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Process Validation 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."
Mayne Pharma Pty., Ltd., 2002-11-21
"inadequate validation of the sterilization process in no microbiological
qualification or determination of the resistance of the biological indicator
challenge system was performed"
D.S.C. Products, Inc., 2002-07-09
"Written procedures do not define how process validation will be conducted or
"Failure to establish and follow validated sampling and testing procedures of in-process materials and drug products to assure batch uniformity and integrity of drug products, as required by 21 CFR 211.110."
St. Gobain Ceramiques Avancees Desmarquest, 2002-04-26
"Failure to adequately validate the tunnel furnace process with a high degree of
assurance and approve according to established procedures, as required by 21 CFR 820.75(a). For example, your xxx furnace validation summary report and additional process validation information do not document that the xxx process parameters are consistently controlled and result in the desired product specifications. The process validation protocol, contained in your March 11, 2002, submission does not describe how the process parameters and product specifications are measured or tested."
"the process validation report does not document that the xxx furnace process itself results in a consistent, predictable outcome of product based upon specific operational process parameters for the furnace. In addition, the xxx furnace process validation
protocol included in your additional information is inadequate because it does not specify: 1, all the data to be collected and the purpose of all the data to be collected; 2, the test procedures to be used to measure the predetermined success criteria; 3, provide a statistical rationale for the number of device per run or the number of runs."
Dayton Water Systems, 2002-03-14
"Failure to validate processes where the results of the processes cannot be fully verified by subsequent inspection and test. For example, the regeneration process for the resin that is placed in the deionize tanks and the process of cleaning the resin regeneration system with chlorine have not been validated."
Tyco International Ltd., 2002-03-08
"Failure to establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met as required by 21 CFR 820.75(b). For example, Radionics' Pyrogen Procedure QS3-09-0065, Rev. A does not specify that all implanted device configurations be tested for pyrogenicity."
"Your firm failed to demonstrate adequate documentation that justifies a decision for not revalidating the sterilization cycle after these changes were implemented."
GOJO Industries, Inc., 2002-02-21
"Fourteen of the 31 OTC drug formulations have no process validation. The remaining 13 formulations have had mix studies completed but final product fill has not been validated. [21 CFR 211.100 and 211.110]"
Biomet Merck Limited Waterton Industrial Estate, 2002-02-19
"The sterilization process used for distributed manufactured product has not been adequately validated because of the failure to relate simulated product to actual product."
"The blister sealing process that seals the current sterile barrier packaging of the Stanmore hip implants has not been validated."
"The Nelipak sealer settings for each lot or batch of devices sealed through the Nelipak blister sealing process have not been documented."
Opti-Med Controlled Release Labs, Inc., 2002-01-09
"Your response suggests you consider process validation to be a test to confirm a batch process is in control and that three samples from the batch is adequate. We consider process validation to be an evaluation of the process to determine the optimum parameters to assure blend uniformity by testing a larger number of samples taken at various times during the blending operation from several locations in the blender."
"The lack of uniformity testing for the critical ingredient Folic Acid. Your failure to perform any folic acid testing, concerns us that the most significant active ingredient in these drugs is not subject to any analytical control testing."
2-2-0 Laboratories, 2001-12-27
"You have no process validation data for any of your drug products, and you have no validation that your cleaning and sanitation procedures prevent significant cross contamination from multi-use manufacturing process equipment."
CFH Laboratories LP, 2001-11-13
"The process validation for xxxxx tablets is incomplete, in that: 1. there is no documentation that processing equipment was qualified during installation, including the tableting machine, planetary blender and mixer, 2. the validation protocol referred to sampling and testing only. There is no documentation to support process parameters, such as machine settings and times for blending, tableting and mixing operations."
Person & Covey, 2001-10-17
"You have not performed process validation for Salbar Zinc SPF 38 yet lots have been released for commercial distribution; the process validation protocols for Xerac and Drysol lacked provisions for testing final filled containers; and there is no final report or approval of the process validation for prescription antiperspirants [21 CFR 211.100(b)]"
"While in some very specific circumstances a retrospective process validation can be demonstrated to provide acceptable data to support current processes, the likelihood is very rare. A very critical analysis of data and production conditions is required for acceptable validation of any process or product. Often retrospective reviews of production records do not reveal sufficient data to perform an adequate evaluation."
