current Good Analytical Laboratory Practices (cGALP)

Give to the world the best you have and the best will come back to you
   Home            Warning letter
Be a social responsible citizen
 
Warning letter


A chart on deviation from cGMP for Year 2010 
 
 
 Most of the deviations are
  1. Inadequate lab control (TOP -15%)
  2. Lack of/Inadequate SOPs
  3. QA systems
  4. Deficiencies in records/reports - Equipment cleaning/maintenance, cleaning validation
  5. Production/process controls
  6. System qualification

Warning Letter by company
 
Dr.Reddys de Mexico
 
1. Your firm did not validate analytical methods used to test APIs.
 
For example, the inspection revealed that your firm had not validated the HPLC method for assay and related substances of (b)(4) (finished API (b)(4) for human use). This is just one example of numerous methods used by your firm that had not been validated according to approved procedures.
 
2. Your firm's cleaning validation was incomplete for non-dedicated manufacturing equipment.
 
For example, during the inspection the investigator observed a chart, dated November 11, 2010, showing your firm's cleaning validation progress by area that indicated the manufacturing equipment in Bay 2 (containing non-dedicated equipment) had no documented cleaning validation. This is just one example of several areas lacking cleaning validation for manufacturing equipment.
 
3. Your firm's out-of-specification (OOS) investigations did not include analysis of all available data.
 
For example, the inspection revealed that your firm rejected three consecutive lots of (b)(4) (an intermediate used in the manufacture of an API for the product "(b)(4)") on February 26, 2010, for appearance problems. The deviation investigation into the cause of the failure did not include an analysis of all available data including batches manufactured prior to the failures.
The inspection also found many deficiencies regarding handling OOS investigations. These include the timeliness of closing investigations, notification of the quality unit (including four to eight-month delays for reporting failing stability batches), and failure to follow written procedures. Although some of your proposed corrections to these individual items appear to be adequate, we remain concerned that a thorough evaluation of your investigation approach has not been conducted. Please include in your response a corrective and preventive action plan regarding handling investigations.
 
4. Your firm's quality unit did not exercise its responsibility to ensure the APIs manufactured were in compliance with CGMP, and met intended specifications for quality and purity.
 
As evidenced by the previous deviations, your quality unit has not overseen the controls required under CGMP to properly produce APIs. Your December 1 response stated that you will assess your firm’s quality needs by April 30, 2011. A quality unit is a basic requirement to ensure that quality APIs are produced at your facility. Please provide a detailed current assessment of this deficiency.
 
 
Impax laboratories
 
1. Your firm has not established written procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug product [21 C.F.R. § 211.110(a)]. For example:
 
a. Your firm failed to demonstrate that the manufacturing process for the Fenofibrate 200mg capsules is capable of controlling weight variations.
 
b. Your firm does not have data to support the temperature range of (b)(4)°C used during the granulation process of Colestipol Hydrochloride 1g tablets (lots 601066, 601067, and 601068). During the validation studies for the granulation process, your firm established a temperature range of (b)(4)°C. Your process validation study does not provide any data to support the process range allowed in the Master Batch Records.
 
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extended investigations to other batches of drug product that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192].
 
 
Aurobindo Pharma Limited
  1. Your firm’s laboratory records fail to include complete data derived from all tests necessary to assure compliance with established specifications and standards [21 C.F.R. § 211.194]. 
For example,
    1. On December 13, 2010, the FDA investigator observed a microbiological plate that contained one (1) large colony forming unit (CFU) of mold. However, your firm’s laboratory documentation reported 0 CFU for the same microbiological plate. 
The inspection found that the laboratory manager had documented “NIL,” (i.e. no growth for this plate), while the same laboratory manager confirmed microbial growth in the presence of the investigators.  Later during the inspection, the FDA investigator asked to see the original plate and was told that it had been destroyed. On December 21, 2010, your firm prepared a corrective and preventive action (CAPA) stating that the laboratory manager misread the plate count, and that this deficiency was the result of a human error. We are concerned that your firm lacks documentation to support this conclusion and moreover, that the original plate was destroyed during the FDA inspection, as reported.
 
 
b.On December 17, 2010, the investigator noted that many microbial plates containing environmental monitoring and personnel samples, collected on December 12, 2010 during production, were missing from the incubator.  Your response confirmed that 33 of 150 (22%) of the personnel monitoring samples were missing and that in one instance, 9 of 10 samples were missing for a single operator.
 
Our inspection found that your environmental monitoring data for 2009 and 2010 reported no alert or action level results in the Grade (b)(4) areas used to manufacture products intended for the U.S. market. This finding is questionable in that during an FDA visit to your microbiology laboratory on December 13, 2010, twenty-eight (28) plates, collected as part of the environmental monitoring program were found inside an incubator in the microbiology laboratory with visible growth of microorganisms.  According to your response to the inspectional observations, many of the microorganisms recovered were identified as “new isolates”, which had not been previously recovered in Unit VI.
 
2. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)].   
 
For example, during the December 2010 inspection, the investigators found that your SOPs related to your environmental programs failed to adequately identify (e.g., diagrams) the locations where active and passive environmental monitoring samples are to be collected from. The inspection also found that your procedure for environmental sampling does not require that employees be sampled (b)(4) time they exit the Class (b)(4) clean rooms.  
                                                                
This deficiency increases our concern regarding the reliability of the data generated and your ability to identify the source of your microbial contamination. We expect that SOPs related to Environmental Monitoring include sufficient instructions to ensure that the plates intended to detect microbial growth are appropriately located. These procedures should also include specific instructions for the collection of microbiological samples.
 
Your firm needs to establish a robust environmental monitoring program capable of generating meaningful data, and that would serve as an early warning system to detect possible environmental contaminants that may impact the sterility of the sterile APIs and finished drug products manufactured at your facility. There is no assurance that your current environmental monitoring program is capable of detecting microbiological contaminants.
 
In addition to the items listed above, the inspection uncovered additional deficiencies that increase our concerns regarding the validity of the data generated in the microbiology laboratory, and the quality of the sterile API and finished drug products manufactured at your facility. These issues include, but are not limited, to: 
  • Discrepancies in the procedures and documentation practices related to use of extra plates to replace missing or damaged plates that are collected as part of the environmental monitoring program.
  • The device used to handle (b)(4) stoppers during the aseptic filling of sterile API is not sampled.
  • Failure to follow established procedures for control of all pages in the batch production records.
III. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example,
 
Investigations related to Field Alert Reports (FARs) submitted to the agency during 2009 and 2010, regarding your packaging and labeling system are found to be inadequate. Your inability to implement appropriate corrections to prevent future significant problems raises concerns regarding the robustness of your quality system.
 
On January 19, 2010, a FAR submitted to the agency reported that a (b)(4) Tablet was found inside a bottle labeled as containing (b)(4) Tablets (b)(4) mg.  Subsequently, on April 12, 2010, and March 24, 2011, your firm submitted FARs reporting that eleven (11) bottles labeled as containing (b)(4) mg were found containing more than 30 (b)(4) Tablets (b)(4)mg; and that a bottle labeled as containing (b)(4) tablets (b)(4)mg, was found containing 90 (b)(4) Tablets (b)(4)mg, respectively.
 
Your investigation into the April 12, 2010 event attributed the root cause to a human error. You concluded that unlabeled bottles of (b)(4) tablets were re-introduced into the packaging line packaged with the (b)(4)mg labels. Your investigation regarding the March 24, 2011 event also attributed human error as the root cause of the problem. In this case the label printer manufacturer (PI) and labeling operations at Production Block-(b)(4) were also related to the product mix-up problems.  We are concerned with your inability to conduct a thorough evaluation of your packaging and labeling systems and identify problems that may lead to subsequent or new incidents of product/labeling mix-ups. It is your responsibility to determine the appropriate corrective actions that will reduce the possibility of future product/labeling mix-up problems.
 
 

 
Reese Pharmaceutical

1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, your firm failed to thoroughly investigate the mislabeling of cold decongestant tablets containing acetaminophen, phenylephrine HCL and chlorpheniramine maleate as a cough expectorant product containing guaifenesin. Your investigation determined that only one lot of cold decongestant (lot 091612) was involved in the mislabeling, while failing to identify a root cause. This lot was recalled.

2. Your firm failed to exercise strict control over labeling issued for use in drug product labeling operations [21 C.F.R. § 211.125(a)]. 

For example, your firm issues various labels for different drug products for production weeks in advance of the labeling operation.  These labels are stored in uncontrolled open boxes increasing the risk for packaging employees to select the wrong labels. 

3. Your firm has not established procedures to reconcile the quantities of labeling issued, used, returned, and failed to evaluate the discrepancies found between the quantity of drug product finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data.  [21 C.F.R. § 211.125(c)]. 

For example, your firm failed to reconcile the number of unlabeled drug product bottles issued to production with the number of labels used for batch records A74859 and A86926.

In your response, your firm states that you will carefully compare and control the product and packaging in the future. Your response, however, is inadequate because you fail to provide an adequate and specific corrective action plan regarding how your firm will reconcile the labeling.

4. Your firm failed to establish written procedures to identify the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch [21 C.F.R. § 211.130(c)].

For example, your firm attached identical labels (i.e., lot 10H572) to two different batch records (A86616 packaged on 9/21/2010 and A65626 packaged on 10/18/2010) without using a unique identifier on the actual label or bottled product to distinguish the two separate label operations. 
 

Allure Labs, Inc.
 
CGMP Violations
 
1. Your firm has failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products [21 C.F.R. § 211.22(a)]. For example,
 
A. Your Quality Control Unit (QCU) failed to reject a lot of Honeysuckle component (lot (b)(4)) after it failed specifications for yeast, mold, and Aerobic Plate Count. The lot was released and used to manufacture three lots of (b)(4) Moisturizing Face Screen (lots (b)(4)). 
 
