Center for Biologics Evaluation and Research
The year 2002 marked the 100th anniversary of the 1902 Biologics Control Act which gave the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) the authority to regulate biological products and ensure the safety of the American public.
Allergen Firm Receives Notice of Intent to Revoke U.S. License
Noncompliance With FDA Regulations Results in License Revocation
A Notice of Intent to Revoke letter was issued on April 17, 2002, to Allergy Laboratories of Ohio, Inc., Columbus, Ohio. The firm manufactures standardized and non-standardized glycerinated and aqueous allergenic extracts for the diagnosis, prevention, or treatment of allergies. Allergy Laboratories of Ohio, Inc., continued to operate in significant noncompliance with the applicable standards and regulations, and management did not implement adequate corrective actions for items noted in the 2000 and 2001 inspections. The firm’s license was revoked effective June 6, 2002.
Recall of IGIV
On March 21, 2002, Bayer Corporation announced the discovery of apparent product tampering for Gamimune® N, Immune Globulin Intravenous (Human), 10%, Solvent/Detergent Treated (IGIV). IGIV is approved by FDA for use in the treatment of Primary Immune Deficiency, Kawasaki’s disease, Chronic Lymphocytic Leukemia, bone marrow transplantation, Pediatric AIDS, and Immune thrombocytopenic Purpura. Bayer received customer reports describing the presence of a white precipitate in the solution in vials of IGIV. Bayer initiated a voluntary recall of two lots of IGIV relating to these vials - lot 648X078, recalled February 1, 2002, and lot 648X062, recalled March 14, 2002. Bayer received no reports of adverse reactions. Bayer also advised health care professionals, distributors, pharmacists, or patients in possession of vials from these lots not to use them and to report them to Bayer Clinical Communications.
CBER’s Bioresearch Monitoring Branch Issues 16 Warning Letters
In Fiscal Year (FY) 2002, regulatory scientists in CBER’s Bioresearch Monitoring Branch, part of the Division of Inspections and Surveillance/Office of Compliance and Biologics Quality, prepared and issued 16 Warning Letters (as compared to 11 in FY 2001) for deviations from regulations (21 CFR Parts 50, 56, and 312) designed to protect the safety, rights and welfare of human subjects participating in research and to assure the validity of data submitted to CBER in support of licensing applications or supplements. All of these Warning Letters may be found in redacted form (i.e., trade secret, confidential commercial or privacy related information which can not legally be disclosed is removed) on the FDA website at http://www.fda.gov/cber/efoi/warning.htm.
Notice of Opportunity for Hearing
On rare occasions, careful evaluation of the evidence concerning the conduct of a clinical trial shows that the clinical investigator appears to have repeatedly or deliberately violated regulations governing the conduct of clinical studies involving investigational biologicals. In such situations, CBER sends the clinical investigator a written notice detailing the alleged violations of good clinical practice regulations (primarily 21 CFR Parts 50 and 312) and initiates an administrative proceeding to determine if the clinical investigator should be disqualified from receiving, in the future, any investigational products regulated by FDA. After the clinical investigator has an opportunity to respond to the allegations, CBER evaluates all of the available evidence and may prepare a Notice of Opportunity for Hearing (NOOH) letter to be issued to the clinical investigator.
The NOOH letter informs the clinical investigator of his/her right to a regulatory hearing under 21 CFR 16.22 and 312.70(a), the next step in the process of determining whether or not he/she should be disqualified. No final FDA decision has been made at the time of issuance of the NOOH letter regarding eligibility to continue to receive investigational products. The following persons conducted clinical investigations regulated by CBER and received NOOH letters in FY 2002:
- James M. Wilson, MD, Ph.D., Philadelphia, Pennsylvania
- J. Michael McGee, MD, Tulsa, Oklahoma
- Roy C. Page, MD, Memphis, Tennessee
These NOOH letters are available in redacted form on the FDA website at http://www.fda.gov/foi/nooh.
Blood Bank’s License Suspended
On July 10, 2002, the Center for Biologics Evaluation and Research (CBER) informed the United States Blood Bank, Inc. (USBB), Miami, Florida, that the U.S. license issued to the facility for the manufacture of blood and blood components had been suspended. Instructions were provided to the firm that interstate shipment of products was prohibited. The firm collects approximately 24,000 units of blood annually, with approximately 50 percent interstate distribution.