Kiel Laboratories, Inc., 2001-08-14
"You have failed to adequately validate the manufacturing processes for all of your drug products. You could not provide documented evidence which established a high degree of assurance that the manufacturing processes in use could consistently produce products meeting their predetermined specifications and quality attributes, both initially and throughout their labeled expiration date."
"No comparison was made in your process validation assessment of the current commercial manufacturing process and the process used in the original biobatch."
Cardinal Health, Inc., 2001-07-10
"Batch records do not accurately reflect the actual manufacturing process. For example, there was no documentation in the batch record that powder blend was reclaimed from the vacuum system of the xxxxx Encapsulator and added back into the virgin blend for process validation."
"Products were manufactured and shipped in interstate commerce before process validation was successfully completed [21 CFR 211.110(a)]."
IVAX Pharmaceuticals, Inc., 2001-05-14
"Your firm had no assurance that this product would meet assay requirements for each of the two active ingredients in this BI-layer tablet. Assay values and weights of individual layers were not evaluated during process validation and flow characteristics such as the rate of flow of each individual ingredient from hoppers to the tablet press were not assessed."
Procter & Gamble, 2001-05-04
"Since the process validation of Dantrolene Sodium was completed in 1997, there has been an increase in lots that needed to be reprocessed (remicronized) in order to meet particle size specifications. This reprocess often causes a decrease in moisture content that results in a rework (dehydration) to comply with the moisture specifications for the Dantrolene Sodium.....No stability samples were collected during the re-hydration validation exercise and the assay of the product was not evaluated during the validation of either step in the re-processing."
Banner Pharmacaps, Inc., 2001-04-16
"There is no scientific justification for testing 30 capsules for content uniformity during process validation. This is a suspension product that is not re-circulated or mixed during filling."
"Not only is your hourly testing for weight variation and seam thickness inadequate for process validation,
we consider the testing frequency outlined in your protocol inadequate even for routine in process testing. Significantly, more testing is necessary to assure uniformity of low dose, low fill volume and/or suspension products.".
Omicron Quimica, S.A., 2001-04-11
"Documentation of process validation for xxxxx was inadequate in that the report indicates that the prospective study was performed in 2000, yet the batch numbers indicate that the validation batches were manufactured in 1997. The validation records lacked operator identification, dates of processing, and signature or date of the person approving the report."
Tianjin Xin Xin Pharmaceutical Corporation, 2000-12-14
"The process validation study failed to define all significant processing steps/parameters and was based only on the review of laboratory data."
"The validation was conducted without identifying all critical process steps and critical operating parameters."
"Our review of the revised validation procedure indicates that you propose to conduct a retrospective revalidation of the xxxxx process once a year by reviewing data on xxxxx continuous batches of a given month. This show a lack of understanding of the principals of process validation."
"Once an existing process has been validated retrospectively, and the process needs to be revalidated due to changes that may affect the quality of an intermediate or API, the
validation should be done prospectively, or in certain limited cases, concurrently. Most important, these changes should be controlled by a formal change control system that evaluates the potential impact of proposed changes on the quality of the intermediate or API. Scientific judgement should determine what additional testing and validation studies should be conducted to justify a change in a validated process."
Duramed Pharmaceuticals, Inc., 2000-12-06
"The process validation for Verapamil HCI ER Tablets, and Acetaminophen and Codeine Tablets is inadequate in that the processes, when operating at the extremes of their established limits, failed to produce results within acceptable limits. Numerous batches run within the established limits failed to meet specifications ranging from assay, thickness, hardness, and friability."
Associates of Cape Cod, Inc., 2000-11-17
"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."
"The cleaning processes have not been validated, and there is no approved procedure for the cleaning."
Sciarra Laboratories, Inc., 2000-11-01
"Failure to validate the performance of those manufacturing processes that maybe responsible for causing variability in the characteristics of in-process materials and drug products [21 CFR 211.110(a)]. Filling operations and sealing/closing processes for sterile talc powder in vials have not be validated."
"The process validation protocol you have submitted only addresses filling. It fails to address sealing and closing operations which are important for drug products intended to be sterile for the duration of the expiatory period."
Akorn Incorporated, 2000-09-28
"The available data from the manufacturing process validation study does not demonstrate that the product can be consistently manufactured to meet all in-process and finished product specifications. For example: 1. three samples of bulk solution collected after mixing, one bulk sample
collected after filtration and one filled ampoule collected at the end of filling failed to meet protocol specifications for doxercalciferol potency, 2. the final validation report does not discuss or evaluate the out-ofspecification results for the mixing sample or the end-of-fill samples, 3. 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, 4. the process validation study did not include the minimum mixing times specified in the master batch production record."
