Data Integrity v praxi FDA - Konference seminare. cz · 3. 21 FR î í. šetření nesrovnalostí a závad v ... audit trail linked to the HPLC instrument. ... the gas chromatograph

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Data Integrity v praxi FDA

CONFORUM

Data integrity ve farmacii

25.05.2017

Vítězslav Kment

Obsah

• Data integrity v praxi MHRA

• Jak v současnosti také mohou probíhat inspekce FDA

• Nedostatky při inspekcích (483)

• Následné akce po inspekci v případě nedostatků uvedených ve formuláři 483

• „smolné knihy“ aneb odstrašující příklady z Warning Letters

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MHRA 2016 top 10

MHRA – data integrity

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HPRA Irsko DI - I

HPRA Irsko DI - II

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HPRA Irsko DI - III

HPRA Irsko DI - IV

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Nejčastější nedostatky FDA 2014

1. 21 CFR 211.22(d) odpovědnosti a postupy jednotky jakosti nejsou stanoveny/dodržovány

2. 21 CFR 211.160(b) laboratorní kontrolní postupy – nedostatečná „vědecká“ úroveň

3. 21 CFR 211.192 šetření nesrovnalostí a závad v záznamech BMR, QC

4. 21 CFR 211.100(a) chybějící písemné postupy pro kontroly ve výrobě a QC

33. 21 CFR 211.68(b) počítačové systémy nejsou pod kontrolou zajišťující pouze autorizované změny v BMR a záznamech o zkoušení

Nejčastější nedostatky FDA 2015

1. 21 CFR 211.22(d) odpovědnosti a postupy jednotky jakosti nejsou stanoveny/dodržovány



4. 21 CFR 211.113(b) písemné postupy pro prevenci mikrobiální kontaminace sterilních léčivých přípravků nejsou ustanoveny nebo dodržovány


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Nejčastější nedostatky FDA 2016 1. 21 CFR 211.22(d) odpovědnosti a postupy jednotky

jakosti nejsou stanoveny/dodržovány



4. 21 CFR 211.100(a) chybějící písemné postupy pro kontroly ve výrobě a QC


FDA 483 pro bioanalytiku

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Warning Letter APR/2017

Your firm limited FDA’s inspection.

FDA entered your facility on October 18, 2016. Your firm’s actions during this inspection significantly hindered FDA from fully assessing your compliance with CGMP. For example, doors to the (b)(4) vessel room and packaging and labeling storage areas were locked, impeding reasonable access for the investigator to these areas, and limiting this inspection.

Warning Letter DEC/2016

Your firm failed to establish written responsibilities and procedures applicable to the quality control unit. (21 CFR 211.22(d))

For example, during the inspection we found that you lacked critical procedures to ensure that you have a functional quality unit, including procedures for review of out-of-specification results, complaint handling, and change control.

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Warning Letter AUG/2016

Your firm 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 CFR 211.22(a)). Additionally, your quality unit approved certificates of analysis (COA) for (b)(4) and (b)(4) API, as well as finished products, prior to conducting all quality control and release testing. Your production manager falsified the documents by signing and dating the “Prepared By” and “Checked By” sections of the COA. Furthermore, your quality unit failed to identify data integrity issues in 11 batch production records reviewed by our investigator. Your production manager admitted that he falsified the signatures of other employees in the “Prepared By,” “Reviewed By,” “Approved By,” and “Authorized By” sections.

Warning Letter OCT/2016

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.

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Your firm failed to thoroughly investigate any unexplained discrepancy or 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 CFR 211.192) You did not adequately investigate media fill and sterility test failures. These failures indicate that there is a lack of adequate sterility assurance in your manufacturing facility. a. Media Fills You did not adequately investigate media fill contamination in your aseptic manufacturing lines. For example, media fill run (b)(4), performed September 14-16, 2015, in the closed Restricted Access Barrier System (RABS) small volume parenteral line in (b)(4), yielded 31 contaminated units. In addition, media fills for other filling lines at your facility yielded one or more contaminants.

Warning Letter MAY/2017

Your firm failed to establish 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 CFR 211.100(a)).