The action was in response to an inspection of the firm by the Florida District Office that found numerous significant deficiencies from the applicable regulations and standards. Deficiencies included the failure to collect blood by aseptic methods and inadequate donor suitability determinations.
In addition, deviations were noted in the firm's records, and training. In addition, Quality Assurance oversight was also found to be insufficient. The firm's initial response to the action was not acceptable, and the firm continued to operate within the State of Florida. As a result of FDA's inspectional findings, on July 23, 2002, the Florida State Department of Health negotiated a cease and desist agreement with the firm that required the firm to bring operations into compliance with FDA requirements before intrastate blood product distribution could resume. The firm subsequently provided an acceptable corrective action plan to FDA, and Florida District Office performed an inspection of the facility and verified that the corrective actions had been implemented. Therefore, on September 16, 2002, CBER notified the firm that its U.S. license had been reinstated.
Plasma Firm’s License Revoked
On July 26, 2002, CBER issued a Notice in the Federal Register announcing the revocation of the biologics license issued to Beaugard Plasma, Inc., DeQuincy, Louisiana; Jackson Plasma, Inc., Jackson, Louisiana; Baton Rouge Plasma, Inc., St. Gabriel, Louisiana; and Claiborne Plasma, Inc., Homer, Louisiana; for manufacture of Source Plasma. FDA initiated proceedings to revoke the U.S. license because authorized FDA employees were unable to gain access to any of the establishment’s locations for the purpose of carrying out a required inspection of the facilities. In addition, manufacturing of products had been discontinued to an extent that a meaningful inspection or evaluation could not be made.
Blood Bank’s License Revoked
On March 14, 2002, CBER issued a Notice in the Federal Register announcing the revocation of the U.S. license issued to Ashford Blood, Bank, Inc., Santurce, Puerto Rico, for the manufacture of Whole Blood and Red Blood Cells. FDA initiated proceedings to revoke the biologics license because authorized FDA employees were unable to gain access to either of the establishment’s locations for the purpose of carrying out a required inspection of the facility. In addition, manufacturing of products had been discontinued to an extent that a meaningful inspection or evaluation could not be made.
Warning Letter Issued to Blood Bank
Deviations from CGMPs for Blood and Blood Components Results in Warning Letter
On February 21, 2002, the FDA’s San Juan District Office issued a Warning Letter to Las Americas Laboratory and Blood Bank, Inc., Hato Rey, Puerto Rico. The firm is a private licensed hospital blood bank. An FDA inspection conducted from December 4 - 12, 2001, revealed deviations from the Current Good Manufacturing Practices (CGMPs) for Blood and Blood Components, and Additional Standards for Human Blood and Blood Products. The deficiencies cited in the letter included the following: failure to store and handle platelets under appropriate temperature conditions; failure to promptly notify the Center for Biologics Evaluation and Research of errors; failure to have a system to record, document and investigate discrepancies related to the quality of blood products; failure to follow appropriate donor screening procedures; and failure to maintain adequate records of the processing and distribution of blood.
FDA Asks Court To Hold American National Red Cross in Contempt of 1993 Consent Decree
FDA Inspections Find ARC in Significant Non-Compliance with 1993 Consent Decree
On December 13, 2001, FDA asked a Federal Court to hold the American National Red Cross (ARC) in contempt of a 1993 consent decree covering ARC's blood program. FDA also asked the court for authority to levy prospective fines against ARC for future violations. ARC supplies approximately 45 percent of the Nation’s blood supply. FDA’s actions followed inspections of ARC facilities over the last 16 years that have shown continuing ARC violations.
These inspections include one from February through April 2000, of ARC's national headquarters, which provides quality assurance oversight for all of ARC’s regional and laboratory facilities, and an inspection of ARC's Salt Lake City facility from March through May, 2001. Despite ARC’s agreement to make substantial improvements, as promised in a consent decree signed in May 1993, these inspections revealed persistent and serious violations of blood safety rules.
“FDA is acting today to ensure that the American Red Cross takes much more seriously its role as guardian of the safety of the Nation’s blood supply, which is essential to the public health,” said Bernard A. Schwetz, D.V.M., Ph.D., FDA's Acting Principal Deputy Commissioner. “Unfortunately to date ARC has exhibited a corporate culture that has been willing to tolerate an unacceptably low level of quality assurance and a lack of concern for the public it is supposed to serve. In our view, these prospective penalties are necessary to ensure that ARC is held financially accountable for each unit of blood it fails to manage properly.”