Rhodia Inc., 2000-07-14
"FDA expects manufacturers to establish appropriate impurity profiles for each API as part of the process validation effort. An API manufacturing process can neither be validated nor can process changes be evaluated without an awareness of the impurity profile."
"If a firm lacks impurity profile data for their established API process, then FDA expects manufacturers to conduct retrospective validation as if they were setting up a new or modified manufacturing process. This retrospective validation would involve ...."
DuPont Pharmaceutical Co., Inc., 2000-06-15
"Failure to conduct adequate review prior to approval of production and process controls as required by 21 CFR 211.100 (a) in that validation protocols for several processes were approved when all specified parameters required by the protocols were not met, for example: 1. During tablet compression validation for Endocet@ tablets, one of the three lots had out-of-specification assay resuIts for the last tablets of the compression run....... 2. A high degree of variability was reported in blend uniformity results for three lots of Percocet@/Endocet@ tablets manufactured..... 3. The media fill validation for lyophilized ampoules was approved after growth was found in some units during all three runs..... 4. The validation protocol for Sustiva@ capsules packaging equipment was approved even though the validation was incomplete....."
American International Industries, 2000-03-30
"You have no process validation procedures for the filling and manufacture of any of your OTC drug products nor have you validated the performance of process equipment, you have no validation that your cleaning and sanitation procedures prevent significant cross contamination from multi-use manufacturing process equipment and no procedures outlining production controls, quality controls, and training."
"You have no validated procedures for the control of your filling operations of your OTC drug products."
H. B. Gordon Manufacturing Co., Inc., 1999-12-20
"You have no process validation procedures for any of your OTC drug products nor have you validated the performance of process equipment. Examples of non-validated process equipment include your deionized water system, compounding tanks, mixers and filling machines used in the
production of your OTC drug products."
"You have no validation that your cleaning and sanitation procedures prevent significant cross contamination of drug products that could arise from multi-use manufacturing process equipment."
IDEC Pharmaceutical Corporation, 1999-11-08
"The procedure entitled 'Cleaning Validation Study of xxxxx and xxxxx Resins at the End of their Lifetime Use' did not demonstrate the removal of endotoxins after the sanitization and cleaning of xxxxx and xxxxx columns."
Pierre Fabre, Inc., 1999-11-05
"You have no process validation procedures for any of your OTC drug products nor have you validated the performance of process equipment. Examples of non-validated process equipment include your deionised water system, homogenisers and filling machines used in the production of your OTC drug products."
"You have no validated sampling procedure for your compound bulk products."
"You have no validation that your cleaning and sanitation procedures prevent significant cross contamination from multiuse manufacturing process equipment."
Catalytica, Inc., 1999-10-29
"The inspection noted that review of process validation summaries lacked assay specifications for in-process blend uniformity samples. The firm's acceptance criterion is a relative standard deviation (RSD) not exceeding 6.0% for each active ingredient, but there is no assay criterion such as 90-110%. A relative standard deviation could be met although some or all samples were outside a 90-110% assay
range; this, in turn would be objectionable without further testing or investigation."
Medefil, Inc., 1999-05-06
"Your process validation studies lacked the following: a written validation protocol; documentation of the amount of Heparin Sodium injected into each xxxxx mL bag of xxxxx Sodium Chloride when validating the manufacturing process for Heparin-Sodium-for-Injection drug products; and assessment of the uniformity of dosage within a bag and within a batch of multiple bags."
Biopool International, Inc, 1999-03-02
"Failure to establish, maintain, and follow procedures for process validation in order to ensure that processes have been adequately validated and that the specified requirements continue to be met [21 CFR 820.75] in that: 1. container closure integrity tests have not been performed, 2. validation studies for bacterial retention and product compatibility have not been conducted on sterile filters, 3. there is no documented review of the need for revalidation after replacement of the heat exchanger and door gaskets."
Watson Laboratories, Inc., 1999-01-11
"Your firm failed to properly validate the manufacturing processes. Although process validation was performed the protocols failed to include: validation lots; validated and consistent sampling techniques or procedures when collecting granulation samples for blend uniformity testing; and/or adequate procedures for evaluating failed blend uniformity testing of samples collected from blenders or drums; and/or specifications for in-process samples were not established prior to validation lots being manufactured."