You have not specified or validated manufacturing processes to ensure reproducible batch quality. For example, your procedures for filling and hold times do not include defined process parameters such as mixing times, blending speeds, and bulk hold times. In addition, our investigator noted that you use a household kitchen blender to mix ingredients

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Odstraňování nedostatků

• Pro FDA do 15 dnů

• Detailní popis CA případně PA

• U závad jako je data integrity a některé další provést retrospektivní analýzu do jaké míry mohlo dojít k ovlivnění jakosti, účinnosti a bezpečnosti – poslat detailní podklady – může a nemusí pomoci

Warning Letter JAN/2015

During the inspection, your management admitted that employees in both of your Quality Control (QC) laboratories had frequently conducted unauthorized “trial” High Performance Liquid Chromatography (HPLC) injections prior to additional injections that were used in the reported test results. Although your management stated that this practice ended in February 2014, FDA investigators discovered evidence that this practice continues. The inspection found that the names assigned to each sequenced injection were often changed during testing, obscuring the traceability of repeated injections. The data from “trial” injections was not reviewed or considered in determining batch quality. For example,

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For the related substances analysis of (b)(4) USP (b)(4) mg Tablets batch (b)(4) conducted on February 25, 2013, there were three sample injections of vial 1_8, all named “TEST,” which were run prior to the reported sample injections. The “TEST” injection data was stored in the “Trial” folder located on a personal computer (PC) with no

audit trail linked to the HPLC instrument.

The trial sample injections were not reviewed and evaluated by your firm when making batch release decisions.


HPLC sequence GSTA130522-DS showed (b)(4) single injections, in addition to the sequenced injections, during dissolution testing of (b)(4) Tablets ((b)(4) drug product) submission stability batch (b)(4). Two of the extra single injections were from vial 15, labeled as “STD,” indicating that the lab may have injected standard solution and not the test sample solution. Notably, the vial 15 contents were then injected a third time and used as the “Sample 6” test result.

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Your firm failed to record and justify any deviations from required laboratory control mechanisms (21 CFR 211.160(a)).

According to your management, a new standard operating procedure (SOP) was approved in February 2014, in order to eliminate your “trial” sample injection practices. However, during our inspection, we observed that your analysts continued these “trial” injection practices after the approval of your new SOP, and that your quality system and your management failed to detect and correct these deviations from the new procedure (see, e.g., Example 1(a)(5) above).

Warning Letter JAN/2015 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)).

QC personnel created unauthorized folders on laboratory computerized systems without appropriate oversight. Our review of the HPLC Empower III data collected in 2013-2014 in the commercial QC laboratory found a data folder entitled “WASH.” According to your management, the folder was intended for column wash injections using blank solvent prior to and following sample runs, although you have no standard operating procedure (SOP) detailing this process. One of your laboratory analysts stated that this folder does not contain any standard or sample injection results. However, our investigator found that this folder contained a total of 3,353 injection results, some of which appeared to be samples.

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On June 23, 2014, during the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples.

For example: Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this

batch were observed in any of the incubation chambers.

Warning Letter FEB/2015

Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

Your HPLC computer software lacked active audit trail functions to record changes to analytical methods, including information on original methodology, the identity of the person making the change, and the date of the change. In addition, your laboratory systems did not have access controls to prevent deletion or alteration of raw data. During the inspection, your analysts demonstrated that they were given inappropriate user permissions to delete HPLC data files.

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Warning Letter FEB/2015

• Moreover, the gas chromatograph (GC) computer software lacked password protection allowing uncontrolled full access to all employees.

Warning Letter APR/2015

Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

You lacked controls to prevent the unauthorized manipulation of your laboratory's electronic raw data. Specifically, your infrared (IR) spectrometer did not have access controls to prevent deletion or alteration of raw data. Furthermore, the computer software for this equipment lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change. Audit trails that capture such critical data about the quality of your batch production should be reviewed as part of the batch review and release process.

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Our inspection noted that your firm did not retain complete raw data from testing performed to assure the quality of (b)(4), API. Specifically, our inspection revealed your firm did not properly maintain a back-up of HPLC chromatograms that form the basis of your product release decisions. Our inspection revealed discrepancies between the printed chromatograms and the operational qualification protocol for the High Performance Liquid Chromatography (HPLC) system, which is intended to demonstrate correct operation of the HPLC. These discrepancies included injection sequences and values to calculate relative standard deviation (RSD).


While investigating these discrepancies, our investigator requested the original electronic raw data. Your quality unit, after consulting with the Information Technology (IT) department, stated they were unable to retrieve the original electronic raw data because back-up discs were unreadable. Your quality unit then stated that back-up disks have been unreadable since at least 2013. Your HPLC system is used to test (b)(4), API for batch release. However, without complete, accurate, reliable, or retrievable raw data about the HPLC system’s qualification, you lacked complete assurance that the system was operating as intended.

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Warning Letter JUL/2015

There is no assurance that you maintain complete electronic raw data for your Gas Chromatography (GC) instrument. FDA investigators observed multiple copies of raw data files in the recycle bin connected to the GC instrument QC-04 even in the presence of “Do Not Delete Any Data” notes posted on two laboratory workstation computer monitors.