B. Your QCU failed to detect an employee miscalculating the microbial results for three lots of (b)(4) Moisturizing Face Screen (lots (b)(4)) finished products by not applying a dilution factor of 10-2. The correct calculation of the results would have shown that these products were Out-of-Specification (OOS). The three lots of (b)(4) Moisturizing Face Screen were released and distributed by the QCU based on the erroneous results.
 
C. Your QCU failed to detect multiple discrepancies in sample weights and dilution factors between the analyst’s notebook and the Calculation Sheet. As a result, incorrect data was recorded for multiple products and finished products not meeting specifications were released. Specifically, a lot of (b)(4) SPF 30 (lot (b)(4)) was released and distributed even though it did not meet the established specification of (b)(4)% label claim. The correct calculation would have reported a (b)(4)% label claim. 
 
Your QCU did not require a second, independent person to review the raw data, calculations and records before releasing these lots for distribution.
 
2. Your firm has failed to establish appropriate written procedures designed to prevent objectionable microorganisms in products not required to be sterile [21 C.F.R. § 211.113(a)].
 
For example, your firm’s microbial limit specifications for finished product permits a microbial load in your drug product that could allow the presence of objectionable and potentially pathogenic organisms in your topical OTC drug products. In addition, your firm does not specifically test for Staphylococcus aureus or Pseudomonas aeruginosa that should be absent from topical drug preparations.
 
3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)]. For example,
 
A. Your firm has failed to provide a scientific justification for how the samples of bulk drugs are representative of the lot when they are collected only from the top of the kettle. Also, the samples are taken using a re-usable spatula sprayed with 70% isopropyl alcohol immediately before use. The presence of the alcohol on the spatulas could affect the validity of the test results. 
 
B. Your firm has failed to validate your Standard Operating Procedure (SOP) (b)(4), “Microbiological Testing of Cosmetics, Raw Materials and Finished Products,” to show the absence of growth inhibition by the tested drug products.
 
C. Your firm has failed to verify the assay methods for zinc oxide, titanium dioxide, and salicylic acid under actual conditions of use to determine the amount of active ingredients in your sunscreen products.
 
4. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)]. For example,
 
A. Your firm’s mixing operations for bulk drugs have not been validated to ensure homogeneity.
 
B. Your firm has failed to evaluate the holding time and handling (e.g., transfer from mixing kettles to intermediate storage containers) of bulk drugs during and after intermediate storage to ensure the bulk drugs continue to meet established specifications prior to filling. There has been no testing of finished products to verify that the transfers to intermediate storage containers, and conditions and duration of storage, do not adversely affect the drug products.
 
5. Your firm has failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform their assigned functions [21 C.F.R. § 211.25(a)].
 
For example, the employees of your firm, including a member of your quality control staff, admitted to our investigators that they were unaware of and were not trained to follow your SOP for handling deviations. There were at least two instances in which an OOS investigation was not conducted. For more information http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm257013.htm
 
Teva pharmaceuticals
 
1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, and you failed to extend the investigation to other batches of the same drug product that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192]. 
 
For example,
a. Your firm did not thoroughly investigate (b)(4)mg (b)(4) mg lot #(b)(4), when it failed to meet the established specification for both the single largest impurity and for total impurities amount. 
Specifically, the laboratory test results for lot #(b)(4) had a single impurity at RRT-(b)(4) minutes of (b)(4) (specification limit NMT (b)(4) %) and total impurity result of (b)(4)% (specification limit (b)(4)%). Your firm subsequently invalidated these results although your investigation was unable to confirm a root cause of the failure. Your firm selectively used passing results from a different analysis to approve the lot.
 
We reviewed your written response dated October 7, 2010. You do not provide adequate justification for invalidating the original results and utilizing retest results to release the batch. In your response you state the investigation results concluded that the original sample was contaminated during the processing of the test sample in the laboratory. However, you fail to describe how that conclusion was determined, or identify the root cause of the sample contamination, other than relying on the retest results being within specification.  In addition, you fail to provide corrective actions to prevent a recurrence.
 
We recommend you review the FDA guidance for industry entitled, "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production," for some basic principles regarding conduct of OOS investigations. The guidance states that when laboratory errors are not convincingly identified in the initial test, there is a lack of scientific basis for invalidating initial OOS results in favor of passing retest results.  In addition, the guidance notes that all test results should be reported and considered in batch release decisions.
 
b. Your firm did not thoroughly investigate (b)(4) mg/(b)(4)mg lot #(b)(4) when black particles were found in the sample powder during laboratory analysis. 
 
Specifically, the investigation no. PRI-030 concludes that the original powder was probably contaminated by a weighing instrument in the laboratory. However, the black particles were not identified and source was not determined. In addition, there was no attempt to determine if the black particles originated from the manufacturing process, or if additional lots were affected.
 
Your response lacks an explanation and documentation to support your conclusion that the powder was contaminated in the laboratory. Provide in your response to this letter the corrective and preventive actions implemented to address this deficiency. 
 
c. Your firm did not thoroughly investigate (b)(4) tablets (b)(4) mg lot #(b)(4) when it failed to meet the finished product assay specification.
 
Specifically, the finished product assay specification result was (b)(4)% (specification of (b)(4)%). A reinjection of the sample obtained a value of (b)(4)%, confirming the original OOS results. Your firm decided to prepare a new working solution. This sample resulted in (b)(4)%, which is on the lower limit of the specification.
 
Your firm retested six new samples from the same original laboratory sample tested and obtained the following values: (b)(4)% (four of the six results were also close to the lower limit of the specification).
Your investigation lacks data to support its conclusion that the OOS results were probably related to samples not being properly extracted during the standard solution preparation stage. It also lacks a thorough evaluation of the manufacturing process and other lots that may have been affected prior to invalidating the OOS results.
 
2. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during drug manufacturing [21 C.F.R. § 211.42(c)]. 
 
For example, your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds (e.g., (b)(4)) at your facility. Your facility contains shared manufacturing areas where you produce potentially hazardous compounds in multi-product equipment that are high powder generating operations, including (b)(4) drug products intended for the U.S. market. Your firm should ensure that a documented justification and well-designed contamination prevention strategy is in place to minimize the possibility of contamination. To achieve proper product protection, sound design and control approaches must be used.  Without proper separation, your firm lacks assurance that one drug does not contaminate another drug.
 
 
Ningbo Smart Pharmaceutical Co. Ltd
 
1. Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.

For example, your Quality Control Unit (QCU) approved the release of four (b)(4) USP batches (#(b)(4)) without data to support that the test for organic volatile impurities (OVI) met release specifications.
 
2. Failure of your QCU to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.

For example, the inspection revealed that your QCU released API lots to the U.S. without assuring that all required tests are performed. It is a basic responsibility of your QCU to ensure that all API lots produced meet specifications for quality and purity prior to being released. Your QCU also failed to detect that your COAs stated that OVI results conformed to specifications, although the test was not performed.

In addition to your failure to test (b)(4), USP, your QCU approved the release of (b)(4), USP batch # (b)(4) with no testing for OVI. This test is required under DMF (b)(4), submitted by your firm in 2005.
 
Sanofi Aventis Deutschland GmbH
 
1. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. For example,
 
For example, in June 2010, your firm failed to identify the organisms recovered from a sterility test for Apidra lot #OF100. Identification of microorganisms recovered from a sterility test is essential when conducting a sterility failure investigation. In addition, the identification of organisms is also a fundamental part of any investigation of environmental or personnel monitoring excursions.
 
Your firm’s failure to identify organisms recovered from a sterility test was also discussed during the December 2008 inspection.
 
We recognize that your firm voluntarily recalled the Apidra, Lot#0F151A, which was  part of the February 2010 production campaign in which there was a significant concern regarding environmental contamination levels. We expect all procedures related to the response for an out-of-limit environmental monitoring sample or a sterility failure to include the appropriate evaluation and remedial measures, as appropriate.
 
2. Your firm has not established separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing. [21 C.F.R. § 211.42(c)]. For example,
 
a) The airflow velocity inside critical areas of the aseptic processing operations of Line (b)(4) was found unacceptable by FDA. The documentary evidence of in-situ air pattern analysis (e.g., smoke studies) reviewed during the inspection confirmed this condition. 
 
With respect to aseptic processing in critical areas, you should be able to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Please note that proper design and control prevents turbulence and stagnant air in the critical areas. It is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination, and that any deficient conditions are addressed.
 
b) Your environmental monitoring program does not give assurance that environmental contaminants are reliably detected. Your practice of collecting samples from the gloves of operators, from left and right hands on alternate days is unacceptable. In addition, your SOP fails to include instructions for the location and duration of samples collected in the critical aseptic processing areas.
 
An adequate environmental monitoring program should be established by your firm. It should capture meaningful data and act as an early warning system to detect possible environmental contaminants that may impact the sterility of drug products manufactured at your facility that purport to be sterile.
 
3. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. [21 C.F.R. § 211.25(a)]. For example,
 
operators involved in the cleaning operations and aseptic connections during filling, were observed demonstrating incorrect aseptic techniques to prevent product contamination. We expect that operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper aseptic techniques are utilized during all operations.
 

 
McGuff Pharmaceuticals Inc.
 
CGMP Violations
                                    
1. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes [21 C.F.R. § 211.113(b)].  For example:
 
a. Your firm has failed to conduct a media fill representative of the different packaging configurations of your drug products for the past two years. Your firm has been using a volume of (b)(4) for media fills; however, commercial products are available in (b)(4) and (b)(4). In addition, you have not established maximum aseptic fill duration.
 
In your response, your firm states that you have amended your Standard Operating Procedure (SOP) (b)(4) to “bracket” the container sizes by utilizing both the (b)(4) and (b)(4) volumes. Your response, however, is inadequate because you have not provided a risk assessment that examines the effects of differences between product fill sizes (i.e., fill speed, operating methods, container opening size, mass) to determine if bracketing is appropriate.  
 
b. Your firm’s qualifications of the Getinge Model 4300 autoclave and the Grieve CLE-500 oven are inadequate in that you have not qualified this equipment with representative loads. Your firm’s practice is to qualify the equipment using minimum loads as opposed to actual loads during routine operation (e.g., Grieve CLE-500 oven was qualified to depyrogenate glass vials using (b)(4) tray when the actual load is a maximum of 60 trays).
 
