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Dissolution Related Warning Letters
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Searle, Ltd., 2002-12-27
"During the validation of the manufacturing process for Plaquenil, two of the
validation lots had out of specification results for the hardness test. However, in your validation report you concluded that lots xxxxx were in compliance because low hardness result tablets pass friability and high hardness result tablets pass dissolution testing. You are also accepting hardness results outside your established specifications for routine manufacturing process."
Neil Laboratories Inc., 2001-10-02
"Your firm averages Out-of-Specification (00S) dissolution results with test data
results that are within specification."
"Procedure for Dissolution Apparatus Calibration Method 002A does not require testing for physical attributes of the bath. The procedure does not assess wobble during calibration"
"Stability Method is stability indicating in that the method does not contain predetermined dissolution specifications."
"Aspirin E/C 325 mg Tablets Method does not have predetermined specifications for percentage of Acid during the Acid Stage dissolution."
Kiel Laboratories, Inc., 2001-08-14
"During manufacture of the xxxxx biobatch the blended granulation was screened and reblended for an additional xxxxx minutes, which is not done in the commercial batches. The biobatch was also blended for xxxxx minutes and the current process specifies a xxxxx minute blend. It is not known what effect, if any, the differences would have on the composition, dissolution, and bioequivalence of these tablets."
Purepac Pharmaceutical Company, 2001-04-09
"Lot497F9, Expiry 5/2001, failed Level 3 dissolution testing at the four hour point, and was released prior to completion of the laboratory
investigation. It was later determined that the lot was released by the QA Supervisor based on bulk reassay results rather than finished product results. This lot was also placed on stability, since it was later discovered that a coating component was used past the manufacturer's warranty date."
DSM N.V., 2001-01-24
"You have failed to maintain adequate documentation to substantiate the invalidation of OOS results. This was noted during content uniformity, assay, and dissolution testing. The inspection noted instances of the failure to follow procedure, substitution of standards, discarding of OOS results without an investigation, and reporting of only passing results."
Leiner Health Products, Inc., 2000-12-11
"Out-of-specification dissolution results were obtained for both lots when finally tested. Although a laboratory investigation was initiated, no further investigation was conducted since the product was beyond expiration date. A determination could not be made as to if these two lots continued to meet specifications throughout their labeled expiration date."
Duramed Pharmaceuticals, Inc., 2000-12-06
"The firm failed to validate the Dissolution Test Method #FV-002 and #FV-003, used to test the product Verapamil HCL Extended Release (ER) Tablets, USP, 120 mg and 240 mg. A. Dissolution test data was invalidated, without conducting a complete, conclusive, or documented investigation into the cause of the failing results. All of the results were invalidated due to air bubbles being trapped in the HPLC System, at the time of the sample run. The problem continued for several months, during which batches were tested, and released."
"Change control procedures in the Laboratory failed to document test method changes to assure accurate, reliable, and reproducible results. The test method did not state whether or not a helix was to be used during dissolution testing."
"Failing S3 dissolution results for Batch #990801, as well as high dissolution results for other batches were attributed to the use of a xxxxx. The firm decided to recall Batch #990801 and #990716, due to the dissolution failure, and perform a market withdrawal of numerous other batches. The referenced batches were then retested without the use of xxxxx. The results were considered acceptable, even though xxxxx was used during the method development and method validation. The recall and market
withdrawal was cancelled."
Perrigo Co., 2000-08-16
"Failure to document approval by the Quality Control Unit for corrective actions taken to preclude in-process granulation dissolution test failures for Coated Acetaminophen raw material."
Hoffmann-La Roche, Inc., 1999-12-17
"A typical dissolution results encountered with Xenical Capsules were attributed to the active pharmaceutical ingredient, Orlistat. An invalidated physical test (wetability) was used to predict batches of active ingredient that would result in finished product failures. However, Orlistat batches with physical test values that had previously resulted in a confirmed finished product dissolution failure, continued to be used in the manufacture of Xenical Capsules. Finally, the wetability method validation had not been performed at the conclusion of our inspection."
"A laboratory analyst failed to record/paste raw dissolution data into their notebook and that same analyst was seen recording data on scrap paper."
Schering-Plough Corporation, 1999-10-23
"Claritin D 12 Hour Repetab was only partially rejected due to a failing in-process dissolution rate of 76% from pan 4 at the third hour dissolution timepoint. Some 61 partial releases were noted for this product for the period 1997-1998."
"This would appear to resolve the issue of partial releases based on the release criteria for this product, but does not resolve the reasons for the in-process dissolution failures. While we acknowledge that a supplement was submitted to relax the in-process xxxxx dissolution specification, pending approval, the current in-process specifications are considered valid and must be followed."
Calvin Scott & Company, Inc., 1998-10-21
"Your firm does not have a written stability testing program, but has conducted a one time composite assay and dissolution test on some of the drug products you repackage. However, you have not tested an adequate number of batches of each repackaged drug product in each container closure system in which the drug product is marketed ..."
"The one time composite assay and dissolution test on some of the drug products you repackage is not adequate to support the use of the bulk drug manufacturer's original expiration date. Therefore, the expiration dates, which are currently used on your repackaged drug products, are not acceptable."
