“483’s / Warning letters related to QC Data Integrity vis-a-vis Regulatory Expectations”

Ranjit Barshikar

Quality by Design / cGMP Consultant

ranjitbarshikar@gmail.com

ranjit@qbdinternational.com

Guidelines…Regulations

Quality Metrics ….. US FDA…2014

Quality Metrics….. QC / Mfg. related

Lagging metrics:

• Batch Failure Rate

• Right First Time

• Out of Specification (OOS) / Laboratory Failure Investigation Rates

Leading metrics:

• Quality System Effectiveness

• Process Capability

• Quality Culture Index Quality Culture Index

US 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 19.

Indian 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 DCGI.

Why 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 Rs.1.1 trillion drug industry, which largely makes generics, exported around Rs.40,000 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 view…

• “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”.

• “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 Alaska

No. of FDA inspections…2012

• 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 211.22) continues to be a concern.

DR Bruce Ross - FDA

FDA - PAI findings

2010

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

• Accurate

FDA 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 paramount….”

Data Integrity

Application Integrity Policy (AIP)

• The Application Integrity Policy is what FDA pulls up when it has questions about a manufacturer’s electronic data.

• Electronic information includes everything, such as emails, adverse events reports, complaints, batch records, and quality control records—everything that’s stored electronically.

• 2013…Indian Generic Cos….10 WL

Scientist Jailed for Falsifying R & D Data

Published by Adeline Siew on 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.

• 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, 2013…News

• 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 $2.2 Billion to End Lawsuit

• MNC reached a settlement to pay $2.2 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.

• The facility had to be closed temporarily, FDA issued warning letters which indicate substantial problems that can affect public safety.

MNC

MNC 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

properly

Consent Decree

Many Cos. …MNCs …Generic have received CD as a penalty for Non Compliance to FDA regulations.

Slide 71

Data Integrity Observations…from 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 ……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 Observations…from Recent Warning Letters…

• 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 Injections

Insufficient 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”

• A co. 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. 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 made.

Failure to investigate and document OOS results…

• Inadequate or No investigation of critical deviations or a failure of a batch.

• QCU failed to conduct an investigation for numerous OOS results (e.g., 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 distribution.

Document 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.

• 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 ( Jan.14) 483

In 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 them.

Delay 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.

• QA Officer removed 20 paper records, none of which included raw data entries identified in the waste area earlier during the inspection.

• Inspector asked three times if there were any more records found in the waste area, and the QA Officer responded to each question, "no, this is all of the records”.

• Inspector then re-visited the waste area and found that the raw data records had been removed and placed in a different holding bag.

• These records included raw data testing worksheets from anti-microbial effectiveness studies, controlled Master Batch Records ", equipment calibration records, and stability protocol records.

• Because Co. provided some, but not all, of the records requested by the investigator that FDA had the authority to inspect, Co. limited access to or copying of records for the FDA inspection.

Withholding truthful information Delaying / Limiting the Inspection

• Firm withheld truthful information, and delayed and limited the inspection.

• The delay and limiting of the inspection extended to a refusal to permit entry or inspection.

• FDA recently released a DRAFT Guidance for Industry (CIRCUMSTANCES THAT

CONSTITUTE DELAYING, DENYING, LIMITING OR REFUSING A DRUG INSPECTION, 7/18/13) that discusses various tactics Industry uses to impede FDA audits at their facilities.

Inadequate Controls over Computers

Co. failed to establish and exercise adequate controls over computers to prevent unauthorized access or changes to electronic data.

• Analyst admitted that he deleted un- investigated failing and/or OOS electronic data from the laboratory database in January 2013 prior to inspection.

QC Senior Manager also acknowledged this laboratory-wide electronic data deletion practice.

Analysts demonstrated to FDA that they could delete any electronic analytical data files from the laboratory computers and external backup hard drives.

