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Center for Drug Evaluation and Research 2002

Bioresearch Monitoring Program

Warning Letter Issued to Clinical Investigator

Bioresearch Monitoring Inspection Finds Serious Violations of FDA Regulations

On June 11, 2002, FDA’s Center for Drug Evaluation and Research issued a Warning Letter to Dr. Leonard J. Caputo, M.D. An FDA inspection on August 29 and 31, 2000, of two clinical studies at the Asthma and Allergy Institute, Mobile, Alabama, revealed serious violations of FDA regulations. Specifically, the Warning Letter identified violations concerning the Proper Conduct of Clinical Studies Involving Investigational New Drugs [21 CFR Part 312].

This inspection was conducted as part of FDA’s Bioresearch Monitoring Program, which includes inspections to validate data from clinical studies on which drug approval may be based and to assure that the rights and welfare of the human subjects who participate in such studies are protected.

The violations cited in the Warning Letter included the following: failure to adequately supervise the clinical study; submission of false information to the sponsor; failure to conduct the clinical study in accordance with the approved protocol; and failure to maintain adequate and accurate record-keeping and case histories.

Good Manufacturing Practices Active Pharmaceutical Ingredients

Inadequate Cleaning Procedures and Test Methods Result in Warning Letter

FDA Inspection Finds Significant CGMP Violations

On October 25, 2001, FDA’s Philadelphia District Office issued a Warning Letter to the president of Enzyme Development Corporation, an active pharmaceutical ingredient manufacturer in Scranton, Pennsylvania. The Philadelphia District conducted an inspection of the firm between June 18 and July 3, 2001, and documented the failure of the firm to comply with current good manufacturing practice (CGMP) for drugs. The inspection revealed that the firm failed to validate cleaning procedures for non-dedicated equipment, failed to demonstrate the accuracy of test methods, failed to ensure that each lot of product conformed to quality specifications prior to release, failed to demonstrate that the manufacturing process consistently produced product meeting quality specifications, and failed to establish the stability of the product through appropriate studies.

The firm sent two letters dated July 19, 2001, and August 16, 2001, in response to FDA’s 483 issued on July 3, 2001. The district judged these responses to be inadequate because they did not provide sufficient details of the firm’s proposed corrective action plan. The district indicated that they would verify corrective actions during the next inspection.

Manufacturers of Finished Pharmaceuticals

Warning Issued for Failure to Conduct Stability Testing

On April 1, 2002, FDA’s San Francisco District Office issued a Warning Letter to the President of Biozone Laboratories, Pittsburgh, California. An FDA inspection of the firm on February 11 - 20, 2002, documented deviations from drug CGMP regulations on stability testing. The firm did not conduct any stability testing all on its drug products, and continued to use a two-year expiration-dating period on its labels. The firm had responded adequately to FDA-483 observations describing other CGMP deviations.

FDA Finds CGMP Problems for Manufacturer of Aseptically Processed Drugs

Firm Fails to Have Controls to Prevent Microbiological Contamination of Product

FDA’s Detroit District Office issued a Warning Letter to the President and CEO of Pfizer, Inc., on January 30, 2002. The Detroit District conducted an inspection from November 6 - December 6, 2001, of the firm’s aseptic drug manufacturing operations at the Terre Haute, Indiana plant. During the inspection, FDA investigators documented numerous significant deviations from drug CGMPs. These deviations included: failure to have a quality control unit adequate to perform its functions and responsibilities, and failure to have and to follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile. In addition, the firm failed to have adequately designed procedures for production and process control and failed to have separate or defined areas, or such other control systems as are necessary to prevent contamination during the course of aseptic processing operations.

Solid Dosage Form Facility Warned

On May 20, 2002, FDA’s New Orleans District Office issued a Warning Letter to Vintage Pharmaceuticals, LLC, Huntsville, Alabama. FDA New Orleans District conducted an inspection on Marcy 25 - 29, 2002, of the firm’s new solid dosage form facility in Huntsville. The inspection revealed the following deviations from CGMPs: inadequate process validation of drug manufacturing processes; failure to follow Standard Operating Procedures for change control and process validation; and, inadequate stability studies.

