than the cost of adoption.
On the bright side, changes are happening now in this industry that can help foster innovation, such as the creation of test protocols, like ASME Bioprocessing Equipment (BPE) Standard Appendix J – Standard Process Test Conditions for Seal Performance Evaluation and the awareness of and collaboration between different industry groups, such as BioPhorum Operations Group (BPOG), ASME BPE, and EHEDGE.
ASEPCO is more than willing to help you with your process/plant evolution. We are constantly evaluating and evolving our own products to help you increase the efficiency of your processes and the quality of your products, while decreasing the cost of maintenance.
We have helped a number of our customers simplify their plumbing to improve the quality of their product. Ask us, and we will help you, too.
- Figure 2 from “How QbD and the FDA Process Validation Guidance Affect Product Development and Operations, Part 1” by Peter H. Calcott (http://www.bioprocessintl.com/analytical/downstream-validation/how-qbd-and-the-fda-process-validation-guidance-affect-product-development-and-operations-part-1-323457/).
- Figure 3 from “After Moore’s Law” by Dr. Jim Greer of Tyndall, in The Economist, March 2016 (http://www.economist.com/technology-quarterly/2016-03-12/after-moores-law).