Comprehensive Data Manipulation: New FDA Warning Letter for European Medicinal Product Manufacturer

Comprehensive Data Manipulation: New FDA Warning Letter for European Medicinal Product Manufacturer

During its inspections, the FDA has been observing insufficient data integrity quite often in the Far East. Now, European production sites are not always exemplary. A Warning Letter recently published for the Czech Company Interpharm Praha describes considerable deficiencies in the area of quality control with regard to API and finished products testing.

Basically, the personnel of the analytical laboratory had full access to the data processing of the HPLC- system. Accordingly, the possibility to delete data, to integrate peak areas "by hand" and to eliminate or add samples from sequences was used extensively. 

These manipulations were visibly clear in the audit trail: among the round 9,000 entries, more than 5,000 actions were traced as data deletion, manual integration of peaks, etc. At the FDA inspectors' request, the employees of the laboratory indicated that such actions are common.

One of the reasons why data had been beautified in such a way is also due to the fact the chromatographic system was not able to execute correct integration of peak areas. The FDA inspector identified partly incomplete or missing integrations of peaks and concluded that the system was wholly inadequate for the purpose. Batch release decisions were thus based on incomplete data, which is a grave GMP-deficiency.

At the end of the Warning Letter, a list of measures is included for the company to fulfil if it still wants to distribute its products on the US American market.

Click here to FDA Warning Letter

Finished Product Violations

1.    Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records or other records (21 CFR 211.68(b)).

For example, our investigator reviewed an audit trail for impurities testing conducted on (b)(4) validation lot (b)(4), number (b)(4) vial # (b)(4), Injections 1 and 2. The audit trail revealed many deleted results and manual integrations.

As discussed above, deleted and altered analytical test results mean that your quality unit is presented with incomplete and inaccurate information about the quality of your drugs.

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 components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Your laboratory procedures allowed analysts to modify and delete chromatographic results without adequate justification, and to use manual integration in uncontrolled circumstances.

For example, our investigator found results deleted after repeated manual integrations for (b)(4) stability lots (b)(4). Unjustified, repeated manual integrations and deletions indicate that your laboratory controls are not scientifically sound and appropriate to test your products.

In your response to this letter, describe all steps you will take to ensure that appropriate laboratory controls have been implemented to support product quality review and batch release decisions. Include the controls you will implement for the modification, deletion, and manual integration of chromatographic test results.   

Click here to FDA Warning Letter

     

Data Integrity Remediation

Your quality system does not adequately ensure the adequacy and integrity of data to support the safety, effectiveness, and quality of drugs you manufacture. We strongly recommend that you retain a qualified consultant to assist in your remediation.

In response to this letter, provide the following.

A.  A comprehensive investigation into the extent of the inaccuracies in data, records, and reporting. Your investigation should include:

·         A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and justification for any part of your operation that you propose to exclude.

·         Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.

·         An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility's operations in which you discovered data integrity lapses.

·         A comprehensive retrospective evaluation of the nature of your data integrity deficiencies.

·         We recommend that a qualified third party with specific expertise in the area where potential lapses were identified should evaluate all data integrity lapses.

B.  A current risk assessment of the potential effect of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse in data integrity, and risks posed by ongoing operations.

C.  A management strategy that includes the details of your global corrective action and preventive action plan. Your strategy should include:

·         The detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to the FDA.

·         A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.

·         Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.

·         Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your data.

·         A status report for any of the above activities already underway or completed.

For further details please see the FDA's Warning Letter issued to Interpharm Praha.

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