Premarin Recalled

Failure to Meet Dissolution Specifications Results In Recall

FDA’s New York District Office reported that Wyeth-Ayerst expanded the firm’s recall of Premarin. The recall was expanded to include 0.625 mg tablets with lot numbers 9001566, 9010254, and 9010255. Premarin is produced at Ayerst Laboratories, Rouse Point, New York. The recall was initiated on February 21, 2002, due to failure to meet dissolution specifications at the 12-month interval. The recall will be limited to wholesalers and repackers. Inspectional follow-up of this recall will be conducted during an upcoming inspection of the manufacturing plant.

FDA Inspection Discloses Metal Fragments in Tablets

On March 11, 2002, FDA’s New Jersey District Office issued a Warning Letter to Berlex Laboratories, Inc., Wayne, New Jersey. An FDA inspection of the firm from January 3 - February 4, 2002, disclosed significant deviations from CGMPs. The Warning Letter cited deficiencies in the firm's Quality and Production systems including a failure to prevent the release of six lots of Quinaglute tablets that contained visible metal fragments from unqualified manufacturing equipment used during production. A visual examination of samples retained by FDA investigators and by representatives of the firm confirmed that numerous tablets from these lots contained visible fragments of metal.

The Warning Letter noted that the procedures and controls used by the firm’s Quality Unit were inadequate to assure the identity, quality, strength and purity of the product. In addition, FDA advised that the firm failed to adequately qualify the metal detector which was used in the Quinaglute tablets manufacturing process.

Urgent Drug Recall of Heparin Sodium Injection

Heparin Recalled Due to Presence of Particulate Matter in Vials

FDA’s New Jersey Office advised that Wyeth-Ayerst agreed to recall Heparin Sodium Injection. The recall was based on the presence of particulate matter in vials of 1,000 units per ml Heparin Sodium produced in their Elkin-Sinn, Cherry Hill, New Jersey plant. Wyeth Pharmaceuticals/ESI Lederle issued an Urgent Drug Recall Notice on April 29, 2002, to all customers. The letter advised that Wyeth Pharmaceuticals and ESI Lederle were voluntarily recalling all lots of Heparin Sodium USP (Porcine Derived) 1,000 units /mL, 1 mL Dosette vials, 10 mL and 30 mL Multiple Dose Vials, IV or SC use, Rx only. The particulate matter found was a crystal-like material containing an antioxidant compound that came from the rubber closures. The recall was extended to the hospital, pharmacy and physician shelf level. Distribution was nationwide and to Costa Rica.

Watson Laboratories Signs Consent Decree

Consent Decree Requires Generic Drug Manufacturer to Correct CGMP Violations

United States v. Watson Laboratories, Inc., et al., (C.D. Cal.). On May 3, 2002, FDA announced that Watson Laboratories, Inc., a Nevada corporation, signed a Consent Decree requiring the firm to take all necessary corrective steps to ensure that its Corona, California manufacturing plant is in strict compliance with FDA’s regulations. The government initiated this action after a series of FDA inspections revealed a pattern of significant CGMP violations that had occurred in the company’s Corona, California plant. The firm is a manufacturer and distributor of 25 generic prescription oral drug products which include a wide therapeutic range of products. The firm had received prior Warning Letters. The most recent inspection on April - May 2001, disclosed numerous significant deficiencies including: failure to adequately validate analytical methods; failure to thoroughly investigate customer complaints of drug products to ensure that they meet specifications; failure to provide adequate training to employees operating manufacturing and testing equipment; and failure to have adequate complaint accountability and controls over computer or related systems for accuracy of records.

This Consent Decree requires Watson to ensure that it’s Corona, California facility complies with CGMPs. In addition, pursuant to the agreement, Watson will hire an independent expert within 45 days to conduct inspections of the Corona facility at least once each year. A report of each inspection by the independent expert will be prepared and submitted to FDA, with an opinion from the expert as to their CGMP compliance at the Corona facility. The first such expert report is due during the first quarter of 2003.

