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Where are you now? Intelligence Services > OOS > Related Warning Letters

OOS (Out-of-Specifications) Related Warning Letters

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PDF PDF file (240 KB)
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."

PDF PDF file (289 KB)
Eight In One Pet Products, Inc., 2002-06-14
"Failure to conduct a thorough investigation of unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications. [21 CFR 211.192]. There is no written investigation of piperazine citrate syrup, batch # 0421054 failure to meet assay specifications. The investigation of piperazine citrate raw material lot 20268 out of specification test results included retesting of new samples which was not thoroughly justified."

PDF PDF file (201 KB)
Vintage Pharmaceuticals, Inc., 2002-05-20
"We also have concerns that out of specification (00S) investigations of Q Bid LA lots, manufactured in the time frame between the 2 sets of validation lots, are not discussed in either validation report, thus providing insufficient assurance that the manufacturing process for Q Bid LA is validated, as required by 21 C.F.R. 211.100(a), 211.110(a), and 211.110(b)."

PDF PDF file (199 KB)
West Agro, Inc., 2002-03-28
"There are no Standard Operating Procedures for the inspection of Out of Specification (00S) results [21 CFR 211.192]."

PDF PDF file (245 KB)
GOJO Industries, Inc., 2002-02-21
"Two lots of GOJO Hand Medic III [165461, 1660951] were released that had final product test results that were out of specification. A complete investigation into the root cause of the problem was not completed before product release. [2 I CFR 211.165(f) and 211.192]."
"Products with out of specification active ingredient assays are reworked. The rework procedures have not been validated. [21 CFR 211.15, 211.100 and 211.110]."
"There was no documented investigation as to why two. Sets of samples were placed on stability and why both sets of samples fell out of specification before the expiration date [21 CFR 211.166]."

PDF PDF file (156 KB)
Cumberland Swan, Inc., 2002-02-11
"The inspection revealed a failure to validate cleaning procedures, routine release of and failure to investigate out-of-specification test results for a mouthwash product."

PDF PDF file (394 KB)
Bachem California, Inc., 2002-01-14
"Your firm failed to conduct investigation(s) of out of specification results obtained during the cleaning validation for lyophilization trays."

PDF PDF file (383 KB)
American Pharmaceutical Partners, Inc., 2001-12-10
"Investigation Report records that Doxorubicin Hydrochloride Injection, USP, lot 01990 14B, was out of specification and lots 190866 and 190879 were out of trend. However, an improper correction in determining the results lowered the actual reported values. Without the improper correction, all lots would have been out of specification...."
  "Out of specification and reported out of trend results for impurities obtained in stability testing three lots of Doxorubicin Hydrochloride Injection, USP, were voided based on the investigations concluding that the approved sample preparation resulted in precipitation of the sample."
  "Folic Acid Injection was tested a total of five times for benzyl alcohol determination prior to acceptable results being obtained. The lot was out of trend from the target specification of xxxxx three times and was out of specification from the finished product specification of xxxxx once. Data from two of the test runs were voided due to HPLC system problems, however a review of the chromatograms showed that system suitability was maintained throughout the run."
  "Out of specification results for finished product and stability testing of impurities obtained in testing four lots of Fluorouracil Injection, USP, were voided based on investigations concluding that the HPLC columns used in testing were contaminated due to improper storage....All out of specifications were overcome with retesting using new sample and standard preparations."
  "Out of specification investigations do not always extend to other lots associated with the specific failure or discrepancy."

PDF PDF file (292 KB)
AccuMed Inc., 2001-11-09
"Your firm failed to follow Standard Operating Procedure (SOP) G-15-I Out of Specification Investigations, which requires an investigation into any results that are outside of the accepted specification. For example: the Certificate of Analysis (COA) showed the presence of Pseudomonas aeruginosa. A second sample was then sent to the contract laboratory, which the results showed no P. aeruginosa. The original failing result was disregarded and product lot was released. No investigation was conducted to invalidate the failing result....."

PDF PDF file (413 KB)
Outsourcing Services Group, 2001-10-05
"Although an out of specification result was noted for coliform growth during validation of the household products line, the testing was merely repeated and the retest results were reported."
  "No procedures were available which described the investigation of out of specification microbiological results."

