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.

2 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. 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.

3 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 . If we are making life-saving medicines then we cannot afford to be negligent.

4 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.

5 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 ?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.

6 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.

7 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.

8 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. 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.

9 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.

10 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 ..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.