Quality by Design in Solid Dosage Processes
How will QbD impact manufacturing?
by Tom Spurgeon
Appropriately for a systemic approach that achieves its aims by applying scientific method to process, Quality by Design, or QbD, developed from a synthesis of management ideas that ranged from theory (Joseph Juran's re-appropriation of Vilfredo Pareto's principle) to breakthroughs in statistical analysis (perhaps most significantly from Walter Shewart and W. Edwards Deming), extending itself outward to behavioral psychology and the sociological observations of Margaret Mead. A counter-conversation to long, widely-held principles regarding quality control by end-testing, QbD has increasing institutional support and a growing, significant presence within the FDA. Despite some unique barriers to widespread adoption, its general principles are beginning to trickle with greater and greater force into general conversations about monitoring and efficiency, changing the culture from one of informational parsimony to one of continuous, rigorous feedback.
There are any number of documents explaining what QbD is and how it relates to the pharmaceutical industry. Dr. Kwok Chow, senior director of PDS Pharmaceutics Technologies at Patheon, Inc., identified Quality by Design as a "key component" of the FDA's Pharmaceutical cGMP Initiative for the 21st Century, and identifies four factors, or principles, within its make-up:
Quality of a product should be built by design and it cannot be tested into products.
Instead of providing the FDA with fixed process para-meters and stability data, the new approach requires that filing companies demonstrate a broader understanding of the formulation and production process to support the establishment of the design space, specifications and manufacturing controls. It isn't so much about arriving at the finished process parameters but how you get there and how you demonstrate the robustness of the formulation and process.
Manufacturing within the approved design space provides opportunities to yield products using a more desirable range of parameters and without filing post-approval changes.
Tools for QbD include Design of Experiment (DoE), miniaturization PAT and robust quality systems to establish design space and control strategies.
Dr. Chow pointed out that QbD has been applied to other industries much more thoroughly than in pharma, and that the early adopters did so in order to pursue "quality, efficiencies and cost reductions." These are goals shared by most industries whether or not they favor process or end-result quality controls; this indicates that not only must pharmaceutical companies adopt new principles, they must fold existing and emerging technologies into this new way of thinking. Dr. Chow described the needed shift in priorities as a surge, and identified a supportive regulatory framework as a crucial element for companies that want to apply these principles.
"If the FDA is to call itself a scientific agency, then it should be able to look at new drug products scientifically, not just in a preconceived pattern," said Dr. John E. Simmons, a former FDA regulator currently heading the consulting firm FDA CMC Consulting, LLC. "And that's a challenge to both the industry and the regulators." According to Dr. Simmons, the application of QbD principles to the pharmaceutical industry is only possible through increased cooperation between industry members and regulators. He commented, "The industry has to come in with the data to support what they're doing, and the agency has to be able to look at it and say, ‘Yes, I understand what you're doing and it's fine.'"
It's the FDA's interest in QbD over the last several years that has led to its position of importance in the pharmaceutical industry, most agree. Dr. Simmons said the FDA's involvement with the idea can be traced back to Dr. Ajaz Hussain's tenure at the agency, which ended in 2005 when he returned to private industry. "He was an academician, and really challenged the system by talking about things like this," Dr. Simmons remarked. "As an academician he had ties to pharmaceutical companies that came to him and said, ‘How can we do this differently?' He wasn't locked into the way things had been done in the past." Dr. Hussain's interest led to reciprocation from companies that were exploring the issue on their own. He also laid the groundwork for currently active guidances and programs within the FDA.
"Quality by Design is really not new to the industry in terms of its approaches," said Patheon's Dr. Chow. "We had been collecting information, we had been doing design space work, we had been monitoring our process. What happened is that the FDA helped us to consolidate these ideas."
"Our role is as a facilitator, and in some cases as a partner," says Dr. Moheb Nasr, the director of the office of New Drug Chemistry at the FDA. Dr. Nasr is the agency's current leading spokesman on QbD. To best fulfill that facilitator role, Dr. Nasr believes the FDA may leave individual process solutions in the hands of the pharma companies, while giving them clear principles through ICH guidance as to what constitutes meeting the expectations of a quality by design.
The reward? If systemic in nature, QbD concepts should bring with them a degree of regulatory flexibility, and with that, greater efficiency, cost benefits, and a greater ability to respond to short-terms market needs. "I can illustrate that fairly easily," said Dr. Simmons. "When you look at doing a quality by design and design space concept for a drug product, all of a sudden, all of the standard characterizations become much more flexible. It gives the company willing to take that plunge into developing their product that way a lot more flexibility to make minor modifications to that dosage form with the QbD boundaries. You have to be pretty confident about your dosage form and about your manufacturing process. You no longer have to specify every single thing with a narrowly defined set of specifications. Now you've got some boundaries.
