Biopharmaceutical firms push for harmonized audits to eliminate cost, duplication of effort.

ATLANTA -- Biopharmaceutical manufacturers are eager for harmonized audits to avoid duplication of effort and save costs, which for some firms can be as high as $400,000 a day to achieve compliance in the U.S., EU and other nations with differing inspection approaches.

Addressing the BIO International Convention here May 19, John O'Connor, Ph.D., Corporate Inspection Management for Genentech, questioned the value of duplicative inspections, which instead of adding value, increase cost.

He pointed to a recent study which showed that manufacturers spent $130,000-$400,000 a day to support inspections and cited Center for Drugs Director Janet Woodcock's assertion that biennial inspections would cost the FDA $225 million per year. These and other adverse results point to the need for harmonized inspections, according to O'Connor.

O'Connor's data is derived from a 2008 report, which compiled five years of data on foreign inspections--agency inspections outside of its region (e.g. FDA in Europe). The study involved 24 pharmaceutical manufacturers and was evaluated by the European Federation of Pharmaceutical Industries and Associations (EFPIA) topic team on foreign inspections, which included representatives from Hoffmann-La Roche, Bayer Healthcare, Boehringer Ingelheim, Astra Zeneca, Novartis and Glaxo SmithKline.

Results from the survey show that the number of foreign inspections continues to increase (from 128 in 2003 to 500 in 2008). O'Connor also mentioned that "Brazil, the U.S. and the EU are by far the most active inspectorates over the years surveyed." Additional observations: a) in 2008, for the first time, Brazil performed more inspections than Europe and the United States (Brazilian rules changed in 2004, requiring them to do active pharmaceutical ingredients), and b) Columbian and FDA inspectorates generally spend more time on site per inspection than other inspectorates.

Analysis of inspection styles showed FDA conducts unannounced inspections and spends 25% of the inspection time touring the facility and 75% reviewing documentation while the EU dedicates 75% of time touring and 25% reviewing documentation. South Korea, Brazil, Japan and Mexico all spent 33% of inspection time touring the facility and 67% of the time reviewing documentation.

Each inspectorate was found to have different areas of focus. FDA, for instance, focused on Deviations/ Investigations, Role of the Quality Unit, Buildings and Facilities, Raw material/Supply chain control, Equipment cleaning and maintenance, and Validation. The EU's top four areas were:

Year                                          2008     2007     2006

Number of companies in survey                   24       22       22
Number of sites in survey                      641      644      663
Total number of inspections                   1287     1168      939
Total number of 'Foreign Inspections'          500      452      337
Total inspector days 'Foreign Inspections'    3591     3054     2023

* Facilities and equipment (Room classifications and Housekeeping/cleanliness)

* Equipment cleaning and maintenance

* Laboratory controls

* Quality agreements between sites and contract labs.

The survey noted Japan's PMDA focused on three main areas: (1) Raw material control, especially regarding potential bovine spongiform encephalopathy issues, and facility cleanliness, especially for pest control, (2) Alignment of specifications/limits with the NDA limits, and (3) Final product appearance/cosmetic defects. (See chart for details on other inspectorates.)

O'Connor concluded that the data points to the need for a global solution that can be acceptable to all authorities. He pointed to a joint pilot inspection program of the EU, FDA and Australian Therapeutic Goods Administration, announced late last year, and also suggested Mutual Recognition Agreements (MRAs), Pharmaceutical Inspection Cooperation Schemes (PIC/S), Certificates of Pharmaceutical Products (CPPs), and sharing inspections.

Steffen Gross, from the Paul-Ehrlich-Institute (PEI) in Germany, told the audience that the European Medicines Agency is pursuing "a harmonized pharmaceutical quality system applicable across the life cycle of the product, emphasizing an integrated approach to quality risk management and science." PEI is responsible for inspections "in connection with the approval of clinical trials and the processing of marketing authorization applications (national and European) [and] participation in inspections carried out by the competent Land agencies in connection with the granting of manufacturing authorizations and the surveillance of medicinal products."

Under a new vision to ensure product quality, the EMEA and PEI are following new ICH guidelines--Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality Systems (Q10)--which they view as "more visionary, less prescriptive, flexible regulatory approaches."

The EMEA's use of PEI to conduct inspections in third countries (outside the EU) in connection with the granting of an import authorization requested by the competent Land authority may not resolve O'Connor's concerns but, according to Gross, there are clear advantages. He advised that PEI experts know different facilities of the same MAH, they are familiar with the dossier (cell banks) and understand the manufacturing process, including validation.

Since April 2007, the European Medicines Agency has been working on a guideline on development, production, characterization and specifications for monoclonal antibodies and related products. It was adopted by CHMP (Committee for Medicinal Products for Human Use) in December 2008 and comes into effect on July 1.

The guidelines replaced "Production and quality control of monoclonal antibodies" (3AB4A) and quality requirements for mAbs set forth in "Radiopharmaceuticals based on monoclonal antibodies" (3AQ21A). Additionally, on May 18, the deadline for public consultation was reached for Regulation (EC) No 1234/2008 Article 4(1)(a) Guidelines on the variations categories.

Brigitte Holst, manager, manufacturing science & quality for Novo Nordisk, also expressed concern over variances among agencies. In her presentation, "EU/U.S. Regional differences," Holst commented that regional differences cost extra money and that harmonization will lower manufacturers' costs. She listed pharmacopeia, terminology, risk assessment, comparability/variations, and counterfeit as the biggest challenges.

Regarding terminology, Holst recommended "terminology from ISO standards to reduce confusion, double workload, and misinterpretation." Regarding risk assessment she said: "To harmonize we must create confidence in performing risk assessment and use ICH guidelines to set a common frame." Holst urged that "Now, globally, the pharmaceutical industry must insist on global requirements, only use the most widespread terminology, create confidence in performing risk assessments and share better practices."

By Tara Y. Coyt

Atlanta Correspondent

Inspections per Site

Year                               2008        2007        2006

Max inspection per site              18          27          15
Sites with 10+ inspections            5           6           8
Sites with 5-9 inspections           33          25          40
Sites with 4 inspections             30          26          17
Sites with 3 inspections             62          59          43