PDF PDF file (520 KB)
Kiel Laboratories, Inc., 2001-08-14
"The first batch produced after the completion of the three validation batches was rejected due to high and low out-of-specification (OOS) assay results for all three active ingredients. These failures were attributed to inappropriate addition rate and a lower mixing rate used to dilute some of the solutions. Neither the Master Batch Record nor the Process Validation Report addressed these critical rates in the process."
  "OOS results were not investigated to determine the cause of the failures, extent of the problem, and potential impact upon other lots."
  "Your firm failed to follow your SOP for handling OOS results. There was no assignable cause for the results but the sample was retested only twice. Adequate justification was not provided for your discounting of the OOS result. No corrective action was taken even though a possible sample preparation error was noted as a potential cause."
  "Low OOS assay results were noted in mixing samples during process validation. A clearly assignable cause for the OOS result was not found. Your firm prepared samples again and retested the lot. Only the passing retest results were reported."
  "OOS assay results were noted and no assignable cause was determined and you failed to follow your retest procedure. You merely reinjected the original sample and one additional sample preparation. These test results were averaged to obtain a passing result. A blend uniformity OOS assay result was obtained and the original sample was reinjected and an additional sample prepared was also tested. The average of all tests was reported as an acceptable result."

PDF PDF file (328 KB)
Cardinal Health, Inc., 2001-07-10
"The Out of Specification (OOS) investigation for xxxxx Capsules, batch 0000498, indicates that the practice of using reclaimed powder during encapsulation will be discontinued, and the batch record will be revised to instruct the operators. However, batch 0002854, the next batch of xxxxx Capsules manufactured, does not indicate that the practice of using reclaimed powder was stopped, nor is there any documentation that operators were instructed or trained to discontinue this practice."
  "Capsules, batch 9805819, was manufactured immediately prior to xxxxx Capsules, batch 0000498, both using reclaimed powder in the manufacturing process. The use of reclaimed powder was identified as the cause of OOS content uniformity results for batch 0000498."

PDF PDF file (366 KB)
Purepac Pharmaceutical Company, 2001-04-09
"Each lot tested exhibited one in-specification and one out-of-specification result and were subsequently released using stability specifications, rather than release specifications."
  "Out-of-specification results, were invalidated due to sampling error, without adequate justification."

PDF PDF file (616 KB)
Perfecto Products Manufacturing, Inc., 2001-03-29
"In addition to the discrepancies discussed above, there were no procedures addressing the retesting of raw materials, the investigation of any out-of-specification results, the inspection and control of labeling, training of employees, and distribution of your drug products."

PDF PDF file (437 KB)
DSM N.V., 2001-01-24
"You have failed to appropriately investigate and respond to out of specification (OOS) analytical results. Numerous inconsistencies were noted in the handling of data and the decisions made in response to these OOS results. 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. Your procedure for the Handling of Out of Specification Results allowed for the improper discarding of OOS results without an investigation. The procedure allowed for the discarding of results without sufficient documentation of the failures and any corrective actions taken to prevent reoccurrence."
  "Your firm has failed to properly investigate and document OOS results obtained from malfunctioning laboratory equipment."

PDF PDF file (554 KB)
Aventis Behring, L.L.C., 2001-01-22
"Process validation was performed using data from eight lyophilization runs. Three lots were rejected, and one lot was not released. On stability testing, passing residual moisture results were reported for four lots based on averaging paired results in which one result was out of specification (OOS)."
  "We have reviewed your revised SOP entitled 'Procedure if an out-of-specification reportable value is obtained' and have the following comments: ...."

PDF PDF file (503 KB)
Xinjiang Pharmaceutical Factory, 2000-12-18
"There are no documented investigations of process deviations or out of specification (OOS) laboratory results. During the inspection, our investigator requested to see investigations of process deviations and out of specification laboratory test results. She was informed that these investigations are conducted but not documented."

PDF PDF file (338 KB)
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."

PDF PDF file (182 KB)
Societa Italiana Medicinali Scandicci, 2000-12-06
"Investigations and follow-up of out of specification results and complaints are inadequate or incomplete."

PDF PDF file (321 KB)
Ultratab Laboratories, Inc., 2000-10-30
"Failure to reject finished drug products which did not meet established test specifications. Specifically, re-worked Hydrocortisone Cream had an out of specification (OOS) finished product test result and was released for distribution [211.165]."
  "The retesting of samples to invalidate legitimate out of specification results is not an acceptable practice. Drug products failing to meet established standards or specifications and any other relevant quality control criteria must be rejected."

