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Presented By: Gaurav Walia April 27th, 2015 (Monday) 1 Avoid CSV Pitfalls by Knowing Warnings from FDA - Overcome CSV’s Top Challenges Presented By: Gaurav Walia Independent Pharmaceutical Industry Consultant

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Page 1: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)1

Avoid CSV Pitfalls by Knowing

Warnings from FDA -

Overcome CSV’s Top

Challenges

Presented By: Gaurav Walia

Independent Pharmaceutical Industry Consultant

Page 2: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)2

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S.

Pharmaceutical Consultant:

Specializing in Consent Decree

Computer Systems Validation

Corrective Actions (CAPA’s)/ Remediation

Page 3: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)3

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S. (continued)

Career filled with a multitude of experience from the beginning as an Analytical R&D Chemist at Searle/Monsanto, Oread/Pfizer.

Transitioning and Expanding to Executive Management Level Positions as Director of Quality Assurance and Regulatory Compliance

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Presented By: Gaurav Walia April 27th, 2015 (Monday)4

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S. (continued)

Within these aforementioned leadership roles I have managed various technical, quality, and compliance groups such as:

Pharmaceutical Research and Development

LIMS (Laboratory Information Management Systems)

Metrology

QC (Quality Control)

Page 5: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)5

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S. (continued)

CSV (Computer Systems Validation)

Consent Decree

Quality Assurance & Regulatory Compliance

Equipment Qualification, Method, Process, Cleaning, and Software Validation

Materials (Import/Export) / Vendor Certification

Page 6: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)6

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S. (continued)

Multi-disciplinary background has resulted in the following:

– Effective Remediation and Acceptance of

Consent Decree Corrective Action

– 100+ Regulatory & Compliance Inspections

(positive) with the FDA, EMEA, IMB,

Chinese sFDA, etc.

Page 7: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)7

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S. (continued)

Overall, my career has not only spanned the Globe but also has traveled across many different key Pharmaceutical, Medical Device, Biological, Aseptic Processes, OTC, Vitamins, Consumer Healthcare, etc.

As well as across key product lines/dosages as Solid, Liquid, Creams, Antibiotics, inhalation devices, patches, etc with Branded/Proprietary, Generic, FDA, etc.

Page 8: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)8

Introduction – Meet Your Speaker

Mr. Gaurav Walia M.S.

Recently, worked on Three Major Consent Decree Projects with:

McNeil/Johnson and Johnson (CSV)

Novartis (Site Project Lead and Quality Systems)

B. Braun (CSV, Overall QA, Compliance and FDA Audits)

Page 9: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)9

Agenda

Critical Terms and Definitions

Historical Backgrounds/Trends

Recent FDA Enforcement Action and Regulatory Compliance

Consent Decree Impact

CSV Pitfalls: Warning from FDA and Top CSV Challenges

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Presented By: Gaurav Walia April 27th, 2015 (Monday)10

Agenda (continued)

Industry Globalization

Pharmaceutical

Medical Device

Biologics

Aseptic Processes

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Presented By: Gaurav Walia April 27th, 2015 (Monday)11

Agenda (continued)

Branded

Generics

OTC

Consumer Healthcare

Vitamins

Cosmetics

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Presented By: Gaurav Walia April 27th, 2015 (Monday)12

Critical Terms and Definitions

Industry Globalization

Pharmaceutical

Medical Device

Biologics

Aseptic Processes

CSV

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Presented By: Gaurav Walia April 27th, 2015 (Monday)13

Critical Terms and Definitions

Consent Decree

MVP (Master Validation Plan)

SDLC (Software Development Lifecycle)

21CFR Part 11

ERES (Electronic Records & Electronic Signatures)

Audit Trail

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Presented By: Gaurav Walia April 27th, 2015 (Monday)14

Critical Terms and Definitions

21 CFR Part 11…What does it mean?

– 21 – Chapter of US Federal Law – Food, Drug & Cosmetics Act circa 1906,

– CFR - Code of Federal Regulation – US Federal Government Law,

– Part 11 – That part of 21 CFR that deals with electronic records & electronic signatures.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)15

Historical Backgrounds/Trends

Computers Systems Validation Requirements and Regulatory Guidance initially resulted in widespread confusion, panic and overall inconsistent results/solutions.

