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Contract manufactures are faced with multiple challenges when determining whether to implement process analytical technology into their clients' or their own infrastructure.
Although process analytical technology (PAT) has been applied in the chemical and food industries for years, adoption by the pharmaceutical world has been slow, largely because of strict regulations, the high cost of new instrumentation, and the belief that it's not worth fixing something that isn't broken.
In the broadest sense, the US Food and Drug Administration defines PAT as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality (1). In theory, PAT is a positive move to improve manufacturing processes.
For contract manufacturers, the decision to invest in PAT is even more difficult to make because any changes in processes must be approved by the client as well as the regulators. That said, many CMOs have moved ahead with their own PAT testing and installations, be they new analytical technology or new hardware that takes some of the effort out of testing.
Pat Coles, director of contract manufacturing quality at Hospira (Lake Forest, IL, www.hospira.com) says that the company tries to include PAT approaches in their designs and processes to meet various quality objectives. "Hospira's philosophy is that we want to make sure that our customers get the benefit of highly evolved manufacturing processes featuring high product quality, improved quality controls, high efficiency, and faster product release, which does have a financial impact on the customer," Coles says.
According to Anil Kane, director of formulation development at Patheon (Mississauga, ON, Canada, www.patheon.com), the key driver for PAT is the FDA initiative, which was created to encourage innovation among all manufacturers. "It reassures manufacturers that moving towards PAT is in their best interest."
Benefits of implementing PAT include:
Patheon wants to take automation one step further by implementing a tool that not only detects a deviation or problem, but also acts as a feedback control to correct errors. "It's not just about installing more sensors to detect things—we have plenty of those," says Enrique Nieves of Patheon.
For example, Mathis Instruments (Fredericton, NB, Canada, www.mathisinstruments.com) has installed an effusivity sensor technology for Patheon that monitors such solid dose processing steps as blending, wet granulation, drying, and roller compaction. Unlike near infrared (NIR) spectroscopy, which uses only one sensor, effusivity monitoring uses as many as eight sensors to measure a material's ability to transfer heat. According to Nancy Mathis of Mathis Instruments, when the client is ready to upgrade, the technology can be used to control the processes. "Right now, we can profile what is going on in operations so that [the CMO] can look for anomalies and scale up and develop processes with more ease," Mathis says.
The PAT solution
PAT means different things to different people, and everyone you talk to is viewing PAT through a different lens, explains R. Gary Hollenbeck, chief scientific officer at UPM Pharmaceuticals (Baltimore, MD, www.upm-inc.com). Historically, the pharmaceutical industry has emphasized post-process testing of pharmaceuticals. Tablets come off the manufacturing line and are tested through disintegration, dissolution, and a variety of assays to determine whether a batch of product is manufactured correctly.
"I see PAT as a shift in the industry toward paying much more attention to monitoring and characterizing the in-process measurements, so that they can assess and improve the quality of the dosage form," Hollenbeck says. "One thing that excited me about PAT was the possibility of ultimately approving a product for release without doing any wet chemistry."
For example, by using NIR spectroscopy, a manufacturer can theoretically scan a tablet at the end of the manufacturing process and nondestructively determine the quantity of each component in the finished drug product. "If you could do that, you could have 100% quality control," Hollenbeck says. "You can pass every tablet under the probe and see if it contains the right amount of active ingredient."
"PAT fits very well with one of our key objectives, which centers on continuous improvement," explains Carolyn Gherardi, vice-president of operations at OSG Norwich Pharmaceuticals (Norwich, NY, www.norwichpharma.com). Norwich Pharma has been exploring the benefits of PAT and has invested in engineers who are trained in PAT methods so as to offer its clients continuous improvement methods and cost-improvement options.
OSG Norwich's first piece of PAT equipment is a portable Raman spectrometer to be used at-line. Before implementation, the manufacturer would receive raw material at the loading dock and then have to send it on to a GMP sampling room. That sample would then be brought up to the laboratory for analysis, taking additional time. With the spectrometer in place, the receiving department can test the material directly, in the sampling room, thereby streamlining the process. The spectrometer uses a non-invasive laser that probes the sample through the clear plastic packaging, rather than use a thief tube to penetrate the product bag to draw a sample.
"The Raman spectrometer is low-hanging fruit," says Bob Bruns, manufacturing engineer at Norwich. "It's fairly low cost and it has a big payback, because we are going to be able to cut our cycle time significantly, and we are going to be able to reduce the amount of people it takes to do the work."
PAT—not just high-tech
According to Philippe Cini of Tunnell Consulting (King of Prussia, PA, www.tunnellconsulting.com), instrumentation is only a piece of the PAT puzzle. "I think there is a wide range of positions taken by contract manufacturing organizations relative to PAT and related subjects," Cini says. "There is no uniformity of strategy amongst contract manufacturers. My view of PAT is one by which we use knowledge and technology that allow us to design a process that is robust, so that we can manufacture the product right the first time. PAT-type techniques can also help bring a product to market faster."