PDF PDF file (482 KB)
Akorn Incorporated, 2000-09-28
"The final validation report does not discuss or evaluate the out-of specification results for the mixing sample or the end-of-fill samples. The mixing samples were re-tested and an average reported in the data table. The report states that the 00S result obtained from testing the end of filtrate sample of Lot xxxxx was an "aberrant value" although re-testing of the sample and a laboratory investigation confirmed the result."
  "Process deviations, in-process test failures and out-of-limit environmental monitoring results that occurred during the manufacturing of the four batches made under the process validation protocol were not evaluated and are not discussed in the final report of the process validation."

PDF PDF file (212 KB)
Perrigo Co., 2000-08-16
"There is no Standard Operating Procedure for trending Out of Specification results other than the Annual Report."

PDF PDF file (152 KB)
Merck Manufacturing Division, 2000-06-27
"Out-of-specification data were averaged with passing data to facilitate the release of several products. In addition, for each lot an average of several test results was reported without mention of the result being an average of multiple test results."
  "Out-of-specification assay results were invalidated on the premise that a sampling error had occurred. No documentation or data was presented or discovered during the inspection to support that conclusion. This lot was repeatedly tested (6times) and the third through sixth re-tests also gave out-of-specification results...."

PDF PDF file (143 KB)
DuPont Pharmaceutical Co., Inc., 2000-06-15
"During tablet compression validation, one of the three lots had out-of-specification assay results for the last tablets of the compression run. Your firm's investigation into this incident led to the conclusion that the blend was not uniform and a decision was made to discard the last two pails from the compression operation. An additional three lots of tablets were manufactured using the revised procedure, but these batches were not subjected to evaluation of all of the criteria established in the validation protocol. The validation was approved using the limited data collected from the production of the second set of three batches and no discussion or justification was made for the failure to evaluate these batches for all of the predetermined criteria."

PDF PDF file (135 KB)
Pharmaceutical Development Center, 2000-06-13
"Neither your firm nor the applicant had clearly assumed the responsibilities of a quality control unit for such critical functions as in-process review testing, review prior to product release, review of third party laboratory results, and initiation of investigation into out-of-specification (OOS) results. These quality control responsibilities should be clearly established prior to initiation of manufacturing at a contract site."

PDF PDF file (178 KB)
Blue Ridge Pharmaceuticals, Inc., 2000-06-13
"Neither your firm, nor xxxxx had clearly assumed the responsibilities of a quality control unit for such critical functions as in-process review testing, review prior to product release, review of third party laboratory results, and initiation of investigation into out-of-specification (OOS) results. These quality control responsibilities should be clearly established prior to initiation of manufacturing at a contract site."
  "You failed to conduct an investigation as required when a drug batch fails to meet its specifications. Your firm also directed the destruction of the remaining portion of the three lots at xxxxx. Analysis of this product could have assisted in the investigation of the OOS result."

PDF PDF file (167 KB)
SmithKline Beecham Pharmaceuticals, 2000-06-09
"Your quality unit rejected initial out-of-specification results of finished product testing without conducting an adequate investigation. The inappropriate handling of out-of-specification results affected release decisions. Upon obtaining an initial out-of-specification result for each lot, your quality unit collected additional samples and based its release decisions on the passing results obtained from the additional samples. The quality unit did not conduct an investigation to determine if production or laboratory problems could have caused the original failing results. Moreover, your quality unit did not report the failing results. All results should be reported and considered in making final release decisions."

PDF PDF file (269 KB)
Schering-Plough Corporation, 2000-05-08
"Failure to perform adequate investigation into the cause of out-of-specification results for stability testing as required by 21 CFR 211.192. Tests for these stations showed out-of-specification results for the presence of benzalkonium chloride. These Out-of-Specification (OOS) results were attributed to problems (probably non-homogeneous packing) with the HPLC column used to test the samples. Based on this conclusion, special composite samples of the lots were prepared from retain samples and tested on a different column. The original OOS results were discarded and the passing results of the composite re-tests were used as the sample results."
  "In performance of the Uniformity of Spray Content Assays, when out-of-specification results were obtained, analysts were instructed to remove the spray tips of the bottles and wash with methanol before running a re-test. This step is not included in the written procedures. In addition, the results of re-tests are averaged and used to replace individual OOS results in the original report of results. This is contrary to the objective of content uniformity testing, which is to determine the variability of results among a number of sequentially tested, randomly selected samples."

