An interview with John Taylor, president and principal, compliance and regulatory affairs at FDA regulatory consulting firm Greenleaf Health
For the last half century, pharmaceuticals have been produced using an approach called “batch manufacturing.” Batch manufacturing has played an important role in bolstering the United States' leadership in the discovery, development, and manufacturing of new and innovative drugs. However, over time, many have come to realize that it is not necessarily the most efficient process nor is it the best process for ensuring product quality. For these reasons and due to advances in manufacturing technology, experts are exploring alternatives to batch manufacturing that have been utilized by other industries. A showcase example of this is “continuous manufacturing.” This approach has several benefits including offering fewer interruptions during production and reducing product failures. Because of its attributes, continuous manufacturing also makes it easier to address the scale-up of materials as the drug is being designed and developed. Additional benefits include a potential reduction in the facility's physical footprint as well as a reduction in overall capital costs.
The petrochemical, chemical, steel casting, and food industries have been using continuous manufacturing effectively for some time. With chemistry as the driver in the petrochemical and chemical formulations, the process made a natural transition to small molecule drug manufacturing, where successful implementations have been completed, such as with Pfizer’s Lipitor. As the industry explores the use of continuous manufacturing, the issue has found itself at a crossroads— there is growing interest in the value of modernizing technology and its potential benefits have been accepted, but how can broader adoption occur when it comes to manufacturing drugs?
The topic of quality remains at the forefront of this discussion. While the FDA is supportive of innovation in pharma, its key concern will always be that the system in place—whatever it might be—is one that produces drugs with the utmost standard of quality. Lapses in the quality of drug manufacturing have the potential to significantly impact patient care and result in product recalls as well as harm to patients. Therefore, the onus falls on vendors and manufacturers to come up with a design process and control strategy that allows them to identify critical process parameters to detect deviations and other issues as soon as possible.
Despite the benefits noted above, continued skepticism has slowed the adoption of continuous manufacturing. This is because of concerns among manufacturers that implementing new technologies may subject them to additional regulatory liability and/or affect the approval timeline (or even the approval itself). However, the FDA has made a concerted effort to educate itself on these concerns as well as on continuous manufacturing, and it is taking proactive steps to foster the drug industry’s implementation of continuous manufacturing. As a result, valuable tools are now in place to facilitate manufacturing changes with the FDA. By not understanding the availability and value of these resources, manufacturers are making a sizeable mistake that could potentially impede the industry’s passage into the next phase of modernized manufacturing.
Manufacturer Fears: Does Switching To Continuous Put Product Approval At Risk?
While FDA officials, such as Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), have communicated the agency’s support for continuous manufacturing, companies are still reluctant to venture down innovative paths in process development. The fear is that, because today’s policies still focus on the GMP regulations designed more than 50 years ago, a manufacturer is taking on additional regulatory liability by trying something new. “When the agency began to advocate for the adoption of modernized technologies, the comment that we heard from some in industry reflected the notion that continuous manufacturing may be something senior officials support, but that does not help if there are pockets within the FDA that still do not support the adoption of these modernized approaches and consider them not compliant with FDA’s Good Manufacturing Practice,” explains John Taylor, President and Principal, Compliance and Regulatory Affairs at FDA regulatory consulting firm Greenleaf Health. "This was a legitimate concern for any company considering the switch because of the perceived regulatory liabilities associated with doing so.” These liabilities can exist in two ways: The first is, if a product is not on the market yet, a manufacturer must prove it will be manufactured in accordance with GMP regulations as part of the product’s approval. This ensures that when the product moves to commercial manufacturing, it retains the safety and efficacy that FDA determined it had at the time it was approved. So, some in industry continued to utilize a batch approach because they feared that adopting a new manufacturing process that may not be in compliance with GMP could prevent the product from being approved.