Hyaluron (Burlington, MA, www.hyaluron.com), a 50-employee CMO that specializes in sterile vial and syringe filling, has begun using simple PAT methods for automating batch records. The company sets up batch records for each client. The records contain timed measurements of critical quality and performance attributes that track all results step by step through the manufacturing process.
Using various software modules, the company can track specific critical items requested by the client. All the analytical quality-control testing must be entered into the batch record before the next step in the manufacturing phase can take place.
"The only reason we can do that is because we are so small," says Kevin DeRosier, quality assurance auditor at Hyaluron. "Once you get larger, there are a lot more dynamics involved and it gets a little bit more delicate and a little more critical that you keep an eye on everything."
The CMOs that stand to reap the biggest reward from PAT are those looking to streamline the start-up process for new-product contracts. By beginning fresh, these companies don't have to decommission or replace working equipment; they can simply begin incorporating PAT from the ground up.
"PAT is much easier to get into if you have a brand new process and you're designing it, because you can put all the bells and whistles in place as you're designing the process," explains Dave Moyer, vice-president of regulatory compliance at Fulcrum (Morrisville, NC, www.fulcrumpharma.com).
UPM Pharmaceuticals is currently ramping up from manufacturing Phases I–II clinical supplies, to working with clients in the Phase III stage. The company intends to be a niche commercial manufacturer within a few years. Hollenbeck explains that the company has an advantage by being able to incorporate PAT from the start rather than add equipment later. "If you want to get a handle on a process, you need to start early and you need to collect the information that will help you institute PAT appropriately," he says.
As manufacturers incorporate PAT into their facilities, they also need to understand the control points of the operation, as well as the modifications that need to be made to existing processes. Every equipment change must be revalidated, which is a concern for CMOs and clients who have had the same systems in place for years. "That's why some people are apprehensive [about PAT], because they have products that have been validated and put in place with particular processes. So to go and look at another technology, the concern is that they have to look at the regulatory risk," Coles says.
As Moyer observes, "You have to have some common sense about what it is that you are going to automate. Sometimes a human being is a better solution than a computer or some PLC (programmable logic) controller."
Hollenbeck, who was on the pharmaceutical sciences advisory committee during the development of PAT, says that the impetus for PAT was a perception that pharmaceutical manufacturing wasn't achieving the same quality standards as other industries. "Our reject rate and failure rate is much higher than what you see in other large industries, and a lot of that is because of the way that pharmaceuticals are regulated," Hollenbeck says. "Currently there is a disincentive to improving your process, because [CMOs] have to file a new submission. If you change your equipment in any meaningful way that doesn't fit the SUPAC (scale-up and postapproval changes) context, you are going to have to do an awful lot of work. So there's almost a built-in incentive to keep your manufacturing processes the same as it was when your product was approved."
Another hurdle CMOs may need to overcome is client apathy. According to most of the contract manufacturers interviewed, clients are not requesting process analytical technology in their outsourced production. Many CMOs, however, are contemplating installing PAT methods on their own in hopes that the increased productivity will boost revenue for both the CMO and the client.
"Our clients are not the drivers [for PAT]," Gherardi says. "When we mention continuous improvement and the use of PAT, they seem to be interested and want to understand how we use it, maybe even get involved to some level in thoughts and application, but they aren't coming to us asking for it."
Danny Shaive, vice-president of pharmaceutical operations at Metrics concurs, "I've heard almost nothing from the clients, and that's something that has led me to think that [the PAT initiative] is Big Pharma led. Most of our clients are virtual companies that really need to get something filed with the FDA as soon as they possibly can, and they are really interested in the time line more than the latest technique."
Often it's the CMO that has to gain experience with PAT and explain to the client how the technology can fit a particular process and how they can both save money down the road.
Because Hospira works with so many different pharmaceutical companies, the company openly discusses PAT with clients and receives feedback from them. Cachich says, "We find it very useful collaborating with our partners and work very closely with one another. To be the most successful you have to have that kind of alliance mentality."
The high cost of PAT
Cost is one of the top concerns amongst CMOs considering implementing PAT methods. "These pieces of equipment come with a high price tag," Gherardi says. "From a contractor standpoint, we really need our customers to create some level of need for PAT as well, so we can partner with them in the right application." CMOs will have to spend money on:
Some contract manufacturers don't look at PAT as a viable commercial option, according to Cini. These companies cite two main reasons: they deal with many different products for many different clients, and they claim that their relatively low profit margins rule out implementing more expensive PAT techniques. "I believe these companies look at this the wrong way," says Cini. "PAT technique is not necessarily about high end, sophisticated, on-line analytical instrumentation that is dedicated to a process."
At the PAT Business Summit held in December in Philadelphia, Cini explained that the initial cost of implementation should be outweighed by the return on investment derived from quality assurance. According to Cini, the large pharmaceutical manufacturers stand to add more than a billion dollars in profits by using various PAT methods. Although the overall gains will be lower for smaller companies, they should still be significant relative to their total revenue."
"Considering the role of our company, we would do the client great justice if we could recommend applications with PAT to put in their processes that would save them money," says Fulcrum's Moyer. "Because at the end of the day, we sell ourselves not necessarily as the cheapest service in town, but what we do is give them a way to get to an endpoint faster. PAT might lend itself to a process that they might not have thought of, and we could recommend where it might fit in and help them get it in place."
