Chapter 1

Center for Biologics Evaluation and Research

Biologic Products

Warning Letter Issued to Plasma Center

The FDA's Baltimore District Office issued a Warning Letter to the President of Sera-Tec Biologicals Limited Partnership, on January 18, 2001. The Warning Letter was issued following an FDA inspection of their Richmond, Virginia plasma center, on November 29 through December 19, 2000.  The Warning Letter cited the firm for the following deviations: failure to maintain and/or follow adequate written Standard Operating Procedures including all steps to be followed in the collection, processing, storage, and distribution of blood and blood products; and failure to maintain and/or follow adequate procedures for conducting a thorough investigation, including the conclusions and follow-up of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications.

Warning Letter Issued to Biologics Firm

The FDA's Center for Blood Evaluation and Research issued a Warning Letter to Bayer Corporation, Biologics Product Division, Berkeley, California, on July 24, 2001. FDA conducted inspections at Bayer's manufacturing facilities located in Clayton, North Carolina, between September 25 and November 12, 2000, and March 13 and 21, 2001, and in Berkeley, California, between November 6 and December 7, 2000. During these inspections, FDA investigators documented violations of the FD&C Act and deviations from the Code of Federal Regulations, Parts 210 and 211 and 600-680.

These deviations included: failure to establish and follow written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product; failure to ensure that reprocessed batches of product will conform with all established standards, specifications, and characteristics; failure to maintain and/or follow written procedures for the production and process control designed to assure that the drug products have the identity, strength, quality and purity that they purport or are represented to possess and to assure that such procedures, including any changes, are drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by quality control.  

Allergen Manufacturer Receives Warning

The FDA's Center for Biologics Evaluation and Research issued a Warning Letter on January 23, 2001, to Allergy Laboratories of Ohio, Inc., Columbus, Ohio. During an inspection on September 19 - 26, 2000, an FDA investigator documented violations of the FD&C Act and deviations of 21 C.F.R. Parts 210-211 and 600-680. These deviations included the following: failure to establish testing programs designed to assess the stability characteristics of drug products; failure to establish the effectiveness or verify the suitability of all testing methods under actual conditions of use; failure to establish written procedures for a review of records associated with a batch, in that annual reviews of records were not performed; and failure to visually examine reserve samples from representative lots or batches for deterioration, at least once a year. During the inspection, the investigator documented at least seven lots of extracts that were recalled after errors were discovered in either the concentration calculations or expiration dates.

Recall of Biologic Ointment

On March 12, 2001, the Center for Biologics Evaluation and Research announced that Advance Biofactures Corporation (ABC) in Lynbrook, New York, was initiating a recall of two lots of Collagenase Santyl Ointment, 30 gram tubes. The firm initiated the recall because the product was found to be super potent using a universal extraction correction factor to determine the potency of the product. This method is part of an approved corrective action plan approved by the Center for Biologics Evaluation and Research. This product is a licensed biologic product, and has a four-year expiration date.

Bioresearch Monitoring

Warning Letter Issued to Institutional Review Board

On August 13, 2001, the Center for Biologics Evaluation and Research issued a Warning Letter to ImmunoGenetics Investigational Review Board, Birmingham, Alabama, in response to an inspection from June 28 - July 9, 2001. The inspection was conducted by the FDA's New Orleans District Office Nashville Branch. The Warning Letter addressed several problems that were discovered during the inspection including (but not limited to) the following: lack of written procedures; failure to properly review research; failure to adequately review and approve informed consent forms; and failure to ensure that protocol changes were not implemented until reviewed and approved by the Institutional Review Board (IRB). The Warning Letter further advised the IRB that no new studies that are subject to DHHS/FDA jurisdiction are to be approved by the IRB, and no new subjects may be admitted to ongoing studies that are subject to DHHS/FDA jurisdiction (previously approved by the IRB).