In addition, your use of biological indicators and penetration thermocouples in the qualification studies are inadequate. Your firm has not used any penetration thermocouples during the qualification of Getinge Model 4300 since February (b)(4), nor have you incorporated the use of biological indicators. During the maximum load configuration study, your firm only used a (b)(4) penetration thermocouple and failed to use any biological indicators. 
 
In your response, your firm commits to evaluate the adequacy of your current procedure, to qualify your minimum and maximum load on each of your manufacturing operations, and to include penetration thermocouples and biological indicators in appropriate areas and in appropriate quantities. However, your response is inadequate because you did not explain how you will determine the appropriate locations and quantities for the thermocouples and the biological indicators. Since your firm is currently manufacturing sterile drug products using unqualified equipment, your response fails to include any additional controls to assure the quality of your drug products while you are evaluating your current procedures.
 
2. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)]. 
 
For example, your firm accepts and relies upon the Certificate of Analysis (COA) from your active pharmaceutical ingredient (API) suppliers without conducting appropriate validation of the supplier’s test results. This is of heightened concern since you have not established endotoxin specifications, nor have you performed endotoxin testing on APIs intended to be used in the manufacture of sterile drugs.
 
In your response, your firm commits to test any APIs with amended specifications in an attempt to correct this deficiency.  However, your response fails to explain which specifications are to be amended or which APIs are to be tested. In addition, you do not describe corrective actions regarding products currently in the market manufactured with APIs of questionable quality.
 
Please note that adequate qualification of suppliers is critical in assuring that your sterile drug products are of the quality intended.
 
3. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]
 
For example, your firm failed to conduct adequate investigations into action level excursions. Your investigations (e.g., (b)(4)) of growth in a media fill did not include a review of the batch records, equipment logs, or HVAC system by the most responsible personnel (e.g., a microbiologist reviewed a batch record). Further, the Quality Assurance Unit did not review and approve the investigation. Finally, your firm failed to implement the corrective/preventative action identified in the investigation. 
 
In your response, your firm states that: 1) your SOP will be revised to require a formal investigation by the Quality Assurance Unit when environmental monitoring action levels are exceeded and 2) retrospective investigations into previous excursions were conducted. You also commit to re-investigate (b)(4) and that any impact on aseptic operations will be assessed by the Quality Assurance Unit. Your response, however, is inadequate because you have not described how you will assess the potential impact on products that have already been distributed.
 
 
Synbiotic Ltd.
 
1. Failure to prepare, review, and approve documents related to the manufacture of APIs.
 
For example, you shipped Lot (b)(4) of (b)(4), to the United States in January 2010 from this site. At the time of shipment, no procedures were in place for change control, out-of-specification investigations, process deviation investigations, laboratory incidents, consumer complaint handling, or annual product reviews. Without these and other basic CGMP procedures in place, there is minimal assurance of appropriate systems to assure product quality.
 
Your response acknowledges that your quality system “was inadequate” and that “critical Quality Assurance functions were missing.” Your response also includes SOPs, covering topics such as change control, out of specification results, deviation control, market complaints and product quality reviews, which were specifically requested during the August 2010 inspection attempt. It is your responsibility to ensure these and other critical procedures and essential quality assurance functions are in place prior to manufacturing. Your quality system will be thoroughly reviewed during the next FDA inspection.
 
2.      Failure of your quality system to provide confidence that your API manufacturing processes will consistently yield a product meeting its intended specifications.
 
For example, at the time of shipment of the above-referenced lot of (b)(4), you had not performed validation of the manufacturing process for (b)(4), nor had you established a process design, a validation plan, or qualification protocols. Process validation is essential to establish initial and ongoing reproducibility of your manufacturing operation. Furthermore, process validation is expected before commercial distribution begins. Without an adequate validation plan or written procedures to execute pre-defined qualification protocols, your manufacturing process can not be confirmed as being capable of reliable commercial manufacturing that consistently delivers a product that meets its pre-defined quality attributes.
 
Your response acknowledges that you have not completed process validation for the (b)(4) process used to manufacture Lot (b)(4). It is our expectation that process validation be complete prior to commercial distribution. Additionally, your response states that Lot (b)(4) met USP requirements at its release and again during retain re-testing and because the product meets the USP requirements, “this batch is completely safe and there are no quality issues.” FDA disagrees with this statement as you have already acknowledged that process validation has not yet been completed at the time of Lot (b)(4)’s manufacture and that your quality system “was inadequate” and that “critical Quality Assurance functions were missing.”
 

GAR Laboratories Inc.
 
CGMP Violations
 
1. Your firm has failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products [21 C.F.R. § 211.22(a)].
 
For example, your firm failed to comply with recommendations by your Quality Control Unit (QCU) to destroy drug products used to treat acne because of failing assay results in three separate instances (i.e., (b)(4) (lot (b)(4)) and (b)(4) (lots (b)(4) and (b)(4)).  At the direction of your firm’s Plant manager, the affected lots were reworked to pass testing without a documented justification.
 
In your response, you stated that your firm would draft a new Standard Operation Procedure (SOP) addressing the QCU’s roles and responsibilities by September, 2010.  Your response, however, is inadequate because you have not yet provided this SOP (b)(4) detailing the  QCU’s authority to approve and reject all in-process materials and drug products.
 
2. Your quality control unit has not approved or rejected all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product [21 C.F.R. § 211.22(c)].
 
For example, the following changes were made to formulations and specifications by your Research and Development Department without QCU review and approval: 
• A material consisting of (b)(4) benzoyl peroxide was substituted for (b)(4) in the manufacturing of the (b)(4)
• The specification for in-process bulk and finished product assay for benzoyl peroxide was changed from (b)(4) of the labeled strength to (b)(4)  of the labeled strength for the (b)(4) and the (b)(4) products.
 
In your response, your firm stated that your QCU shall review and approve written procedures that are drafted, reviewed, and approved by the appropriate organizational unit.   However, your response is inadequate because you have not provided any documentation to demonstrate that QCU review and approval of daily production and control record is being performed.
 
3. Your firm’s quality control unit has failed to review and approve all drug product production and control records to determine compliance with all established and approved written procedures before a batch is released or distributed; and your firm does not maintain a written record of investigations including conclusions and follow-up [21 C.F.R. § 211.192].  For example,
a. Your firm’s QCU has failed to review batch production records prior to release and distribution of the batch.  The batch record for (b)(4) (lot (b)(4)) was observed without a signature for final release by the QCU.
 
In your response, your firm states that the QCU will be required to review and approve all production records to determine compliance with procedures prior to release or distribution, effective August 2010.  However, your response is inadequate because you have not provided any documentation to demonstrate that your QCU has started this review of batch production records.
 
b. Your firm did not perform and document investigations into Out-of-Specification (OOS) results on topical drug products that included (b)(4) and (b)(4). Your firm did not perform and document investigations into conflicting OOS microbiological results obtained from in-house testing and testing performed by a third party contract laboratory. 
 
c. Your firm failed to investigate the cause of at least twenty-five (25) out-of-limit results for the deionized water system.
 
In your response concerning example (b) and (c) above, you state that you will revise your current SOP (b)(4) to include a more detailed procedure of investigation.  Your response, however, is inadequate because you have not provided your revised procedure or any documentation to show that it has been appropriately implemented.
 
4. Your firm does not have adequate written procedures, and does not follow those procedures, for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100].
 
For example, your firm has failed to validate a number of procedures and processes used in the manufacture of your drug products.  Specifically, your firm does not have data to verify that the mixing times used for bulk drug products are adequate to produce homogeneity.  Further, you have not provided any data to demonstrate that your bulk drug products, such as the (b)
 
(4) can be stored for extended periods of time under ambient conditions without altering their identity, strength, quality, and purity.
 
In your response, you state that you are “fielding expert individuals” to establish proper process controls.   Your response, however, is inadequate because you fail to: (1) provide timelines for implementing your corrective actions; (2) reference the specific processes you intend to validate, or; (3) provide the validation protocols or plans you intend to implement.
 
5. Your firm has not established or followed written procedures for the cleaning and maintenance of equipment [21 C.F.R. § 211.67(b)].
 
For example, your firm does not have data to demonstrate your cleaning processes for non-dedicated manufacturing equipment (i.e., blending tanks, storage totes, fillers, and transfer piping) and utensils are adequate. 
 
In your response, your firm states that you will draft procedures for the cleaning of manufacturing equipment by October 2010, and that these will be effective November 2010.  Your firm is responsible for assuring the adequacy and robustness of these procedures, and we will evaluate this issue during the next inspection.
 
6. Your firm has not established scientifically sound appropriate specifications, standards, sampling plans, and test procedures designed to assure that in-process materials and drug products conform to appropriate standards of identity, strength, quality and purity [21 C.F.R. § 211.160(b)].  For example,
 
a. Your firm does not use reference standards obtained from an official source for the (b)(4) testing of APIs (i.e., (b)(4) USP and (b)(4) USP) that are used in your firm’s OTC drug products.
b. Your firm does not ensure that the samples taken for release testing are representative of the entire batch.  There is no data to show that the samples taken for assay and microbiological analyses from the top and bottom of your compounding tanks are sufficient to demonstrate batch uniformity.  Additionally, there is no statistical rationale for the number of samples collected for finished product sampling. 
c. Your firm has not validated your testing procedures.  Your laboratory methods for microbiological analysis of purified water used in the manufacture of your drug products have not been validated to demonstrate accuracy and equivalence to compendial methods. 
d. Your firm has not performed or documented system suitability tests for the (b)(4) assays to verify that the resolution and reproducibility of your (b)(4) system are adequate prior to your analysis of product samples.
 
