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Center for Drug Evaluation and Research 2001

Chapter 3

Last Update: August 07, 2003

Bioresearch Monitoring Program

Warning Letter Issued to Clinical Investigator

Clinical Investigator Fails to Personally Supervise the Clinical Trial

On July 25, 2001, the FDA's Center for Drug Evaluation and Research (CDER) issued a Warning Letter to Candace S. Brown, Pharm. D./FNP, University of Tennessee Medical Group, Memphis,Tennessee, regarding deviations from good clinical investigation practices in a study of an investigation drug. The FDA's New Orleans District Office/Nashville Branch conducted an inspection on April 12 - 14, 2000. During the inspection the FDA investigator observed the following deviations: failure to personally conduct or supervise the investigation, which led to an overdose of study drug in two subjects; failure to conduct the study in accordance with the relevant current protocol; failure to notify the sponsor prior to making changes in the protocol; and failure to promptly report to the Institutional Review Board (IRB) of a change in the study plan.

Warning Letter Issued for Clinical Trials Involving Children

FDA Inspection Finds Significant Violations Regarding the Study of An Investigational Drug

On July 6, 2001, the FDA's Center for Drug Evaluation and Research (CDER) issued a Warning Letter to Lori A. Nesbitt, Pharm. D., M.B.A., CEO of Discovery Alliance, Inc. (formerly d/b/a Gulf Coast Clinical Services, Inc.), Mobile, Alabama. An August 2000 inspection by the FDA's New Orleans District Office revealed significant deviations regarding the study of an investigational drug. Study subjects ranged in age from 6 to 17 years who had been diagnosed with Generalized Anxiety Disorder.

Deviations observed during the inspection and cited in the Warning Letter included the following: failure to adequately protect the safety and welfare of human subjects by failing to involve a physician in clinical assessments that should be performed by a physician; failure to follow the study protocol by failing to have a qualified physician review and sign the case report forms; failure to accurately inform the IRB about medical oversight of the study; and failure to obtain IRB approval for recruitment advertisements prior to enrolling subjects in the study.

Good Manufacturing Practices

Active Pharmaceutical Ingredients

Inadequate Cleaning Procedures Result in Warning Letter
On June 25,FDA Inspection Finds Significant CGMP Violations Including Failure to Conduct Investigations in a Timely Manner

On July 6, 2001, the FDA's Chicago District Office issued a Warning Letter to the President and CEO of Ferro Corporation, an active pharmaceutical ingredient manufacturer in Waukegan, Illinois. The Chicago District conducted an inspection of the firm between December 21, 2000, and January 19, 2001, and documented the failure of the firm to comply with current good manufacturing practice (CGMP) regulations for drugs. The inspection revealed that the firm failed to have adequate cleaning procedures, had not validated all cleaning verification testing methods, lacked validation for all manufacturing processes, and did not conduct investigations thoroughly and in a timely manner.

FDA's Chicago District officials and representatives from Ferro met on March 13, 2001, to discuss the firm's response letter to the FDA inspectional observations on FDA 483. At that time, FDA indicated that the responses appeared adequate. The district indicated that they would verify corrective actions during the next inspection.

Manufacturers of Finished Pharmaceuticals

Warning Issued to Pharmaceutical Manufacturer

On September 5, 2001, the FDA's Denver District Office issued a Warning Letter to Syncor Pharmaceuticals, Inc., Golden, Colorado. During an inspection conducted by the Denver District from July 13 - 23, 2001, investigators documented significant CGMP deviations for Finished Pharmaceuticals. Deficiencies included the following: incomplete Master and Batch records; incomplete calibration records; failure to follow written procedures; inadequate label controls, and others.

Although the firm's response to the FDA-483 promised full correction, the Warning Letter noted that the firm also promised corrections to deficiencies observed during a previous inspection in 1998. The Warning Letter recommended that the firm address their deficiencies at the systems level to ensure similar problems are corrected.

Aseptic Manufacturing Operation Has CGMP Problems
CGMP Problems Include Failure to Assure All Media-Filled Bottles are Incubated

On March 2, 2001, the FDA's Detroit District Office issued a Warning Letter to Eli Lilly and Company, Indianapolis, Indiana, for their aseptic drug manufacturing operations. An FDA inspection from January 29 to February 23, 2001, revealed significant deviations from CGMPs for drugs. These deviations were documented in the Warning Letter and included the following: failure to have a Quality Control Unit adequate to perform its functions and responsibilities; failure to assure that all media filled bottles were incubated; failure to establish appropriate written procedures designed to prevent microbial contamination; failure to demonstrate the adequacy of the facility as it related to flow of air, people, and product, and failure to appropriately validate equipment.