Schering-Plough Products, Inc., 1998-06-29
"Failure to submit, within three working days, an FDA Field Alert Report (FAR) for Theo-Dur 300 mg. Extended Release Tablets, which failed to meet the 6 and 8 hour NDA dissolution specifications at the 12 month stability test station. [21 CFR 314.81(b) (1)]. Your firm submitted your initial FAR for this lot on 9/15/97, after your investigation had been completed; however, records reviewed show this lot failed S1 dissolution on 8/17/97. Dissolution S2 & S3 testing done on 8/20/97 and 8/24/97, respectively, confirmed the failing result."
S. S. S./Pfeiffer Company, 1998-03-30
"The 30 day accelerated testing failed aspirin assay and had initial dissolution failures. A retest contained additional dissolution failures. The method was changed twice and acceptable results were obtained."
"The 60 day accelerated testing revealed acetaminophen assay and dissolution failures. The method utilized however was the initial method used at product release. A retest was conducted using the new method which also yielded dissolution failures. The product was retested a second time utilizing the new method and failing results were obtained. The recommendations from the OOS investigation were to further develop the sample preparation for assay and to change the formulation of the product."
PF Laboratories, Inc., 1998-03-23
"Your firm's response stated that although the isolated batch adjustments involving the addition of water were not validated, dissolution of the active ingredient in water was previously validated. " Although the initial addition of water was validated, supplementary water additions were not. The rationale for deviating from established batch records must be supported by data (development and/or validation data) prior to implementation."
Watson Pharmaceuticals, Inc., 1998-01-28
"No determination of cause for the higher than normal dissolution results obtained."
Alra Laboratories, Inc., 1997-08-29
"Your firm has failed to establish a valid dissolution method, ... , failed to determine stability of the product and investigate failures of dissolution and hardness."
LNK International, Inc., 1997-05-27
"Failure to follow established complaint handling procedures. Complaints involving the dissolution failure of batches of Enteric Coated Aspirin Tablets were not entered onto the records, logs, and reporting system as required in the written standard operating procedure."
ICN Pharrnaceuticals, Inc., 1997-05-06
"Failure to adequately validate the formulation and processing of Trisoralen@ to assure the tablets meet USP dissolution requirements throughout their labeled expiration date."
"Failure to either follow the USP dissolution test method or validate that the method used is equivalent or superior to the USP method."
"Failure to conduct adequate investigations and take appropriate remedial action when dissolution failures were, identified."
"You do not indicate what specific parameters will be examined in relation to the dissolution failures, such as active ingredient particle size or the effect of humidity on the active ingredient, inprocess material and bulk tablets, nor do you provide any timeframes as to when your process validation will start."
"Several of the test results obtained during the inspection indicate that your product is failing dissolution even when the current xxxxx method is used. Conversely, the lots tested prior to 1994 apparently passed dissolution using the xxxxx method. This was the basis for your five year shelf life. In fact, most of the immediate finished product dissolution tests performed using this xxxxx method passed USP dissolution requirement. Almost all failures were observed later in stability testing. Your response does not explain why this dissolution method yielded apparently acceptable results for all immediate analyses, and for stability testing from 1984 through 1994, yet is now found to be unacceptable for stability testing." .....
Ortho-McNeil Pharmaceuticals, 1997-04-21
"Grifluvin Tablets - four out of xxxxx batches made in 1995-1996 were rejected for failure to meet dissolution requirements. As a result of your investigation, process changes were made and not validated."
"Changes were made in the temperature of the xxxxx preparation used for Grifulvin 250mg Tablets. These changes were implemented as a process improvement after several lots failed to meet dissolution specifications. These changes have not yet been validated."
Rhone-Poulenc Rorer Pharmaceuticals, Inc.,, 1997-03-06
"It is your practice to selectively blend aliquots of four different batches containing non-conforming pellets in order to produce a final product that meets dissolution specifications. The batch to batch variability in dissolution profiles for theophylline pellets raises concerns about the adequacy of your process to produce uniformly coated extended release pellets."
"Quality is literally tested into the product since it is resampled and retested to meet final product specifications for dissolution."
G & W Laboratories, Inc., 1997-02-12
"Initial failing dissolution results for one lot of Prochlorperazine Suppositories at the 6 month stability station, was invalidated after retesting a QC retain sample stored below controlled room temperature, resulted in passing results. Additionally, there was no documentation to support that the dissolution method used for this product was validated."
Searle and Company, 1997-01-31
"The decision on how to manufacture any individual batch is made on a case by case basis depending on the in process dissolution testing of the beads. For this reason, the uniformity of the dissolution within a batch, of beads as well as the representativeness of the inprocess sampling and dissolution testing must be validated."
"Coating with xxxxx the final step in the bead manufacturing process, should reduce the dissolution rate. However, your in process testing records say that on the xxxxx occasions, the dissolution rate increased after a xxxxx step. This shows there is a problem in that either the xxxxx process is ineffective, there is no xxxxx of xxxxx within a batch of beads or the in process testing of the beads does not give an accurate picture of the xxxxx characteristics of the batch."
"The study showing a decrease in dissolution was for capsules stored in open dishes at 40°C and high humidity. Six months of data at 40°C can not be used to invalidate 29 days of data at 28-29°C." ....
Neil Laboratories Inc., 1997-01-03
"Two Vanderkamp 600 6-spindle dissolution testers have not been validated."