In your response, you state that you will (1) draft new sampling procedures, (2) begin using USP reference standards for (b)(4) analysis, and (3) begin top, middle and bottom sampling to evaluate blend uniformity.  Your response, however, is inadequate because you have not provided documentation to demonstrate that you are using USP standards as the reference standards for (b)(4) testing.  In addition, you have not provided any documentation of the new sampling procedures to evaluate blend uniformity or your new (b)(4) that describes how sampling will be based on “the quantity produced.”  Further, your response does not address the validation of the methods used for the microbiological analysis of purified water samples.
 
7. Your firm has failed to use equipment in the manufacture, processing, packing, or holding of drug products that are of appropriate design, of adequate size, and suitably located to facilitate operations for its intended use [21 C.F.R. § 211.63]. 
 
For example, your firm has failed to validate the deionized water system that supplies the process water used in all drug products manufactured at your facility.  Further, your firm has not established a maintenance program for your water system or validated the biweekly sanitization process to ensure that it extends to all areas of the recirculation loop and that the deionized water meets specifications. 
 
In your response, your firm plans to include additional sampling points for your water system to qualify the water quality of the holding tank.  Your response is inadequate because you fail to specify where these sampling sites are located.  In addition, your response does not include any details describing the following:  (1) the 12-month study to determine whether an increase in sanitization frequency is required; (2) the monitoring of conductivity and Total Organic Carbon (TOC), or; (3) documentation for revising the Piping & Instrumentation Diagram (P&ID).   Also, the minimum acceptable quality standard for water used in drug product manufacture is found in the United States Pharmacopeia.  Please see the Purified Water, USP, monograph.  Also, see FDA’s Guide to Inspections of High Purity Water Systems (1993) for discussion of appropriate microbial action levels and water system validation approaches.
 
8. Your firm has failed to follow your written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expirations dates [21 C.F.R. § 211.166(a)]. 
 
For example, your procedures require the first three lots of each product “to be placed on stability testing,” and for stability studies to be performed on the first lot of each product produced in subsequent calendar years.  These procedures were not followed in that the first lot of each product was not placed on stability in subsequent years.  You do not have stability data for any of your drug products to demonstrate these products will meet the intended finished product specifications for the shelf life of the product. In addition, your bulk lot (b)(4) and bulk Lots (b)(4) and (b)(4) of (b)(4) were found to be out of specifications after 7-9 months in storage.
 
In your response, your firm states that you will be finalizing your stability program procedure by October 2010.  However, your response is inadequate because you do not provide any details concerning the stability program or any specific information or documentation to demonstrate that your products will meet specifications at expiration.
 
9. Your firm has not established or followed written procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to assure that the reprocessed batches will conform with all established standards and performs reprocessing of batches without review and approval of the quality control unit [21 C.F.R. § 211.115(a) and (b)].  For example,
 
 a. Your firm has failed to establish any written procedures for reprocessing bulk drug  products.
 b. Your QCU did not review and approve the reprocessing of two bulk lots of (b)(4) and one bulk lot of (b)(4).
 
In your response, you state that you will draft a written procedure that defines the roles and responsibilities of the QCU by October 2010.  However, your response is inadequate because you do not address the QCU’s review of batch reprocessing or the establishment of any written procedures pertaining to that review and approval.
 
10. Your firm has failed to maintain all production and control records associated with a batch of drug product for least one (1) year after the expiration date of the batch [21 C.F.R. § 211.180(a)].  For example,
 
a. Your firm failed to maintain records regarding the adjustments made to the bulk product for (b)(4) (lot (b)(4)) prior to the filling and distribution of the bulk material.  
b. Your firm failed to maintain records for the reprocessing or reworking of drug product batches, specifically when the drug product failed to meet specifications after long-term storage in plastic totes.  The remaining portion of Lot (b)(4) of (b)(4) was found to be OOS for assay and pH when re-tested seven months after manufacture.  Representatives of your firm stated this lot was reworked by adjusting the bulk material prior to filling.  However, there is no documentation of this occurrence. 
 
11. Your firm’s laboratory records failed to include complete data derived from all tests, examinations, and assays necessary to assure compliance with established specifications and standards [21 C.F.R. § 211.194(a)].
 
For example, your firm failed to maintain records derived from the (b)(4) analyses of in-process bulk and finished drug products.  Laboratory notebooks containing sample information such as analytical dates, sample weights, calculations, and analytical results for all your products analyzed from August 2009 to February 2010 were not maintained. 
In your response, you indicate that you will implement corrective actions, including necessary documentation in your laboratory notebooks.  Your response, however, is inadequate because you have not demonstrated how or when you will implement these changes.
 
12. Your firm failed to store drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity are not affected [21 C.F.R. § 211.142(b)].
 
For example, your storage warehouse area (Building (b)(4)) is not temperature-controlled when storing raw materials, in-process bulk product, and finished drug products.  On July 19, 2010, temperatures in this warehouse area were observed to range from 88.7º F to 93.5º F. 
In addition, your firm has not performed temperature or humidity mapping studies in the in-process bulk and finished products area to determine if the warehouse is capable of consistently providing conditions that meet the storage requirements. 
In your response, you state that you will be “fielding expert individuals” to assess temperature and humidity controls.  Your response is inadequate because you do not provide definitive corrections or a corrective action plan.
 
13. Your firm failed to establish written procedures to evaluate, at least annually, the quality standards, including provisions for a review of complaints, recalls, returned or salvaged drug products, and investigations conducted for each drug product [21 C.F.R. § 211.180(e)(2)].
 
For example, your firm has failed to establish written procedures for annual product reviews.  To date, your firm has not conducted any annual product reviews for any manufactured drug products. 
 
In your response, your firm states that you are currently conducting an annual review of your drug products with a completion date of December 2010.  Your response, however, is inadequate because you have not provided any documentation as evidence of this review.  In addition, your timeframe for completion (i.e., December 2010) is unacceptable.
 
 
Claris Lifesciences ltd.
 
CGMP VIOLATIONS

1. Your firm has failed to thoroughly investigate the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

a. The complaint investigation discussed in the undated report submitted with Claris India’s July 2010 response to the FDA Form 483 and titled, “Complaint Investigation Report Metronidazole Injection USP Ondansetron In 5% Dextrose Injection” (Complaint Investigation Report), is inadequate. It lacks sufficient evaluation of several complaints of intravenous (IV) bag contamination, and does not provide scientific justification and supporting evidence regarding the root cause identified. For example:
 

1) On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.
 

On May 5, 2010 the same customer (Sagent Pharmaceuticals) reported that another lot of Metronidazole Injection USP bags (A090742) was contaminated with fungi (Mucor species).
 

The Complaint Investigation Report does not adequately address either of this complainant’s contamination findings, or the root cause of the problems. For example, your customer’s test results confirmed the presence of visual contaminants without discovering any leaks in the intravenous (IV) bags. You have claimed that the uniqueness of your firm’s method to detect leaks supersedes the customer’s methods. Accordingly, you disregarded their findings regarding the integrity of the IV bag because their test was not performed or supervised by your own laboratory. This does not address the presence of fungi. For instance, the investigation conducted by Sagent involving Metronidazole Injection USP bags (lot A090744) did not detect a leak on the IV bag tested (dye penetration by injection), even though fungi (Cladosporium species) were found inside the IV bag.
 

Furthermore, your firm’s conclusions were based solely on the returned bags examined, and do not take into account the overall implications, extent, or root cause of the detected contamination.
 

In your response to this letter, include your final investigation, assessment, rational and the corrective actions implemented addressing your failure to initiate the complaint investigation promptly. Also, explain if the Dye Ingress method (Container Closure Integrity) is still used to release your IV bags to the market, or if a different method was developed as part of the investigation to detect leakage in the bags.
 

2) On May 6, 2010, your firm received a complaint from the (b)(4) indicating a problem when they opened a case that contained six Metronidazole Injection USP IV bags (lot A090460). The technician from the pharmacy observed that fungi were in the IV bag (as well as inside the overwrap). Claris submitted a Field Alert Report (FAR) on June 3, 2010, however, your Complaint Investigation Report indicates that no leak or contamination was found in the bags received from (b)(4). Please explain this discrepancy in your response to this letter.
 

3) On May 31, 2010, your customer (Pfizer) reported that Metronidazole Injection USP IV bags (lot A090722) were contaminated with fungi (Cladosporium species) and Gram positive bacteria (Brevibacterium casei). Pfizer returned 33 unopened Metronidazole Injection USP bags, but your Complaint Investigation Report failed to identify the contaminants that Pfizer visually observed in at least 31 of these bags.
 

4) Through its investigation your firm identified defective printing stereos, along with packaging, shipping, and handling as the primary root causes of the contamination. The Complaint Investigation Report, however, failed to explain why a defective printing stereo would only have affected IV bags that were returned by your customers, and not other lots produced and released for distribution. Moreover, the Complaint Investigation Report lacks supporting evidence to demonstrate that the packaging, shipping, and handling contributed to the contamination.
 

In your response to this letter, address those issues, and also explain why these stereos were being used during the manufacturing process and how the suppliers of these defective stereos were qualified, and provide a complete explanation of how and when Claris became aware of the defect(s). In your written response to this letter, provide specific information regarding the requalification of the printing operation, and any formal study conducted to demonstrate the new printing parameters that the response states your firm adopted will prevent recurrence of the problem.
 

5) Claris India acts as a contract manufacturer for IV bag products marketed by other firms, as well as a distributor of some batches under Claris’s own label. Your responsibility as a contract manufacturer is to inform all of your customers of a significant production problem or possible product hazard immediately. In fact, Claris India’s Quality Agreements with its customers requires that your firm notify the other party within (b)(4) business days of any quality issues related to the product. We note that your firm received worrisome complaints of lost IV bag package integrity and contamination. Yet, the Complaint Investigation Report fails to indicate what steps Claris took to ascertain whether other customers were affected by this issue, or to notify all customers of the potential for significant contamination. Please explain how and when Claris identified and informed all customers affected by your IV bag manufacturing problems. Also include your SOP describing how you keep customers promptly informed of significant occurrences (e.g., complaints, OOS, rejections, major deviations or discrepancies, any potential product hazard), concerning the products you manufacture for them.
 

