Published on February 6, 2014
Data Integrity firstname.lastname@example.org
- Definition - Criteria for integrity of laboratory data - GMP Regulatory Requirements - Barriers to Complete Data - Possible data integrity problems - Warning Letters - Conclusion Contents email@example.com
Definition of Data Integrity • Integrity as being the quality or condition of being whole or undivided; completeness. • In the context of laboratory data integrity within a GMP environment, this can be defined as… “generating, transforming, maintaining and assuring the accuracy, completeness and consistency of data over its entire life cycle in compliance with applicable regulations.”
Criteria for integrity of laboratory data • Attributable — who acquired the data or performed an action and when? • Legible — can you read the data and any laboratory notebook entries? • Contemporaneous — documented at the time of the activity • Original — written printout or observation or a certified copy thereof • Accurate — no errors or editing without documented amendments • Complete — all data including any repeat or reanalysis performed on the sample • Consistent — all elements of the analysis, such as the sequence of events, follow on and are dated or time stamped in expected sequence • Enduring — not recorded on the back of envelopes, cigarette packets, Post-it notes or the sleeves of a laboratory coat, but in laboratory note books and / or electronic media in the CDS or LIMS • Available — for review and audit or inspection over the lifetime of the record Analytical scientists need to understand these criteria and apply them in their respective analytical methods.
GMP Regulatory Requirements for Data Integrity Derived from the laboratory data integrity definition and the applicable 21 CFR 211 GMP regulations there are some of the following points: • Instruments must be qualified and fit for purpose [§211.160(b), §211.63] • Software must be validated [§211.63] • Any calculations used must be verified [§211.68(b)] • Data generated in an analysis must be backed up [§211.68(b)] • Reagents and reference solutions are prepared correctly with appropriate records [§211.194(c)] • Methods used must be documented and approved [§211.160(a)] • Methods must be verified under actual conditions of use [§211.194(a)(2)] • Data generated and transformed must meet the criterion of scientific soundness [§211.160(a)] • Test data must be accurate and complete and follow procedures [§211.194(a)] • Data and the reportable value must be checked by a second individual to ensure accuracy, completeness and conformance with procedures [§211.194(a)(8)]
Barriers to Complete Data However, data integrity and the lack of complete data over the record retention period can be compromised in a number of ways, such as: • Human errors when data is entered by mistake (an uncorrected fat finger moment), stupidity (not being aware of regulatory requirements or poor training) or willfully (falsification or fraud with the intent to deceive) • Selection of good or passing results to the exclusion of those that are poor or failing • Unauthorized changes to data made post-acquisition • Errors that occur when data is transmitted from one computer to another • Changes to data through software bugs or malware of which the user is not aware • Hardware malfunctions, such as disk crashes • Changes in technology, where one item is replaced when it becomes obsolete or no longer supported, making old records unreadable or inaccessible.
Possible data integrity problems According to the FDA, the following are possible data integrity problems in the laboratory that have been observed in the past: • Alteration of raw, original data and records (e.g., the use of correction fluid) • Multiple analyses of assay with the same sample without adequate justification • Manipulation of a poorly defined analytical procedure and associated data analysis in order to obtain passing results • Backdating stability test results to meet the required commitments • Creating acceptable test results without performing the test • Using test results from previous batches to substitute testing for another batch
Warning Letters - 2013 firstname.lastname@example.org
Failure to record all quality activities at the time they are performed. a. On October 26, 2012, the investigator noticed that during an inspection of the packaging area for (b)(4) #(b)(4) a production employee had recorded the final packed quantity of the batch in Step (b)(4), even though the quantity was not yet known because the operator had not yet weighed the batch. Immediately after observing the incident, the investigator requested a copy of page 6 of the batch record containing Step (b)(4) and was given a photocopy. A full batch record provided later that day did not include the original page 6. Instead it included a new version of page 6. b. The investigator observed at least two examples when a manufacturing step was recorded in the batch record before it occurred: i. The production operator had already recorded the start time for step (b)(4) for (b)(4) #(b)(4) as 12:15 PM on October 26, 2012, although it was still 11:00 AM when our investigator noticed this situation. ii. For the (b)(4) # (b)(4), at approximately 11:00 AM on the same date, a production officer had already recorded (b)(4) of (b)(4) used for (b)(4) the API (b)(4) in the (b)(4) at step (b)(4) in the batch production record, although the (b)(4) step had not yet occurred. The (b)(4) had not been pre-weighed or otherwise measured out in advance. Reference : WL: 320-13-22 / Aarti Drugs Limited 7/30/13