PDF PDF file (305 KB)
Schein Pharmaceutical, Inc., 2000-03-02
"The firm ignored initial out-of-specification results, performed retesting, and released product for distribution without conducting adequate laboratory investigations. In one instance, the Director of Quality Control crossed out the analyst's statement of true results and determined the low results were due to laboratory error without any evidence or investigation of the results."
  "Laboratory controls are deficient in that the firm established a written procedure, which allowed for the averaging of out-of-specification and within-specification analytical test data results."

PDF PDF file (319 KB)
American Pharmaceutical Partners, Inc., 2000-02-07
"Some investigations of incidents and out-of-specification test results are not completed and reported in a timely manner...."
  "Laboratory investigations of out-of-specification test results do not consistently include detailed information regarding the conduct of the investigation. Additionally, conclusions of investigations are not always justified."
  "There is no documentation of the source of additional samples tested as a result of out-of-specification investigations."

PDF PDF file (184 KB)
Thatcher Company, 1999-12-20
"Investigation of xxxxx, which fell out-of-specification during stability testing was inadequate in that it did not include a review of records and manufacturing procedures for deviations or errors, including assessing the potentially negative impact of storing the product in temporary containers for over 30 days while additional ingredients were ordered."

PDF PDF file (604 KB)
Hoffmann-La Roche, Inc., 1999-12-17
"Your firm released for distribution the Naprosyn Suspension despite initial testing showing results outside release specifications. Repeat testing for those samples showed both lots exceeded USP specifications, and a third test on lot 2 again showed results exceeding USP specifications. This partial batch release was made without evidence to show the repeat OOS results were conclusively linked to only a portion of the batch."
  "Your firm rejected out-of-specification (OOS) results based solely on inconclusive laboratory investigations and retesting. Formal failure investigations should have been initiated and all results reported in making a decision whether a product conformed to relevant specifications. Specifically, the following OOS results were rejected based on inconclusive laboratory investigations: ...."

PDF PDF file (292 KB)
Bio-Pharm, Inc., 1999-08-10
"Your response to Observation #l does not address the impact of the out-of-specification (OOS) TOC results obtained for purified water used in the manufacture of your pharmaceutical drug products. Your firm did not investigate these OOS TOC results and cannot provide scientific data regarding the identification of the contaminants causing the OOS TOC results."
  "We recognize that you continued to use the U.S.P. test for Oxidizable Substances and obtained satisfactory results for your water. However, the fact remains that you continued to manufacture human drugs with an OOS specification raw material and made no attempt to correct the problem."
  "The OOS SOP provides little or no detail regarding retesting. The retesting section of the SOP should be very detailed regarding the specific course of action to be pursued when an OOS event is encountered."

PDF PDF file (263 KB)
Linweld, Inc., 1999-08-02
"Acknowledge that your system, by design, does not record results that are out-of-specification. Only parameters that are within specifications may be recorded."
  "The system prompts an operator when equipment detects that an Oxygen potency value is non-conforming, and permits the operator to record a value that is within specification, but does not record the original out-of-specification value."

PDF PDF file (165 KB)
FDC, Ltd., 1999-04-08
"Standard Operating Procedure on Investigation of Out of Specification Data allows the acceptance of material with OOS results after duplicate analysis of a resample only, even when no sampling or testing errors are found."

PDF PDF file (134 KB)
Knoll Pharmaceutical Co., 1998-12-14
"Your firm released one lot of Vicodin Tablets despite out-of-specification results for content uniformity (for Acetaminophen) and relative standard deviation. The retest for content uniformity was incorrectly performed, per the USP procedure, resulting in out-of-specification results for both Acetaminophen and Hydrocodone Bitartrate for assay. A second re-test was performed incorrectly in that the previous product sample was used with a new standard. In addition, the product had failed three specifications prior to being re-tested the second time."
  "Your firm's quality control/quality assurance unit failed to adequately investigate out-of-specification results for Ibuprofen USP active pharmaceutical ingredient, Vicodin Tuss Liquid finished product, and Vicoprofen in-process tablet cores. Your firm's documentation of the three above examples does not support the investigational conclusions."

PDF PDF file (201 KB)
Proviron Fine Chemicals, NV, 1998-11-18
"Written laboratory procedures allowed product with initial out-of-specification results to be released based on a single retest."

PDF PDF file (256 KB)
Thames Pharmacal Co., Inc., 1998-10-06
"Fluocinolone acetonide solution failed initial and repeat assay for strength. The lot was assayed a third time, contrary to the firm's SOP for out of specification results, and subsequently released for distribution based on the third assay. There was no recorded justification for deviating from the established SOP as required by 21 CFR 211.160(a)."
  "Out of specification temperature and relative humidity chart recordings were not identified, investigated, and evaluated as to their impact on product stability."
  "There were no calibration schedules for certain manufacturing equipment, and calibration reports with out of specification results from outside contractors (e.g., QA003 and QA006) were not investigated and evaluated to determine their impact on drug products."