6) The Complaint Investigation Report also reflects a number of other shortcomings in the investigation. For example, the Complaint Investigation Report fails, among other things, to:
 

(a) Identify when the problems that lead to the damaged IV bags and contamination of the product started.
 

(b) Provide a thorough evaluation and supporting evidence regarding the origin of the contamination that extended to at least eight batches of two products - Metronidazole Injection USP bags and Ondansetron Injection USP in 5% Dextrose Injection bags. The contamination was reported through at least five complaints.
 

(c) Provide a rationale why other products filled in the same packaging line, with the same bags and printing process, were not affected or contaminated. Similar complaints of contamination extended to batches distributed outside the United States, but the Complaint Investigation Report provides no details of when the complaints were received, or whether an investigation was conducted.
 

(d) Include an evaluation of the time that elapsed between the manufacturing/filling and printing process of the different batches, and the time the contamination was detected and reported by Claris India. The investigation also lacks details regarding the number of examined lots on hand, tests performed, and the sampling plan used.
 

(e) Supply an evaluation of the set up process, as well as the number and type of damaged bags generated during the set up. We are concerned with your proposed identification of root causes, because it fails to explain how the sharp edges and stereos only affected the bags that complainants identified, and not any of the bags remaining under your control, or other released batches.
 

Your firm’s response dated July 3, 2010 (July 2010 response), does not provide sufficient information regarding the aforementioned issues. Please include in your response to this letter information regarding each of the issues noted above, and include the nature and origin of contamination or leakage complaints received for lots of the same products that may have been distributed outside of the United States. In addition, please provide a summary of your shipping and handling validation studies under stress conditions.
 

b. Your investigation into an incident involving IV bag filling rooms and Laminar Air Flow (LAFs) losing positive pressure is inadequate. For example,
 

During the production of Metronidazole Injection USP bags (lot A000241) the bag filling room and LAFs – intended to provide a constant flow of clean air out of the work area to prevent potentially contaminated air from entering – lost positive pressure. Your July 2010 response indicated that your firm rejected only the bags filled after 9:30 a.m. until the line was stopped, despite the fact that in the same response, your firm indicated that the last acceptable positive pressure was at 9:21 a.m. The deviation report, however, failed to provide an adequate rationale for not rejecting all the bags at risk. Specifically, the July 2010 response indicates that the reason for not rejecting the bags filled after 9:21 a.m., which potentially could have been affected, was because the microbial environmental monitoring results were within acceptable limits. This approach, however, is unacceptable because the loss in pressure may also have affected the accuracy or reliability of the environmental monitoring results; there is, thus, no assurance that all bags filled after 9:21 a.m. were unaffected by the loss of positive pressure, and therefore free of microbial contamination.
 

Your written procedures related to bag filling and environmental monitoring should be revised. They should ensure that all units of drug products filled between the time the last acceptable differential pressure reading was obtained, and the time the room returns to acceptable conditions, be rejected.
 

As noted above, we are concerned about the inadequate investigation into the contamination of your IV drug products, process deviation, and the inappropriate documentation practices cited during this inspection. Please provide a corrective action plan that describes your revised procedures, corrective and preventive actions, and controls to ensure product quality.
 

This plan should include a comprehensive retrospective review of your root cause analysis and the effectiveness of your corrective/preventive actions of the contamination in your drug products, raw material suppliers, equipment adequacy, sterilization cycles, and cleaning and maintenance procedures implemented to ensure that all products produced and released by your quality unit meet specifications. It should also include an evaluation of the independence, authority, and effectiveness of your firm’s quality unit to rapidly address significant manufacturing issues. A robust quality unit will be essential for your firm to address any emerging or ongoing manufacturing issue in the future, and prevent the distribution of adulterated product.
 

2. Your firm does not have adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)]. For example:
 

The inspection revealed that your firm fails to have a procedure or process in place to evaluate in-process units that are rejected due to defects during the filling of Metronidazole Injection USP bags. In fact, the investigators documented that for Metronidazole Injection USP bags (lot A000247), 48 rejections occurred during the filling process No deviation was documented and no investigation was conducted, and you have not documented whether or not the rejected units were caused by a significant process deviation that directly affects the integrity of the other IV bags in the production lot.
 

Your July 2010 response is inadequate because it fails to include your rationale for releasing production lots with unexplained deviations, on the basis that the filling yield was found within limits.
 

Please provide a retrospective analysis of the in-process and finished units of Metronidazole Injection USP bags, Ciprofloxin Injection USP bags, and Ondansetron Injection USP bags that were rejected due to defects found during your filling, printing, and packaging operations. Include the amount of defective units in this analysis. We also recommend that an adequate timeframe be considered for this study to enable you to establish trends regarding the amount and type of defect, and amount of rejected units per batch. Provide information on the type of defects identified, and the corrective and preventive actions implemented.
 

3. Your firm failed to assure that equipment used in the manufacture, processing, packing, or holding of a drug product is of appropriate design for its intended use [21 C.F.R. § 211.63]. For example:
 

The calibration of thermocouples (TCs) used during the validation of your terminal steam sterilizers is not performed before or after the autoclave cycles. Your response failed to provide data to support that the TCs used during the validation runs are within acceptable calibration range. The calibration of these TCs provides assurance of an accurate reading of the temperature in the sterilizer. Please provide your sterilization cycle summary for all the terminal sterilizers and cycles used by your facility, with the appropriate parameters and conclusion of the data generated.
 

4. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. For example:
 

The written procedures related to the production simulations – “media fills” - conducted to validate your capability to aseptically produce small volume parenteral (SVP) were found to be inadequate. The media fills for this line did not represent actual operations used in the aseptic production of ampoules and vials. For instance, the media fill performed by your firm in October 2009 failed to simulate the interventions performed in actual, routine production. For example, a routine production of a (b)(4) Injection vials lot would take approximately (b)(4) hours to be filled. Your written procedures (reflected in production protocols and batch record forms) for routine production require that an intervention take place every (b)(4) minutes for fill-weight verification measurements. Our review found, however, written procedures for the media fill simulation (reflected in media fill protocol), require performance of this fill-weight verification measurement only (b)(4) times throughout the media fill process. In your response to this letter, provide the finalized protocol and the summary report including all data generated during the execution of this media fill.
 

5. Your firm does not clean and maintain equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 C.F.R. § 211.67(a)].
 

During the inspection the investigators observed three dispensing vessels used in the step prior to terminal sterilization that were labeled clean, however, the vessels had liquid residue inside. Your response indicated that this liquid is from final cleaning with (b)(4) rinse. The presence of liquid residue in a vessel (labeled as clean) that is later used to manufacture sterile drug products is unacceptable. In your response to this letter, provide the production lot numbers that included use of these vessels. Additionally, provide documentation to support that your firm’s cleaning procedures and practices are adequate to prevent contamination of your products. Lastly, provide the investigation report with your findings including the cleaning methods performed, as well as the corrective and preventive actions for all of your other equipment.
 

6. Batch production and control records prepared for each batch of drug product produced do not include complete information relating to the production and control of each batch [21 C.F.R. § 211.188]. For example:
 

FIELD ALERT REPORTING VIOLATIONS

FDA “Field Alert” reporting requirements require applicants to submit certain information about distributed drug products, including information concerning bacteriological contamination, any significant chemical, physical, or other change or deterioration product, or any failure of a distributed batch to meet the specifications established for it, to the appropriate FDA district office within three working days of receipt by the applicant [21 C.F.R. § 314.81(b)(1)]. The regulation helps establish an “early warning system” by requiring that applicants bring significant problems to the Agency’s attention promptly in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential safety hazards with drug products manufactured in the future.
 

Based on the observations and information obtained during the inspection, Claris failed to submit Field Alert reports as required by 21 C.F.R. § 314.81(b)(1)(ii). For example:
 

a. Your firm received visibly contaminated Metronidazole Injection USP bags (lot A090744) on April 15, 2010. The field alert report submitted to FDA was dated May 6, 2010.
 

b. Your firm received a contaminated sample of Metronidazole Injection USP bags (lot A090460) on May 6, 2010, but the field alert report was sent to FDA on June 3, 2010.
 

c. Your customer ((b)(4)) found three instances of a leaking bag with possible microbial growth of Metronidazole Injection Solution Bag and reported this to Claris India on May 20, 2009 (lot A080758), November 10, 2009 (lot A080784), and May 4, 2010 (lot A080765). None of these complaints were sent to FDA.

UNAPPROVED NEW DRUGS VIOLATIONS

Observations and information obtained during the July 2009 and January/February 2010 inspections, and review of labeling, further indicate that Claris, including by and through its wholly-owned subsidiary Claris U.S., has marketed an unapproved new drug in violation of the Act. Specifically, information obtained during those inspections indicates your firm has marketed the following prescription drug:
 

• Sodium Bicarbonate Injection (8.4% w/v; 250 mL and 500 mL glass vials)
 

ADVERSE DRUG EXPERIENCE REPORTS

Section 505(k)(1) of the Act [21 U.S.C. § 355(k)(1)], and 21 C.F.R. §§ 314.80 and 314.981, require an applicant to establish and maintain records and make reports to FDA of adverse drug experiences, along with certain other data or information. Failure to comply with section 505(k) of the Act is a prohibited act under section 301(e) of the Act [21 U.S.C. § 331(e)]. In addition, section 310.305 of FDA’s regulations, [21 C.F.R. § 310.305], requires manufacturers, packers, and distributors who market prescription drug products that are not the subject of approved drug applications, to establish and maintain records and make reports to FDA of serious, unexpected adverse drug experiences associated with the use of their drug products.