Bottom Line:

Lots of Money Spent but Problems not Solved!!!

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Presented By: Gaurav Walia April 27th, 2015 (Monday)16

Historical Backgrounds/Trends

Data Integrity and Fraud

Proper Data Handling, Integration and Reporting

Computerized/Software Systems Controlled Access & User Defined Roles/Functionalities

Quality Control Laboratory CSV Controls

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Presented By: Gaurav Walia April 27th, 2015 (Monday)17

Historical Backgrounds/Trends

(continued)

Stand Alone vs. Networked Systems

Password Security: Login Credentials

Data Back-up and Recovery Systems

Verification/Validation of Data Systems

Ability to Produce Data in a Printable/Readable Format

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Presented By: Gaurav Walia April 27th, 2015 (Monday)18

Historical Backgrounds/Trends

(continued)

Missing IQ/OQ/PQ

Missing secondary reviewer

No Quality review

Altered Data and Changes are not uniquely captured or time stamped

Audit Trail Functions are well defined and/or reviewed

Electronic Methods/Protocols are not Controlled for Change/Revisions

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Presented By: Gaurav Walia April 27th, 2015 (Monday)19

Historical Backgrounds/Trends

(continued)

Altered Data and Changes are not uniquely captured or time stamped

Audit Trail Functions are well defined and/or reviewed

Page 20: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)20

Historical Backgrounds/Trends

(continued)

Electronic Records and Electronic Signatures

Can electronic signatures be used instead of handwritten signatures for master production and control records?

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Presented By: Gaurav Walia April 27th, 2015 (Monday)21

Historical Backgrounds/Trends

(continued)

Electronic Records and Electronic Signatures

Yes. An electronic signature may be used to fulfill the requirement in § 211.186(a) as explained in the Federal Register on September 8, 2008 (73 FR 51926). Firms using electronic signatures should document the controls used to ensure that they are able to identify the specific person who signed these records electronically.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)22

Historical Backgrounds/Trends

(continued)

Raw Data/Originally acquired Chromatograms were not saved.

Instrument/Method Parameters were not captured

System Suitability Parameters were not captured

Patches were added to system with no pre-assessment/evaluation for impact to system

No validation after changes to computerized system

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Presented By: Gaurav Walia April 27th, 2015 (Monday)23

Historical Backgrounds/Trends

(continued)

Stand Alone vs. Networked Systems

Password Security: Login Credentials

Data Back-up and Recovery Systems

Verification/Validation of Data Systems

Ability to Produce Data in a Printable/Readable Format

Page 24: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)24

Historical Backgrounds/Trends

(continued)

Password Security: Login Credentials

Why is FDA concerned with the use of shared login accounts for computer systems?

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Presented By: Gaurav Walia April 27th, 2015 (Monday)25

Historical Backgrounds/Trends

(continued)

Password Security: Login Credentials

Appropriate controls must be exercised to assure that changes to computerized master production or control records or other records, or input of laboratory data into computerized records, are only made by authorized personnel and there must be documentation controls that ensure that actions are attributable to a specific individual (§211.68(b), § 211.188(b)(11), § 211.194(a)(7) and (8)).

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Presented By: Gaurav Walia April 27th, 2015 (Monday)26

Historical Backgrounds/Trends

(continued)

Password Security: Login Credentials

When login credentials are shared and a specific individual cannot be identified through the login, this would not conform to the CGMP requirements in 21 CFR part 211. FDA requires systems controls, including documentation control, to be designed to meet CGMPs (§ 211.100).