Maxair Inhaler Recalled

Press-and-Breath Inhaler Recalled - Firm Offers Replacement

On May 8, 2002, 3M Pharmaceuticals Division announced a voluntary recall of 16 lots of the prescription medication Maxair Inhaler (pirbuterol acetate inhalation aerosol). This is a press-and-breathe metered-dose inhaler. The recall was issued as a precaution to address the remote possibility that a Maxair press-and-breathe aerosol inhaler may stick intermittently and patients may not receive the expected puff of medication.

This recall did not affect Maxair Autohaler (pirbuterol acetate inhalation aerosol), a breath-actuated metered-dose inhaler. Patients using the Maxair press-and-breathe inhaler were advised to return the product to their pharmacy. 3M was unable to offer patients an exact replacement unit at the time, as the Maxair press-and-breathe inhaler was currently unavailable at that time. Patients could obtain the same medication in a different delivery device. 3M provided the Maxair autohaler in exchange for the Maxair press-and-breathe inhaler.

Firm Pays Fines Pursuant to Consent Decree

FDA Imposes Fines When Firm Fails to Come Into Compliance with CGMPs

On October 4, 2000, a Consent Decree of Condemnation and Permanent Injunction was filed in a District Court against Wyeth-Ayerst Pharmaceuticals, Inc., et al. Stipulations under the decree included monetary fines if the firm fails to satisfactorily complete one or more actions with respect to its manufacture of drug and biologic (vaccine) products. These actions were designed to bring the firm into compliance with CGMPs.

On January 25, 2002, and February 20, 2002, FDA notified the firm of payments due in the amount of $1,635,000 and $2,520,000, respectively, for its failure to complete various actions in accordance with the timetables.

Seized Pharmaceuticals Destroyed

On February 7, 2002, FDA’s Los Angeles District officials from the Phoenix Resident Post, Phoenix, Arizona, and the U.S. Marshals Service witnessed the destruction of approximately 4,100 vials of various injectable products seized from Phyne Pharmaceuticals, Inc., Scottsdale, Arizona, during late July 2001. The products had been manufactured for Phyne in the absence of Current Good Manufacturing Practices by AMRAM, Inc., Rathdrum, Idaho. Following inspections by FDA, AMRAM and Phyne recalled the products beginning December 2000. The value of the destroyed items was approximately $36,500.00.

Schering-Plough Signs Consent Decree of Permanent Injunction

Consent Decree Requires Firm To Pay Equitable Disgorgement of $500 million to U.S. Treasury

On May 20, 2002, a U.S. District Judge signed and entered a Consent Decree of Permanent Injunction between the Department of Justice, on behalf of FDA, and Schering-Plough Corporation and Schering-Plough Products, and two corporate officers. The Consent Decree provides for injunctive relief aimed at ensuring the defendants’ compliance with Current Good Manufacturing practice (CGMP) regulations at Schering’s manufacturing facilities in Kenilworth and Union, New Jersey, and Manati and Las Piedras, Puerto Rico. The Consent Decree requires that the company pay equitable disgorgement of $500 million to the U.S. Treasury based on profits from the sale of drugs that were not manufactured in compliance with the CGMP regulations. The consent decree also requires that Schering reimburse the U.S. Treasury $471,500, for the cost of conducting and reporting FDA’s prior inspections of the firm’s New Jersey and Puerto Rico facilities.

Under the terms of the Consent Decree, Schering must retain independent expert consultants to audit each product and to perform comprehensive inspections of its New Jersey and Puerto Rico facilities. Schering must submit to FDA comprehensive work plans detailing the steps that will be taken at each facility to ensure full compliance with the CGMP regulations and drug applications held by the company. If Schering fails to meet the time frames in any schedule of corrections approved by FDA, the company must make payments which include $15 thousand per business day for each corrective action not completed, up to a cap of $175 million.

The consent decree also requires that Schering retain independent expert consultants to certify that all manufacturing and testing requirements are met before distribution of each batch of drug product that FDA has determined is medically necessary. Additionally, Schering is required to assign individuals to review management controls at each facility on a full-time basis and to report findings directly to the Senior-Vice President of Quality; to retain independent expert consultants to audit management controls and to conduct yearly inspections to evaluate compliance with CGMP regulations at each facility. The results of the independent consultants’ audits and inspections must be reported to top level management and to FDA. The decree provides FDA with the authority to order the defendants to, among other things, cease manufacturing and distribution at the New Jersey and Puerto Rico facilities if FDA determines that there are significant violations of Current Good Manufacturing Practice.