During our July 2009 and January/February 2010 inspections of Claris U.S., FDA investigators identified violations of post-marketing adverse drug experience reporting regulations of Title 21, Code of Federal Regulations Parts 310 and 314, and section 505(k)(1) of the Act [21 U.S.C. § 355(k)(1)]. We acknowledge the responses, dated August 12, 2009, October 7, 13, and 30, 2009, and February 24, 2010, from Arun Menon, President of Claris U.S., to the FDA Form 483s issued following the inspections, and Claris’s stated commitment to developing and implementing adequate written procedures, including a number of promised additions and changes to Claris India procedures (SOPs) for handling ADE reporting. Indeed, information obtained from the inspections and the Claris responses also indicates that Claris India and Claris U.S. have shared responsibility for activities involved in meeting their ADE reporting obligations under FDA regulations. Claris also indicated certain activities have been transferred to an independent contractor, (b)(4). We note, however, that Claris has not provided all of the SOPs noted in its correspondence and, hence, the revised procedures for certain ADE reporting activities remain unclear. We request that Claris meet with FDA staff to discuss a resolution to this situation.
 
 
 
CP pharmaceuticals
 
1. Your firm has not established separate or defined areas or such other control systems to prevent contamination during aseptic processing [21 C.F.R. § 211.42(c)]. For example,

a. There is no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Your firm failed to demonstrate that the appropriate design and controls are in place to prevent turbulence and stagnant air in the critical area. It is essential that you evaluate airflow patterns for turbulence that can act as a channel for air contamination. The studies should be well documented with written conclusions, and should include an evaluation of the impact of aseptic manipulations (e.g., interventions) and the equipment design.

b. Your aseptic processing control systems and operations do not provide assurance that the production rooms and equipment maintain aseptic conditions. Additionally, your environmental monitoring practices do not include adequate routine examination of the facilities and equipment to ensure that possible contaminants can be detected.

The inspection documented mold contamination in the class 100 production room and poor conditions of a wall in the freeze dryer room, even though maintenance is conducted on the freeze dryer every (b)(4) months. An incident report, initiated in November 2009, identifies holes in the ceiling and visible light coming from the roof near the ventilation system, bubbling of the vinyl and disintegration of the wall under vinyl in the freeze dryer room, visible black mold on the wall, a poor drain system for the freeze dryer steam venting system, and a soft (spongy) wall.

c. Operators involved in the filling operations for the sterile drug products manufactured at your facility do not practice adequate aseptic techniques to prevent product contamination. The environmental monitoring performed at the end of the production run consist of sampling the chest and the hand most frequently used (right or left) of the employee's gown. Also, this procedure is performed by the gowned operator and is not monitored by a second qualified person (e.g., supervisor; quality unit personnel) to ensure the proper techniques are being applied. This practice is unacceptable. We expect that all operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper techniques are utilized during all operations, including aseptic filling operations and personnel sampling.

2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, your firm’s microbiology laboratory does not perform species identification on a routine basis of the yeast and molds detected in your production area. There was no identification raw data available for the media fill that failed in November 2009. Additionally, your firm does not perform challenge testing to the sterility media with environmental isolates from the environmental monitoring program.

3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example, at the time of the inspection the validation data for several laboratory methods was incomplete or unavailable (i.e. total viable aerobic count for the API, total viable aerobic plate count of raw materials, and bacterial endotoxin testing for ((b)(4)). However, you approved the validation for these methods without the complete data in place.

For more information click link http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm233036.htm

Kabco pharmaceuticals
 
1. You failed to determine whether specifications are met before use of components as required by 21 CFR 111.75(a). Specifically,
  • You failed to conduct at least one appropriate test or examination to verify identity of a dietary ingredient prior to its use. From the time period between June 25 and October 6, 2009, you did not perform identity testing on any dietary ingredients that you received, and during the time period between October 6, 2009 and May 10, 2010 you only performed identity testing on randomly selected dietary ingredients. Examples of some of the dietary ingredients that you failed to test include, but are not limited to the following: L-carnitine (used to manufacture (b)(4) Tablet Lot (b)(4), valerian root (used to manufacture (b)(4) Capsules Lot (b)(4) and ginkgo biloba leaf extract (used to manufacture (b)(4) Lot (b)(4) ).
  • You failed to qualify suppliers of components (other than dietary ingredients) by establishing the reliability of the suppliers' certificate of analyses through confirmation of the results of their tests or exams, prior to their use. During the time period of June 25, 2009 through May 10, 2010, your firm did not qualify suppliers of any such components by establishing the reliability of the suppliers' certificate of analyses. Examples of some of the suppliers that you failed to qualify include, but are not limited to, the following: (b)(4) (supplier of D-calcium pantothenate), (b)(4) (supplier of Magnesium Stearate), and (b)(4) supplier of L-Selenomethionine).
2. You failed to include in your master manufacturing record (MMR), the following elements required by 21 CFR 111.210:
  • The weight or measure of each dietary ingredient and component used in the production of your (b)(4) Tablet (Lot (b)(4)) and (b)(4) Capsule (Lot (b)(4) ) as required by 21 CFR 111.210(a) and 21 CFR 111.210(c).
  • Procedures for sampling in the MMRs for (b)(4) Tablet (Lot (b)(4)), (b)(4) Capsule (Lot (b)(4)), (b)(4) Tablet (Lot (b)(4)), and (b)(4) Capsule (Lot (b)(4) ), as required by 21 CFR 111.210(h)(2).
3. Your batch production records (BPR) did not include complete information as required by 21 CFR 111.255(b) and 21 CFR 111.260. Specifically,
 
  • Your BPR for (b)(4) Tablets (Lot (b)(4)), (b)(4) Capsules (Lot (b)(4)), (b)(4) Tablet (Lot (b)(4)), and (b)(4) Capsules (Lot (b)(4)) contain numerous omissions and errors such as missing supervisor signatures, use of white out, missing data, incorrect units of measure, and misplacement of decimal points.
  • Also, your batch production records (BPR) did not include documentation at the time of performance that quality control reviewed the BPR for the results of any tests and examinations on the finished batches of dietary supplements and approved and released, or rejected the batches for distribution to comply with 21 CFR 111.260(1)(1)(ii) and 21 CFR 111.260(1)(3). Specifically,
  • Your BPR does not contain documentation at the time of performance that quality control personnel reviewed the results of tests and examinations conducted on finished batches of dietary supplements before releasing the product. For example, the Bill of Lading (No. (b)(4)) for was signed off on for shipment to the customer on 05/06/2010, however, the analytical testing, including the physio-chemical specifications results, were not approved until 05/07/2010.
4. You failed to use effective measures to protect against the inclusion of metals or other foreign material in your dietary supplements as required by 21 CFR 111.365(i). Specifically, on June 21, 2010, our investigators observed the dietary supplement (b)(4) Capsules (Lot (b)(4)) on a conveyor belt packaging line without passing through a metal detector, which is the manner in which your firm chooses to comply with 21 CFR 111.365(i).
 
5. You failed to meet the requirements for holding and distributing under Subpart M of the CGMP [21 CFR 111.453 - 21 CFR 111.475]. Specifically,
 
  • You did not follow written procedures for holding and distributing operations as required by 21 CFR 111.453. For example, on June 21, 2010, our investigators noted that the following components did not have a status label: Spirulina Pacifica (b)(4), Tri Tab Gyean (b)(4), Hydrous Calcium Sulfate (b)(4), and Calcium Citrate (b)(4). Also the component Calcium Ascorbate (b)(4) had the incorrect status label (b)(4) applied to it. According to your SOP 11.16, (b)(4) product such as (b)(4) etc. You did not follow the procedures in this SOP.
  • You failed to hold components, dietary supplements, packaging, and labels under conditions that do not lead to the mix-up, contamination, or deterioration of components, dietary supplements, packaging, and labels as required by 21 CFR 111.455(c). For example, on June 21, 2010 our investigator observed (b)(4) Caps (Batch (b)(4)) identified as (b)(4) but stored with (b)(4) raw materials.
6. You failed to fit each freezer, refrigerator, and other cold storage compartment you use to hold components or dietary supplements with an indicating thermometer, temperature measuring device, or temperature recording device that indicates and records, or allows for recording by hand, the temperature accurately within the compartment as required by 21 CFR 111.27(a)(5)(i). On June 21, 2010, our investigator noted that the refrigerator containing Probiotic (b)(4), Bifidobacterium lnfinitis (b)(4), Bifidobacterium Bifidum (b)(4) , NADH (b)(4), and L. Casei Subsp (b)(4) did not include an indicating thermometer or temperature-measuring device.
 
Choksi Laboratory
 
1. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that tested products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].
For example,
 
      a) The gas chromatographic analysis performed and the data provided to the application    sponsor is not traceable to raw data. The original chromatograms could not be located during the inspection.
 
      b) In-house laboratory procedures for various laboratory tests were either non-existent or inadequate. For example, the entire GC and HPLC test procedures address only a few precautions to be taken in running the instruments. Routine practice consisted of performing test procedures provided by customers, and then destroying these procedures as soon as the analyses were completed.
 
      c) Your firm's standard operating procedure #CLL-PKL-SOP-10, “Maintenance of Integrity of Sample,” is inadequate in that it does not assure complete integrity of documentation related to sample analysis. It specifies the assignment of a “booking number” to each sample, but no further procedures regarding subsequent documentation are included. Certain elements of sample integrity are addressed in other SOPs, but none of the procedures explicitly call for maintaining sample integrity throughout the testing of the sample.
 
      d) Performance of test methods such as loss on drying, residue on ignition, and sulfated ash is not adequately documented. Certain steps such as time in and time out of the oven are not recorded, and the laboratory record does not provide a format for recording such data.

      e) Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use. This has not been done for any method provided by your clients.
 