GMP Problems Found in Manufacture of Finished Pharmaceuticals
Firm Cited for Failure to File ANDA Alert

The FDA's San Juan District Office issued a Warning Letter on May 22, 2001, to Zenith Laboratories Caribe, Inc., Cidra, Puerto Rico, a drug manufacturing facility. The Warning Letter was issued as a result of an FDA inspection from February 1, 2001, to April 3, 2001, of the facility in Cidra, Puerto Rico. The inspection disclosed serious deviations from CGMPs, including the following: failure to have an adequate tracking system to evaluate the trend of failure investigations; failure to follow their stability program; failure to have adequate procedures in the packaging operations to prevent discrepancies; failure to file an ANDA Field Alert; and other deviations.

The Warning Letter also stated that FDA had received the firm's response letter dated May 4, 2001, and concluded that some of the issues found during this inspection were systemic deficiencies that needed prompt attention.

Subpotent Prenatal Vitamins Result in Warning and Recall
FDA Lab Analysis Finds Vitamins Subpotent for Folic Acid

The FDA's Detroit District Office issued a Warning Letter to the President of M.E. Pharmaceuticals, Economy, Indiana, following an inspection of the manufacturing facility. An FDA inspection conducted from April 25 - May 3, 2001, disclosed numerous CGMP violations. These deviations included: failure to establish a Quality Control unit; failure to establish written procedures; failure to establish master production and control records; failure to establish adequate batch and control records for each batch of drug product; failure to maintain complete records of the periodic calibration of scales; failure to have written specifications, tests and/or release procedures for some components and finished drug products; and failure to have an ongoing stability program to determine appropriate expiration dates.

FDA collected two physical samples of prescription vitamins during the inspection. FDA analyses revealed that both samples were subpotent for folic acid. When FDA advised the firm of the analyses, the firm initiated a voluntary recall for all lots of the three prescription products.

Micronase Tablets Recalled
Fungal Organisms Found In Anti-Diabetic Medication

On September 24, 2001, FDA announced to pharmacists and healthcare professionals of a voluntary recall of Micronase lots 84DWB (1.25 mg, bottle of 100); 91DYR (2.5 mg, bottle of 100); 67FPP (5 mg, bottle of 100); and 42 different lots of Greenstone Brand Glyburide Tablets. The recall was initiated because fungal organisms had been detected in some lots of Micronase and Greenstone Brand Glyburide Tablets, traced to a raw material used in the formulation. Micronase is an oral antidiabetic medication used to treat type 2 diabetes.

Vanceril Recall

The FDA's New Jersey District Office received notice of a recall situation at Schering Corp., Kenilworth, New Jersey. The recall involved four lots of Vanceril 42 mcg (Beclomethasone Dipropionate, 42 mcg) inhalation aerosol, 16.8g and 200 metered actuations per canister. The reason for the recall was the lack of assurance that the canisters could meet the specifications. According to the firm, only four lots of Vanceril entered into commerce. The firm issued a recall on July 13, 2001, by letter. The product was distributed nationwide and involved 322,644 canisters. The district monitored the recall to completion.

Moldy Cream Destroyed
Progesterone Cream Contaminated with Mold

On June 25, 2001, the FDA's New York District Office witnessed the destruction of four lots of Femgest, a Progesterone Cream. The firm NBTY voluntarily recalled the product in December 2000, when mold was discovered in the product (Recall #D-083-1). A total of 13 skids consisting of 17,604 2-ounce glass jars and 28,978 blister packs, valued at $36,028. were transported from NBTY's warehouse, Ronkonkoma, New York, to American Ref-Fuel, Westbury, New York, and the product was incinerated.

Phyne Pharmaceuticals

FDA Issues Urgent Recall of Injectable Drugs
Products Recalled Due to Lack of Assurance of Sterility and Potency

On January 25, 2001, the FDA issued an urgent warning advising individuals, health care organizations and medical product distributors to stop dispensing and/or distributing certain injectable medications marketed by Phyne Pharmaceuticals of Scottsdale, Arizona. AMRAM, Inc., of Rathdrum, Idaho manufactured these products for Phyne Pharmaceuticals, who was their sole customer. The FDA issued the warning because Phyne Pharmaceuticals delayed taking prompt and appropriate action to remove these products from the market. On December 14, 2000, AMRAM, Inc., notified Phyne Pharmaceuticals that AMRAM Inc. was recalling these products because they were manufactured under sub-standard conditions.