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Presented By: Gaurav Walia April 27th, 2015 (Monday)27

Historical Backgrounds/Trends

(continued) Warning Letters represent two of the three steps

that are important to a GxP assessment of deviations.

The first step are deviations reported on the well-known FDA-483 Form by an FDA inspector at the time of inspection.

A Warning Letter is issued if the EIR (Establishment Inspection Report) written by the inspector has been checked by the head office and the deviations have been classified as significant or the statement on the elimination of the faults has been classified as insufficient.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)28

Historical Backgrounds/Trends

(continued)

If the answer to the Warning Letter is also insufficient from the FDA’s point of view, they enforce step three:

The inspected site cannot manufacture products for the US/American market until further notice

Page 29: Avoid CSV Pitfalls by Knowing Warnings from FDA CSV Pitfalls by Knowing Warnings from FDA - ... (CSV) Novartis (Site Project Lead and Quality ... and Top CSV Challenges

Presented By: Gaurav Walia April 27th, 2015 (Monday)29

Historical Backgrounds/Trends

(continued) What are the most notable deviations that result in FDA-

483 forms and Warning Letters?

No individual passwords which can cause repudiation problems

Insufficient system security

No electronic audit trail

(Electronic) raw data not saved or lost

No correlation between e-records and paper print-outs

No back-up of data

No prevention of data deterioration during archiving

Lack of or inadequate computer system validation

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Presented By: Gaurav Walia April 27th, 2015 (Monday)30

Consent Decree Impact

Significant Increase in the Number of Consent Decrees over the last Seven Years

Significant Increase in Global Regulatory/Compliance Implications

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Presented By: Gaurav Walia April 27th, 2015 (Monday)31

Consent Decree Impact

Recent Consent Decrees

Hospira

Ranbaxy

Novartis

Johnson & Johnson

Ben Venue Laboratories, etc.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)32

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

Validation of Systems According to their Intended Use

Security and Data Integrity

Electronic Records and Electronic Signatures

Audit Trail/21CFR Part 11

COTS vs. In-House Software Systems

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Presented By: Gaurav Walia April 27th, 2015 (Monday)33

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Integration of Key Systems in Functional Areas.

Enterprise Wide Software Management Systems

Tracking and Trending Master Validation Plan and Software Development Lifecycle

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Presented By: Gaurav Walia April 27th, 2015 (Monday)34

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Consent Decree Action

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

Change Control System

Document Control Systems

Electronic Submissions

Data Acquisition Systems

Laboratory LIMS Systems

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Presented By: Gaurav Walia April 27th, 2015 (Monday)35

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

How do the Part 11 regulations and "predicate rule requirements" (in 21 CFR Part 211) apply to the electronic records created by computerized laboratory systems and the associated printed chromatograms that are used in drug manufacturing and testing?

.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)36

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

Some in industry misinterpret the following text from “The Guidance for Industry – Part 11, Electronic Records; Electronic Signatures –Scope and Application” (Part 11 Guidance; lines 164 to 171) to mean that in all cases paper printouts of electronic records satisfy predicate rule requirements in 21 CFR Part 211.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)37

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued) Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

“Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be ‘using electronic records in lieu of paper records’ under §§ 11.2(a) and 11.2(b). In these instances, the use of computer systems in the generation of paper records would not trigger part 11.”.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)38

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

The Part 11 Guidance also states (in lines 150-152), that:

“…persons must comply with applicable predicate rules, and records that are required to be maintained or submitted must remain secure and reliable in accordance with the predicate rules.”

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Presented By: Gaurav Walia April 27th, 2015 (Monday)39

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

For High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC) systems (and other computerized systems involving user inputs, outputs, audit trials, etc.), the predicate rules, such as 21 CFR 211.68 and 21 CFR 211.180(d), require the electronic records themselves to be retained and maintained in accordance with those regulations.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)40

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

21 CFR 211.180(d) requires records to be retained “either as original records or true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records.” 21 CFR 211.68 further states that: “[Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained” (emphasis added).