"Companies are starting to look at how we design a dosage form, how we design a manufacturing process, what are the critical process parameters that have to be monitored, and what variances within those critical process parameters can be tolerated," Dr. Simmons continued. "That's a slightly different way of looking at it than we have in the past. In the past, a company could come in, they'd have a dosage form that they've manufactured many, many times. They would list all the process parameters, all of the characterization parameters, all of the release parameters, and once that was done and in place and approved, that was it. It didn't change much. The only changes were for economic reasons, like a dislocation in raw material supply or the opening up of additional plants around the world. But under QbD precepts, you can build those in."
Dr. Nasr noted that many companies are at least exploring aspects of QbD, but that the principles are a long way from being fully met. Roadblocks to the full and effective implementation of QbD include:
Conservatism: General resistance to change from pharma companies of all kinds, in some cases because existing policies have been effective in the past.
Perceived cost: While there are some processes for which QbD is a natural, such as solid dosage form manufacture from companies featuring an integrated, well-defined process, there are a number of pharmaceutical products that only fulfill a niche product and are not big moneymakers. Implementing principles like QbD and design space and PAT means investing more time and effort into coming up with a dosage form that may not seem to justify the added cost.
Limited implementation: QbD is properly implemented and yields its greatest benefits on the systemic level. Implementing QbD principles on only part of the production process can lead to a misunderstanding as to what QbD actually means. Shifting the regulatory agencies' relationship to the pharmaceutical industry, at least in this instance, from one of reacting to tragedy to proactive leadership.
Segmentation: Divisions within companies or different agencies throughout a process may discourage more systemic approaches and the clean, consistent trade of information.
Irregular levels of participation: Some companies have made few if any steps in the direction of understanding their manufacturing, dosage form, etc., and some forms of manufacture may be less monitored than others
PAT reliability: Companies have to implement monitoring programs from process to process that facilitate the continual flow of information required in QbD concepts. While technology may be developed as the need pushes innovation in this area -- the aforementioned surge in Resources , confidence and interest made real -- companies also have to be able to count on the technology's long-term reliability.
"It's growing slowly, probably as it should," said Dr. Simmons. He noted that several companies have taken part in the CMC Pilot program for new drugs, whereby information is exchanged and companies are given the opportunity to study their manufacturing process and apply such things as process analytical technologies towards their monitoring. Dr. Simmons seems sanguine as to how many in the program grasp it entirely from the get-go, noting the importance of process even within the program: "Implementing QbD requires a critical mass of people and resources that you tend to find at larger companies."
Given the constant need for shared information to make QbD work, the role of contract manufacturers and specialty pharmaceutical businesses stands out. In general a desire to participate in the growing market should pull smaller companies after the bigger. Patheon's comments on these issues, as prepared by Dr. Chow, note that the company has initiated QbD in some of its programs with expansion on the way, in accordance with FDA guidance, in order to differentiate itself from any competition that fails to do the same. In fact, they may encourage clients to adopt the standards as well.
"We always partner with other companies to do any technologies that can benefit from Quality by Design processes, but we also do it ourselves," said Dr. Chow. "We of course respect the confidentiality of information coming from our clients. When a client is working with us, we can apply our technology or collaboratively applied technology with another organization to improve formulation, to develop formulation, process and manufacturing technology."
Kevin McCarthy, the director of marketing at Patheon and Chow's co-worker, noted QbD allows for a framework from which a contract manufacturer can apply their specific technological expertise. "I think when you get into specific technology components of Quality by Design, like PAT, there are a lot of different individual technologies that get applied differently, and they have different applications for different dosage forms or even molecule types in those processing techniques," said Mr. McCarthy. "QbD is a lot broader than that, as far as designing formulation and the physical design of an experiment. It's a lot bigger than PAT."
It also extends into multiple dosage forms: "Each dosage forms has unique features," said Dr. Chow. "For example, we recently published some work on granulation in terms design space. But the overall umbrella approach of QbD is pretty much transparent between dosage forms."
Dr. Simmons goes further, suggesting that contract manufacturers have a unique contribution to make by sharing information across product type in addition to up and down the entire process. "The market model for larger companies is changing, and specialty companies, specialty contract companies are arising and dabbling in this. The contract manufacturers are in a unique position to adapt some of this across product lines, across therapeutic classes, because that's the nature of their business. I'll give you an example -- there are specialty manufacturers that handle a variety of transdermal products. What a wonderful opportunity to get a handle on this. I'm encouraged."
"Some work is done in house by our scientists on control technologies," Dr. Chow noted. "Because of the way we have to educate our clients and keep people understanding what we're doing, that will encourage us to develop technology for different platforms. For example, some of the technologies we apply, we'll apply to a number of companies together. That is an opportunity for us."
Dr. Simmons noted a bottom line: "The payback in regulatory relief is there if companies are willing to do it. But it's not easy. It's something to watch and evaluate."