Data Integrity 483’s / Warning Letters

1 483 s / Warning Letters related to QC Data Integrity vis-a-vis Regulatory Expectations Ranjit BarshikarQuality by Design / cGMP Metrics .. US QC / Mfg. relatedLagging metrics: Batch Failure Rate Right First Time out of specification (OOS) / Laboratory Failure Investigation RatesLeading metrics: Quality System Effectiveness Process Capability Quality Culture Index Quality Culture IndexUS FDA Surprise Inspections .. Until now, FDA s inspections of Indian pharma plants have always been with prior notice. The surprise checks and aggressive surveillance are being considered because of instances of fabrication of documents and human errors . India s growing importance as a hub of Generic producers and rising compliance problems prompt regulator to consider the plan FDA expanded its inspection team in India from 12 to FDA Increasing Inspections. Recruiting about 100+ inspectors in India. Move towards surprise inspections. About 3 B $ budget approved as per Dr.

2 Panda Finance Secretary Govt. of India. US FDA working closely with Surprise checks ? The root cause of compliance issues is often linked to human elements, including the culture and the attitude of the people at the facilities and in the senior management said Dr. Ajaz Hussain India is home to 135 FDA-approved manufacturing units and its trillion drug industry, which largely makes generics, exported around ,000 cr. of drugs in 2012. 30% of this value being exported to the US alone. "FDA wants to ensure that Generic Cos. understand the risks associated with their product's processes and ensure compliance to FDA's regulations. "The FDA is confident that many companies understand and have implemented Good Manufacturing Practices (GMPs) . We also remain vigilant and will take appropriate action if, or when, lapses, occur." FDA interactions with industry, will take the necessary steps to self-correct. My Data Integrity Issue is across the Globe . NOT an India-centric problem.

3 If we are making life-saving medicines then we cannot afford to be negligent . Need to be very careful . Its absolutely fair . Don't think Indian Cos. are targeted . FDA Enforcement Statistics Summary -2012 FDA conducted 40,000+ inspections in 2012 Actually, 41,129 to be exact. That s almost 5 inspections per hour for the entire year of 2012. Based on data obtained from the FDA, here are some other interesting statistics: 2 inspections in Bangladesh 1 inspection in Botswana 223 inspections in China 241 inspections in India 1 inspection in Guantanamo Bay 16 inspections with companies with Merck in its name 366 inspections in AlaskaNo. of FDA Total GMP inspections in US decreased(from 1512 in FY 2011) to 1447 in FY 2012. Foreign inspections increased from 876 to 991. More than 50% of all GMP Warning Letters in 2012 went to drug manufacturing companies overseas,while in 2011 it was less than half. Most top 483 citations are unchanged from the past. QC citations (21 CFR ) continues to be a Bruce Ross -FDAFDA -PAI findings2010 What is Data Integrity ?

4 What is Data Integrity ?Data Integrity is critical to regulatory compliance, and the fundamental reason for 21 CFR Part 11. Attributable Legible Contemporaneous Original AccurateFDA Definition of data Integrity used for internal training: Data are of high quality if they are fit for their intended uses in operations, decision-making and planning .. as data volume increases, the question of internal consistency within data becomes Data IntegrityApplication Integrity Policy (AIP) The Application Integrity Policy is what FDA pulls up when it has questions about a manufacturer selectronic data. Electronic information includes everything, such as emails, adverse events reports, complaints, batch records, and quality control records everything that s stored electronically. Generic WLScientist Jailed for Falsifying R & D DataPublished by Adeline Siewon April 19, 2013 under Europe News Steven Eaton, a scientist working in a US company, has been jailed three months for falsifying preclinical safety data on experimental anticancer drugs due for clinical evaluation.

5 He was found guilty at the Edinburgh Sheriff s Court in March following a prosecution under the Good Laboratory Practice (GLP) Regulations, introduced in the UK in 1999. MNC Falsified clinical trial data ? July 14, The Yomiuri Shimbun -Although the Kyoto University of Medicine has concluded that clinical research data on a high blood pressure drug were falsified, it remains unclear whether a former employee of the maker of the drug was involved in manipulating the information. In its report on its internal investigation, the university pointed to the possibility that manipulation occurred during the process of compiling analysis data. MNC Pays $ Billion to End Lawsuit MNC reached a settlement to pay $ Billion to finish off a lawsuit from investors who say that the firm was concealing failures in quality control that resulted in a sweeping recall of medicines for children, which led to safety concerns for some users of the drugs. MNC had to take about 40 OTC products off the market in 2010.