Knoll Pharmaceutical Co., 1998-12-14
"Your firm released one lot of Vicoprofen Tablets prior to validation of the manufacturing process. That lot was initially a cleaning validation batch, which was disqualified for a reason you were unable to disclose to our investigator. The process validation for Vicoprofen Tablets was conducted on three consecutive lots manufactured following the release of the disqualified lot."
"Your firm's process validation for Vicoprofen Tablets is inadequate. Disqualified batches are not identified in the validation report. The validation protocol did not specify lot numbers and amendments and addenda to the protocol did not allow for the provision of resuming validation via three consecutive lots following a disqualified or failed batch."
AccuMed Inc., 1998-06-09
"The process validation was not adequate in that there was no validation protocol with predetermined specifications, there was inadequate sampling and testing of in-process and finished product, and your firm was unable to supply the data for the validation report."
ImmunoGenetics, Inc., 1998-05-08
"Manufacturing process validation for Liquichlor with Cerumene, Cerumite and Laxatone were found to be inadequate, in that: 1. The current retrospective review of validation data does not include justification of established process parameters, such as mixing and temperature ranges. 2. Particle size specifications have not been established for the active substances used in Liquichlor with Cerumene, Suspension. 3. There is no in-process testing to evaluate the effect of the colloid milling process on the active ingredients in suspension."
Ohio Medical Instrument Co., Inc., 1998-05-01
"The ethylene oxide sterilization process for Biopsy Kits, Skull Mount Kits, and MRI Skull Mount"Kits was not adequately validated."
"The following lots of devices were distributed prior to the validation of the Ethylene Oxide (ETO) sterilization process for the devices: Biopsy Kits, lot #38119395 and Skull Mount Kits, lot # 38007295 and lot # 38019395. These lots of kits were originally a part of a four and one half hours ETO validation sterilization cycle run which failed sterility testing; the lots of kits were then subjected to an additional six and one half hours ETO cycle which failed sterility testing. The lots of kits were then broken down, repackaged, and sterilized using an eight hours ETO sterilization cycle. None of these ETO sterilization cycles were validated and no product functionality or residual ETO testing was performed on the kits prior to their release for distribution." ....
Sovereign Pharmaceuticals, Inc., 1998-03-12
"The Validation Protocols are not complete and do not provide all the required information. For example, descriptions of manufacturing processes, equipment performance qualifications and range of operating parameters, processing water quality and source, mixing times, and number or replicate processing runs to be made are not included in the protocols."
Haemachem, Inc., 1998-01-28
"Failure to establish, maintain, and follow procedures for process validation: 1. aseptic media fills have not been performed to validate your filling process, 2. revalidation was not performed following changes to your approved manufacturing process including modification of in-process specifications and addition, deletion, and rearrangement of manufacturing steps, 3. data are not available to support the effectiveness of storage of finished product, raw materials, and crude lysate in the walk-in freezer."
Hoffmann-La Roche, Inc., 1998-01-27
"The steam sterilization cycle for the empty syringes used for the filling product is not validated."
"The process validation for Bactrim Pediatric Suspension is inadequate, 1. No established mixing speeds or times during compounding, 2. There is no microbiological evaluation of the active pharmaceutical ingredients, 3. Temperatures during compounding were not specific and were not recorded in the batch record." ...
Bivona Medical Technologies, 1998-01-23
"Concurrent validation cannot be performed on components that have been routinely manufactured, but you may be able to review historical data for a retrospective validation. In any event, this information must be documented, parameters must be established for the equipment and/or components manufactured, and a completion date for this process must be established."
Advanced Pharmaceutical, Inc., 1997-06-24
"Failure to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug process."
"Manufacturing process validation protocols are inadequate because they fail to: a) indicate the number of drug batches per product to be validated; b) include installation qualification studies for equipment used to manufacture tablets and capsule; c) describe the equipment used for manufacturing and sampling, the sample collection method, a description of length and duration of the study, criteria for study, and the reasons for revalidation."
Ortho-McNeil Pharmaceuticals, 1997-04-21
"Manufacturing process validation for several product lines were found to be inadequate, for example: process parameters were not evaluated including the effect of additional drying steps and ranges established for mixing times, granulation and temperature; A matrix approach was used, allowing production batches made at mixed sites and not sequentially manufactured, to be used in support of process validation; There is no validation data to support bulk storage and filling process; Analytical methods and/or specifications have not been developed for antimicrobial preservatives; Packaging validation studies have yet to be conducted."