Regulatory Beat: Biotech Manufacturers Face Streamlined Inspection Programs

Published on: 
BioPharm International, BioPharm International-11-01-2006, Volume 19, Issue 11
Pages: 40–45

FDA is working more closely with foreign regulators to keep abreast of drug and vaccine quality issues in their regions.

Food and Drug Administration officials have been establishing a host of initiatives to use increasingly limited resources more effectively to monitor drug and biotech manufacturing facilities in the US and abroad. A main FDA strategy is to use risk models to determine which manufacturing operations and which products are more risky and require closer scrutiny. Agency officials look to further integrate preapproval (PAI) and GMP (good manufacturing practices) inspections to reduce redundant site visits. To clarify when a PAI is or is not necessary, FDA is updating preapproval inspection procedures for drugs and biologics. The agency also aims to expand systems-based inspections and to cooperate more with international regulatory agencies to better identify those foreign facilities that merit closer scrutiny.

Jill Wechsler


One important effort has been to establish a risk-based approach for identifying top priority drug manufacturing sites for GMP inspections. FDA also is applying risk models to selecting drug samples for laboratory testing as well as companies that warrant review of their adverse-event reporting systems.


Of some 1,200 to 1,400 drug manufacturing sites that FDA inspected in 2006, about 500 were categorized as high-risk based on plant size and operations, product types, process control, and contamination potential. The Office of Compliance in the Center for Drug Evaluation and Research (CDER) is issuing an updated white paper that describes the program's first year of operation and, based on this experience, has refined its methods for making priority inspection assignments for 2007. FDA hopes to inspect high-risk facilities every two years. Low-risk plants, the agency concedes, may be visited only every five or six years unless the manufacturer experiences production problems or runs into difficulties maintaining product quality.


While risk-based models are proving useful in identifying manufacturers and products that warrant closer and more frequent regulatory scrutiny, this approach may be less appropriate for many biotech products, according to Mary Malarkey, director of the Office of Compliance and Biologics Quality in the Center for Biologics Evaluation and Research (CBER). She pointed out at the PDA/FDA Joint Regulatory Conference in Washington in September that almost all therapies regulated by CBER are fairly high risk, so "there's not much wiggle room." In fact, CBER recently decided to inspect vaccine makers annually—instead of every two years— due to recent concerns about vaccine quality and supply, and CBER continues to review its production inventory on a biannual basis.

At the same time, Malarkey is looking to make CBER's compliance program more efficient. The agency is continuing efforts to better integrate preapproval and GMP inspections and to implement a systems-based inspection approach for biological drugs and blood and source plasma establishments; Malarkey's office plans to update this program in 2007.

CBER has developed a risk model to set inspection priorities for the large number of facilities involved in processing human cells, tissues, and cellular and tissue-based products (HCT/Ps) that have evolved into a major new industry. This approach is part of a formal compliance and inspection program established in 2005 as part of a broader FDA Tissue Action Plan. However, FDA is likely to ramp up its oversight of HCT/P operations due to a number of serious incidents involving falsified records and manufacturing deficiencies. FDA issued a guidance in September clarifying that tissue establishments are responsible for ensuring that contractors comply with good tissue practices, and a Task Force on Human Tissue Safety is evaluating the need for increased inspection and regulation of human tissue firms.


Another initiative involves updating the Team Biologics program. FDA conducted a broad reassessment of Team Biologics two years ago as part of its GMP modernization initiative. The basic conclusion was to make some changes while continuing this program for overseeing biotech manufacturers, including blood facilities, vaccine makers, and biotech therapies now regulated by CDER.

A Team Biologics Operations Group, which includes officials from CBER, CDER, and the Office of Regulatory Affairs, has developed a Quality Management System to improve Team Biologics operations and revise standard operating procedures and quality assurance programs for inspection and compliance activities. A main initiative has been to develop metrics to assess the impact of the Team Biologics program on industry. To this end, the Pharmaceutical Quality Research Institute conducted an online survey of manufacturer opinions on Team Biologics' effectiveness; the results are being evaluated, even though industry response has been sparse, Malarkey pointed out.

Team Biologics has provided the model for establishing a Pharmaceutical Inspectorate to assess drug manufacturing facilities, particularly those that adopt innovative production and quality control systems. This group has about 45 field officers certified for their expertise in understanding quality systems in order to tap them for evaluating quality-by-design production approaches.


A major drain on FDA's resources is the need to inspect a growing number of foreign manufacturing facilities that produce drugs and biologics for the US market. In order to identify those facilities that are most important to inspect, FDA is working more closely with foreign regulatory agencies to keep abreast of quality issues related to drug and vaccine makers in their regions. After the Chiron debacle two years ago, FDA signed a formal confidentiality agreement with the United Kingdom's medicines agency that allows sharing of regulatory information. FDA also has agreements with Canada and the European Medicines Agency for quality information sharing and is pursuing additional agreements.

FDA hopes to expand its access to GMP information around the world by joining the 29 other nations in the Pharmaceutical Inspection Cooperation Scheme (PIC/S). Most European regulatory authorities plus inspection officials from Australia, Canada, Malaysia, and Singapore are members of this organization that seeks to build consensus on manufacturing standards and inspection procedures. PIC/S provides a forum for representatives of regulatory agencies to exchange information and experiences related to GMPs, quality inspection systems, and inspector training. Members share inspection reports, but there is no obligation to accept the findings of other authorities. The group develops guidances on manufacturing and compliance issues, organizes training seminars, and operates a rapid-alert system to inform other nations of product recalls. A main goal is to promote international harmonization of GMPs.

FDA has long been an observer of PIC/S activities involving drugs and biologics, with particular involvement in programs for blood and blood products, notes Malarkey. Last year, FDA applied for formal membership, as did Argentina, Israel, South Africa, and several other nations. This launched a multiyear review process for PIC/S officers to assess FDA's internal system for conducting quality inspections, for training investigators, and for ensuring industry compliance with GMPs. A main issue is that FDA does not issue any kind of manufacturing site authorization, as do the Europeans, explained PIC/S chairman Jacques Morenos at the PDA/FDA conference. Even CBER no longer requires biologics licenses for biotech production facilities. PIC/S officials would like FDA to explain more fully how its GMP inspection program can ensure that a manufacturer meets regulatory requirements as does the European authorization process.

FDA officials recognize the PIC/S approval process may take time, but anticipate playing a more active role in developing recommendations and guidelines on manufacturing regulatory and compliance issues such as validation and sterility testing.

PIC/S aims to work more closely with the World Health Organization and international health organizations in Asia and other regions with an eye to ensuring the competency of inspectorates around the world.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634,