ROCKVILLE, Md.—In a report entitled Pharmaceutical cGMPs for the 21st Century—A Risk Based Approach, the Food and Drug Administration (FDA; www.fda.gov) has summarized substantial changes ahead for manufacturing, inspection, disputes, and for streamlining the pharmaceutical approval process.
The goal is to modernize FDA's regulation of pharmaceutical quality for human drugs, biological products such as vaccines, and veterinary drugs, as well as to remove many bottlenecks that exist under the current system. Specific changes include the adoption of technological advances in manufacturing; modern quality system approaches to production and quality assurance; a move to a risk-based approach; regulatory review, compliance, and inspection—all based on state-of-the-art pharmaceutical science; and coordination and consistency of regulatory programs.
Moving from guidance
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The FDA’s former chemistry, manufacturing, and controls (CMC) review system was based on fifteen remote clinical divisions where chemists decided whether products went to market. Speaking to the inadequacies of the old plan, Helen Winkle, director of the Office of Pharmaceutical Science, says, “CMC relies on guidance which tells us how to do things instead of focusing on the science behind that particular product. Because we were so spread out, guidelines seemed to be what was most important to ensure consistency. Since chemists were hired into the fifteen clinical divisions, drug approvals were often decided by chemists who had a lack of expertise in critical areas. They had so many questions and issues that they constantly went back and forth with industry trying to get clarification.
“Until now, the FDA required no information from companies regarding their pharmaceutical development process, such as experiments performed, particle size, changes put in place, etc.,” explains Winkle. “Ascertaining real risks in the absence of this information is difficult at best.”
Gerry Migliaccio, Vice President of Global Quality Operations for Pfizer, agrees: “The FDA's initiative is an aggressive and beneficial program based on unprecedented communication for both the FDA and the industry. Under the initiative, there is a move to science-based compliance, a focus on scientific principles and passion for process understanding instead of focusing on blind compliance based on someone's perception.”
Migliaccio adds that “there is a real attempt to see where the potential is for failure.” Migliaccio stresses that the changes under the FDA initiative are the industry, academia, and the FDA working together toward creating better solutions.
Under the new assessment program, the FDA will require a quality overall summary of the issues and the product, covering the risks and level of scrutiny necessary for that particular application. An independent chemistry office will house all chemists under one roof. Chemists, chemical engineers, pharmacists, and other specialists will make decisions in a team approach.
Manufacturing advances
Today, advances in manufacturing technology include Near-IR, which can detect whether a pill is made to standards, and probes added to mixers for real-time information. Currently, during the mixing process, a sample is extracted and evaluated in a lab to see if it's mixed well. All the while, product sits in a holding bin. If the results show that it's not well mixed, the product must be discarded and the process started again. With newer technology, however, an electronic probe placed into a mixer calculates in real time when the mixing process reaches a well-mixed state.
While it isn't likely that the FDA will require the use of advanced technology, it is encouraging industry to use these and other modern technologies in its processes. Such technologies, the FDA believes, lets the user see what the product looks like as it comes through the various stages, and also uncovers the root cause of such problems as particle size or excess moisture.
According to Winkle, when industry made any kind of change to its manufacturing process, they were required by the FDA to virtually defend changes with studies and reams of paperwork just to make a simple change—such as adding a probe to a blender. Under the new initiative, however, changes are easier to push through FDA's regulatory machine. At the beginning of the new system, the FDA says it has processed only six applications with changes.
One manufacturing dispute in a year
The FDA inspects all pharmaceutical firms every two years, yet the chemists that review applications and supplements have never been part of those inspections. In the future, they will either actively participate, or at least talk with the inspector up front to make sure all concerned are informed.
When inspectors went to work under the old system, they brought their observations back and the FDA would then determine whether to take regulatory action. Under a new technical dispute resolution process, however, there is now an opportunity for companies to discuss the observations—including the science, manufacturing process, and reasons for conducting operations in a certain way.
The FDA expected to have a deluge of disputes under the new process. It hasn't happened, they say. Companies are more satisfied that they have a chance to resolve issues on the spot. “Instead of a lot of disputes, there has only been one all year,” says Winkle. “Before, nothing could be disputed. Now, everything can and there are no disputes.”
Now, it is possible to send in a comparability supplement to the FDA up front explaining various process changes that are expected in the future. Then, when the change is actually made, all that is required is a simple supplement rather than a complicated one. For example, with the comparability protocol, a statement could be filed that suggests there might be better ways to blend product—and the company understands that if it changes the blender it will have to consider particle size, moisture, etc. The FDA knows that the company understands the potential issues involved with the change.
“There is a real give and take of information now,” says Migliaccio. “The initiative has raised the level of expertise and the willingness to work together. The move now is towards knowledge.”
Manufacturing site checks
Inspection of manufacturing sites is a major part of the FDA's responsibility. The new initiative provides for an improved risk-based site selection model that factors in such elements as the results of previous inspections, types of products made, and the potential risks associated with making these products. Using a well-known risk tool—expert elicitation—the FDA polled its review colleagues, staff in the office of compliance, and field investigators, taking their experiences and loading them into the model. As a result, the agency says it is better able to prioritize the highest risk facilities for the most frequent inspections.
When asked if this system would have helped in the case of flu vaccine manufacturer Chiron, Joseph Famulare, director of the Division of Manufacturing and Product Quality/Office of Compliance, says: “Looking at Chiron, there were problems in all aspects—process, training, handing things over to manufacturing, etc. We see many cases where companies develop processes and then don't respond to variables over time. We're trying to establish a more modern method where you input variables—and you can control [them]. The process must adjust so that the end product will have the quality attributes and specifications that it was intended to meet.”
International collaboration
Recognizing the difficulties global companies face in complying with the standards, practices and procedures of multiple international regulatory authorities, the FDA recently joined the International Conference on Harmonization (ICH). ICH focuses on creating common technical documents for regulatory process understanding. The groups are attempting to achieve an understanding of the manufacturing process early on so that appropriate specifications are based on an understanding of the prime risks involved. The intent is to reduce the need for filings with several regulatory bodies, yet foster continuous improvement over the lifecycle of a product.
The FDA has also joined the Pharmaceutical Inspection Cooperation Scheme (PICS), an organization of international inspectors that publish documents that, while not obligatory, reflect common understanding. The goal is to have a more common application of GMP inspections worldwide and common inspection approaches, and to share information between regulators.