Animal & Veterinary
CVM’s Division of Manufacturing Technologies: Developing an Effective Operation and Motivated Staff
by Jon F. Scheid, Editor
FDA Veterinarian Newsletter January/February 2006 Volume XVII, No VI
About 10 years ago, as it was implementing its new strategic plan, the Center for Veterinary Medicine (CVM) consolidated into a new division all of its responsibilities for evaluating the drug chemistry, manufacturing, and controls (CMC) portion of a new animal drug application. The CMC evaluation determines a company’s ability to continuously produce drugs that meet adequate standards of quality. CVM titled the new group the Division of Manufacturing Technologies (DMT), and named William Marnane as Division Director.
During the 10 years that followed, the consolidated Division was able to coordinate CVM’s work with the rest of the Food and Drug Administration (FDA), improve relations with the animal health industry, and build a motivated staff.
Mr. Marnane’s managerial skills helped DMT achieve these goals and more. Earlier this year, Center Director Dr. Stephen Sundlof presented Mr. Marnane with the CVM Director’s Award, the highest the Center offers, with the citation: “For providing exceptional leadership in the management of personnel and critical manufacturing initiatives important to the mission and goals of the Center.”
As part of a look back at the history of CVM during this year of the FDA’s Centennial, FDA Veterinarian interviewed Mr. Marnane, who recently retired, and three DMT staff—Dr. Dennis Bensley Jr., Deputy Director of the Division; Mai Huynh, Supervisory Team Leader in the Division; and Mary Leadbetter, who recently retired as Supervisory Team Leader—to find out how the Division met the challenges.
CVM put sharp focus on reviewing the manufacturing part of the animal drug application about 10 years ago when it consolidated all parts of that review into the new DMT.
Because of that change, the Center has been able to speak to the animal drug industry with one voice, resulting in less confusion. The new DMT also started new programs, beginning with the Alternate Administrative Process program, but more recently with the Quality by Design (QbD) program, under which drug sponsors can speed the review process if they are willing to do more work before the application is -submitted.
At the same time, DMT increased the ability of FDA field inspectors to thoroughly review a manufacturing plant’s ability to produce an animal drug. Generalized inspections FDA used before were replaced with specialized inspections, designed to see if the plant could successfully produce the drug as required by the quality criteria specified in the application. This increased scrutiny was not always welcomed by the animal drug industry, but is necessary as animal drug production techniques become more sophisticated.
The DMT is the only pre-market review group within the Center that is involved with manufacturing changes through the entire life of products—“from product birth to death,” Mr. Marnane said. The nature of animal drug production and the emphasis on continuous improvement and incorporation of new technology must all be considered during the life cycle of a drug product. Manufacturers frequently change drug substance suppliers and the manufacturing processes during the life of a drug. Analytical methods change, too. CVM must consider all of these post-approval changes within the context of the original approval and the possible effect on safety and efficacy of the drug product, Mr. Marnane said.
Origins of DMT
The decision to place all the manufacturing chemistry portion of drug review into a single division came from an internal review of CVM operations.
Mr. Marnane’s deputy, Dr. Bensley, was part of that review team that recommended to Dr. Sundlof that the manufacturing review functions should be consolidated in CVM. “At the time,” Dr. Bensley said, “the Division of Chemistry included human food safety and the Chemistry, Manufacturing, and Controls (CMC) review branches. As expected, human food safety issues rather than CMC issues dominated the time of the Division Director” at the expense of the CMC review, he said. He added that part of the CMC review resided in CVM’s Division of Surveillance, which “caused a number of problems,” including a reduction in CVM’s ability to communicate with sponsors on CMC issues with a single voice.
Said Mrs. Huynh, the consolidation of CMC functions into one division gave that birth-to-death consistency in CMC review. It allowed for continuous review by only one Division. The reviewers in the Division were able to establish effective new functions “integrating pre-approval inspection and the review of the post-approval annual reports.” She said that the creation of the DMT added efficiency of the review and improved communication within the Center as well as with sponsors, “because it allows our reviewers to stay with the same product from pre- through post-approval. It certainly made life easier for our sponsors to always communicate with the same group for CMC related issues.”