Additionally, our investigators found backdated batch production records dated February 10 to February 25, 2014, signed by your Production Manager and Technical Director in the “Batch Manufacturing Record Reviewed [sic] by” section. Employees responsible for supervising or checking significant steps in manufacturing operations must do so and appropriately document their review of critical steps (for example, records must not be backdated and signatures must be authentic).

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Warning Letter SEP/2015

During the inspection, we noted that you had no unique usernames, passwords, or user access levels for analysts on multiple laboratory systems. All laboratory employees were granted full privileges to the computer systems. They could delete or alter chromatograms, methods, integration parameters, and data acquisition date and time stamps. You used data generated by these unprotected and uncontrolled systems to evaluate API quality.

Multiple instruments had no audit trail functions to record data changes.

Warning Letter SEP/2015

During the inspection, the investigator found no procedures for manual integration or review of electronic and printed analytical data for (b)(4) stability samples. Electronic integration parameters were not saved or recorded manually. When the next samples were analyzed, the previous parameters were overwritten during the subsequent analyses.

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You also failed to have proper controls in place to prevent unauthorized manipulation of your laboratory’s raw electronic data. Our inspection revealed your HPLC system did not have access controls to prevent alteration or deletion of data. Your HPLC software lacked an audit trail recording any changes to the data, including: previous entries, who made changes, and when changes were made. During the inspection, we also noted that all laboratory employees shared a common log-in and password to access the system.

Warning Letter NOV/2015

Your employees did not complete batch production and control records immediately after activities were performed. When QA reviewers noticed missing entries in the batch records, they made a list of all the missing items on separate, uncontrolled pieces of paper that were provided to the production manager. Data were later entered into CGMP documents after operations had already ended as though they had been entered at the time of the operation.

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Warning Letter DEC/2015

Your firm failed to adequately control the use of computerized systems in the quality control laboratory. Our inspection team found that the laboratory manager had the ability to delete data from the Karl Fischer Tiamo software. During our limited review of your Karl Fischer data, we found that one file had been deleted. However, because the audit trail function for the Karl Fischer Tiamo software was not activated, and because eight different analysts share a single username and password, you were unable to demonstrate who performed each operation on this instrument system. You do not have a record of the acquisition of all data, nor do you have records of changes to or modifications of such data.


Our investigator also noted that your firm copied raw data to a CD (b)(4), and then deleted the data from the (b)(4) system to free space on the hard drive. Files copied to the CD were selected manually; the selection process was not supervised. Without audit trail capabilities or supervised file selection, there was no assurance that all raw data files were copied to the CD before they were permanently deleted from the system.

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Additionally, our investigators found backdated batch production records dated February 10 to February 25, 2014, signed by your Production Manager and Technical Director in the “Batch Manufacturing Record Reviewed [sic] by” section. Employees responsible for supervising or checking significant steps in manufacturing operations must do so and appropriately document their review of critical steps (for example, records must not be backdated and signatures must be authentic).


For the related substances analysis of (b)(4) USP (b)(4) mg Tablets batch (b)(4) conducted on February 25, 2013, there were three sample injections of vial 1_8, all named “TEST,” which were run prior to the reported sample injections. The “TEST” injection data was stored in the “Trial” folder located on a personal computer (PC) with no

audit trail linked to the HPLC instrument.

The trial sample injections were not reviewed and evaluated by your firm when making batch release decisions.

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Failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent manipulation and omission of data.

During the inspection, we reviewed an audit trail from your Empower-2 system that stored 8,906 entries. Of these, well over half indicated some form of data deletion or manipulation, including at least 1,441 instances of deleted results, at least 3,643 instances of manual integration, and at least 194 instances of altered running sample sets. Your personnel confirmed that these actions are common during chromatographic data processing. We found that you did not have a procedure in place to indicate the requirements and level of restrictions for users of the automated system


There is no assurance that you maintain complete electronic raw data for your Gas Chromatography (GC) instrument. FDA investigators observed multiple copies of raw data files in the recycle bin connected to the GC instrument QC-04 even in the presence of “Do Not Delete Any Data” notes posted on two laboratory workstation computer monitors.

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FDA – CAPA I

FDA strongly recommends that if you decide to resume production of sterile drugs, your management immediately first undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, maintenance materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug processing expertise should assist you in conducting this comprehensive evaluation.

FDA – CAPA II

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:

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FDA – CAPA III

• 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.

FDA – CAPA IV

• 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.

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FDA – CAPA V

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.

FDA – CAPA VI 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.

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Data Integrity v praxi FDA - Konference seminare. cz · 3. 21 FR î í. šetření nesrovnalostí a závad v ... audit trail linked to the HPLC instrument. ... the gas chromatograph