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Where are you now? Intelligence Services > Validation > Related Warning Letters > Method Validation

Method Validation Related Warning Letters

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PDF PDF file (282 KB)
Mayne Pharma Pty., Ltd., 2002-11-21
"The reproducibility of the method was not demonstrated. For example, only one result following a negative recovery was used to validate the method." "It clarified that the counts used to initially inoculate the test and control samples are quantified, but you don't explain how the procedure is done. It also states that an update to the validation requirement such that three validation tests will be performed in order to comply with the rewements of Validation from Pharmacopeial Articles"

PDF PDF file (266 KB)
Earlham College, 2002-07-29
"No validation of the test method for analysis for the in-process materials and finished dosage forms supplied by the contracting manufacturer."
"No verification that the test method using HPLC for Folic Acid analysis, following changes made by the laboratory from the official USP compendium method, is suitable for conditions of use in the testing of the contracting manufacturer's in process and finished dosage forms."

PDF PDF file (334 KB)
D.S.C. Products, Inc., 2002-07-09
"Data is not available to establish that the analytical methods used to assay finished products meet proper standards of accuracy and reliability as applied to the product tested."
"Failure to ensure that the cleaning methods used to clean equipment and utensils are adequate to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond established requirements, as required by 21 CFR 211.67."

PDF PDF file (289 KB)
Eight In One Pet Products, Inc., 2002-06-14
"Failure to verify the suitability of all testing methods under actual conditions of use. [21 CFR 211.194]. There are no records of test method validation to assure accuracy and reliability. The adequacy of the contract testing laboratory has not been established, such as, by audit. [21 CFR 211.221]"

PDF PDF file (198 KB)
Neogen Corporation, 2001-12-06
"Failure to use a validated test method for release testing. The assay method for guaifenesin in Spec-TussTM Palatable Expectorant Powder has not been validated for accuracy, sensitivity, specificity and reproducibility. [21 CFR 211. 165(e)]"
  "As a manufacturer of veterinary drugs, you are responsible for assuring that your overall operation and the products which you manufacture are in full compliance with the law. This includes assuring that your manufacturing process and controls, test methods, and expiration dates are valid. Your response uses the excuses that the manufacturing rights to this product were purchased from another company and you lacked of knowledge that the test method was not validated. This in no way negates your responsibilities. The Certificate of Analysis from the invalidated test method specifically states that 'The method(s) used are not validated' and 'Results are for your information only'. It is your responsibility to assure and verify that your suppliers and contract laboratories are providing appropriate raw materials, labeling, packaging and testing services."

PDF PDF file (292 KB)
AccuMed Inc., 2001-11-09
"Your firm uses an in-house analytical method for the product Sennosides Tablets USP that has not been proven to be equivalent or better than the USP method. There is no data to demonstrate that the raw material and finished drug product tested using the in-house method will meet all specifications outlined in the USP monograph."
  "Method validation for the product Sennosides is inadequate in that the data does not assess all variables, such as different mobile phase concentrations and analysts, to demonstrate that the method can sustain variances."

PDF PDF file (320 KB)
Person & Covey, 2001-10-17
"Your cleaning validation report for Hydrocortisone lotion lacks documentation that your cleaning method removes the product from the equipment."

PDF PDF file (520 KB)
Kiel Laboratories, Inc., 2001-08-14
"The process validation samples were assayed using an HPLC method that had not been validated. The method validation used for both products did not include a protocol that included specifications and acceptance criteria. The validation failed to include any determination as to the accuracy of the method, The method validation was not reviewed and approved until during the current inspection. Lots of both products were released for distribution prior to completion of the method validation."

PDF PDF file (310 KB)
Granules India Limited, 2001-04-19
"Cleaning validation studies for multiple use xxxxx equipment were inadequate in that the validation protocol did not identify the cleaning procedure, total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person."

PDF PDF file (235 KB)
Omicron Quimica, S.A., 2001-04-11
Laboratory test methods fail to show that all batches of xxxxx conform to appropriate specifications in that the method used is not scientifically appropriate. Specifically, the method used is substantially different than the method described in current compendia. The method used has not been demonstrated to be equivalent to the current compendia method to determine that the product meets current compendials limits."

PDF PDF file (562 KB)
Tianjin Xin Xin Pharmaceutical Corporation, 2000-12-14
"Validation of the analytical method for detecting residual solvents remains inadequate." The FDA inspection revealed many method validation and revalidation deficiency.

PDF PDF file (448 KB)
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."
  "Method Validation Studies conducted for Acetaminophen and Codeine Tablets were incomplete in that it does not include an adequate determination of the levels at which impurities could be quantitated."

PDF PDF file (472 KB)
Spolana a.s., 2000-10-30
"FDA expects companies to complete calibration of instruments and validation of analytical methods before use in order to demonstrate that the analytical instrument and procedures are suitable for their intended use. All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether they are used for in-process, release, acceptance, or stability testing."

PDF PDF file (401 KB)
Rhodia Inc., 2000-07-14
"The current method used by your firm to determine release specifications for known impurities of xxxxx has not been validated to show equivalence or superiority to USP methods."
  "USP 24 Chapter 1225, Validation of Compendial Methods, describes 'typical analytical performance characteristics that should be considered in validation' of analytical methods. Furthermore, this new method should not be used prior to validation and evaluation to show that it is equivalent or better than the USP method(s)."