The second concern involved potential regulatory liability for products that have been approved and are already on the market. “For example, if a vaccine has been manufactured with batch processing for the last 20 years without issue, its safety and efficacy profile has been well-established and maintained,” explains Taylor. “A company would be reluctant to change its manufacturing process, even if the current one is less efficient and does not necessarily lead to the optimal quality profile. The concern was that, if a change was made to their process and the FDA determines the modernized approach is not in compliance, a company could be subject to a regulatory action. In a worst case scenario, the agency could either halt manufacturing or seize the product until compliance is achieved.” Despite Taylor’s acknowledgment that these are legitimate concerns, he believes the FDA has taken great strides to overcome the perception that it would be uncooperative. “In recent years, the FDA has worked with academics to learn more about continuous manufacturing and redoubled its efforts to allay industry’s concerns,” says Taylor. “Representatives have talked to people within the industry to get a better understanding of the steps the agency can take to make a company feel more comfortable about adopting these more modernized approaches.”
Other factors, such as drug shortages, also brought the two sides closer together. Failures in product or product quality can be a major factor when it comes to disruptions in manufacturing and limited product availability. Around 2012, the pharmaceutical industry saw an alarming increase in drug shortages. The reasons for this varied. In some cases, manufacturers voluntarily stopped manufacturing to achieve an improved quality profile. The issue was not that they had fallen out of compliance over time; instead, manufacturers began to recognize the consequences that can occur when relying on practices that are over 50 years old. “Just because your facility is GMP-compliant, that does not mean you are producing drugs with the highest level of quality,” notes Taylor.
In other cases, the shutdowns were the fallout of manufacturing lapses or the weakening of certain manufacturing approaches by industry that led to failures in product quality. Regardless of the reason, this led to a greater willingness by the industry to consider continuous manufacturing. It also resulted in a commitment by the FDA to show it was willing to change its longstanding thoughts on what is considered GMP-compliant.
What Has The FDA Done For You Lately?
In 2004, the FDA issued a draft guidance titled Guidance for Industry PAT (Process Analytical Technology): A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance. In it, the agency states the guidance’s intent was to “encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance." The document describes the FDA’s strategy to encourage consideration of these new approaches to manufacturing and, as it states within the guidance, “to alleviate concern among manufacturers that innovation in manufacturing and quality assurance will result in regulatory impasse.” This was the first major undertaking by the FDA to show its acceptance of modernized manufacturing approaches, such as continuous manufacturing. In January 2015, the CDER established the Office of Pharmaceutical Quality (OPQ). This office provides “a uniform drug quality program,” where the industry’s questions and concerns about manufacturing modernization can be addressed. It was the formation of the FDA’s Emerging Technology Team (ETT), though, that has really painted the clearest picture of the agency’s acceptance and support.
The ETT is responsible for working with companies that wish to, as part of the approval of their products, move towards a continuous manufacturing approach. According to the FDA’s website, ETT “includes representation from all FDA pharmaceutical quality functions, to provide cross-functional expertise to the questions posed by program participants on their proposed technology.” A company can use the ETT as a resource to ask questions about the process as modernization is taking place within their facility. “In the case of new drugs, FDA wants to prevent the company from going in the wrong direction or taking missteps that might threaten the eventual approval of the product,” explains Taylor. “Consequently, it devotes resources to work collaboratively with companies that want to make this change. When the time comes to seek approval of the product, the FDA is then already familiar with the company’s manufacturing concept.” The ETT intends to address the industry’s fears about approval while also achieving the FDA’s overall goal of ensuring the product will be subsequently manufactured in a way that ensures its safety and efficacy. The ETT released the guidance document Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base as another resource to help with this transition. The ETT provides similar support and guidance when a company is contemplating modernizing its manufacturing process for drugs that are already approved and on the market.
