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LAL-Endotoxin Related Warning Letters
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Cleveland Clinic Foundation, 2002-03-26
"You did not perform the protocol-required tests for endotoxin and
mycoplasma prior to the infusion of the investigational xxx for all study subjects."
Dayton Water Systems, 2002-03-14
"The cause was that the LAL test results were not within specifications....There was no documentation that a failure investigation was performed and no corrective action was implemented for the LAL test failures."
Tyco International Ltd., 2002-03-08
"Radionics' Pyrogen Procedure QS3-09-0065, Rev. A does not specify that all implanted device configurations be tested for pyrogenicity."
Medical Device Services, Inc., 2001-12-13
"The validation testing for sterilization process, LAL bioburden, and residuals will be completed by October 10, 2001. This response is inadequate in that calibration by itself cannot provide assurance that the requirements of a sterilized product can be consistently fulfilled."
Ferro Corporation, 2001-07-06
"Investigations were not completed for several incidents of Purified Water not meeting specifications for microbial contamination and endotoxin levels during the Performance Qualification testing."
Eli Lilly and Company, 2001-03-02
"There is no written procedure that describes an evaluation process in order to verify and confirm the integrity of HEPA filters in the depyrogenation tunnel's hot zone."
Associates of Cape Cod, Inc., 2000-11-17
"Serum vials, failed to meet the optical density specifications. The vials were released and the failure was not investigated."
"During shipping and packaging operations of Limulus Amebocyte Lysate (LAL) Gel Clot, 133 cracked vials (including 15 broken vials) were identified. The cause of the defects was not identified. No investigation or corrective and preventive action was implemented."
"No corrective and preventive actions were implemented when visible black smudges were observed on 5-mL glass vials (25,410 vials). Procedures were implemented to discard 5-mL glass vials that are received with visible black smudges, but no preventive actions have been established."
"There is no documentation to demonstrate that the autoclaving of the LAL product stoppers during the wash and depyrogenation process will not affect the stopper's performance."
"Stability studies have not been conducted to support the dating period assigned to buffers and manufacturing components used to manufacture LAL products." .......
International Medication Systems. Limited, 2000-03-22
"Test data such as temperature of heat block incubator, sample identification number, and order of sample loading into the heat
bIock incubator was not recorded during the actual performance of Limulus Amebocyte Lysate (LAL) testing for Bacterial Endotoxins."
Schein Pharmaceutical, Inc., 2000-03-02
"The Quality Control Unit failed to: conduct adequate studies to determine the effectiveness of the sterilization and depyrogenation procedures on equipment surfaces that contact sterile products."
Associates of Cape Cod, Inc., 1999-12-22
"The stopper wash/depyrogenation processing for autoclave has not been completely validated."
"There are no provisions for the monitoring of lots of Limulus Amebocyte Lysate (LAL) products that are released after unusual processing conditions or test results."
"Container closure integrity studies have not been performed for LAL products."
"When qualifying a Control Standard Endotoxin (CSE) for use with a turbidimetric test, there are no specifications as to the range of potencies that can be averaged to obtain the mean standard potency."
"Endotoxin testing of the water is not always performed as required by the SOP."
Hoffmann-La Roche, Inc., 1999-12-17
"The pH of the product-lysate mixture of the USP Bacterial Endotoxin test was either not performed or not recorded on validation product batches."
Bio-Science Research Institute, Inc., 1999-11-10
"Inhibition/Enhancement tests are not performed to validate product Limulus Amebocyte Lysate (LAL) testing."
"LAL test records do not record sensitivity or product tests documenting dilutions used, endotoxin and lysate lot numbers or their sensitivities, incubation times or temperatures and calculation of results."
"Lysate sensitivity tests and positive product control containing 2 Lambda endotoxin are not performed for each test as required."
"Thermo-probes used to monitor rabbit temperatures during pyrogen testing are not calibrated to the required sensitivity."
"The room housing the rabbit colony (used for pyrogen testing) is not temperature monitored or controlled to the required sensitivity."
IDEC Pharmaceutical Corporation, 1999-11-08
"Variance Report reported an out of limit result for a Limulus Amebocyte Lysate (LAL) test at a process stage. Although the report states that endotoxin was removed downstream of this step, a thorough investigation has not been conducted to demonstrate that the remaining downstream processing steps including the xxxxx Column Chromatography process and xxxxx Column Chromatography process will remove or reduce levels of endotoxin."