PDF PDF file (257 KB)
Mallinckrodt Inc., 1998-08-07
"You have failed to appropriately respond to out-of-specification (OOS) conditions which could directly impact upon the quality of released product. You have failed to consistently react to, investigate and correct OOS conditions noted during packaging inspection."
  "The OOS conditions are not routinely recorded and documented on the Reject Limit Response form as required by Mallinckrodt procedure. Of the approximately thirty lots noted by our investigators to have OOS findings, only twelve such forms were filed. Most of the OOS lots reviewed by the investigators did not have documented investigations or any record of corrective actions taken. Your firm was noted to routinely release the OOS lot without further reprocessing, rework, or an independent verification by quality assurance of the lot."

PDF PDF file (359 KB)
PF Laboratories, Inc., 1998-03-23
"An initial out of specification assay, was obtained using a radial compression method which was approved in the original ANDA for use by the original holder of the ANDA. The radial compression method was not evaluated for use in your laboratory. In addition, the out of specification result was invalidated using an experimental HPLC method."
  "An additional 20 minute mixing step was implemented during the manufacture, due to an out of specification blend assay result. This additional manufacturing step was not documented."
  "Your response to observation #l stated that the out of specification blend assay result was due to a lack of granulation uniformity. As a result, you blended all ingredients for an additional 20 minutes. Initiating a reprocessing step that is not validated and not included in a ANDA/NDA is unacceptable."

PDF PDF file (400 KB)
Watson Pharmaceuticals, Inc., 1998-01-28
"Discarding and averaging of Out of Specification test results without explanation."
  "Failure to investigate Out of Specification test results."

PDF PDF file (421 KB)
Purepac Pharmaceutical Co., 1997-11-26
"Laboratory investigations and retests were incomplete in determining assignable cause and/or lacked documentation to invalidate initial out of specification test results, for example: Diclofenac Sodium, 50 mg tablets, was retested due to a high blend uniformity result. The sample retest yielded an out of specification result. Resampling at 12 locations yielded in specification results. Initial results were attributed to sampling and analyst errors, without supporting documentation. This lot was used in support of validation for this product."

PDF PDF file (275 KB)
Alra Laboratories, Inc., 1997-08-29
"Out-of-specification (OOS) results are dismissed without adequate justification (e.g., Eryzole assay for Sulfisoxazole was OOS and the results dismissed for purely hypothetical reasons -- low powder fill or incorrect sample preparation) ."

PDF PDF file (528 KB)
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. For example: a) In following up on out-of-specification LAL results for Heparin Sodium, your firm released the drug based on results of retesting alone without further investigation to identify possible causes, such as environmental bioburden, water systems, etc.; b) In following up on out-of-specification LAL results for Topical Heparin, your investigation did not attempt to determine whether the results may have been caused by high bacterial counts in the water system."

PDF PDF file (277 KB)
Ortho-McNeil Pharmaceuticals, 1997-04-21
"Re-test procedures were found to be inadequate, in that out-of-specification results are included in a grand average used to determine product release. Products were released based on the average of five test results without determining the assignable cause of the initial out of specification result."
  "Re-test investigations were incomplete in the determination of assignable cause and/or lacked documentation to invalidate initial out of range results, for example: a) an initial out of specification assay was invalidated without adequate documentation to support the conclusion that a pipetting error occurred; b) there was no data or adequate documentation to support the conclusion that the initial sample was improperly prepared."
  "The investigation of this event was incomplete and deviated from the retest procedure, in that it did not include an evaluation of the manufacturing process or raw materials."

PDF PDF file (401 KB)
Roberts Pharmaceutical Corp., 1997-02-24
"For stability lot CN 500243, the stability sample tested at 26 months was out-of-specification for Sodium Bisulfite content. Your firm neglected to conduct an investigation to determine the probable causes of the failure to meet specifications."
  "Out-of-specification results for 4-ETC/TC ratio at the 24 month test interval were averaged with passing results derived from testing a second sample. In the 1994 annual report submitted to FDA, your firm reported the passing average value only, without any mention of the initial failures. As mentioned above, no investigation was conducted to determine the probably causes of failure."

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