The nationwide recall followed FDA's inspections of Phyne Pharmaceuticals and AMRAM, Inc. During the inspections, FDA found violations of requirements of CGMPs for pharmaceuticals. The violations that FDA found demonstrated that the products lacked assurance of sterility and potency. FDA advised anyone in possession of these products to return the products to Phyne Pharmaceuticals.

The following is a list of products under recall by Phyne Pharmaceuticals. Some of the products were labeled with both AMRAM, Inc. and Phyne Pharmaceuticals. However, some bore one or the other company's name as the manufacturer and/or distributor with or without the other company's name listed. All lot numbers and codes, strengths and sizes and expiration dates of the following injectable products were included in this recall:

Adenosine Monophosphate
Ascorbic Acid Injection
Beet Ascorbic Acid Injection
Vitamin B-12(Cyanocobolamin)
Disol, USP Brand of EDTA
Echinacea Homeopathic Injection
Edetate Disodium
Adrenal Cortex Extract (ACE)
Folic Acid
Germanium Sesg.(Sesguloxide)
L-Glutathione or Glutathione
Human Chorionic Gonadotropin
Hydrochloric Acid
Iron 59 Injection
Liver Injection, Crude
Lypo-Vite Injection
Magnesium Chloride Injection
Procaine Hydrochloride Injection
Pyridoxine HCL (B-6)
Sodium Thiosalicylate
Superoxide Dismutase (S.O.D.)
L-Taurine Injection
Thiamine HCL
Thymus Extract
Choline Chloride
Chlorpheniramine Injection
Hydrogen Peroxide
MIC with Folic Acid
Pangamic Acid
FDA advised patients who believed they might have been injured by these products to immediately consult with their health care provider. FDA received information of three serious injuries associated with the use of one of the recalled products, Colchicine, labeled as containing .5mg/ml but actually formulated at a concentration of 5mg/ml.

FDA Warns Public Phyne Pharmaceuticals Is Not Recalling Adrenal Cortex Extract

On January 29, 2001, FDA issued a Note to Correspondents stating that Phyne Pharmaceuticals, Inc., had informed the FDA that the firm was not recalling vials of injectable Adrenal Cortex Extract (ACE). The product was manufactured by AMRAM, Inc. The Note to Correspondents stated that the FDA had the same safety concerns about ACE as it did with products manufactured by AMRAM, Inc. The safety concern involved the fact that the ACE was manufactured under conditions that violated CGMPs for pharmaceuticals. In the statement FDA strongly recommended that the product not be used, and that ACE be disposed of by destroying the product in such a manner as to render it unusable.

Seizure at Phyne Pharmaceuticals

The FDA's Los Angeles District Office reported that a seizure was successfully accomplished on July 27, 2001, of recalled injectable drug products manufactured by AMRAM in Idaho for Phyne Pharmaceuticals in Arizona, and subsequently distributed by Phyne. The Arizona Board of Pharmacy assisted by placing an embargo on the goods. FDA initiated the seizure because of concerns that the products (subject to a nationwide recall) would not be properly destroyed.

Wyeth-Ayerst Laboratories Signs Consent Decree
Firm Agrees to Pay $30 Million to U.S. Treasury and Comply with CGMPs

On October 3, 2000, the FDA announced that Wyeth-Ayerst Laboratories Division of American Home Products Corporation and Wyeth- Ayerst Pharmaceuticals, Inc. (Wyeth) signed a consent decree of permanent injunction in which Wyeth agreed to a series of measures aimed at ensuring that the products manufactured at Wyeth's Marietta, Pennsylvania, and Pearl River, New York facilities are made in compliance with FDA's CGMP regulations. The government's action followed inspections completed at the Marietta and Pearl River facilities during which FDA found deviations from CGMP regulations, including issues related to quality control.

The consent decree signed by Wyeth and three of its top corporate executives will ensure that Wyeth keeps its commitments to the agency. Under the consent decree, Wyeth will retain independent expert consultants to conduct comprehensive inspections of its Marietta and Pearl River operations. Their reports will be provided to FDA. The firm agreed to address any observations made by the expert consultants in accordance with a schedule approved by FDA and to pay $15,000 per day for failure to meet the schedule (up to a $5,000,000 cap). FDA will re-inspect both facilities when the agency believes it is appropriate.

Wyeth also agreed to pay $30,000,000 to the U.S. Treasury within 15 days after the consent decree was entered by the court. The government sought this money as the equitable remedy of disgorgement based on the firm's deviations from the CGMP regulations. Previous FDA inspections of the Marietta facility in August- September 1995, June 1996, and September-October 1998 found CGMP deviations that resulted in the issuance of two warning letters and a regulatory meeting between FDA and Wyeth.