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Presented By: Gaurav Walia April 27th, 2015 (Monday)41

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

The printed paper copy of the chromatogram would not be considered a “true copy” of the entire electronic raw data used to create that chromatogram, as required by 21 CFR 211.180(d). The printed chromatogram would also not be considered an “exact and complete” copy of the electronic raw data used to create the chromatogram, as required by 21 CFR 211.68.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)42

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

The chromatogram does not generally include, for example, the injection sequence, instrument method, integration method, or the audit trail, of which all were used to create the chromatogram or are associated with its validity. Therefore, the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211. The electronic records created by the computerized laboratory systems must be maintained under these requirements.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)43

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

We recognize that there are cases where it could be appropriate for the printed chromatogram to be used within laboratories for the review of test results. Similarly, it also may be acceptable to provide the printed chromatogram during a regulatory inspection or for application review purposes. However, the electronic record must be maintained and readily available for review by, for example, QC/QA personnel or the FDA investigator.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)44

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

In summary, decisions on how to maintain records for computerized systems should be based on predicate rule requirements. We recommend that these decisions be supported by a sound risk assessment.

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Presented By: Gaurav Walia April 27th, 2015 (Monday)45

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Paper-based vs. Hybrid vs. Fully Automated Electronic Data Systems

References: Guidance for Industry – Part 11, Electronic

Records; Electronic Signatures – Scope and Application

21 CFR 211.180(d): General Requirements 21 CFR 211.68: Automatic, Mechanical, and

Electronic Equipment

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Presented By: Gaurav Walia April 27th, 2015 (Monday)46

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

Training Systems

CAPA Programs

Equipment Qualification/Calibration and Software Validation Software

Clinical Trail Software Systems

ERP

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Presented By: Gaurav Walia April 27th, 2015 (Monday)47

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

TOP REGULATORY TRENDS:

International Impact of Regulatory findings of CSV and Data Integrity

Quality Control Data

Impact of Mergers and Acquisitions to Business Practices and Quality Systems

Increase in Clinical Trials/Data

Significant increase in Consent Decrees

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Presented By: Gaurav Walia April 27th, 2015 (Monday)48

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

TOP REGULATORY TRENDS:

Warning Letters Issued to and Dates Issued:

Marck BioSciences Ltd. – July 2014

Apotex Pharma Chem India Pvt. Ltd –

June 2014

Sun Pharmaceutical Industries – May 2014

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

Warning Letters Issued to and Dates Issued:

Canton Laboratories – February 2014

USV Limited – February 2014

Wockhardt Limited – November 2013

Agila Specialities Private Limited –September 2013

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

Warning Letters Issued to and Dates Issued:

Posh Chemicals Private Limited –

August 2013

Aarti Drug Limited – July 2013

Wockhardt Limited – July 2013

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

Warning Letters Issued to and Dates Issued:

Fresenius Kabi Oncology Ltd. – July 2013

RPG Life Sciences Limited – May 2013

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

All laboratory analysts share the same password

Shared the same username and password

common PC login used by all ..analysts

..the analyst misused the administrator password to delete and overwrite the actual data logged in the audit trail

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

There is no system in place to ensure that all electronic raw data from the laboratory is backed up and/or retained. your firm provided only the printed copies of the raw data Missing /deleted / non existent data Failure to have complete data as per 211.194 data was not consistently archived

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CSV Pitfalls: Warning from FDA

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(continued)

TOP REGULATORY TRENDS:

our inspection found 5,301 deleted chromatograms

Users can delete data

computer folders and files could be easily altered or deleted

Data is deleted to make space for the most recent test results

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Presented By: Gaurav Walia April 27th, 2015 (Monday)55

CSV Pitfalls: Warning from FDA

and Top CSV Challenges

(continued)

TOP REGULATORY TRENDS:

HPLC raw data files can be deleted from the hard drive

(no) access controls to prevent deletion or alteration of raw data.

