Failure to validate and monitor the water purification system to ensure that water is of appropriate quality and suitable for its intended use ?

During FDA inspection, investigators observed specific deviations including, but not limited to, the following.

1.    Failure to validate and monitor the water purification system to ensure that water is of appropriate quality and suitable for its intended use.

During the inspection, our investigators found that your water purification system was not adequately monitored and controlled. Because you use water as a drug component and for cleaning your facility and equipment, these failures pose significant risk to the safety of your drugs.

Source water

You failed to test the source water for your (b)(4) water system. The source water emanates from a nearby river and passes through farmland, where it is subject to agricultural runoff and animal waste, before reaching your facility. Your firm stores the source water in an (b)(4) tank that has a large (b)(4)-facing hole that is open to the environment. Your storage method does not protect your water from dirt and other contaminants, or from the ingress and proliferation of pests and objectionable organisms.

Sanitization and validation

You did not follow your own sanitization procedures for your (b)(4) water system. Your procedures specify (b)(4) of sanitization at (b)(4), yet our investigators identified instances where you sanitized for as little as 10 minutes without justification.   

During the inspection, you stated that in March 2016 you initiated, but have not yet completed, a performance qualification of the (b)(4) water system. Your firm has used this unqualified system routinely since its installation in 2014, despite having no scientific evidence that the system is capable of producing water of adequate quality.

Testing

Our investigators found that you were aware that the total aerobic microbial counts (TAMC) for all in-process water samples (b)(4) had exceeded your limit of (b)(4) colony forming units (cfu)/mL for multiple months. You failed to investigate these deviations.

Furthermore, your firm did not demonstrate an adequate understanding of the process that your (b)(4) water system relies on to kill microorganisms. (b)(4) is typically (b)(4) sanitization steps. However, you only use (b)(4) to reduce TAMC to acceptable levels in the (b)(4) water. This suggests that it is a critical step in your process, but you did not consider operating parameters that affect performance, such as water flow rate, (b)(4), water (b)(4), and (b)(4) age. Additionally, your interpretation of your results is confounded by the fact that your methods are not verified.

In your response, you committed to testing your source water for microbiological contamination. You indicated that you set microbial limits of (b)(4) cfu/mL for the source water, and that you removed the microbial limits for the in-process samples of your (b)(4) water system. 

Your response is inadequate. You failed to provide sufficient detail about how you will remediate your (b)(4) water system. In response to this letter, provide:

·         a plan to address the open (b)(4) source-water storage tank

·         a status update of the performance qualification that you initiated in March 2016

·         corrective and preventive actions if source water test results exceed the limits

·         scientific rationale for setting microbial limits

Contaminated (b)(4) water has been the root cause of multiple recalls by other drug manufacturers of non-sterile (b)(4) liquids, including instances of adulteration with Burkholderia cepacia, an opportunistic pathogen. Therefore, it is imperative that appropriate action and alert limits be established based on validation data; these limits must be low enough to signal significant changes from normal operating conditions.

2.    Failure of your quality unit to prepare, review, and approve documents related to the manufacturing of API.

On August 16, 2016, our investigators found a large number of trash bags behind a building on your property. The trash bags contained torn original laboratory and production records, such as analytical test reports, (b)(4) water testing reports, and sample notebooks. The information on these discarded, torn documents did not match the official records. Your quality unit did not investigate these discrepancies. On August 18, 2016, when our investigators revisited the area where the trash bags had been, they found that the documents had been removed from the site. These findings indicate that your quality unit is not exercising its responsibilities. 

           

In your response, you admitted that a “gap exist[ed] in the Quality Assurance department” concerning document control. You stated that you implemented enhanced document controls and trained employees to complete records contemporaneously.

However, your response is inadequate because you did not provide any details of your corrective and preventive actions. You also did not address any changes made to ensure that discrepancies are properly investigated. Furthermore, removal of the trash bags containing additional torn documents prevented our investigators from examining these documents. It also prevented your firm from performing a global reconciliation of all torn documents with their official versions.

In response to this letter, provide:

·         details and a summary of the system that you established for reviewing CGMP documents to ensure documents are tracked and disposed of properly

·         your procedure for handling discrepancies and ensuring ongoing quality unit oversight 

·          

3.    Failure to verify the suitability of analytical methods.

You failed to ensure that the methods used by your contract testing laboratory, (b)(4), have been verified as suitable for their intended use. It is your responsibility to use a qualified contract testing laboratory that produces accurate and reliable results.

Your firm contracts with (b)(4) for release testing. Your quality assurance agreement with (b)(4) does not specify method validation responsibilities. During the inspection, our investigators requested the method verifications for the residual solvent, impurity, and microbiological tests performed by (b)(4). You stated that the requested documents were located at (b)(4) and that you would retrieve them within 15 days.  

In your response, you did not provide the requested documents from (b)(4), but instead provided draft protocols for the residual solvent, impurity, and microbiological testing. You stated that these protocols would be verified by December 15, 2016, but it is unclear which company would perform the verification experiments. 

Your response is inadequate. In response to this letter, clarify which company performed the verification. Also, provide the results of an internal review of all the other test methods for your drugs to determine the need for method verification or method validation, as appropriate. If verification or validation is needed, provide a timeline for completion and the company that will perform the verification or validation.

4.    Failure to adequately investigate critical deviations.

(b)(4) sent you impurity testing chromatograms that contained unexplained discrepancies in run times as well as aborted runs and reprocessing of data for at least six batches over at least three months. You did not document or investigate these discrepancies.  

In your response, you stated that your firm “did not have expertise to interpret, review the outcome of the HPLC chromatograms as to the standards of regulatory agencies.” You proposed having (b)(4) retest the six batches in the presence of an “expert representative” from Badrivishal to ensure “good chromatographic practices.” Moreover, your quality assurance agreement with (b)(4) does not specify communication of out-of-specification results or discrepancies. 

Your response is inadequate because it lacks details. In response to this letter, describe the corrective and preventive actions you have taken, such as on-site audits and method validations or verifications, that show (b)(4) is now qualified to test your drugs. Also, provide proof that your “expert representative” has sufficient education, training, and experience to perform the indicated function. In addition, provide details about your proposed “outside laboratory data review unit” and laboratory review training content to show they can achieve their intended quality control unit oversight purpose. 

Source: FDA

Warning letter issued to: Badrivishal Chemicals & Pharmaceuticals

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