Elan Pharmaceuticals Signs Consent Decree
Serious CGMP Violations Lead to Consent Decree

On May 21, 2001, FDA announced that Elan Holdings, Inc., a wholly-owned subsidiary of Elan Corporation plc of County Westmeath, Ireland, signed a consent decree of permanent injunction setting forth measures to assure that the firm's Gainesville, Georgia manufacturing facility fully complies with FDA's good manufacturing practice (CGMP) requirements.

Company executives who signed the consent decree included Donald J. Geaney, Chairman and Chief Executive Officer of Elan Corporation plc and President of Elan Holdings, Inc., William C. Clark, President of Elan Pharmaceutical Operations, Hal Herring, Vice President and General Manager of Elan Holdings, Inc., and Cheryl Schuster, Manufacturing Manager of Elan Holdings, Inc. Along with the FDA, the case was prosecuted by the Department of Justice Office of Consumer Litigation, and the U.S. Attorney's Office for the Northern District of Georgia. The government took this action after a series of FDA inspections over the past six years revealed a pattern of significant CGMP violations that had occurred in the company’s Gainesville, Georgia plant. The facility manufactures various forms of Verapamil Hydrochloride capsules - drugs used in the treatment of high blood pressure.

Despite repeated warnings from the FDA, plant officials continually failed to assure that these drugs met required quality standards. Among other things, the company failed to conduct adequate laboratory tests and investigations to ensure their product met the required standards before release. Additionally, the company failed to complete the validation of products before release, as well as maintain laboratory analytical equipment in good repair and keep adequate records of test results.

Although none of these violations is known to have caused an immediate risk to public health, their occurrence lessened the level of assurance of safety and effectiveness that would have existed had the drugs been manufactured under proper conditions. Under the terms of the consent decree, the company and the individuals identified above (collectively "the company") are permanently enjoined from violating FDA manufacturing requirements. Thus, if the company further violates these CGMP requirements, FDA may seek the court to hold the company in civil or criminal contempt of the decree.

The company is also required to hire an independent expert - subject to FDA approval - who will conduct inspections of this plant at least once a year, for three years. In addition, the company will reimburse FDA for all necessary follow-up inspections the agency conducts to verify plant compliance.

In the event that FDA determines that this plant is not in compliance with CGMPs in the future, FDA may order the company under the terms of this decree to immediately cease the plant's operation. If that were to occur, the plant would not be allowed to resume operation without explicit permission from FDA.

Order of Contempt for Camall Company
Firm Sells $3 Million of Drug Product in Violation of 1999 Consent Decree

United States v. Undetermined quantities of bottles of phentermine hydrochloride (E.D. Mich.) Following a hearing on May 9, 2001, United States District Judge Denise Page Hood signed an order that prohibits Camall Company and its president, Eugene Schmall, from taking any action as to any active or inactive pharmaceutical ingredient subject to a consent decree entered by the Court on October 20, 1999, other than destruction. The Order remains in effect pending the Court's resolution of FDA's Motion for an Order to Show Cause why Defendants Camall and Schmall should not be held in contempt of the October 1999 consent decree.

FDA initiated the contempt proceeding after defendants Camall and Schmall sold approximately $3 million of Phentermine HCL without FDA supervision, in violation of the October 1999 consent decree. Before FDA discovered that the sale had taken place, the Phentermine HCL sold by the defendants had been used by the purchaser to manufacture finished drug products, which had been distributed to consumers. To remedy the defendants' violation, FDA's proposed Order of Contempt seeks destruction of the remaining raw materials subject to the consent decree, imposition of conditional fines, payment in escrow of nearly $3 million, and imposition of investigatory costs and attorneys' fees.

On September 28, 2001, the United States District Court Judge Denise Page Hood held Camall Company and Eugene M.. Schmall in contempt of a Consent Decree based on their $2.9 million sale of phentermine to Eon Labs Manufacturing, Inc., without FDA supervision. The Court agreed with FDA that, without knowledge of the phentermine sale, the agency could not have supervised that sale. Camall's failure to provide FDA with advance notice was undisputed.

The Court also found that Camall and Schmall violated the Consent Decree by failing to return the drugs subject to the initial seizure to the United States Marshal, as they were required to do upon a breach of the Decree's provisions. The Court found that FDA did not act arbitrarily or capriciously in requesting that the goods be returned. The Court held that, as a result of Camall and Schmall's violations, the government is entitled to attorneys fees and costs, as well as investigational costs, incurred in its enforcement of the Decree. Further, the Court granted the government's motion for leave to obtain discovery and to depose Camall, its officers and employees, and any third-party witnesses who may have information regarding whether the defendants are in compliance with the Decree. The Court granted the motion to enable FDA to determine whether there are any other breaches of the Decree "given that the public's safety is at issue in this case."