HPLCs showed data was deleted

deleted electronic files with no explanation

data could be deleted using a common OS log on

your firm tested a batch

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(continued)

TOP REGULATORY TRENDS:

(no) proper controls in place to prevent the unauthorized manipulation of your laboratory’s raw electronic data. Ignoring failing injections and recalculating without performing trial standard and sample analysis prior to official analysis is a standard practice re integrations occur without a valid procedure

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(continued)

TOP REGULATORY TRENDS: “unofficial” testing outside Enterprise CDS

and not reported, or retested till passing Entire PC’s hidden from inspector to conceal data manipulation performing "trial" sample analysis for HPLC analyses prior to collecting the “official” analytical data performs “unofficial testing” of samples, disregards the results, and reports results from additional tests the running of “trial testing” prior to performing system suitability and the formal testing

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(continued)

TOP REGULATORY TRENDS:

Should... investigate all electronic data generated using Audit trail capabilities

HPLCs had the audit trail functions disabled

computer software lacked active audit trail functions

Switching off audit trails

loss of instrument activity logs (audit trails)

audit trail function for the chromatographic systems was disabled

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(continued)

TOP REGULATORY TRENDS:

“The complete records, including failing results, are needed to carry out investigations” Your firm failed to review and investigate ..laboratory deviations Details of a trial that failed impurity analysis and a follow up one that passed failed to adequately examine why your analysts hid or deleted these runs Non Contemporaneous documentation

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TOP REGULATORY TRENDS:

Incorrect batch records with incorrect calculations, no signatures and missing information Failure to investigate: customer complaints, OOS results, Failure of Quality unit to find the errors the investigator did your quality unit is not able to fully exercise its responsibilities.

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TOP REGULATORY TRENDS:

Not established and documented the accuracy, reliability and performance of your computer systems

No verification of access controls

No Validation

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(continued)

TOP REGULATORY TRENDS:

CSV is designed to provide documented evidence that procedural control, administrative controls, technical controls, are in place and configured correctly to meet user requirements. Proper CSV would highlight

incorrect configuration of users

too generous abilities for roles

opportunities for mal behaviors

highlight areas of risk

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(continued)

TOP REGULATORY TRENDS:

“the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211. The electronic record must be maintained and readily available for review by, for example, QC/QA personnel or the FDA investigator”

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(continued)

TOP REGULATORY TRENDS:

– Hiding the evidence for previous:

Injections/Processing “Oh those were trial

injections so we deleted them”

– “We only permit users to process data once”

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(continued)

TOP REGULATORY TRENDS:

SUMMARY

–Deliberate falsification of results / hiding non conformities

–Failed injections deleted

–Discrepancies in raw data /lack of raw data

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(continued)

TOP REGULATORY TRENDS:

SUMMARY

–Inadequate review and control of computerized laboratory results and systems

–Insufficient Qualification of Equipment

–Quality Control deficiencies including; inadequate records, lack of specificity in analytical methods, failure to investigate unknown peaks

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(continued)

TOP REGULATORY TRENDS:

International Impact of Regulatory findings of CSV and Data Integrity

Numerous Consent Decree and Significant FDA and Foreign Regulatory Agency Action on Foreign Firm Compliance Issues!!!

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(continued)

TOP REGULATORY TRENDS:

Quality Control Data

Many example noted during this presentation stem from QC Lab/Data Systems

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(continued)

TOP REGULATORY TRENDS:

Impact of Mergers and Acquisitions to Business Practices and Quality Systems

Mergers/Acquisition due to Consent Decree

Many Inconsistent Quality System Practices due to Non-Standardization of Procedures and Controls.