Failure to record all quality activities at the time they are performed. c. On October 27, 2012, our investigator noticed that a QC analyst was performing a Loss on Drying (LOD) analysis for (b)(4) Lot # (b)(4) and had recorded the completion time as "(b)(4)" and total time as "(b)(4)" in the usage log book for the LOD oven usage logbook although the step was not yet completed. d. The investigator observed that a QC analyst had recorded completion times of laboratory analyses that had not yet occurred. Specifically, a Loss on Drying (LOD) analysis was performed for (b)(4) Lot #(b)(4) and (b)(4) Lot #(b)(4) at approximately 10:55 AM. The investigator noted that the analyst had already recorded the completion time as "(b)(4)" for two (b)(4) samples and "(b)(4)" for one (b)(4)sample although the step was not yet completed. Our investigator asked the analyst why he recorded the completion time for each of the three samples if the step was still in progress. The analyst did not offer an explanation. Moreover, our investigator also found that weights for these three samples were recorded on blank pieces of paper and not directly onto the test data sheets. Reference : WL: 320-13-22 / Aarti Drugs Limited 7/30/13
Failure to maintain laboratory control records with complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays.. b. The inspection at this facility documented that there is no raw data for the related substance preparation of (b)(4) testing for lots (b)(4) of (b)(4) USP and there is no raw data for the standard and sample preparation for the residual solvent testing of the same lots. When weighing samples, reagents, and other laboratory materials, QC analysts write weight values on small pieces of paper, transcribe the values onto the analytical worksheets, and then destroy the original paper on which the weights are written. This was reported to be a normal practice within the laboratory. Our investigator also observed the practice of writing the weight values for samples on a small piece of paper and not on the analytical worksheet. This is an inappropriate documentation practice. Reference : WL: 320-13-22 / Aarti Drugs Limited 7/30/13
We observed and documented practices during the inspection that kept some samples, data and results outside of the local systems for assessing quality. This raises serious concerns regarding the integrity and reliability of the data generated. For example, a. Our review of the Chromeleon and Empower II software found that your firm was testing samples unofficially, and not reporting all results obtained. Specifically, “test,” “trial” and “demo” injections of intermediate and final API samples were performed, prior to performing the tests that would be reported as the final QC results. b. Out-of-specification or undesirable results were ignored and not investigated. c. Samples were retested without a record of the reason for the retest or an investigation. Only passing results were considered valid, and were used to release batches of APIs intended for US distribution. d. Unacceptable practices in the management of electronic data were also noted. The management of electronic data permitted unauthorized changes, as digital computer folders and files could be easily altered or deleted. Reference : WL: 320-13-20 / Fresenius Kabi Oncology Ltd 7/1/13
Failure to follow and document quality-related activities at the time they are performed. • During this inspection, your QC Chemist admitted that, under the direction of a senior colleague, he had recorded false visual examination data in the logbooks for reserve samples. This QC Chemist was responsible for multiple entries in the (b)(4) API logbooks. • Your firm’s failure to prevent, detect, and rectify the falsification of your GMP documentation is concerning. In response to this letter, describe your investigation into this misconduct and clearly explain how you determined the extent of the data falsification. Describe the role of the senior colleague who advised the QC Chemist during this incident. Also describe your plans for and outcome of a thorough investigation into data integrity at your facility, both in documents produced by the QC Chemist involved in this incident and by all other personnel at your site. • Our inspection also found that your laboratory failed to take note of a trend in the total impurity test results reported for this API. A striking number of the long term room temperature stability results show a drop in the total impurities result (for the most recent test) regardless of whether that is the 12, 24, 36, 40 or 48 month test interval. Reference : WL: 320-13-23 / Posh Chemicals Private Limited 8/2/13
Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)). • For example, your firm did not retain any raw data related to sample weights and sample solution preparations for the HPLC assays of (b)(4) tablet batches (b)(4) and (b)(4) that you conducted on July 18, 2012. In addition, you did not include those results in the calculation of the final assay values. Instead, you repeated the analysis the next day using a new set of sample solutions, and reported the retest results on the certificates of analysis (COAs). Other examples were also noted during the inspection. • In response to the FDA-483, you conducted a retrospective investigation and concluded that the analyst realized he recorded the initial data incorrectly in the HPLC “trial folder” instead of the regular folder. Thus, he repeated the test the next day using the same sample solutions. However, your QC manager stated during the inspection that the initial injections were trial runs, and that performing trial standard and sample analysis prior to official analysis is a standard practice in your QC laboratory. Moreover, our review of the final QC worksheet revealed that you prepared the new retest samples on July 19, 2012, the day after you performed the trial injections. (Continued …) Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)). • Our investigator also observed (b)(4) trial HPLC injections during the period of January 5, 2012 to November 16, 2012. Your response acknowledged that a number of these trial injections involved sample testing. However, you provided no evidence that your firm retained laboratory records and raw data associated with these sample tests. • Additionally, during an audit of the data submitted in support of the (b)(4) regarding (b)(4) tablets USP (b)(4) mg, our investigator requested to review the electronic analytical raw data to compare the values for (b)(4) assay and degradation products. However, your firm provided only the printed copies of the raw data because your firm did not have the software program available to view the electronic raw data. Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