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].For example,
 
      a) Your firm's out-of-specification (OOS) procedure #CLL-PKL-SOP-01, Ver. #3 is inadequate in that the procedure for invalidation of an OOS result is inappropriate. The procedure does not specify re-analysis of the original sample solution or stock solution before re-sampling of a new portion of the original sample, or using a fresh sample obtained from a client. Additionally, the procedure specifies invalidation of an OOS result if the results of (b)(4) subsequent analyses of a new sample portion or of a fresh sample from the client are within specifications.
 
      b) Documentation is not maintained for every OOS event. Your firm only conducts OOS investigations when the client provides additional payment for such an investigation.
 
3. Your quality control unit has not approved or rejected all procedures or specifications impacting the identity, strength, quality, and purity of the drug product; all procedures applicable to the quality control unit are not in writing, and all procedures are not followed [21 C.F.R. § 211.22]. For example,
 
      a) SOP revisions are not performed and documented appropriately. For example, for SOP #CLL-PKL-SOP-01, the recorded history shows that version 02 was issued on March 10, 2009, version 03 on April 2, 2009, and version 02 again on March 14, 2009.
 
      b) Records are issued from the record storage room without any written checkout procedures, and instead upon verbal direction by the QA manager.
 
      c) The document control SOP lists “quality manager” and “technical manager” under“Responsibility” for document control, but does not clarify the individual roles of each.
 
4. Your firm has not established procedures for investigation of complaints, and for initiation of corrective and preventive actions based on results of such investigations [21 C.F.R. § 211.198]. For example,
 
      a) Five complaints received in 2009 were related to the reporting of incorrect batch numbers. Root cause was attributed to unintelligible handwriting, but no preventive actions were taken.
 
      b) Five complaints received in 2008 were based on incorrect or missing information on the customer analysis reports, but no corrective or preventive actions were taken.
 
 
Advanced Testing Laboratories
 
1. Your firm has failed to establish scientifically sound and appropriate test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. §211.160(b)].
 
2. Your firm has failed to calibrate instruments and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met [21 C.F.R. § 211.160(b)(4)].
 
3. Your firm has failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211. 165(e)].
 
4. Your firm has failed to follow written responsibilities and procedures applicable to the quality control unit [21 C.F.R. § 211.22(d)].
 
5. Your firm has failed to follow and document, at the time of performance, established test procedures and laboratory control mechanisms. Any deviation from the written test procedures and laboratory control mechanisms shall be recorded and justified [21 C.F.R. § 211.160(a)].
 
6. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, nor have you extended investigations to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192]. For more information click link http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm229262.htm
 
 
Absolute packaging
 
1. Your firm has not established or followed written procedures and responsibilities applicable to your quality control unit [21 C.F.R. § 211.22(d)].

2. Your quality control unit has not approved or rejected all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product [21 C.F.R. § 211.22(c)].

3. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].

4. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

5. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. §211.192].

6. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].
 
For more information click the link below.


Sun Pharmaceutical Industries Inc

 
1. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extended investigations to other batches of drug product that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192].
3. Your firm has failed to ensure the responsibilities and procedures applicable to your quality control unit are followed [21 C.F.R. § 211.22(d)].
4. Your firm does not adequately inspect the packaging and labeling facilities immediately before use to assure that all drug products have been removed from the previous operations [21 C.F.R. § 211.130(e)].
5. Your firm has not established and followed written procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps taken to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics [21 C.F.R. § 211.115(a)], nor does your firm perform reprocessing with the review and approval of the quality control unit [21 C.F.R. § 211.115(b)].
 
 
BENEV Company Inc
 
1. Your firm has not thoroughly investigated any unexplained discrepancy or the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example,
 
2. Your film failed to follow procedures for the handling of all written and oral complaints regarding a drug product, including specific complaint information or a reason that an investigation was found not to be necessary. [21 C.F.R. § 211.198].
 
3. Your firm failed to reject any lot of components that did not meet the appropriate written specifications for identity, strength, quality and purity [21 C.F.R. § 211.84(e)].
4. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
 
5. Your firm failed to prepare batch production and control records for each batch of drug product produced that includes an accurate reproduction of the appropriate master production or control record [21 C.F.R. § 211.188(a)] and documentation of weights and measures of components used in the course of processing to demonstrate that each significant step in the manufacture and processing of the batch was accomplished [21 C.F.R. § 211.188(b)(4)]. ,
 
6. Your film does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 C.F.R. § 211.166(a)]. 
 
7. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].
8. Your film has not established written procedures for cleaning and maintenance of equipment [21 C.F.R. § 211.67(b)].

9. You failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform their assigned functions [21 C.F.R. § 211.25(a)].
For example, your "QC/ R&D Chemist" has not been trained to perform specific tasks such as microbial limits testing under USP <61>.
 
AMPAC Fine chemicals
 
1. Failure to properly maintain buildings used in the manufacture of API production in a manner that prevents contamination.
 
2. Failure to ensure documentation of cleaning of major equipment after each batch is processed; and failure to clean non-dedicated equipment between the production of different APIs to prevent cross-contamination.
 
3. Failure to identify and quarantine returned APls.
 
For more information click
 
 
L.Perrigo
 
1. Your firm failed to reject drug products failing to meet established standards or specifications and any other relevant quality control criteria [21 C.F.R. § 211.165(f)].

For example, your firm failed to reject a lot of lbuprofen Tablets 200 mg that was contaminated with metal shavings due to an equipment failure. Although your firm segregated a portion of the lot that was affected, you released and shipped a subportion of that segregated lot, resulting in a recall of the entire lot.

2. Your firm failed to thoroughly investigate the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed and extend investigations to other batches of the same drug product and other drug products that may have been associated with the specific failure [21 C.F.R. § 211.192].

For example, your firm did not thoroughly investigate possible foreign tablet contamination in your filling equipment. After finding a brown, round Ibuprofen tablet in a lot of brown, oval Ibuprofen caplets , you did not inspect the lot of orange, round Ibuprofen tablets .Without extending your investigation to other lot there is no assurance that this lot was not also contaminated.

Your response is inadequate it that it neither provides scientific rationale for excluding a lot from your investigation, nor does it address examination of any remaining product.

3. Your quality control unit (QCD) failed to follow written procedures [21 C.F.R. § 211.22(d)]. 
 
For detailed information click warning letter-L.Perrigo 
 
Teva parenterals medicines, Inc -NEW
 
1) Failure to subject each lot of a component with potential for microbiological    contamination that is objectionable in view of its intended use, to microbiological tests before use [21 CFR 211.84(d)(6)].
 
For example, your firm has not tested each lot of raw materials used in the manufacture of Propofol Injectable Emulsion finished products to determine the presence and levels of bacterial endotoxin
.
2) Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, Whether or not the batch has already been distributed, or to extend the investigation to other batches of the same drug products or other products that may been associated with the same failure or discrepancy [21 CFR 211.192], For example:

A) Your firm's analysis of pooled samples from customer .complaint vials of finished product (Lot#(b)(4)) revealed an endotoxin concentration of (b)(4). Your firm failed to identify a root cause and failed to implement a corrective action.

3) Failure to establish adequate acceptance criteria for the sampling and testing conducted by the quality control unit to assure that batches of drug products meet appropriate statistical quality control criteria as a condition for their approval and release [21 CFR 211.165(d)].

For example, your firm's finished product sampling plan for (b)(4) and (b)(4) in Propofol Injectable Emulsion is not representative of the batch produced. A total of thirteen units are sampled per lot, with three tested for bacterial endotoxin and ten tested for bioburden. This sampling of thirteen units is irrespective of lot size, which may vary from (b)(4) to (b)(4) units (vials) per lot.

4) Failure to test in-process materials for quality and purity as appropriate, at the commencement or completion of significant phases of the production process [21 CFR 21I.110(c)].

For example, your firm has not tested in-process non-sterile bulk solution after the (b)(4) process, as well as, end-of-run samples (b)(4) for the presence of bacterial endotoxin.

5) Failure to test, through appropriate laboratory testing, each batch of drug product required to be free of objectionable microorganisms [21 CFR 211.165(b)].

For example, the bacterial endotoxin test methods used for the final release of Propofol Injectable Emulsion were not adequate to ensure detection of bacterial endotoxin as described below.

A) SOP (b)(4), is deficient because there is no requirement for vortexing the finished product vials of Propofol Injectable Emulsion prior to sample preparation.

B) The pH was not checked by mixing a portion of the sample preparation with (b)(4) first before adjusting the pH of the sample preparation solution. Failure to do this may result in a pH in the sample-(b)(4) combined solution that is outside of the range specified by the reagent manufacturer.
 
C) There is no assurance that the (b)(4) is protected from vibration during testing of bacterial endotoxin via the (b)(4) test method.
 
6) Failure to demonstrate equipment used in the manufacture, processing, packing, or holding of drug products is of appropriate design to facilitate operations for its intended use [21 CFR 211.63]. For example
 
7) Failure to clean and sanitize equipment and utensils at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 CFR 211.67(a)]. For example:

A) You did not demonstrate that the (b)(4) system was adequate to ensure that the microbial bioburden and endotoxin levels of equipment meet predetermined acceptable limits.
 
B) Your corrective actions to remove bacterial endotoxin from the Water for Injection (WFI) ports are to "flush for (b)(4) minutes." Your corrective actions also include using the (b)(4) washer to wash the Reverse Osmosis (RO) ports. However, there is no data to validate that a "flush for (b)(4) minutes" or washing the sampling ports in the (b)(4) washer can remove or reduce the presence of bacterial endotoxin in a water system.
 
C) You stated that the (b)(4) "carrier cart," used to off-load washed and depyrogenated vial stoppers from the (b)(4) wash equipment, is cleaned only with (b)(4).

Your firm does not properly clean and sanitize the (b)(4) "carrier cart" used to off-load washed and depyrogenated vial stoppers from the (b)(4) wash equipment. Your use of (b)(4) to clean the "carrier Cart" is not a proper method for reducing the presence of bacterial endotoxin. Furthermore, you lack any documentation to show that the "cattier cart" is periodically cleaned.