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(continued)

TOP REGULATORY TRENDS:

Increase in Clinical Trials/Data

Decrease in Drug Approval/Time Elapse

Many Firms Increasing number of clinical trials to get one drug approved and to market

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(continued)

TOP REGULATORY TRENDS:

Significant increase in Consent Decrees

See example within

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(continued)

TOP REGULATORY TRENDS:

Significant increase in Consent Decrees

The consent decree is judicial recognition of an agreement between FDA and drug maker that usually bars the drug maker from manufacturing and distribution until it can prove, via third party, that it has achieved and can sustain regulatory compliance. The decree often involves 7- or 8-figure financial penalties that the offending company pays to the government general fund

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(continued)

TOP REGULATORY TRENDS:

Significant increase in Consent Decrees

But seven years is quick. Of 16 consent decrees, one has stretched for 21 years and is still in force; another, 17 years and counting. The majority of manufacturing consent decrees linger, remaining in force with no official closeout.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 1999Financial penalties: $212 million End Date: still pending

Abbott was cited for nonconformance with quality system regulations for in vitro diagnostic products at an Illinois facility. An initial $100-million fine was followed by a $112 million penalty after the company failed a follow-up inspection.

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2008Financial penalties: noneEnd Date: still pending

Actavis was cited for GMP violations in all of the products made at the three New Jersey facilities of its Totowa subsidiary. The FDA blocked all production at the plants. Actavis was required to retain a third-party expert to ensure GMP compliance, and it hired PAREXEL.

The drug maker replaced the management team at its Little Falls plant for oral-dose manufacturing, where it makes Oxycodone products. The other plants involved were Riverview, also a site of oral-dose manufacturing, and Taft, a packaging facility.

Oxycodone production resumed in 2009.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 1998Financial penalties: noneEnd Date: 2001

The consent decree agreement was made in February 1998, stemming from GMP violations at a Los Angeles plant. Alpha was forced to cease drug-making operations twice before it resumed manufacturing and distribution of all of its products in June 2001.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 1993; amended 2003Financial Penalties: $53.2 million cumulativeEnd Date: still pending

Violations concern the mismanagement of blood products. The most recent issues involve a failure to identify problems that occurred during collection and processing, leading to quality problems. The Red Cross has made progress in addressing the quality issues by standardizing procedures, updating its testing labs, and increasing oversight. But it needs to make additional progress on all issues to comply with federal regulations.

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2009Financial penalties: noneEnd Date: still pending

Unresolved GMP violations in Caraco's Michigan facilities prompted a visit by U.S. Marshalls, who seized 33 medications and drug ingredients at plants in Detroit, Farmington Hills and Wixom.

The product seizures followed a series of drug recalls stemming from manufacturing defects. Contamination figures prominently in a warning letter issued to the company in October 2008, as do shortcomings in the procedures used after its discovery.

Caraco was forced to cease manufacturing at the sites, and to hire a consultant to oversee the operations overhaul.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2001Financial penalties: noneEnd Date: 2004

Nonconformance issues at a Georgia facility prompted this consent decree, which is comparatively mild given its three-year timeframe and lack of financial penalty. Issues included inadequate equipment maintenance and lack of testing and final validation.

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 1989Financial penalties: noneEnd Date: Still pending

This consent decree stems from GMP violations at a facility in Puerto Rico. A reorganization yielded groups within the company designed to prevent conflict of interest.

Although no financial penalty was assessed, Eli Lilly suffered the delayed approval of two drugs when inspectors found GMP issues during a pre-approval inspection in 2001. The company and FDA agreed on fixes in 2002, but subsequent violations have left the matter unresolved

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2010Financial penalties: $175 million, plus fines for missed deadlinesEnd Date: still pending

This high-visibility consent decree started with manufacturing quality problems at the biopharma's Allston Landing plant, just outside Boston. GMP violations discovered during a fall 2008 inspection led to a warning letter in February 2009. But the big trouble started when a virus contaminated a bioreactor, leading to a plant shutdown for decontamination. The shutdown seemed to roll into a consent decree remediation effort, which ultimately involved an operations restructuring