Clinical Investigator Receives Warning Letter

The FDA's Center for Biologics Evaluation and Research issued a Warning Letter to Michael R. K. Jacoby, M.D., Mercy Ruan Neurology Clinic, Des Moines, Iowa. An inspection conducted on November 3, 2000, as part of FDA's Bioresearch Monitoring Program disclosed serious deficiencies from the Code of Federal Regulation 21 C.F.R. Parts 321 and 50. These deviations included the following: failure to promptly report to the Institutional Review Board (IRB) all changes in the research activity; failure to obtain informed consent in accordance with the provisions of 21 C.F.R. Part 50; failure to ensure that the investigation is conducted according to the investigational plan; and failure to prepare and maintain complete and accurate case histories.

Investigator at Research Center Warned

An investigator from the FDA's Philadelphia District Office and a Medical Officer from the FDA's Center for Biologics Evaluation and Research visited the headquarters of the Institute for Human Gene Therapy at the University of Pennsylvania. The inspection was conducted from November 20, 1999, to January 19, 2000. Based on information obtained during the investigation, FDA determined that Mark L. Batshaw, M.D., Children's National Medical Center, Washington, D.C., violated regulations governing the proper conduct of clinical studies involving investigational new drugs.

The FDA issued a Warning Letter to Dr. Batshaw dated November 30, 2000, which identified the following violations: failure to ensure that an investigation is conducted according to the investigational plan; failure to assure that the Institutional Review Board (IRB) would be responsible for the initial and continuing review of the clinical study by failing to submit accurate reports regarding the safety of the study and failing to accurately and completely identify changes to the protocol for the IRB's review and evaluation; and failure to obtain informed consent in accordance with the provisions of 21 C.F.R. Part 50.

Blood

Warning Letter Issued for Failure to Screen Donors

The FDA's Chicago District Office issued a Warning Letter on August 3, 2001, to Coral Blood Services, Inc., Chicago, Illinois. This firm is an unlicensed blood bank that has only been in operation since June 1, 2001. An FDA inspection of the firm on July 11 and 18, 2001, revealed deviations from 21 C.F.R. Parts 600 - 680. The Warning Letter cited the firm for storing collected units of whole blood at room temperature for at least the duration of the collection day.

In addition, the Warning Letter cited Coral Blood Services for its practice of separating red blood cells from the whole blood several days after collection, and processing at room temperature which causes the temperature of the blood to increase. In addition, the firm was cited for not recording the answers to all of the questions required to be asked of prospective donors, and for failure to elicit sufficient information from donors to determine if they had traveled to areas at risk for malaria.

Warning Issued for Failure to Follow CGMPs for Blood Products

On August 27, 2001, the FDA's Florida District Office issued a Warning Letter to Lee Memorial Health System, Ft. Myers, Florida. An FDA inspection of this unlicensed blood bank on June 11 - 20, 2001, documented serious violations of the FD&C Act and CGMP regulations for blood and blood components. For example, the firm failed to determine, among other things, the suitability of persons to serve as whole blood donors; failed to adequately train personnel and to maintain employee training records; failed to establish and implement a written quality assurance program; failed to establish written procedures for receiving and evaluating information on possible product deviations; failed to establish written procedures for review and evaluation of post donation information; and failed to maintain adequate written procedures for performing Rapid Plasma Regin test [a seriologic test for syphilis] in accordance with the manufacturer's directions.

Firm Fails to Notify Physician of Donor Reaction

On March 29, 2001, the FDA's Seattle District Office issued a Warning Letter to the CEO of SeraCare Inc., Los Angeles, California. The FDA conducted an inspection of one of the firm's facilities on 2802 Hoyt Avenue, Everett, Washington, on February 5 - 9, 12 and 14, 2001. During the inspection FDA investigators documented serious violations of the FD&C Act and 21 C.F.R. Parts 600-800. These deviations included the following: failure to maintain and follow written Standard Operating Procedures to include all steps to be followed in the collection, processing, testing, storage, and distribution of blood and blood components. For example, the firm failed to notify the center physician/physician substitute of a donor reaction as required by SeraCare's Standard Operating Procedures. In addition, the firm failed to assure that all personnel have the training and experience necessary for the competent performance of their assigned functions.