D) Your firm has not performed a fogging validation study to support SOP # (b)(4). This SOP describes fogging procedures for (b)(4) and (b)(4) production areas, (b)(4) vestibule and testing suite, and equipment in the (b)(4) pass-throughs. Additionally, you do not follow the frequency of testing, which is stated in this SOP as being conducted "(b)(4)." Rather, the fogging sanitization is conducted on an "as needed" basis under the direction of the microbiology or filling departments.

8) Failure of the quality control unit to take responsibility to approve and reject all procedures or specifications impacting on the identity, strength, quality, and purity of drug products [21 CFR 211.22(c)]. For example:

Your firm has not submitted a Post Approval Change or a Change Being Effected-30 (CBE-30) for ANDA (b)(4) that addresses (b)(4), nor have you provided the scientific rationale for the (b)(4) impact this may have on the "Sterility Assurance Validation" of the finished product.

9) Failure to define the responsibilities and procedures applicable to the quality control unit in writing [21 CFR 211.22(d)].

There is no written procedure to describe the review and approval of work orders performed for routine, on-demand maintenance, and repair of production equipment by the quality control unit (QCD). For example, the (b)(4) was repaired for batch (b)(4), without QCD review. In another example, a work order was issued for an alarm sounding on the (b)(4), related to production lot# (b)(4). There was no notation made in the production batch record to indicate that an alarm occurred during the (b)(4). Since neither event was reviewed, the QCD may not be aware of the problems or issues related to production equipment.

10) Failure to implement systems for maintaining equipment used to control aseptic conditions in aseptic processing areas [21 CFR 211.42(c)(10)(vi)].

For example, your firm has not adequately investigated the root cause for three (b)(4) filter failures located in Room (b)(4).

11) Failure to maintain records for the cleaning and sanitizing of equipment [21 CFR 211.67(c)]. For example:
 
A) Your firm has failed to maintain records to document that the manufacturing areas and production equipment are exposed to sanitization solutions for the contact time of (b)(4) minutes. This requirement is described in the procedure entitled (b)(4)
 
B) There is no record to document that the (b)(4) "stock pot" is periodically cleaned and sanitized prior to use. This "stock pot" is used to manually transfer approximately (b)(4) of bulk solution from the bottom of the (b)(4) mixing jacketed vessel to the top of the tank following the (b)(4) Process.

12) Failure to maintain an adequate system for monitoring environmental conditions of the aseptic processing areas [21 CFR 211.42(c)(10)(iv)].

For example, your firm's SOP for monitoring surface adhering microorganisms, air particle counts, and the microbiological monitoring of air in (b)(4) are deficient. Specifically, you do not require Environmental Monitoring (EM) sampling for (b)(4) areas such as the (b)(4) Room (b)(4) and the (b)(4) Room (b)(4) during manufacturing operations.

13) Failure to establish written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)].

For example, your SOP (b)(4) does not address environmental monitoring of personnel working in the (b)(4) Room (b)(4). In general, you do not require or document the sampling of the gloves and gowns of personnel working in (b)(4) areas.
 
For more information click
 


Hospira Inc - NEW

1.Your firm has failed to ensure the responsibilities and procedures applicable to your quality control unit are in writing and are followed [21 C.F.R. § 211.22(d)].

 
2.Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extend investigations to other batches of drug product that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192].

3.Your firm has not established acceptance criteria for the sampling and testing conducted by the quality control unit to assure that the batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release [21 C.F.R. § 211.165(d)].
 
For more information
Pfizer - Sponser -NEW
 
1. You failed to ensure proper monitoring of the investigation [21 CFR 312.50].
 
2. You failed to ensure that the investigations were conducted in accordance with the general investigational plan and protocols contained in the IND [21 CFR 312.50].
 
For more information

APOTEX Inc, Canada - NEW
 
1. Your firm’s quality control unit failed to follow the responsibilities and procedures applicable to release of the drug product [21 C.F.R. § 211.22(d)].
 
2. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
 
3. Your firm fails to thoroughly investigate unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 C.F.R. § 211.192].
 
4. Your firm fails to have an adequate equipment cleaning and maintenance procedure or program to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond other established requirements [21 C.F.R. § 211.67(a)].
 
FIELD ALERT REPORTING VIOLATIONS
 
Field Alert Reports must be submitted for confirmed and unconfirmed problems meeting the definition of the regulation within three working days of becoming aware of the problem.
 
For detailed information click link below

 
Balchem Corporation
 
1. Your firm failed to reject in-process materials required to be tested as appropriate, and approved or rejected by the quality unit [21 CFR 211.110(c)]. In addition, your firm has not established written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile [21 CFR 211.113(a)].
 
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that in-process materials conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)].

Xian Libang Pharmaceuticals co. Ltd
 
1. Failure of your quality unit to ensure that materials are appropriately tested and the results are reported
 
For example, your firm used the infrared spectra for the raw material (b)(4), lot # Y584-090301, tested on March 5, 2009, to support the release of two subsequent incoming lots of (b)(4) # Y584-090401 and # Y584-090701.
 
2. Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.
 
For example, your quality control unit failed to detect that IR spectra were being substituted by a laboratory employee and therefore, misrepresenting the actual results of the tested incoming material. Your response is inadequate in that it does not address the ability of your quality unit to control and detect the manipulation or alteration of laboratory documents.
 
3. Failure to have adequate controls to prevent manipulation of raw data during routine analytical testing.

 
For example, your firm's laboratory analyst had modified printed raw data related to the IR Spectra test of (b)(4) and (b)(4). We are concerned that the lack of security or system controls allows for this practice.
 
For more information please go through link below 
 

Centaur, Inc
 
1. Failure to make written records of investigations into unexplained discrepancies as required by 21 C.F.R. 211.192. For example, a specific gravity analysis for isopropyl alcohol did not meet specifications. There was, however, no documented record regarding this failure to meet specifications. There was also no written record of any related investigation, including documentation of conclusions and follow-up, as required by 21 C.F.R 211.192.
 
2. Failure to provide and/or document education, training, and experience, or any combination thereof, to enable employees to perform their assigned functions as required by 21 C.F.R. 211.25(a). For example your firm failed to provide documentation establishing that your lab analyst, who performs QC laboratory analyses, including microbial tests, was trained and qualified to perform laboratory tests. Your standard operating procedure, SOP #(b)(4) Employee Training, states that a (b)(4)." No such log was available to establish that your lab analyst was adequately trained in accordance with this procedure.
 
3. Failure to include the initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards as required by 21 C.F.R 211.194(a)(8). Copies of testing records from your laboratory notebook were collected of 3 different product lots to show examples of original records without required initials or signature of a second person.
 
4. Failure to follow written procedures applicable to the quality control unit, as required by 21 C.F.R. 211.22(d). For example, there are documented instances of failure to follow SOP #(b)(4) Oven Temperature Mapping; SOP #(b)(4), USP Purified Water System; SOP #(b)(4), Sampling and Testing; SOP #(b)(4), Employee Training; and SOP #(b)(4) version #(b)(4), Investigation.
 
5. Failure to identify and control rejected in-process materials under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable as required by 21 C.F.R. 211.110(d). For example, three expired laboratory reagents were in use during the inspection.
 
6. Failure to provide adequate equipment for the control of humidity and temperature when appropriate for the manufacture, processing, packing or holding of a drug product as required by 21 C.F.R. 211.46(b). For example, your warehouse used for storage of raw materials, containers, and finished goods has no equipment to control temperature and humidity. This is especially critical considering that several of your drug products are labeled to be stored in controlled temperature ranges. These include (b)(4)%, (b)(4), (b)(4)%, (b)(4)%, and (b)(4)- all of which are labeled with instructions to store between (b)(4) and (b)(4) degrees Fahrenheit. (b)(4)%, (b)(4)%, and (b)(4)% are all labeled with instructions to store between (b)(4) and (b)(4) degrees Fahrenheit
 
For more information go through the link below

Sunrise Pharmaceuticals, Inc

1. Your firm has not established laboratory control mechanisms, including any change, and has failed to document quality control unit review and approval at the time of performance [21 CFR 211.160(a)]. For example,

a. Out-of-specification (OOS) humidity levels for the controlled room temperature stability chamber were noted on January 27, March 17, and April 5 and 6, 2009. Investigations and corrective actions were not conducted at the time to address these out-of-specification results. During the inspection, however, the Quality Unit presented back-dated service requests to investigators as evidence of proper OOS result handling when in fact, no actual service requests were initiated.

b. Investigation report #05072009 dated May 7, 2009, was initiated following a power failure during the coating of Senna & Docusate Sodium Film Coated Tablets, 8.6mg/50mg, lot 0904004. According to the report, the lot was inspected for peeled film tablets during May 8-26, 2009; however, the corrective actions and disposition of drug product were approved by the Quality Unit on May 7, 2009.
 
2. Your firm has not established an adequate written testing program designed to assess the stability characteristics of your drug products in determining appropriate storage conditions and expiration dates since your program does not include reliable, meaningful, and specific test methods [21 CFR 211.166(a)(3)].

Specifically, some of your firm's analytical methods have not been validated to demonstrate that they are stability indicating. In other instances, test methods that you claim to be stability indicating are inadequate or not followed by your firm. For example,

a. A stability indicating test method has not been developed and validated for Senna & Docusate Sodium tablets.

b. Stability indicating test methods are developed, but not validated, for Guaifenesin and Dextromethorphan HBr Tablets, and impurity specifications have not been established for the finished product release or stability samples. as required by 21 CFR 211.160(b).

c. Validated stability indicating test methods are established, but are not followed, to analyze impurity levels for Phenazopyradine HCI Tablets, Bisacodyl Tablets, and (b)(4). Further, impurity specifications have not been established for any of the aforementioned finished product release testing or stability samples as required by 21 CFR 211.160(b).
 
For more information go through link below
 
 
 
Its a free flow of knowledge sharing. Share your comments, query, answer and thoughts.