Medical Gases

Warning Letters for Medical Gases

  • On April 23, 2002, FDA’s Minneapolis District Office issued a Warning Letter to RWK, Inc., a medical oxygen transfilling operation, located in Mankato, Minnesota. During an FDA inspection of this medical oxygen transfilling facility on February 26 - 28, 2002, investigators documented a number of violations of Current Good Manufacturing Practices (CGMP) for Finished Pharmaceuticals. Some of the violations documented in the Warning Letter included the following: failure to adequately calibrate the oxygen analyzer; failure to provide CGMP training to personnel responsible for trans-filling medical oxygen; failure to calibrate gauges; and failure to establish Standard Operating Procedures (SOPs).
  • On April 23, 2002, FDA’s Seattle District Office issued a Warning Letter to Breathing Easy, Inc., Canby, Oregon. This firm is a medical gas repacker engaged in processing and distributing medical oxygen. An FDA inspection of the firm on February 26 - 28, 2002, disclosed serious violations of the regulations for Current Good Manufacturing Practices (CGMPs) for Finished Pharmaceuticals. The firm was cited for the following violations: failure to properly calibrate their oxygen analyzer; manipulating the oxygen analyzer during the filling operation resulting in four years of purity testing results that could not be verified; failure to establish written procedures for the calibration of the oxygen analyzer; failure to have adequate written procedures for purity testing and release for distribution of medical oxygen; and failure to maintain a written record for the inspection and maintenance of the oxygen analyzer.
  • On December 10, 2001, FDA’s Baltimore Office issued a Warning Letter to the CEO of Bon Secours Health System, Inc., Marriottsville, Maryland. An FDA inspection of this medical gas facility located in Richmond, Virginia, on November 13, 14, and 16, 2001, disclosed significant deviations from CGMP regulations for Finished Pharmaceuticals. The deviations cited in the Warning Letter included: failure to test each batch of drug product for identity and strength of each active ingredient prior to release; failure to establish written procedures designed to assure that drug products have the identity, strength, quality, and purity that they purport or are represented to possess; and failure to establish and document the responsibility of the quality control unit.

Consent Decree of Condemnation in Oxygen Case

Firm Must Discontinue All Manufacturing and Distribution of Gas for Medical Use

United States v. Undetermined Quantities of Articles of Drug (N.D.N.Y.). On December 20, 2001, a U.S. District Judge entered a Consent Decree of Condemnation and Forfeiture for articles of drug that were seized because they were adulterated and misbranded. Upon entry of the decree, the Claimant, Albany Edison Oxygen Company, Inc ("AEO"), had to (1) discontinue all manufacturing and distribution of gas for medical use; (2) destroy the seized gases; and (3) sell the seized high pressure cylinders and stand tank under the supervision of FDA. If AEO did not sell the items within six months, the U.S. Marshal was to destroy or dispose of the items at AEO's expense. In addition, AEO would have to pay all costs incurred by FDA in supervising AEO's compliance with the terms of the decree.

The mass seizure was accomplished December 5, 2000, and covered all medical oxygen produced at the firm’s Albany New York facility. The seized product, included liquid oxygen in a 500,000 gallon bulk stand tank and gaseous oxygen in 218 high-pressure cylinders. The seizure warrant charged that the oxygen was adulterated because it was not produced in accordance with drug CGMPs, and misbranded because the filed cylinders lacked an accurate statement of the quantity of contents.

The firm has had a violative inspectional history dating back to 1996. Despite repeated written notices from FDA, the firm continued to disregard CGMP requirements for the transfilling of medical oxygen. Continuing deficiencies included the following: failure to perform identity-testing; failure to perform adequate pre-fill operations; and failure to establish and follow adequate written procedures. Following the seizure, a claim and answer were filed and, after extended negotiations, a Consent Decree containing injunctive provisions was signed by the claimant and filed in Northern District of New York, on December 21, 2001. Compliance with the Decree required not only the destruction of the seized oxygen, but also the sale and removal from the premises of the bulk stand tank and oxygen cylinders, with the sale pre-approved and supervised by FDA’s New York District Office.