“The consolidation within CVM gave the Center a much better ability to communicate and work with the rest of FDA,” Mr. Marnane added. It also put CVM in a good position to better coordinate with the “field forces” of FDA, who do the pre-approval inspections to make sure facilities are up to the task of producing animal drugs that meet the production standards specified in the sponsor’s application.
The pre-approval inspection of a manufacturing facility’s ability to meet current Good Manufacturing Practices (cGMP) is done by FDA’s Office of Regulatory Affairs (ORA). However, since its formation, the DMT has gradually increased its role in the pre-approval inspection process and made the inspections more tailored to the standards specified in the drug application.
During his tenure, Mr. Marnane focused attention on coordination with the ORA field forces to achieve a more synergistic outcome. “The heart of a successful pre-approval inspection program is good communication between headquarters reviewers and FDA field investigators. The Division’s organizational structure facilitates frequent interactions between pre-market review staff (at CVM) and FDA field investigators. To further enhance communication with the FDA field, reviewers from the Division participate in on-site pre-approval inspections with field investigators to provide technical support when necessary,” he said.
CVM officials who review drug applications had little contact with ORA’s field inspectors before DMT was formed, Dr. Bensley said. After the DMT was formed in 1996, “we started acquiring more and more” of the responsibility for the technical requirements of the pre-approval inspection program. Today, the program is an integral part of the review and approval process. Because of these increasing responsibilities, “we started having more direct interaction with field personnel, including participation on inspections,” he said.
Mr. Marnane said that now when a pre-approval cGMP inspection assignment is sent to the field forces, it frequently “contains requests by the reviewer to focus on specific portions of the manufacturing -process.”
ORA field inspectors still do the work, but DMT personnel supply technical expertise and information to the field forces, so they can do a more in depth inspection, based on the requirements specific to the drug under review.
According to Mrs. Mary Leadbetter, who recently retired from DMT, “Special areas of interest are communicated to investigators. DMT reviewers have accompanied investigators on inspections as technical experts.” ORA inspectors and DMT personnel also train together and jointly attend meetings, she added.
Working with Drug Sponsors
In 1996, the newly formed Division started looking for a more efficient and effective way to work with the animal drug industry, and it developed a program changing the way the industry could report minor manufacturing changes to CVM without filing an application for a supplemental approval. The program, dubbed the Alternate Administrative Process, was developed that same year. It allowed drug sponsors to report minor manufacturing changes on a biennial basis in special reports.
Mr. Marnane and Dr. Bensley developed the concept by working within the existing regulations. Trying to change the regulations would have taken more time and resources than the young Division had to spare. Mr. Marnane and Dr. Bensley presented the concept to CVM management, won approval there, and then “sold” it to industry. “We desperately needed this program, since we were being swamped with supplemental applications,” Dr. Bensley said.
The Alternate Administrative Process lasted only a few years, though. Its goals were taken up a few years later in the FDA Modernization Act (FDAMA), which was effective across the Agency and revamped many of the regulations under which FDA operates. FDA began implementing FDAMA in 1997. “FDAMA actually has had more of a positive impact on our workload than the Alternate Administrative Process by allowing for more reporting mechanisms, depending on the type of change,” Dr. Bensley said.
Pharmaceutical cGMP initiative
FDAMA was followed by an FDA initiative, “Pharmaceutical current Good Manufacturing Practices (cGMP) for the 21st Century.” The program was designed to improve “FDA’s regulation of pharmaceutical quality for veterinary and human drugs...,” FDA said in a report. The initiative was started in June 2002 and allows FDA to take into account improvements in pharmaceutical sciences and the lessons learned that FDA acquires from its experience in drug CMC.
