As we all know, biopharmacology (as well as the pharmaceutical industry, in general) is highly regulated. In fact, experts in the area believe that it is one of the most highly regulated industries around the world. The groups that develop guidelines, standards, certifications, validations, and so on are focused on an extremely high level of quality from the pipes, tanks, and valves of the plant all the way through the finished product. Cleanability, sterility, and reproducibility are the focus — and perfection is the goal.
Figure 1. A view of the BioPharmaceutical world from a regulation perspective.
Figure 1 depicts the BioPharm purview of each group that influences guidelines, standards, and regulations. The influential agents (the ovals — BPSA, ASME-BPE, ISPE, FDA) cover different levels of the plant and manufacturing process (from base-level components to the actual production process). The entities (such as Suppliers, Distributors, and Drug Manufacturers) involved with development of each component, equipment used, or drug in these areas, are listed above their area of interest in the graph.
Of course, our description of these groups is a major simplification, because the organizations that we describe below are the ones that US-based companies predominantly deal with. Each global region typically has its own guidelines and standards for biopharmaceutical processes. And, each country has its own regulation body that is equivalent to the FDA. But the more that these national bodies can use internationally recognized standards, the fewer the hurdles that biopharmaceutical plants operating globally must overcome.
In the last 10 or so years, the industry has been pushing for two things, namely increased plant efficiency and manufacturing globalization; and this, in turn, has put pressure on plant automation. Each group involved in the standards, certifications, and validations has been working hard to keep up with the industry’s needs and to stay in sync despite the changes in the manufacturing processes.
Biopharmaceutical Standards and Certifications: How Did We Get Here?
In 1989, an Ad Hoc committee on Bioprocessing Equipment (BPE) was established to create a standard for bioprocessing equipment. The committee began by creating guidelines that covered the mechanical portion of bioprocessing in factories, specifying how to best design and build equipment used in the production of biopharmaceuticals. This standard was originally a set of best practices designed to ensure both manufacturing safety as well as consistent product quality and purity.
In the mid-1990s, the American Society of Mechanical Engineers (ASME) stepped in and requested that the guidelines be turned into a true set of standards that they could adopt; and in 1997, the first edition of the ASME-BPE Standard was approved and published. Although this standard is considered to be international, it is not universally adopted around the world. Many countries or regions have their own standards, which causes significant issues for companies who want to use the same factory equipment, design, and processes in multiple global locations.
In the last 10 years, the ASME-BPE has embarked on a certification process for all the components that are used to construct biopharmaceutical plants. The effort is designed to protect those who build the plants from purchasing sub-standard parts from new manufacturers around the world. The effort started with simple parts, such as tubing and fittings, and currently they are working on certification for gaskets. Each of these parts brings up complicated issues associated with material composition of the parts and specifics about allowable design features. And each of these decisions influences the other standards/regulatory agencies, all the way to the FDA.
The ASME-BPE and other certification authorities continue to march through this process. In our opinion, they have yet to hit some of the most interesting issues. Although biopharmaceutical plants are predominantly comprised of nearly static plumbing of tanks, pipe, and valves, automation has been sneaking into these plants. Pneumatic actuators and sensors (such as thermometers, blood gas analyzers, and nutrient monitors) are continuously controlled and monitored by software to ensure safety, cleanliness, and detection of issues. Through Bluetooth and WIFI links, the biopharmaceutical processes are now monitored by both plant operators walking around the floor (often with handheld monitoring devices) along with one or a few operators in a control room looking at displays and warning systems. Future steps will likely tie the control of the process to bioreactors and chromatography skids that will create the ability to continuously monitor the quality of the product. Another pressure is that the manufacturing process is moving from discrete batches to a continuous flow of product.
There is significant controversy concerning automation of pharmaceutical plants as pointed out by Scott and McLeod:
Often the point is made that making drugs (especially biologics) is too complicated to automate, that the regulatory requirements get in the way. [Christopher] Procyshyn [CEO of Vanrx PharmaSystems, Inc.] counters: “We can’t make cars that kill people, either.” The larger difference, he says, is in cost pressures and efficiencies. “With more pressures from global healthcare peers now,” he said, “we are seeing automation take hold. People want to put more into their R&D, and automation saves money. It doesn’t cost more if it’s done properly.”
While the speed at which automation is adopted is slower than other industries due to the cost of fail batches and revalidation with the FDA, the upside of automation, especially in aseptic processing is that you limit human intervention that might cause contamination. And, of course, operating costs go down.
Automation Software
Some of the more sophisticated plants are using commercial products like Rockwell Automations’ DeviceNet as a basis for communication between the sensors, valve controllers, and the control room. These products typically have certifications that indicate their reliability or ability to withstand harsh manufacturing conditions. They also have significant redundancy and robustness requirements, because their level of criticality is often significant. Critical failures of these plants rarely cause an environmental biohazard or serious explosion; however, a failure can cause the manufacturer many millions of dollars in lost product.
Commercial communication and control software products must also follow relevant ISO and IEEE software development standards as adopted by the FDA or other national bodies, such as the EMA (in Europe) and the MHLW (in Japan). These products are thoroughly specified, verified, validated, and tested. The use of common commercial technology and software cuts down on recertification of the software. But can pharmaceutical plants get by without customizing the standard commercial controlling software for their own plants? Scott and McLeod report from an interview with Martin Rhiel of Novatis that it likely isn’t that simple:
“It would be really nice to just buy it and implement it, but this doesn’t always work. In my personal opinion, a big hurdle is the regulatory environment. If you have a registered [validated] process, it’s difficult to change it, so that’s a big hurdle. Of course, there are cost pressures. Changing and revalidating a process and getting approval again, that’s a huge cost. So it was easy to use common technology that works well enough with the health authorities, and it was easier to get approval. If you’re at the forefront [of automation] and going to the health authority, it’s always difficult. But nowadays, the FDA is working together with pharmaceutical companies in implementing new technologies.”
It is clear to us that the biopharmaceutical plant automation train is going to continue down the tracks. It is obvious that when changes to control systems – software or electronics – are made, careful testing must be performed, because as many of us have experienced from software updates in less critical situations, they don’t always go as planned. The cost of mistakes in this arena are high.
As you can imagine, there are a lot of questions that people are asking at this point about testing and revalidating biopharmaceutical plant automation and the answers are not obvious:
Does there need to be software/electronics standards specifically for the biopharmaceutical area, or do the current medical device and medical software standards (such as IEEE 11073) suffice?
How are changes to the plant software going to affect the need for FDA revalidation? Can a company get by with just revalidating the part of the software process that changed? Is that even feasible in some situations?
What about software customization? How much harder is It going to be for a drug manufacturers to use customized software or special computer hardware? How difficult will it be to revalidate the process? How about validation of the use of non-specific hardware, like tracking or controlling the processes using an app on an iPad?
And how is certification and validation going to be done as these systems are internationalized to work with operators all around the world? Are the regulatory bodies in different countries going to work together to come up with agreed upon standards so that a manufacturer doesn’t have to revalidate a plant or process in every country where a copy exists? Or will internationally recognized SDOs like the IEEE and ISO take up the challenge?
As increasing amounts of technology and automation are used in bioprocessing facilities; finding answers to these questions (and others) will help improve the standards of the industry, which is why ASEPCO is involved in defining these standards. Perhaps, more importantly, it should lead to a reduction in risk when new technology is implemented. After all, an inherent component in striving for improvements on cleanability, sterility, and reproducability is the peace of mind that comes with reduced risk, which is something Asepco provides with all of its products.