On January 28, 2002, FDA and the U.S. Marshals Service witnessed the destruction of seized medical gas in 180 H size cylinders, 38 E size cylinders, and liquid gas in a bulk stand tank, valued at $31,171 at Albany Edison Oxygen Co., Inc., Albany, New York.

Seizure and Consent Decree of Condemnation of Medical Oxygen

Consent Decree of Condemnation Requires That Firm Vent All Medical Oxygen Into Atmosphere

United States v. Undetermined Quantities of an Article of Drug, Gas for Medical Use, (D.Neb.) A seizure of medical oxygen at Island Supply Welding Co., Norfolk, Nebraska, was accomplished on February 26, 2002. All containers holding medical oxygen including a very large stand tank with a capacity of 155,000 gallons were seized. Other containers seized included cylinders, dewars, and cryogenic home units. The Court appointed the firm "custodian of the seized goods" so that nothing had to be removed from the premises. The seizure action was based on the firm's failure to comply with CGMPs.

On August 19, 2002, a U. S. District Judge entered a Consent Decree of Condemnation, condemning medical gas manufactured by Island Supply Welding Company at its Norfolk, Nebraska facility. The gas was condemned because it was: (1) adulterated in that the methods used for manufacturing, packing, and holding did not conform to current good manufacturing practice, and (2) misbranded in that the labels on the medical gas containers failed to contain an accurate statement of the quantity of the contents. The decree provided for, inter alia, the destruction of all seized medical gas by venting into the atmosphere; the cessation of all medical gas manufacturing at Island Supply's Norfolk facility; consultation and inspection by an independent CGMP expert, along with 90-day notice and authorization by FDA, before Island Supply could manufacture medical gas at its Norfolk facility in the future.

FDA Shuts Down Medical Gas Facility

Firm Agrees to Comply with CGMPs But Fails to Follow-Up

FDA announced on June 18, 2002, that the Agency had shut down certain operations of Air Liquide America Corp. (ALAC), a medical gas facility in Coatesville, Pennsylvania. The company failed to assure that its industrial grade trailers (also used for storing and hauling medical gases) were clean, purged, and completely free of contaminants prior to having them filled with medical gas, thereby creating a potential hazard for patients who use this product.

Previously, ALAC had agreed to comply with FDA’s Current Good Manufacturing Practice regulations (CGMPs) in a Consent Decree which the firm signed in November 1997. However, an FDA inspection on April 2, 3, and 10, 2002, found that the Coatesville facility had failed to meet the agreed upon standards. As a result, the inspected plant had to stop having their trailers filled with medical gas and stop distributing gases.

Repackers of Pharmaceutical Products

Warning Letter Issued for Deviations from CGMPs

FDA Inspection Finds Significant Deviations From CGMPs Resulting in Numerous Complaints and Two Recalls

FDA’s Florida District Office issued a Warning Letter on August 6, 2002, to TYA Pharmaceuticals, Tallahassee, Florida, based on an inspection conducted on February 11 - 15, 2002. The firm is a drug repacking/labeling facility. The inspection found numerous deviations from current good manufacturing practices (CGMP) regulations, which may cause products repacked and/or relabeled to be adulterated. The following violations were observed during the inspection: failure to establish written procedures for numerous firm operations; failure to maintain stability data to support the expiration dates used; failure to document qualifications of major equipment; failure to perform process validations and equipment cleaning validations; and failure to have a training program for employees in CGMPs. In addition, the firm's recall procedures were not followed or documented, and the firm maintained no complaint files.

The Warning Letter noted that the lack of adequate control over the repacking operation led to numerous complaints (Medwatch reports) including: mislabeled drug products; lots with multiple expiration dates; poor blister pack seals; no package insert or the wrong insert; the lack of an Rx legend; and the wrong drug in the unit dose containers. These complaints generated two recalls by the firm in the past year, both of which were undocumented and inadequately handled.

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