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and Top CSV Challenges

(continued)

TOP REGULATORY TRENDS:

Significant increase in Consent Decrees

Genzyme can trace its current takeover bullying by Sanofi to the consent decree issued May 2010. The French drug maker's offer is pinned to the company's post-consent-decree valuation, rather than the higher pre-decree valuation that Genzyme prefers. The biopharma also can trace to the decree its past bullying by investor Carl Icahn, who cited the manufacturing problems in his successful attempts to make changes to the company's board

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

The FDA deemed $175 million of the company's earnings as unlawful profits from the products made at the plant, chiefly Cerezyme and Fabrazyme. Genzyme was forced to make a "disgorgement" of those profits, in consent decree lingo. A subsequent shortage of one of the drugs led the FDA to ask a Genzyme competitor to offer its experimental treatment under an expanded access program

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2005Financial penalties: $650 million bondEnd Date: still pending

The subject of this consent decree was GSK's failure to meet quality standards for the diabetes medication Avandia met and antidepressant Paxil that it manufactured in Cidra, Puerto Rico.

The regulator began investigating the plant in 2002, and U.S. Marshalls raided it in 2005, seizing inventory. The bond was contingent on the drug maker reconditioning or destroying the seized drugs. GSK ultimately closed the plant in 2009

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2009Financial penalties: noneEnd Date: still pending

Product recalls involving oversized tablets and other causes, which followed FDA discovery of manufacturing problems in a 2008 inspection, ultimately led to this far-reaching consent decree. It stretches beyond KV to subsidiaries Ther-Rx and ETHEX, all three of which were forced to stop manufacturing and distribution operations due to adulteration and, for some drugs, lack of market approval. ETHEX, ultimately, was shuttered.

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(continued)

TOP REGULATORY TRENDS:

Significant increase in Consent Decrees

The regulator enlisted the help of U.S. Marshalls, who seized more than $24 million in products following KV's continued production after the FDA-ordered halt. KV hired GMP expert Lachman Consultants to oversee the production restart, a process that's still underway

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2005Financial penalties: noneEnd Date: still pending

This case mixes marketing and manufacturing violations. The regulator cited the company for nonconformance

with manufacturing regulations at a California facility that made over-the-counter eye drops. The FDA found also that two of the company's eye drop brands were unapproved, and that products had inadequate warning labels.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2000Financial penalties: noneEnd Date: 2005

Scope involved GMP violations in the methods, facilities and controls for Fluogen, an influenza vaccine. The violations occurred in manufacturing, processing and packaging. The FDA also identified process validation problems related to Aplisol, a diagnostic agent for detecting tuberculosis, but addressed them separately.

The consent decree was issued in March 2000 and was lifted in July 2005.

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2002Financial penalties: $500 million; missed-deadline fines; $500,000 for initial inspections; unknown cost of subsequent inspectionsEnd Date: 2007

The scope and fines give this decree legendary status, and it embodied in 2002 an aggressive FDA posture that's similar to its posture today around executive prosecutions. "The agency has allowed itself to get into this situation of issuing warning letter after warning letter to the same company, without taking any action," said Eric Blumberg, the FDA's deputy chief counsel for litigation, in May 2002 when he signed the consent decree. And just this month, in reference to pharma marketing violations, he said, "It's clear we're not getting the job done with large, monetary settlements. Unless the government shows more resolve to criminally charge individuals at all levels in the company, we cannot expect to make progress."

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

GMP violations concerning its albuterol inhaler contributed to this consent decree, which was described in 2002 as a shot across the bow of the pharma industry. The action affected four manufacturing sites and 125 products, about 90 percent of the drug maker's offerings. Production was suspended for 73 of them.

Transgressions spanned the operations spectrum: manufacturing, quality assurance, equipment, laboratories, packaging and labeling.