The initiative’s objectives are:
Encouraging the pharmaceutical industry to adopt early new technological advances;
Making sure that FDA’s regulatory review, compliance, and inspection policies are based on state-of-the-art pharmaceutical science;
Facilitating industry’s adoption of modern quality management techniques, including implementation of quality systems approaches;
Enhancing the consistency and coordination of FDA’s drug quality regulatory programs, in part, by further integrating enhanced quality systems approaches into the Agency’s business processes and regulatory policies concerning review and inspection activities; and
Encouraging the implementation of risk-based approaches that focus on critical areas.
DMT was heavily involved in this initiative, because it handles the CMC responsibilities.
Mr. Marnane described the initiative as a way to incorporate “the most up-to-date concepts of risk management and scientific advances, encouraging innovation and continuous improvement, to ensure that submission review and cGMP inspections are coordinated and work synergistically.”
The initiative looked both at pre-approval product review and at cGMP regulations for ensuring consistent product quality.
Dr. Bensley said that the initiative “is more than just providing opportunities to industry to upgrade its approaches to manufacturing and control. Rather, it emphasizes and allows the use of risk analysis in the decision process.” DMT “has always been open to innovative approaches. However, the cGMP Initiative has given us additional leverage to implement or allow the implementation of innovative approaches,” he added. In other words, the DMT approach fit well into the Pharmaceutical cGMP Initiative.
One of those innovative approaches, which the initiative embraces, said Mrs. Huynh, is the use of product specialists on inspections. DMT always tried to use specialists, but limited resources and a heavy workload sometimes prevented that. The initiative “has allowed CVM to be recognized for its innovative approach to CMC and cGMP and provided us an opportunity to draft several joint guidances with other Centers,” she added.
Mr. Marnane used the principles of the Pharmaceutical cGMP Initiative to reach out to the animal drug industry.
“Primary among the opportunities provided by the initiative are the concepts of QbD,” which, in part, is a means for a sponsor to improve the quality of the submission, Mr. Marnane said. If the concept of QbD is “embraced by drug manufacturers, it could lead to less regulatory burden and shorter review time consistent with DMT’s efforts to move toward One-Cycle-Review.” The one-cycle review concept suggests that the sponsor will understand what is needed in the drug application completely before submitting it. Therefore, CVM reviewers will not have to send the application back to the sponsor for revisions, which would lead to multi-cycle reviews.
Mr. Marnane said, from a regulatory review perspective, his Division sees QbD “as a demonstration of process knowledge by providing scientific, risk assessment, and quality system information in a pharmaceutical development report” submitted for the application.
According to Dr. Bensley, “QbD is actually an old concept being repackaged as something new.” It is based on the idea that quality cannot be “tested into” a product. Instead, it must be built in.
Mrs. Huynh explained that the QbD concept is a “formal way to ask the sponsor to share with us the experiences and lessons learned in product development,” to give the CMC reviewers a better idea of the background of the application.
Drug manufacturers are not required to adopt the QbD concept, and the animal drug industry has not yet as a whole embraced it. “We do have some -sponsors currently using this concept and getting some regulatory relief,” Dr. Bensley said. “It is too early to say that it (QbD) will accelerate the approval process; however, those companies that have started using this concept have had higher quality submissions,” he added.
In addition, DMT has used the Pharmaceutical cGMP Initiative internally to work toward a one-cycle review for the CMC portion of the review of a drug application.
"As part of the Division’s effort to move toward one-cycle review (under the initiative), we also expended a great deal of effort to create a database detailing the type of deficiencies that we encounter in the review of CMC information.” The Animal Health Institute and the Animal Drug Alliance—trade associations that represent most of the animal drug manufacturing industry—saw the database as containing “very valuable information that may lead to identifying and correcting areas of CMC submissions where there are recurrent issues leading to applications not being approved,” Mr. Marnane said.
Industry, Center relations
Relations between the Center and the animal health industry have from time to time been strained. Under Mr. Marnane, DMT has intensively worked to improve relations with the industry through various meetings and other types of communications.
The improved relationship, he said, “is the result of more and better communication between a well organized Division and its customers.” An example of the outreach the Division has undertaken is the series of four workshops the Division helped organize for the pharmaceutical industry on the issue of drug sterilization. These workshops brought FDA review scientists, field investigators, and the pharmaceutical industry together in a common forum to address scientific and inspectional issues.