Very Recent 483 (Jan.14) – Computer Systems

Computer System Issues:

• No appropriate usernames and passwords to allow appropriate control over data collected by Co. computerized systems including UV, IR, HPLC, and GC instruments

• SOP does not have provisions for any audit trail reviews to ensure that deletions and/ modifications do not occur

• Co. did not implement security control of laboratory electronic data

• There is no system in place to ensure that all electronic raw data from the laboratory is backed up and/or retained

• Electronic raw data would not exist for most HPLC assays over two years old because data is not backed up and storage space is limited

API Cos. - Similar Issues Globally…

WL on Raw Data

Access Control – 211.68 (b)

FDA Audit Trail - Warning Letters

What FDA has to say about Raw Data

Data integrity issues FDA has been finding include:

• Backdating/Postdating/Missing Signatures

• Fabricating/faking data

• Copying existing data as new data

• Re-running samples

• Discarding data/ omitting negative data (like OOS or eliminating outliers)

• Releasing failing product

• Test until release

• Hiding/obscuring SOP or protocol deviations

• Not saving electronic or hard copy data

• Poor Document Control & retention/Version Management

• No /Inappropriate Audit Trail

• Inadequate Access Authorization/ Privileges

• Inadequate reporting of failure and deviation management

• Data Back ups & Disaster Recovery

• Use of un validated software applications/Spreadsheets

• Mismatch between reported data and actual data

• No links/traceability b/w source documents (original data) and stored record

Top 10 issues in QC Lab

• Raw Data

• Software not validated

• Raw Material Vendors

• Equipment not validated/calibrated

• Change Control/Unauthorized Access

“Data Integrity”

GMP News 27 Jan. 2014

Impact of Non-Compliance

• Cultural & Ethical Issues

• ANDA / DMF affected

• Credibility / Image / Business Loss

• RISK TO PATIENTS

Way Forward….

Way Forward….

So what can a QCU do to prevent data integrity problems?

• Encourage Co. to establish a “Data Integrity policy” to show that you are serious about falsification of data and that it is a cause for termination. Train on this policy.

• Establish a general standard for GDP so that even the most innocent recording issues cannot be perceived as fraudulent. Train on this standard.

• Establish a specific procedure on sampling/testing requirements and laboratory data recording to be clear about incoming, in process, and final testing requirements. Train on these procedures.

• Provide specific training for secondary reviewers/approvers to ensure GDP are followed and suspicious results and trends are investigated.

• The QCU must be able to demonstrate that it has established and trained on policies and procedures that are designed to take data integrity seriously

• Total Compliance to Part 11

Proactive and cross-functional best practices for ensuring data integrity.

• Form a cross-functional e-data working group

• Clearly define accountabilities vs. responsibilities

• Rely upon your records retention schedules

• Take advantage of and reuse IT controls to monitor

• Incorporate e-data archive audits into internal quality audits

• Verify progress (and identify gaps) with a Part 11/Annex 11 mock FDA audit

• Training ….Training…..Training

Quality Metrics Leads….

Jewel in the hands of Quality Unit..

Every one Needs to PROTECT it

It’s time to Repose the Confidence…!

It’s Time to Rebuild the IMAGE..!

It’s time to satisfy the Patients.!

Thanks….!

Quality Culture IndexAttributes that could be measured:

People

• Technical/QA Training/Education Rate – All employees with direct impact on product/data (Design of Experiments, Six Sigma, etc.)

• Effectiveness of Training/Education

• Management Accountability for Cultural development; promoting and supporting quality

Places

• Investment spent in new and existing facilities, equipment, utilities (possibly PAT investments?)

Performance

• Frequency of Quality Management Performance Review Meetings

• Level of proactive actions and assessing trends for signals to drive Continual Improvement projects

Prevention

• Quality Risk Management Processes (Risk Assessment linking QTPP-CQA-CPP)

• Internal Audit Programs

• Global CAPAs – Systemic Assessment across networks

• Best Practice Sharing to drive continual improvement Quality Metrics….. QC / Mfg. related

Consent Decree

• Abbott

• Eli Lilly

• Schering-Plough

• Wyeth

• American Red Cross (blood banking procedures).

• Johnson & Johnson

• Boeringer Ingelheim-Ben Venue Lab

• Ranbaxy

Etc……