FDA laws and regulations establish overlapping safeguards designed to protect the blood supply. Because there is always some degree of risk, however small, in receiving blood products, each individual safeguard is considered critical to minimizing that risk.
Although the failure of an individual safeguard, such as improper record keeping, does not automatically translate into the release of unsafe products, it may increase the potential risk. ARC’s violations of the consent decree and blood safety regulations have decreased the margin of safety.
The need for strengthening ARC's motivation for compliance was particularly evident from the findings of FDA's sixth and most recent inspection of ARC's national headquarters in February-April 2000. This inspection revealed violative conduct, including the following:
- incorrect labeling and release of blood potentially contaminated with cytomegalovirus;
- lack of adequate quarantine and inventory controls;
- inadequate donor registration controls and failure to maintain accurate and current lists of deferred donors; and
- erroneous, premature release of computerized "holds" on blood donations.
An FDA inspection during March - May 2001, of the Salt Lake City facility further demonstrated that ARC had not corrected these violations. Numerous violations were observed relating to quality assurance and ARC's continuing failure to monitor and exercise effective control over its regions. For example, possibly unsuitable donors were not deferred appropriately and quality assurance personnel did not investigate these deviations or attempt to correct them.
Dr. Schwetz emphasized that, as FDA works to improve blood safety, patients requiring blood transfusions should not hesitate to receive blood. “The risk of not receiving a needed transfusion far outweighs the risk of receiving blood,” he said. “I also want to encourage Americans to continue to donate blood. Giving blood is a safe and unselfish act. The health of millions depends on it,” he added.
FDA's legal action consisted of a motion asking a federal court to issue an order requiring ARC to show cause why it should not be held in contempt of a 1993 consent decree and to impose on ARC prospective fines to encourage future compliance. The motion and supporting documents were filed in the United States District Court for the District of Columbia.
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 medial 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 thus supports the regulation of those devices by CBER.
Class I Recall Syphilis G Elisa Test Kit
Test Kit for Syphilis Could Provide False Negative Results
On July 22, 2002, Trinity Biotech, IDA Business Park, Bray, Co., Wicklow Ireland, recalled the CAPTIA Syphilis G Elisa Test Kit, Lot numbers K00841, K00842, K00838, and K00839. The product is a diagnostic test used to detect syphilis in the blood and to screen blood and/or plasma donors by blood banks to rule out a history of syphilis. The reason for the recall was as follows: blood and/or plasma samples tested with the affected lots could provide a false negative result. In other words, blood and/or plasma samples with a history of syphilis could return a result of no history for syphilis.
The potentially false negatives were due to a shift in the performance of the Low Titre Positive Control in the lots mentioned above. This shift in performance can cause blood/plasma samples to result in low positive readings equivalent to negatives. The product was distributed in California, Florida, Minnesota, New Jersey, and Pennsylvania between May 16, 2002, and May 31, 2002. FDA considers there to be a high risk of adverse health consequences from continued use of the above name lots. Blood and/or samples tested on these lots should be retested.
Regulation of Human Tissue
The Center for Biologics Evaluation and Research (CBER) currently regulates, under 21 CFR Part 1270 and 1271, human tissue intended for transplantation that is recovered, processed, stored, or distributed by methods that do not change tissue function or characteristics and that are not currently regulated as a human drug, biological product, or medical device. Examples of such tissues are bone, skin, corneas, ligaments and tendons. Part 1270 requires tissue establishments to screen and test donors, to prepare and follow written procedures for the prevention of the spread of communicable disease, and to maintain records. 21 CFR Part 1271 requires the phased-in registration of tissue establishments.
FDA is in the process of revising the regulation of human tissues, cells, and cellular and tissue-based products. The proposed regulatory approach would address a broader scope of products, include more comprehensive requirements to prevent the transmission of communicable disease, and would apply tiered requirements based on the characteristics of such products.
FDA Issues Warning Letter to Tissue Firm
On June 17, 2002, FDA’s Atlanta District Office issued a Warning Letter to the president and CEO of CryoLife, Inc., Kennesaw, Georgia. The Atlanta District Office conducted an inspection of the firm from March 25 - April 12, 2002. The investigation determined that the firm manufactures and distributes cryopreserved heart valves. FDA investigators documented significant deviations from the Quality System Regulations, 21 CFR Part 820.