Dr. Bensley said, “I think we have had a significant improvement in our relationship, especially after the formation of our Division. We readily communicate with the animal drug sponsors and attend a number of meetings every year. Our more recent interactions with the Animal Health Institute and the Animal Drug Alliance include discussions on achieving one-cycle reviews and other CMC issues.”
Developing the Division’s staff
The Division’s staff members, while mostly not new to CVM at the time of DMT’s formation, had to adapt to a new organizational paradigm, and Mr. Marnane’s job was to get the staff coordinated. He relied on the management strategy Dr. Sundlof introduced to the Center at the same time the Division was formed, called “High Performance Organization (HPO).”
"Building the concepts of the HPO into the Division made sense, because the vision and values (contained in HPO) are consistent with the kind of Division that we wanted to build,” Mr. Marnane said. “Quality of life, alignment with Division, Office, and Center goals and objectives, transparency, empowerment, stewardship, metrics, and business-plan-objectives being sought by the Division are all key components of HPO.”
Mr. Marnane made it his goal to give the Division staff as much responsibility as possible to achieve the goals. He let his staff make recommendations on bonus awards for individual staff members that were based on performance, interview and recommend candidates for positions within the division, and tackle long-standing issues pertinent to consistent review quality across DMT.
Staff development has resulted in improved work product, Mr. Marnane said. Those improvements developed into an internal “Quality Management System” (QMS) being developed within DMT. Under QMS, the staff helps define the critical elements of the Division’s business plan. The business plan must address the Division’s mission of determining “whether an animal drug will have and maintain the necessary quality, strength, purity, and identity” for approval.
To make QMS more than a concept, it must be put into place. The implementation plan should include written plan execution procedures, process flow charts and standard operating procedures to document the plan’s implementation, adequate staff training, ways to measure the plan’s effectiveness, and a mechanism for reviewing and improving the plan, Mr. Marnane said.
Dr. Bensley added, “We are still in the early stages of developing a fully functioning QMS, and this will be an on-going process. There is currently only limited interest from industry, since the Division QMS impacts only our internal processes.” However, he said, the Division’s ultimate goal is to streamline its business processes, resulting in more efficient review, which he expects should be well received by industry.
As Mr. Marnane prepared to retire from CVM and from government service, he noted several DMT procedural milestones, which help not only point the Division in the right direction, but also give it its identity. DMT has mapped its processes and found out where it needed to place more attention (by performing a “gap analysis”), completed 10 Standard Operating Procedure documents and began another 20, completed the first of what will be annual reviews of the SOPs, and completed its first internal audit.
Mr. Marnane’s work has improved the Center’s rapport with the industry. “We do believe that CVM’s relationship with industry, as it pertains to CMC review, has changed and has improved. The metric used to come to this conclusion is simply the diminishing number of negative comments and the increased amount of positive feedback,” he said.
Dr. Bensley said, “The formation of a division to specifically address CMC issues has significantly improved internal and external communications. In addition, it helped by bringing to the forefront that CMC is critical to ensure product quality, safety, and efficacy in animal drug products. The rest is history.”
DMT’s Director William Marnane
William Marnane was the Director of the Center for Veterinary Medicine’s Division of Manufacturing Technology (DMT), a position he held since DMT was formed in 1996 until his recent retirement.
He is a chemist and has a master’s degree in biochemistry, which combines organic chemistry and biology. He was a high school science teacher early in his career. He later went to work in the private sector with contracting firms. He entered government service as a research chemist at Walter Reed Army Institute of Research in 1976.
In 1983, he started with FDA in the Center for Drug Evaluation and Research. In 1988, he arrived at CVM, and became branch chief of the Chemotherapeutics Team, Division of Chemistry. In 1996, he became Director of CVM’s DMT.
Bill Marnane, right, led CVM’s Division of Manufacturing -Technologies from its inception until he retired in January 2007. Dr. Dennis Bensley, Jr., left, is the Division’s Deputy.