In addition to the financial penalties levied, the FDA withheld approval of the company's allergy medication Clarinex. Company shares fell 15 percent in a day, and investors filed a $165-million class action suit

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 1993Financial penalties: $10 millionEnd Date: 2005

This is a classic consent decree in all respects but one: Warner Lambert pleaded guilty to charges of intent to defraud and mislead the government, says PRTM. Decrees often spare the company from any admission of wrongdoing.

Conditions included third-party certification of manufacturing process compliance with GMPs.

Certification by consultants also was required for facility laboratories, and lab workers were retrained

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(continued)TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2002Financial penalties: noneEnd Date: 2004

This case involved nonconformance with GMP practices at a facility in Corona, CA. The consent decree stemmed from a 1999 FDA inspection that uncovered poor training, documentation and lab control practices. The regulator wanted assurance that once corrections had been made, the plant would remain compliant with cGMP regulations in the future.

Watson had hired cGMP-compliance consultancy KMI/PAREXEL for the QA overhaul in 2000. No product manufacturing was suspended. Watson added 30 employees to its quality assurance department.

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2000 Financial penalties: $297 million plus 18.5% of salesEnd Date: still pending

This case involves GMP violations at plants in Pennsylvania and New York that were producing FluShield. FDA inspectors identified the issues during plant visits that date back to 1995. Because the flu vaccine was considered a medical necessity, the FDA permitted its manufacture at a noncompliant location but assessed the percentage-of-sales penalty. The product was ultimately discontinued and Wyeth closed two plants

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(continued)

TOP REGULATORY TRENDS: Significant increase in Consent Decrees

Start Date: 2000 Financial penalties: $297 million plus 18.5% of salesEnd Date: still pending

This case involves GMP violations at plants in Pennsylvania and New York that were producing FluShield. FDA inspectors identified the issues during plant visits that date back to 1995. Because the flu vaccine was considered a medical necessity, the FDA permitted its manufacture at a noncompliant location but assessed the percentage-of-sales penalty. The product was ultimately discontinued and Wyeth closed two plants

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Summary

Top CSV Regulatory Challenges and Trends

International Impact of Regulatory findings of CSV and Data Integrity

Quality Control Data

Impact of Mergers and Acquisitions to Business Practices and Quality Systems

Increase in Clinical Trials/Data

Significant increase in Consent Decrees

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Summary

– Find the root cause of issues and OOS

“Human error” and “no root cause” are not

acceptable

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FDA Recent Updates

Updates to FDA Guidances:

Guidance Agenda:

New & Revised Draft Guidances CDER is Planning to Publish DuringCalendar Year 2015

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Summary

Updates to FDA Guidances:

CATEGORY —Electronic Submissions

Providing Regulatory Submissions in Electronic Format – Manufacturing Establishment Information

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Summary

Updates to FDA Guidances:

CATEGORY —Electronic Submissions

• Providing Regulatory Submissions in Electronic Format – Bioanalytical Methods Data Standards

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Where to Get More Information

Other training sessions

www.fda.gov

Guidance Agenda:

New & Revised Draft Guidances CDER is Planning to Publish DuringCalendar Year 2015

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Where to Get More Information

References:

Guidance for Industry – Part 11, Electronic Records; Electronic Signatures – Scope and Application

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Where to Get More Information

References:

21 CFR 211.180(d): General Requirements

21 CFR 211.68: Automatic, Mechanical, and Electronic Equipment

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Question and Answer Session

Q & A

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Speaker Contact Information

Mr. Gaurav Walia

Email Address: [email protected]

Cell Phone Number: (516) 695-6410

AVAILABLE AND READY TO HELP YOUR ORGANIZATION NAVIGATE THROUGH EVEN THE MOST DIFFICULT OF PROBLEMS

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Presented By: Gaurav Walia April 27th, 2015 (Monday)108

Speaker Contact Information

Mr. Gaurav Walia

Email Address: [email protected]

Cell Phone Number: (516) 695-6410

THANK YOU!!!