6 One of them was Children s , in what FDA said was the biggest recalls of kids medicine in the history of the agency. Some of the problems included bacterial contaminants in active pharmaceutical ingredients and extremely dirty equipment. The facility had to be closed temporarily, FDA issued Warning Letters which indicate substantial problems that can affect public once again was cited for many serious cGMP violations. Some of these included: Failing to investigate consumer complaints Failing to do annual product reviews Failing to extend their investigations of problems into all lots of product that were affected Not filing field reports on time, and failing to store stability samples properlyConsent DecreeMany Cos..MNCs ..Generic have received CD as a penalty for Non Compliance to FDA 71 Data Integrity Recent Warning Letters Firm did not identify, report, or investigate the out-of- specification (OOS) results. 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.

7 2012. Repeated the analysis the next day using a new set of sample solutions, and reported the retest results on the certificates of analysis (COAs). OOS Rate One of major Quality Metrics Data Integrity Recent Warning Co. discarded OOS lab records and deleted OOS electronic data. Co. also disregarded OOS data without investigations, and selectively reported only passing results. The lack of reliability and Integrity of data generated is a serious CGMP deficiency that raises concerns with all data generated by Co. OOS Rate One of major Quality Metrics 1: Trial InjectionsInsufficient controls to guard against data manipulation of unfavourable results. QC analyst label sample trial injections as standard rather than by the actual sample batch numbers Aco. accepted that actual batch samples were used in trial analysis but were labelled as standard sample. Seniors want batches passing at any cost , QC unable to stand up to the owners to inform the failure. 2 : Deletion of Data FDA found Co.

8 Had deleted all of its internal trial injection data after FDA found deficiencies at its other manufacturing facility in July 2013, implying that the company was looking to cover up data fudging. Company deleted multiple HPLC data files acquired in 2013 allegedly to clear up hard drive space without creating back-ups. No audit trail or other traceability. Analysts do not have unique user names and passwords. QC analysts use a single shared , common password to access and manipulate multiple stand-alone systems. 3 : Not documenting activity when it is done. The FDA found an operator performing in process weight checks memorizing two " weights" , going to the next room where the batch records are kept and documenting the same from memory. Difficult to believe that this is the " truth". All of us know that it is very difficult to remember long numbers. In process operators , analyst and manufacturing chemist in many companies do not document activity in appropriate records. The documentation is first done on loose sheets of paper , an evaluation is done if values meet specifications, if there is a failure then the primary data is fudged and manipulated and then "final" called as " fair" record is to investigate and document OOS Inadequate or No investigation of critical deviations or a failure of a batch.

9 QCU failed to conduct an investigation for numerous OOS results ( , for colony forming units, conductivity, assay, etc.) QCU approved and released a batch .. despite an initial OOS result. These results were later confirmed through repeat testing, but further testing of additional samples produced passing results. 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 .. was released and distributed even though it did not meet the established specification of .. % label claim. QCU did not require a second, independent person to review the raw data, calculations and records before releasing these lots for Falsification Failure to follow and document quality-related activities at the time they are performed. During inspection, QC Chemist admitted that, under the direction of a senior colleague, he had recorded false visual examination data in the logbooks for reserve samples.

10 Firm s failure to prevent, detect, and rectify the falsification of GMP documentation is a concern. The audit trail function for the chromatographic systems was disabled at the time of the inspection; therefore, there is no record for the acquisition of data or modifications to laboratory data. Very Recent ( ) 483In General the issues are .. Not reporting failing results Conducting unofficial analysis Deleting electronic data Disabling audit trails in electronic data capture systems Fabricating training data Having unofficial batch sheets and analytical reports Trial analysis Re analysing failing samples till passing results are obtained Back dating Not reporting stability failures appears to be common. This is not related to training or understanding a particular technical or quality concept but mainly related to honesty and ethical issues. Further what is more disturbing is that senior management and company owners appear to either support such practices covertly or overtly and in many instances encourage in InspectionFirm repeatedly delayed, denied, limited an inspection or refused to permit the FDA inspection: Torn raw data records in the waste area ,asked to QA Officer to show these for inspector s review.