Wyeth is incorporating manufacturing quality assurance assessments into its drug R&D process as part of its efforts to ensure the company continually meets good manufacturing practice standards.

"We now include corporate QA as part of the product development and commercial introduction process," Wyeth Pharmaceuticals VP-Global Quality Operations Peter Kitz told a PDA/FDA joint regulatory meeting Sept. 8 in Washington, D.C.

"We have developed quality gates, which require certain quality criteria be met by R&D prior to entering a new phase of development. Also, we will now include R&D in the review of performance metrics after the product is commercialized," Kitz explained.

Raising the visibility of manufacturing within drug development appears to be a trend among manufacturers, especially those that have recently run into trouble with FDA for not meeting GMPs. Lilly, which had several drug approvals delayed because of manufacturing problems, is now emphasizing manufacturing as having the same level of importance as R&D and marketing (¹ Also see "Lilly Revisits Priorities: GMPs Awarded Same Status As R&D, Marketing" - Pink Sheet, 7 July, 2003., p. 12).

Marketing departments have secured a strong influence over most firms' R&D programs in the past decade.

Kitz described Wyeth's implementation of an approach to sustainable GMP compliance since entering into a consent decree with FDA in October 2000 (² Also see "Wyeth Will Lose 18.5% Of Marietta Sales If Firm Does Not Comply With GMPs" - Pink Sheet, 9 October, 2000., p. 3).

Wyeth took an "overall systems view" to improving management controls and QA/QC controls, focusing on four areas: methods/processes/materials; equipment/facilities/technology; people; and environment.

The "methods, processes & materials" area included the incorporation of QA into R&D. It also included creation of a "sustainable compliance initiative."

The initiative includes computerized system management and three levels of policies: global standards; conformance standards, "which are required elements to ensure compliance with these policies;" and "site-specific [standard operating procedures], or simply the how-tos," Kitz explained.

The initiative also involves 27 quality system elements. "Of these, we have prioritized our efforts on batch records, investigations, training and validation."

Each site's efforts to meet the compliance initiative's standards are "verified on the plant and corporate levels for compliance," he said.

In business process re-engineering, Wyeth is developing a simplification plan where relevant. In addition, "we are focusing on a committee and team approach rather than individual decision power to ensure broader risk analysis on issues," Kitz said.

In addition, "one of the most significant activities that's going on at Wyeth right now is the standardization and integration of various electronic systems."

"Supplier rationalization" was also undertaken, "specifically reducing complexity of our suppliers and ensuring that 1) we had supply and quality agreements and 2) they were up to date," Kitz said.

Revamping the methods area also involved "product rationalization."

"The creation of business units allowed the company to not only focus on key brands but also to divest and eliminate a large number of products and SKUs that were not deemed core to the business," Kitz said.

In the months following the consent decree, products Wyeth let go included influenza vaccine FluShield , ocular surgery treatment Wydase , rattlesnake bite antitoxin Antivenin and DTaP vaccine Acel-Imune .

"Given our product rationalization, we needed to reshape the site network," Kitz said, as he explained some of the changes Wyeth made in the equipment and facilities area. The company reviewed individual sites and developed a master plan for each one.

"We looked at each of the sites in terms of where they would be one year from now, three years from now and five years from now and developed those plans accordingly," Kitz said

"In terms of setting priorities for infrastructure and expenditures, we focus on new product introduction," the exec continued. "Five years from now, where will those products go? What site do we intend to use?"

Wyeth instituted a capital prioritization process that ranks facility upgrade projects "based on compliance opportunities," Kitz said. "Significant funding" was provided for capital improvements in facilities and equipment.

At the same time, Wyeth "reorganized personnel into focused product units, eliminating barriers between function of group, and developed a common focus on infrastructure."

In the "people" area, Kitz said "the most significant undertaking was reorganizing the business and leadership staff in plant functions. This included the co-location of people within newly created business units in order to enhance collaboration, teamwork and a common vision."

Focused product units enhance the collaboration within sites and between those that co-manufacture products, he said.

Quality personnel have "separate and distinct reporting lines" that allow them to report on the plant level or the corporate quality level.

Another Wyeth personnel goal was the "increase in visibility and responsibility of supervision, especially on the shop floor. We are striving to meet a one to 10 supervisor to staff ratio."

"We have reviewed the staffing levels in QA and QC in both the site and corporate functions, and as a result we have significantly increased resources in order to ensure that not only we fulfill our compliance expectations but we can run the day-to-day business."

Training is also an important aspect of the plan, which includes a program to qualify trainers, creation of curricula for all levels of the organization, competency assessments and an electronic tracking tool to monitor employees' training activities.

"Our focus moving forward was not just SOP training, but overall process education and competency development," Kitz noted.

Improvements in Wyeth's manufacturing environment include having "clear accountability at every level of the organization" and recognizing "quality and compliance efforts through a global recognition program," Kitz said.

"We have created levels of rewards which are site-wide and include quality system acknowledgements, as well as rewards for best practices within a quality system."

Wyeth has made the organization "more bottom heavy," with the corporation providing sites with the tools, resources and capital funding they need.

To help the company's leadership fulfill its oversight responsibilities, Wyeth has created an integrated management report, to monitor "key metrics" and provide "an early warning mechanism for management to take prompt action and to drive improvement," Kitz said.

The company also has a "quality council" to "address quality issues on a real-time basis." The council "provides a cascade of communication from the site to the business unit to the division and vice versa," Kitz explained.

One other oversight group is a "sustainable compliance steering committee" of senior managers, which meets weekly to monitor compliance activities. Senior managers make more frequent visits to manufacturing sites.

Senior management also has maintained open lines of communication with FDA and meets with the agency to discuss issues when needed. Kitz noted that "we did talk to FDA with regard to the programs that we put in place. A lot of them we developed on our own and a lot were developed in concept with consultants."

All activities "are directed towards communication and awareness to ensure senior management as well as the FDA are consistently made aware of issues and a proper direction and resolution is promptly instituted," Kitz added.

Asked how to get a company's senior management to pay attention to manufacturing issues in the absence of a consent decree, Kitz recommended that FDA observations in 483 forms "are circulating up and down the organization as well as across."

"Take heed of the early warnings that come from the agency, especially in terms of 483s, and don't dismiss any of those as being light observations. Really jump on them as quickly as possible," he said.

Wyeth Manufacturing Improvements Extend To Drug R&D, Exec Says

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