PDF PDF file (164 KB)
Jiangsu Hengrui Medicine Co., LTD., 2000-06-19
Laboratory equipment, methods, and procedures were deficient. The equipments were not calibrated, there was no SOP for calibrating the xxxxx apparatus, analytical methods were different than what is described in the subject DMFs, system suitability tests were not performed, degradation studies were not performed, the analytical method for residual solvents was not validated."

PDF PDF file (269 KB)
Schering-Plough Corporation, 2000-05-08
"Failure to have documentation of Method Validation for the stability assay method for Trilafon@ Injection."
  "21 CFR 211.194 (b) requires that the suitability of all testing methods shall be verified under actual conditions of use and that the records of determination of the suitability of the method shall be identified in the laboratory records."

PDF PDF file (110 KB)
Muro Pharmaceutical, Inc., 2000-02-16
"Failure to have an accurate, sensitive, specific and reproducible test method for the mean content analysis of Volmax@ Tablets."
  "Failure to validate the changes you have made to the sample preparation steps for the mean content test method for Volmax@ Tablets. For example, you have modified the sample preparation steps for this assay by performing a second xxxxx of the sample and also by using xxxxx to initially dissolve the tablet. There were no validation studies performed to demonstrate that these charges were effective or did not compromise the final test results."

PDF PDF file (604 KB)
Hoffmann-La Roche, Inc., 1999-12-17
"The current SOP for total plate aerobic count microbiological analysis for active pharmaceutical ingredients (API's), final dosage forms and raw materials calls for a minimum incubation period of three days' time, whereas the validation of this method was executed with a five day minimum incubation time."
  "Analysts failed to observe the minimum pH of product in testing broth, as called for in your validation of the test method for API's, final dosage forms and raw materials, and failed to adjust to xxxxx also as called for in the procedure."

PDF PDF file (228 KB)
Bio-Science Research Institute, Inc., 1999-11-10
"Inhibition/Enhancement tests are not performed to validate product Limulus Amebocyte Lysate (LAL) testing."
  "Validation of Chemistry Test Method HPLC assay for xxxxx does not include linearity, precision or accuracy determinations."

PDF PDF file (255 KB)
Specialties Septodont, 1999-09-24
"Inadequate container closure integrity qualification using fluorescent dye. There was no validation of the method performed to determine whether the dye in the concentration used would be detectable in the container using UV light."

PDF PDF file (165 KB)
FDC, Ltd., 1999-04-08
"System suitability was not performed and there were no chromatograms of standard injections for the API or impurities for the forced degradation studies conducted as part of the validation of stability indicating methods."
  "Testing for Organic Volatile Impurities was reportedly conducted by the USP method, but did not follow USP 23 in that replicate injections were not performed and relative standard deviation was not calculated."

PDF PDF file (158 KB)
Forest Laboratories, Inc., 1999-03-12
"Your procedure for estimating the accuracy of quality control (QC) samples based on the validated value is not accurate. Contrary to your response, the mean values of QCs estimated in the validation (i.e. validated values) only reflect the accuracy of the analytical method."

PDF PDF file (201 KB)
Proviron Fine Chemicals, NV, 1998-11-18
"Evaluation of the effectiveness of the cleaning procedure prior to the manufacture of batches in 1998 was inadequate because analytical methods and laboratory procedures were not sufficient to assure accurate determination of residual levels, and depended on a xxxxx approach. The cleaning procedure is not consistent and has not been validated."
  "The xxxxx assay method has not been adequately validated, and the laboratory did not have a copy of U.S.P. 23 or any U.S.P. xxxxx standard."

PDF PDF file (329 KB)
S. S. S./Pfeiffer Company, 1998-03-30
"You have failed to establish validated analytical methods to assure that they have the required accuracy, sensitivity, specificity, and reproducibility. Many of the methods validated since our previous inspection have been brought into question by S.S.S. management due in part to the short period time in which they were developed. You freely acknowledge that problems with the methods are becoming evident as products are manufactured and subsequently tested. No additional work has been undertaken to investigate these questionable methods unless it is in\r\ndirect response to a failed analytical result. Previously validated methods have been changed when in-process, finished product, and stability testing failures occurred. No additional analytical data or documented rationale was available to justify these changes in methodology.\r\n"Our inspection noted inconsistencies in the method validation protocols for similar products containing similar ingredients."
  "These inconsistencies were noted in the requirements for"

PDF PDF file (306 KB)
Irotec Laboratories, Ltd., 1997-05-16
"There is a lack of adequate raw data to support analytical method validation data contained in the Drug Master Files. The inspection disclosed: that the only raw data available was chromatograms; there was no raw data for standard weights, samples, volumes, dilutions and calculations. For example, there was a lack of adequate raw data to support residual solvents test method validation data contained in the Drug Master File."

PDF PDF file (480 KB)
Tri-Med Laboratories, Inc., 1997-03-26
"Method Validation has not been completed for all analytical methods for all products."
  "Accuracy, sensitivity, specificity, and reproducibility has not been established for all analytical test methods and in-house methods have not been shown to be equivalent to USP methods." "Analytical methods used for cleaning validation studies have not been validated for Limit of Detection or Limit of Quantitation." "The method for calculating potency of Simethicone has not been shown to be equivalent to the USP calculation." ......

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