When James Munson, director of analytical development at DSM (Greenville, NC, www.dsmpharmaceuticals.com) joined the company two-and-a-half years ago from a large pharmaceutical manufacturer heavily involved in PAT, he realized that there wasn't enough funding to build a true PAT system at DSM. "Another way PAT can be looked at is to take the data that you have now and compile things and do trending and correlation," Munson explains. "This is relatively inexpensive. You don't have to go out and buy instrumentation, you just use the data you have right now." This includes looking at raw material specifications and then correlating that data with finished product performance to look for irregularities.
Some CMOs are partnering with instrumentation companies to test some of these correlation techniques (the research relationship between Mathis Instruments and Patheon is one example). These outsourced manufacturers understand that PAT lets them produced higher quality products for their clients—quality they can produce at lower total cost, because they have better control and fewer rejects.
Cost sharing. Alliances open up the potential for cost sharing. Whether a client should pay for the benefit of having its product manufactured using a PAT-enabled system depends whether the new technology can be used for multiple product lines or solely for that particular client. "If we want to use a PAT application on a blender, but there really is only one customer that we feel will benefit from this, then we might approach the customer for a shared-cost model," Gherardi says.
In some cases, the CMO does not purchase the equipment and has no control over including PAT methods. "We've had situations where the client buys the instrumentation—they own it—and if the project is going to stay here, we will continue to use it," Munson says. "But if they decide to use it elsewhere, they can take it away. It's more of a partnership in that way."
CMOs versus Big Pharma
If a major drug company is manufacturing one blockbuster product, it can streamline a PAT initiative to focus on that one product, with an emphasis on the active ingredient. Most contract manufacturers, however, work on multiple products and can't invest in configuring manufacturing equipment to do PAT measurements for one product when that equipment is going to be used for a different product in the next cycle. This makes it more difficult for CMOs to implement PAT in existing systems, according to the companies interviewed.
"For CMOs, there are certain unit processes that we can attack, like drying," Hollenbeck explains. "When you're drying, you're basically getting rid of water and it doesn't matter what pharmaceutical product you're manufacturing: it's the disposition of the water that you're focusing on." In that case, a small CMO can introduce in-process control measurements to help build a portfolio for PAT development.
Other broad points of entry include the granulation process, in which heat and work developed can be measured in a standard way that can be applied to every process without focusing on the active ingredient.
"We need to keep in mind that as a CMO, we are typically executing our client's processes," says Lloyd Bailey, quality operations director at Dow Pharmaceuticals. "We don't own the processes ourselves, so we aren't responsible for developing those processes, unless the client contracts with us to further develop a process. Since we don't own the processes, we can't go off on our own and apply PAT to our pharma processes."
Although the prospect of revalidating equipment for PAT implementation might seem daunting to some manufacturers, most CMOs are reassured that the US Food and Drug Administration is one of the strongest advocates of PAT.
Hollenbeck says, "The [FDA's] PAT guidance is a unique document that has a lot more philosophy, and science written into it. It seems to focus on good process development and it rewards companies that do that."
PAT implementation, however, is taking so long "because everything is tied into the regulations," Moyer says. "You have to file a regulatory submission, and everything you desire to change requires a supplemental application or some consideration about how it's going to affect the product, so even with all the movement involving SUPAC, it's still not that simple. So making changes to an existing process does take a little bit of time."
According to Cini, Ajaz Hussain, the former-deputy director of FDA's Office of Pharmaceutical Science, ensured that safeguards are in place to alleviate fears that PAT might expose some of the weaknesses in the commercial processes that could lay the manufacturers open to regulatory sanctions: that sort of negative fall-out would slow down the endorsement of PAT. Instead, FDA has told manufacturers that PAT-generated data will have a safe harbor.
CMOs also were concerned that, although CDER representatives were well versed in PAT, field inspectors might not be. They might, for example, write up a plant for using evolving PAT applications that would have passed central-office review. FDA responded by identifying PAT-trained inspectors, and stipulating that only they conduct inspections at PAT sites. "FDA is going out of its way to really address fears and concerns that the industry has," Cini says.
Some CMOs continue to worry, however, that the unprecedented control that PAT offers could jeopardize the manufacturer by making it easier for regulators to catch variances or errors in manufacturing. Theoretically, an FDA reviewer can remotely log onto a company's enterprise system and observe the compaction force measurements for a particular batch of aspirin tablets, for example, monitoring on-line whether this process is up to specifications.
"While the FDA is encouraging folks to pursue PAT, there are a lot of folks still taking a wait-and-see attitude in regard to how the agency is actually going to regulate it ultimately," Bailey says.
1. FDA, Center for Drug Evaluation and Research: Office of Pharmaceutical Science, "Process Analytical Technology (PAT) Initiative." http://www.fda.gov/cder/OPS/PAT.htm, accessed Dec. 15, 2005.
2. G.F. Roberts, "The PAT Team and its Role in Your Success." Power Point presented at the PAT Business Summit, Philadelphia, PA, Dec. 5–6, 2005.