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, you analyzed (b)(4) API lot (b)(4) on February 14, 2011, at 2:55 a.m., and then retested it at 2:05 p.m. using a new sample solution. You did not maintain any raw data associated with the initial test. • In your response, you stated that the retest was performed due to data deletion of the original analysis. You concluded that the analyst misused the administrator password to delete and overwrite the actual data logged in the audit trail. The ability of your analysts to alter and delete electronic analytical data raises serious concerns regarding laboratory controls in place at your facility. • During the inspection, our investigator also identified a backdated QC worksheet in the analytical report of (b)(4)API raw material batch (b)(4). When your analyst affixed the related substance and IR weight printouts to theFormat for Blank Sheet for Printout (Format No. F2/QCD/F/026-00), he signed and dated this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet, also signed and dated it as July 29, 2011. However, your QA department did not issue this worksheet until July 31, 2011. Your analyst acknowledged during the inspection that he backdated this worksheet on July 31, 2011. Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
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, you analyzed (b)(4) API lot (b)(4) on February 14, 2011, at 2:55 a.m., and then retested it at 2:05 p.m. using a new sample solution. You did not maintain any raw data associated with the initial test. • In your response, you stated that the retest was performed due to data deletion of the original analysis. You concluded that the analyst misused the administrator password to delete and overwrite the actual data logged in the audit trail. The ability of your analysts to alter and delete electronic analytical data raises serious concerns regarding laboratory controls in place at your facility. • During the inspection, our investigator also identified a backdated QC worksheet in the analytical report of (b)(4)API raw material batch (b)(4). When your analyst affixed the related substance and IR weight printouts to theFormat for Blank Sheet for Printout (Format No. F2/QCD/F/026-00), he signed and dated this worksheet as July 29, 2011. A second analyst, who reviewed this worksheet, also signed and dated it as July 29, 2011. However, your QA department did not issue this worksheet until July 31, 2011. Your analyst acknowledged during the inspection that he backdated this worksheet on July 31, 2011. • Your response stated that the analyst incorrectly dated the worksheet as July 29, 2011, instead of July 31, 2011, and that there was no intention to deliberately backdate the document. However, your response contradicted your analyst’s backdating admittance during the inspection. In addition, your response did not explain the reviewer’s signature which was also dated July 29, 2011. Backdating documents is an unacceptable practice and raises doubt about the validity of your firm's records. Reference : WL: 320-13-17 / RPG Life Sciences Limited 5/28/13
Your firm failed to follow 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, and to document same at the time of performance (21 CFR 211.100(b)). • Poor documentation practices during in-process testing. Specifically, an operator performed the in-process tablet (b)(4) testing for the (b)(4) mg tablet batch #(b)(4)without the batch record or a manufacturing form to document the results contemporaneously. The FDA investigator was informed that the pre-test and post-test weight values are documented in the batch record located in a separate manufacturing room rather than in the same room where the actual weights are measured. Moreover, your operator stated that he records the two weights with (b)(4) significant figures into the batch record from memory. • Additionally, the investigator noticed that the balance used in production was not level, which can result in inaccurate weights. The investigator asked how long the balance had not been level, and you indicated that you would investigate the matter and respond to the investigator. To date, you have not responded to FDA explaining your resolution of this matter. Reference : WL: 320-14-01 / Wockhardt Limited 11/25/13
Conclusion • The integrity of data generated by any regulated laboratory is a prime factor in determining the credibility of that laboratory. • The finding of a single instance where data integrity is compromised casts a shadow over the whole of the data generated. • Remember that inspections and audits can only sample, finding one instance of falsification raises the question of how many more instances of non-compliances exist? Therefore, ensuring data integrity is of major importance to analytical scientists, managers and quality assurance of any organization, as the consequences of getting it wrong are very costly and it will take a long time to rebuild regulatory trust. • The extended FDA regulation and draft guidance now also impact the laboratory data integrity issue, as failure to provide complete records means that any drugs are now classified as adulterated under the new extension of the Food Drug and Cosmetic Act as amended in 2012.
Data Integrity Part II will be continued …. as Presentation on Chromatography Data System (CDS) email@example.com
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