The Warning Letter detailed the following deviations: failure to fully validate and approve a process whose results cannot be fully verified by subsequent inspection and test; failure to use sampling plans, which are based on a documented valid statistical rationale; failure to revalidate a process conducted in response to changes or process deviations; failure to adequately inspect or test incoming product to verify conformance of incoming product to specifications; failure to fully document process validation activities and results; and failure to fully monitor and control the component and device characteristics during production.
FDA Orders Cryolife to Recall Human Tissue
Contaminated Human Tissue Results in Recall
On August 14, 2002, FDA issued a Press Release announcing that the agency had ordered Cryolife, Inc., of Kennesaw, Georgia, a human tissue-processing firm, to recall distributed human tissue processed between October 3, 2001, and August 14, 2002. Under the order, the firm must also withhold from the market or destroy tissue processed after that date. FDA took this action because the agency determined that Cryolife could not ensure that the human tissue it processed for transplantation was free from fungal and bacterial contaminants.
Donor tissue that had been processed by Cryolife on or after October 3, 2001, was associated with the November 2001 death of a patient who received a soft tissue implant during reconstructive knee surgery.
“This order not only protects patients from the unacceptable level of risk associated with tissue processed by Cryolife, it sends a clear signal that FDA stands ready to take whatever action is necessary to ensure the safety of human tissue,” said Dr. Lester M. Crawford, FDA Deputy Commissioner.
During an inspection of Cryolife from March 25 through April 12, 2002, FDA found numerous significant violations of FDA regulations. FDA issued a Warning Letter to Cryolife on June 17, 2002, after determining, among other things, that the firm had neither adequately investigated its validation of processing and testing methods, nor implemented recommendations from the Centers for Disease Control and Prevention (CDC), or any other procedures to ensure that tissue processed by the firm was not contaminated.
Current federal regulations for human tissue require firms to prepare, validate, and follow written procedures to prevent infectious disease contamination or cross-contamination during tissue processing. Contamination may be caused by a variety of infectious disease agents, including viruses, bacteria, fungi, and transmissible spongiform encephalopathy (TSE)-associated prions.
After determining that Cryolife had failed to take adequate corrective measures to address possible infectious disease contamination of tissue in inventory and distribution, and after reviewing information provided by the firm in response to FDA’s warnings, FDA issued the present order.
FDA’s concerns described in the order related specifically to bacterial and fungal contamination of soft tissues such as cartilage and tendons. FDA’s investigation revealed, among other things, that, of those standard operating procedures implemented by Cryolife to prevent infectious disease contamination or cross-contamination, many were not followed. In addition, Cryolife improperly distributed tissue from a donor after the firm confirmed the presence of harmful microorganisms in tissue samples from the same donor.
The FDA Press Release stated that, “If a bacterial or fungal infection were to occur following a tissue transplant, the signs and symptoms would usually appear within days to weeks after transplantation. Therefore, it is unlikely that patients who have not recently received a transplant are likely to be at future risk. However, concerned patients are encouraged to contact their physicians.”
On August 21, 2002, FDA issued a Public Health Notification to Health Care Providers regarding Cryolife heart valves:
“Allograft heart valves processed and supplied by Cryolife have not been included in the FDA recall order. This is because these devices are essential for the correction of congenital cardiac lesions in neonate and pediatric patients and no satisfactory alternative device exists. Under these circumstances, the benefit of these devices outweighs the risk associated with the current manufacturing deficiencies.”
“Even though FDA has not included allograft heart valves in the FDA recall order for the reason stated above, FDA still has serious concerns regarding the processing and handling of allograft heart valves by Cryolife because patients who receive these devices may be at increased risk for infection.”
Recall of Hepatitis A Vaccine
Vaccine Recalled Due to Subpotency
In April 2002, Merck & Co., Inc, West Point, Pennsylvania, recalled Hepatitis A Vaccine, Inactivated (VAQTA) (packaged in single dose pre-filled syringes) Pediatric/adolescent formulation: 25 U / 0.5 mL single dose syringe - Adult formulation: 50 U /1 mL single dose syringe.
The reason for the recall was that some syringes may have antigen levels below the minimum product specification limit. As a result, a possibility exists that persons vaccinated with the indicated lots may have been insufficiently protected against Hepatitis A. The lots were distributed in the international market and have been recalled specific to the international governing regulations and in accordance with local regulatory authorities in these countries.