Recent success stories within the industry offer examples of how these efforts by the FDA to encourage and support continuous manufacturing can pay off. The first is with Vertex, the maker of the cystic fibrosis drug Orkambi (lumacaftor/ivacaftor). As part of Vertex’s approval process, the company met with the FDA prior to submitting its approval for the drug, in order to seek feedback for the continuous manufacturing facility devoted to the manufacturing of Orkambi. When it came time for the agency to review Vertex’s application, both the drug and the manufacturing approach were approved because of the FDA’s familiarity with the facility. Janssen’s approval of its manufacturing change from batch to continuous manufacturing for the HIV drug Prezista (darunavir) in April 2016 is another example of the success the industry has had working directly with FDA. Janssen cites the ETT guidance document as a resource that facilitated its manufacturing advancement.
The Regulatory Road Ahead
Switching to a more modern manufacturing approach is not just about keeping up with the latest trends or reacting to a drug quality issue. In fact, by calculating the value of quality based strictly on whether their current process is GMP compliant, there are regulatory restraints, or people have been harmed by poorly manufactured products, Taylor says a manufacturer may be looking at the value proposition of continuous manufacturing too narrowly. “The assumption that a product has achieved optimal quality just because it has not harmed anyone draws the wrong set of conclusions about whether to adopt these new technologies,” he explains. “There are other industries, such as food and steel, that do not have a risk profile as acute as pharmaceuticals, yet they have embraced continuous manufacturing. With pharma being an industry that has a major impact on public health, it stands to reap the most benefits when it comes to proactively improving product quality.”
As much as quality means to any drug manufacturer, the costs of switching to these approaches has to be a consideration. A considerable amount of money has been poured into designing facilities around the world based on old principles and approaches, so it is only natural to be reluctant to turn on those investments. However, Taylor says it does not have to be an all-or-nothing decision. “There are certainly upfront costs of buying new software and adopting new systems. However, even if a company is reluctant to adopt a fully-integrated continuous manufacturing process, companies like Finesse offer manufacturers an opportunity to adopt a hybrid approach that is part continuous and part batch. This option does not does not require a full investment in a new system, yet it can still realize several advantages.” So, what should manufacturers do as they begin to make this journey into the next phase of manufacturing?
“First and foremost, review the information the FDA has put out to date regarding its stance on modernized manufacturing, in general, and continuous manufacturing, in particular,” says Taylor. “This is not just to ensure you understand the agency’s expectations but to also allay any concerns you might have about the desire of the agency to work you toward this goal. Next, initiate a dialogue with the FDA about the emerging technology you are in the process of developing and hoping to adopt.” He advocates this be done prior to any submission document, and it must be done early. This allows both sides to anticipate, address, and discuss any problems that could delay the introduction of the new approach and, therefore, the approval of the drug product. Taylor continues, “Ask the agency to provide tangible feedback on adjustments that should be made in order to meet the FDA’s goals and objectives.”
Finally, he urges manufacturers to seek a vendor that has honed in on developing technologies and equipment that does more than just manufacture products well. There are undoubtedly modifications that will need to be made and they must address the concerns the agency has articulated in the past when it comes to adopting these new types of technologies. Also, an ideal vendor does not just help you design and develop a process; they continue to support your new manufacturing approach after it is approved by the FDA. “Any good vendor sees themselves as a partner in your endeavor, not just its own commercial success,” he explains. “They should be willing to have an open dialogue with you that embraces the fact that adjustments might have to be made. Your partner should welcome that knowledge and act on it early so time and money are not poured into a suboptimal approach. Do your due diligence when it comes to vendor selection in order to forge a true interactive relationship.” The goal is to speak in one voice that articulates the same expectations, as opposed to risking a disconnect that will emerge during your discussions with the FDA.
“These are just the first steps a manufacturer must take in order to execute a seamless transition to a manufacturing approach that delivers the quality both the FDA and the public expect,” says Taylor. “The biggest mistake anyone can make is not using the tools and resources the FDA has worked so hard to create. Seeking the agency’s insight and doing so early allows you to make adjustments in a way that is less burdensome than what you contemplated, thereby giving you a clearer path for success.”