Medical Gases

Warning Letters Issued

  • On June 5, 2001, the FDA's New Orleans District Office Nashville Branch issued a Warning Letter to L&M Medical Inc., Leighton, Alabama, a medical gas repacker. An FDA inspection conducted from May 8 - 11, 2001, revealed serious CGMP deviations including the following: failure to assay each filled cryogenic vessel for identity and purity prior to release; failure to perform identity analysis on incoming bulk liquid medical oxygen; inadequate Standard Operating Procedures; no documentation of supervisory review of batch records; no Quality Control Unit; and inadequate employee training in CGMPs.
  • The FDA's Chicago District Office issued a Warning Letter to Savant Medical Supply, Inc., Forest Park, Illinois. The Warning Letter charged that this Compressed and Liquid Oxygen USP transfiller failed to follow CGMP regulations in its transfilling operations. An FDA inspection from November 30, 2000 - February 2001, revealed significant CGMP deviations including: failure to test each batch of Liquid Oxygen USP for identity and purity prior to release; failure to establish batch production and control records for each batch of drug; failure to properly calibrate the Oxygen analyzer; failure to have written procedures for handling all written and oral complaints; and failure to establish a quality control unit.
  • On March 14, 2001, the FDA's New Orleans District Office issued a Warning Letter to Home Care Supply, LLC, d.b.a. Medi-Rents and Sales, Metairie, Louisiana. The firm manufactures liquid Oxygen USP in cryogenic vessels. An inspection of the facility conducted from January 11 - February 1, 2001, revealed significant CGMP deviations. These violations of CGMPs included the following: failure to establish adequate batch production and control records; failure to document the initials or signature of the person who performed final product testing on cryogenic vessels of oxygen and to document the date of all final product testing of liquid Oxygen USP; failure to follow procedures for assigning lot numbers; using labels that did not meet written specifications; and failure to document employee training in CGMP requirements in the production of oxygen.
  • The FDA's Atlanta District Office issued a Warning Letter on March 7, 2001, to Barnes Health Care Services, Valdosta, Georgia, a medical oxygen transfilling facility. An inspection conducted from February 12 - 14, 2001, revealed significant CGMP deficiencies. These deficiencies included: failure to record purity and identity test results for 2 production lots; failure to always document the calibration of the analyzer prior to use; failure to maintain adequate batch production and control records; failure to establish written procedures designed to assure that correct labels and labeling are used; failure to exercise strict control over labeling issued for use in drug labeling operations; failure to maintain training documentation for all employees performing Oxygen USP activities; and failure to adequately calibrate the thermometer, pressure and vacuum gauges.
  • On March 23, 2001, the FDA's New Orleans District Office Nashville Branch issued a Warning Letter to Pioneer Express Respiratory Care Inc., Coldwater, Mississippi, as the result of an FDA inspection on February 28 - March 1, 2001. The inspection disclosed serious non-compliance with CGMPS in the repacking of medical oxygen. These deviations noted in the Warning Letter included the following: failure to calibrate the analyzer used for purity and identity assays; incomplete batch production records; no Quality Control Unit; and no written Standard Operating Procedures.
  • On May 10, 2001, the FDA's Seattle District Office issued a Warning Letter to Willett Brothers, Inc., Lewiston, Idaho, for deficiencies with the firm's production of medical oxygen gas. The FDA conducted an inspection on March 14 and 15, 2001, at the Lewiston facility. During the inspection investigators documented numerous violations of the CGMP regulations for medical gases. These deviations included the following: failure to test batches of medical oxygen gas packed in compressed cylinders for identity and purity after the first batch of the day; failure to have a Quality Control Unit that had the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products; failure to record the percent of calibration for the strength and purity on the maintenance log; failure to follow their own written procedure of using a scale when filling liquid cryogenic vessels and for the calibration of the temperature thermometer attached to the compressed Oxygen USP cylinders.

Oxygen Transfiller Cancels Registration

The FDA's Baltimore District Office conducted an inspection on May 17, 2001, at Home Care Equipment, Inc., Lebanon, Virginia. The firm is a medical oxygen transfiller. The inspection was conducted as a follow-up to a Warning Letter issued in January 2000. The May 2001 inspection noted several significant CGMP deficiencies, many of which were repeat violations, such as, no documentation of purity analysis and missing documentation on production records. FDA held a meeting with firm management in a subsequent visit to discuss the significance of the deficiencies. The president voluntarily opted to vent all of its oxygen cylinders into the atmosphere, discontinue all transfilling operations, and cancel the firm's FDA registration.

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