"The procedure did not demonstrate the removal of endotoxins after the sanitization and cleaning."
"Please provide additional information that demonstrates that the implicated lots of product do not contain elevated levels of endotoxin. Please note that we are aware that endotoxin removal has not been evaluated in your purification process."
Medeva Pharma Ltd, 1999-10-21
"Any monovalent blend pool with unacceptable endotoxin level may be reprocessed by xxxxx and concentration in the xxxxx ultrafiltration system; however, there is no data available to demonstrate that this system has been validated to remove unacceptable levels of endotoxin."
"It is unacceptable to mix monovalent blend pools that exceeded the endotoxin internal specification with monovalent blend pool that met internal endotoxin specification."
Specialties Septodont, 1999-09-24
"There were 10 endotoxin failures at the WFI compounding point-of-use which occurred during a 25 month period. Actions to determine the root cause of repeated failures and corrective measures to preclude contamination were not implemented."
"Lack of validation of the washing step to demonstrate removal of endotoxin from plungers."
Long March Pharmaceuticals, 1999-09-07
"Our inspection found that Bacterial Endotoxin Testing of water and finished product did not conform to USP XXIII. Specifically, routine finished product testing did not include the positive product control containing two Lambda endotoxin, as required by USP. LAL reagent sensitivity tests are performed only once, and not at the time of each analysis as required by USP. The xxxxx Control Standard Endotoxin lots were not standardized against the USP Endotoxin Reference Standard."
"Rather than minimizing the contribution of endotoxin, our inspection found that operating conditions at your firm allowed for an unpredictable and often high contribution of endotoxin to the parenteral-grade drug substance."
"Variability in endotoxin has not been evaluated via testing discrete parts of a batch."
"Deionized and tap water was used for equipment cleaning. Your firm had performed no testing of this water for endotoxin purity."
BioWhittaker, Inc., 1999-08-02
"Failure to investigate the cause of nonconformities related to product, processes, and the quality system, [21 CFR 820.100(a)(2)], in that: a) the investigation into Product Incident Report, which involved chromogenic LAL test kit, did not include an evaluation of other kit lots and related components to determine the scope of the failure and there was no record to indicate that a review of the device history record was performed during the investigation. b) stability test results for Chromogenic Lysate, failed at 18 months. A failure investigation was not conducted. c) stability test results for Chromogenic Lysate, failed at 12 months. The product was retested and passed. There was no investigation into the initial test result failure, d) the final Quality Control test for the Kinetic-QCL test kit failed on initial testing. The test was repeated and passed, and the kit was released for distribution, There was no investigation into the initial test result failure."
"Specifications have not been developed for the plastic microplates, recommended in the package inserts for the QCL-1 000, Kinetic-QCL, and the Pyrogent-5000 test kits and used for in-house testing in Quality Control and Production."
"Optical Density (OD) readings of the unused wells have higher OD readings than wells with LAL and endotoxin standards."
Abbott Laboratories, Inc., 1999-07-09
"Tubes containing sample preparations and positive/negative controls for LAL testing are not identified with sample numbers or control types."
"The calculation and check calculation of the geometric mean in the acceptance testing of Bacterial Endotoxin Gel Clot Test Reagents is not documented."
"There is no documented justification for the acceptance criteria used to evaluate the ability of xxxxx processors to reduce or remove endotoxins from stoppers."
"The WFI used by the bag rinsers is not sampled from the points of use for microbial and endotoxin testing."
Charles River Endosafe, Inc., 1999-04-27
"No investigations have been conducted into test kits which failed the initial moisture test and passed a retest."
"There are no validation data to support mixing times for LAL product formulation."
"The xxxxx holding time for glassware and metal equipment after depyrogenation has not been validated. In addition, there is no established storage time for rubber stoppers used for the product vials."
College Pharmacy, 1999-04-07
"Your Riboflavin Injection was administered intravenously to two patients who were subsequently hospitalized after experiencing septicemia. Our laboratory analysis of this drug from an intact vial confirmed the presence of Pseudomonas aeruginosa, a gram-negative bacteria, as well as a bacterial endotoxin level greater than 1,250 Endotoxin Units (EU) per milligram of riboflavin."