Hospital Blood Bank Receives Warning Letter

The FDA's Cincinnati District Office issued a Warning Letter to a hospital blood bank at Aultman Health Foundation, Canton, Ohio. An FDA inspection of the facility from June 5-6, 2001, disclosed deviations from the FD&C Act and 21 C.F.R. Part 606. The FDA investigator's findings included the following: failure to calibrate or properly calibrate equipment used to determine donor suitability; failure to calibrate equipment used in blood component preparation; failure to follow written Standard Operating Procedures; failure to review all records and failure to investigate errors prior to the release of blood products.

FDA Inspection Reveals Firm Failed to Maintain Accurate Records

The FDA's Atlanta District Office issued a Warning Letter to the Director, Quality Assurance-Compliance, Seramed, Inc., d/b/a Aventis Bio Services, Knoxville, Tennessee, on June 29, 2001. An FDA inspection on April 19-20 and May 30 - June 6, 2001, of the firm's facility in Greenville, South Carolina, disclosed violations of the FD&C Act and 21 C.F.R. Parts 600-680. The investigator documented the following deviations: failure to maintain and/or follow adequate written Standard Operating Procedures to include all steps to be followed in the collection, processing, storage, and distribution of blood and blood products; failure of personnel to have a thorough understanding of the procedures or control operations they perform, and/or the necessary training or experience in their respective functions; and failure to maintain complete and accurate records.

In-Vitro Diagnostic Test Kits

Note: Jurisdiction of medical device review by the Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH) is governed by the FDA Intercenter Agreement between CBER and CDRH (October 31, 1991).

CBER regulates medical devices related to licensed blood and cellular products by applying appropriate medical device laws and regulations. The medical devices regulated by CBER are intimately associated with the blood collection and processing procedures as well as the cellular therapies regulated by CBER. CBER has developed specific expertise in blood, blood products and cellular therapies and the integral association of certain medical devices with those biological products supports the regulation of those devices by CBER.

Warning Letter Issued to Medical Device Distributor

The FDA's Florida District Office issued a Warning Letter on July 9, 2001, to World Diagnostics, Inc., Miami Lakes, Florida, a distributor of in-vitro diagnostic test kits. An inspection at the firm located on 60th Avenue, Miami Lakes, in January/February 2001, determined that the firm purchases and distributes the Smart Check TB, Smart Check Strep Q, Smart Check Cotinine, Smart Check/Strip Opiates, Dengue IgM and IgG Double Spot, and other in-vitro diagnostic test kits (IVDs). These IVDs are devices under the FD&C Act. In addition, these IVDs are adulterated in that they are Class III devices and there are no approved applications for premarket approval in effect and no approved applications for investigational device exemptions.

The firm failed to conduct internal quality audits; failed to establish and maintain procedures for receiving, reviewing and evaluating complaints by a formally designated unit; and failed to establish and maintain an adequate organizational structure to ensure that the devices are designed and produced in accordance with the Quality System Regulation.

Firm Warned for Lacking MDR Reporting Procedures

The FDA's Chicago District Office issued a Warning Letter on June 11, 2001, to TheraTest Laboratories, located in Chicago, Illinois. An inspection on February 12 - 14, 2001, determined that the firm manufactures in-vitro diagnostic devices. The inspection disclosed violations of the Quality System Regulation for Medical Devices. The Warning Letter cited the firm for the failure to control/monitor the production process and for an absence of quality audit procedures, and design control procedures. The letter also cited the firm for lacking Medical Device Reporting (MDR) procedures.

Tissues

Warning Letter Issued to Tissue Eye Bank

On May 30, 2001, the FDA's Detroit District Office issued a Warning Letter to the Indiana Lions Eye Bank, Inc., Indianapolis, Indiana. The FDA conducted an inspection of the tissue bank from March 26, 2001, - April 3, 2001. During this inspection, the investigator documented significant violations of the Public Health Service Act and 21 C.F.R. Part 1270. The Warning Letter cited the tissue bank for the following violations: failure to follow written procedures for designating and identifying quarantined tissue; failure to quarantine human tissues until donor screening has been completed for HIV, Hepatitis B and Hepatitis C; failure to maintain accurate records which identify the person performing the work, etc.; failure to have written procedures for all significant steps in infectious testing; and failure to have written procedures for performing all significant steps for obtaining, reviewing, and assessing the relevant medical records of the donor readily available to personnel who may perform the procedures.

