FDA to create drug 'Pharmaceutical Inspectorate,' team audits; PAT advances. (Inspections/PAT).

FDA plans to mimic the "Team Biologics" approach to GMP inspections by creating a well-trained "cadre" of product specialists to join field investigators on audits, plus a new "Pharmaceutical Inspectorate," to coordinate human and animal drug inspections with the Office of Regulatory Affairs (ORA).

In addition, the agency announced Feb. 20 it will create incentives for firms to implement process analytical technology (PAT) in drug manufacturing, plus a "complete and published comprehensive implementation plan for this cGMP initiative by mid-year," said CDER Director Janet Woodcock, M.D.

In announcing a six-month progress report on its "Pharmaceutical GMPs for the 21st Century Initiative" at a news conference for trade press, FDA stated:

"Pharmaceutical manufacturing is evolving from an art form to one that is now science and engineering based. Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. This initiative is designed to do just that through an integrated systems approach to product quality regulation founded on sound science and engineering principles for assessing and mitigating risks of poor product and process quality in the context of the intended use of pharmaceutical products."

Under the new Inspectorate plan, CDER, ORA and Center for Biologics officials told the briefing that inspection teams will focus their efforts on identifying drug manufacturers that pose the greatest risk.

"We want to ensure our limited resources have the greatest impact and focus those on where FDA intervention is to happen," CDER Compliance Director David Horowitz said. He explained that the agency would concentrate its resources on drug manufacturers where non-GMP compliance has the greatest public health impact.

Thus, for the current 2004 fiscal year, FDA will be focusing audits on sterile drugs, "sites making prescription drugs" and new registrants not previously inspected. The agency hopes to develop more complex risk-based models for directing inspections for next fiscal year, he said.

Woodcock said the new Inspectorate agreed to work together to develop a group to concentrate specialties on pharmaceutical manufacturing. Members will co-train with Center staff and the first members are anticipated to be on board by the end of fiscal year 2003.

Key to this will be the inclusion of "product specialists," much like the ones already used in the biologics teams (see related story, page 2). During inspections, a specialist will be responsible for evaluating test methods and method validation, as well as reviewing and interpreting raw analytical data that may be outside the field investigators' expertise. For biological products, a specialist is instrumental in assessing purification processes related to active pharmaceutical ingredients.

Ironically, the effectiveness of Team Biologics has never been formally evaluated, but has been criticized by industry--chiefly biotech companies--because of the difficulty of hosting so many FDAers in a plant at one time.

Asked why FDA would spread the team concept to human and animal drugs before seeing whether it has worked well for CBER-regulated products, CBER Compliance Director Steve Masiello told the press briefing that there is an ongoing re-evaluation of team inspections. "Team Biologics fits well within this [GMP] initiative, including internal quality management systems."

However, John Taylor, associate commissioner for Regulatory Affairs, said the organizational structure for inspections will not change within the agency.

Hoping to give industry an incentive to use new technologies, Woodcock announced a new "comparability protocol" guidance that would now cover small molecules. For example, she said if a company improves its manufacturing processes and files a comparability protocol it can make changes quickly without waiting for preapproval.

In addition, to boost industry acceptance of PAT and move away from the "don't use" or "don't tell" approach to PAT in drug manufacturing, FDA's PAT Working Group reported it was "essential that FDA enhance the complementary scientific and technological knowledge of its headquarters and field staff to positively impact the supply of safe and effective drug products."

FDA said it has accomplished the following milestones to help implement PAT:

* Building consensus within and outside the agency on PAT applications and opportunities for improving the efficiency of manufacturing and associated regulatory processes

* Evaluated a "pro forma" submission from one company and four other companies have expressed interest to discuss with FDA their planned applications

* Successfully recruited three pharmaceutical/chemical engineers with expertise in PAT

* Established and initiated a specialized training program for the review-inspection team

* Organized several scientific workshops in U.S. and Europe

* Initiated a research program on PAT and published one paper and several presentations

* Collaborative Research and Development Agreement with a major pharmaceutical company on PAT applications developed and is currently under review at the FDA

This collaborative initiative between CDER, ORA and CVM is designed to address many of the objectives of the GMP initiative. Draft guidance for industry on a regulatory process for applying PAT is currently being developed and a review-inspection team has been assembled and is currently in a training and certification program. Additional information on this initiative is available at the new PAT located at http://www.fda.gov/cder/OPS/ PAT.htm

In addition, FDA announced an April 22-24 a workshop co-sponsored with the Product Quality Research Institute (PQRI) entitled, "A Drug Quality System for the 21St Century." The workshop is designed to provide an overview of FDA activities and current thinking and to give industry an opportunity to share with FDA their perspectives and ideas on FDA's current thinking on the GMP initiative. For more information on the workshop, visit www fda.gov/cber.

In addition, Ajaz Hussain, Ph.D., director of the Office of Pharmaceutical Scientist and FDA's lead protagonist for PQRI and PAT, said the agency plans to bring on more chemical engineers to help with the efforts to improve pharmaceutical manufacturing.

FDA's objectives involve much more than current GMP requirements. "The initiative also includes the pre market review of chemistry and manufacturing issues as part of the application process," FDA Commissioner Mark McClellan, M.D., told agency employees.

"Using state-of-the-art approaches in FDA's review and inspection activities will encourage innovation and continuous improvement in drug manufacturing to minimize production problems, and that will make it easier to get safe, high quality medications to patients who need them," McClellan added.

Other highlights of the GMP initiative's six-month report include:

* Center review of drug cGMP warning letters. Starting March 1, all drug GMP warning letters will be reviewed by the relevant Center prior to issuance. This will help identify possible program inconsistencies and resolve them before warning letters are issued, FDA said.

* Implementation of a technical dispute resolution process for GMP disputes. FDA issued a progress report from the Dispute Resolution working group. FDA is accepting comments on the issues and processes discussed in the progress report. FDA plans to consider and implement dispute resolution procedures for GMPs that allow for discussing scientific and technical issues, that bring the best technical expertise on a particular issue, and that allow for developing of best practices and policies across FDA, as well as improving transparency of the regulatory process.

* Evaluating optimal mechanisms to effectively and efficiently communicate deficiencies. FDA will clarify the status of the observations that are noted on the 483s and highlight avenues for further discussion with FDA on the inspectional observations.

* Creating a risk-management role in CDER: Effective Jan. 27, CDER reorganized its Office of Compliance, creating a new Division of Compliance Risk Management and Surveillance to enhance the Office's capacity to implement risk management approaches.

Additional information on the initiative can be found online at www.fda.gov/cder/gmp/ index.htm.