Allergan, Inc., 1998-10-06
"The Analysis Procedure - In House 12IR, entitled 'Bacterial Endotoxin Testing xxxxx' appears adequate for retesting, however, it does not address the requirement for an investigation prior to retesting."
"Analysis Procedure - In House 12IR, entitled 'Bacterial Endotoxin Testing xxxxx ', does not provide sufficient detail regarding retesting and does not provide for an investigation in the event that the retest produces results that conflict with the initial test"
Mallinckrodt Inc., 1998-08-07
"You have failed to implement appropriate controls to ensure that all drug components and closures have the appropriate quality and purity when introduced into production. You have failed to validate the washing process used for rubber closure components (stoppers, pistons, and caps). The sequence of processing steps has never been validated by your firm to be effective in reducing endotoxin levels of these
"Serious deficiencies were also noted pertaining to the operation and maintenance of the washer used for the cleaning and depyrogenation of plastic syringes."
Dentsply International, Inc., 1998-08-06
"Failure to ensure that the process used to manufacture medical and dental needles will consistently produce non-pyrogenic needles. The validation of the dry heat sterilization process for depyrogenation efficiency was performed in July 1993. The validation did not include a challenge of the worst case parameters. Also, the water used to rinse the cannulas (at several steps in the process) is not tested for endotoxin and there is no routine cleaning and maintenance program currently in effect for the water system."
Merck & Co., Inc., 1998-06-16
"Failure to assure that incoming drug product closures, specifically, rubber stoppers, consistently conform with all applicable written procedures in that your firm has been unable to consistently meet the validation parameters identified for the stopper depyrogenation process."
"We suggest that
consider the following items, in its next planned validation run: a) the successful and consistent adherence of the endotoxin challenge to the "spiked" stoppers; b) the validation of the endotoxin recovery laboratory method; c) the consistency of the sources (i.e. vendor and microorganism number) of endotoxin challenge used; d) the consistency of the stopper vendor's manufacturing process as well as the controls the stopper vendor has in place to reduce the endotoxin load on the stoppers post-processing; e) tie endotoxin load on the silicone; f) the appropriateness of the frequency of screen cleaning."
Bristol-Myers Squibb Company, 1998-05-28
"The reliance on finished product testing, particularly under conditions where the presence of endotoxin-producing bacteria has been reported in the process water, is not considered adequate to assure the absence of endotoxins in the finished product."
"Failure to adequately monitor, investigate and take action on utility design features and utility malfunctions which could have an adverse effect on the purity and quality of sterile or non-pyrogenic bulk pharmaceuticals...."
Haemachem, Inc., 1998-01-28
"Failure to notify the Director, Center for Biologics Evaluation and Research (CBER), of proposed changes in location, equipment, responsible personnel, and manufacturing methods for your product, Limusate@ Limulus Amebocyte Lysate (LAL), [21 CFR 601.12] in that: a) modifications to the approved manufacturing process for your product have been made; b) a xxxxx was installed and is being utilized in the freeze drying of your product."
"Your standard operating procedure (SOP) is not followed in that only one potency assay has been performed on one vial of each lot of LAL in the stability study since 1991."
"device history records for LAL were not maintained."
"Final product containers are not cleaned prior to depyrogenation and filling."
Seikagaku Corporation, 1997-12-16
"The two ovens used for depyrogenation of product vials and manufacturing glassware and the three autoclaves used to sterilize rubber stoppers where initially validated in June 1992 and have not been revalidated."
Centeon Pharma GmbH, 1997-12-08
"The dry heat ovens had not been revalidated since 1983, to demonstrate that the depyrogenation ovens can remove or reduce known levels of endotoxin."
Pharmacia Hepar, Inc., 1997-08-12
"Failure to adequately investigate out-of-specification LAL endotoxin test failures, when there is no evidence of laboratory error, in that Investigations do not extend to examination of environmental bioburden and water systems."
"We feel application of potable water specifications to soft water is not appropriate since soft water may introduce pathogens or endotoxin into the product."
"Endotoxin retesting is acceptable provided the cause of the initial test failure is known, thereby invalidating the original results i.e. investigation reveals that the test system was compromised. It cannot be assumed that the initial endotoxin test failure is a false positive."
"Endotoxin has an affinity for glass surfaces. Please provide validation which addresses the change in sample conditions that occur over time. Endotoxin retest procedures should incorporate measures to assure that conditions of the original sample, upon resampling, are controlled to provide reliable results."
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