Vaccines

Rabies Vaccine Recalled

In March 2001, the FDA's San Francisco District Office reported that Chiron Corp. of Emeryville, California, was recalling certain lots of RabAvert brand Rabies Vaccine for Human Use in 3cc glass vials because sterility may have been compromised as evidenced by broken or cracked vials. Chiron Behring GmbH & Co., of Marburg, Germany, manufactured the product. The firm received several consumer complaints of broken or cracked vials.

The problem was observed during preparation of vaccine and prior to patient injection of vaccine. The firm initiated an internal investigation to determine the extent and the root cause of the breakages. The firm indicated that for the 2 affected lots (261011 and 273011) some of the vials were packaged glass bottom to glass bottom. The firm's investigation concluded that the glass to glass contact may have resulted in vial breakage during shipment. The firm estimated they will recover 95 percent of the total product. The FDA's San Francisco District Office monitored the recall to termination to assure proper disposition of returned product.

Warning Letter and Recall for Hepatitis B Vaccine

United States v. Amscot Medical Labs, Inc., (S.D. Ohio) On August 2, 2001, the United States District Court for the Southern District of Ohio entered a Consent Decree of Permanent Injunction prohibiting defendants, Amscot Medical Labs, Inc., and George Kindness, M.D., Ph.D., from manufacturing, processing, packing, labeling, promoting, and distributing a vaccine known as Theracine, any similar drug or any biologic product, or any other drug that is a new drug. The government's Complaint for Permanent Injunction alleged that defendants manufactured and distributed the Theracine vaccine for use in the cure, mitigation, treatment, or prevention of cancer. The government further alleged that defendants introduced into interstate commerce biological products for which a biologics license application had not been approved, and that such products were adulterated in that they were not manufacture d in compliance with CGMPs.

On September 6, 2001, the New England District Office issued a Warning Letter to the President of Bindley Western Industries, Inc., Dublin, Ohio. The significant deviations noted during the inspection and cited in the Warning Letter included the following: returning to the marketplace drug products that had been subjected to improper storage conditions; failure to assure that all prescription drugs were stored at appropriate temperatures and under appropriate conditions; failure to assure that drug products were held under conditions that are in conformance with storage requirements set for those drugs; failure to consider the conditions under which a drug has been held, stored, or shipped before or during its return; failure to establish, maintain, and to adhere to written policies and procedures.

Consent Decree of Permanent Injunction Entered for Amscot Medical Labs

United States v. Amscot Medical Labs, Inc., (S.D. Ohio) On August 2, 2001, the United States District Court for the Southern District of Ohio entered a Consent Decree of Permanent Injunction prohibiting defendants, Amscot Medical Labs, Inc., and George Kindness, M.D., Ph.D., from manufacturing, processing, packing, labeling, promoting, and distributing a vaccine known as Theracine, any similar drug or any biologic product, or any other drug that is a new drug. The government's Complaint for Permanent Injunction alleged that defendants manufactured and distributed the Theracine vaccine for use in the cure, mitigation, treatment, or prevention of cancer. The government further alleged that defendants introduced into interstate commerce biological products for which a biologics license application had not been approved, and that such products were adulterated in that they were not manufacture d in compliance with CGMPs.

Under the Consent Decree, the defendants are prohibited from manufacturing and distributing the Theracine vaccine, or any similar drug or biologic product, unless and until they obtain appropriate premarket approval for such product and (1) hire a qualified outside expert who certifies to FDA that defendant's facilities and methods of operation are in conformity with CGMP; (2) submit a written report to FDA setting forth the actions it has taken to ensure conformity with CGMP; (3) FDA representatives review and evaluate the certification and report submitted and make inspections as deemed necessary; and (4) defendant receives written authorization to resume manufacturing from the agency. The Consent Decree also provides the government with the authority to require future shutdown in the event of further violations, destruction of goods on hand, recall of distributed articles, and inspectional costs.

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