how to face overseas audits

HOW TO FACE OVERSEAS AUDITS

S.M. MUDDA1


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WHY AUDITS ?MANUFACTURER’S PERSPECTIVE

Facing overseas audits and getting the regulatory approval of the importing country is the first requirement any manufacturer, intending to export drugs has to fulfill.


WHY AUDITS ?REGULATORY PERSPECTIVE

Minimizing risks to the health of the consumers in the country importing the drugs is the mandatory responsibility of the regulatory agencies

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WHY AUDITS ?REGULATORY PERSPECTIVE

The guiding philosophy of the regulators for accepting the drugs for import is based on the assumption that drugs not produced under GMP conditions are deemed to be adulterated.

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WHY AUDITS ?


Purpose of the audit therefore is to confirm that adulterated drugs are not allowed to be imported. This is done by verifying that the drugs aremanufactured in accordance with the GMP guidelines/requirements of the importing country

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REGULATORY REQUIREMENTS


Therefore it is essential for the companies to know the regulations of the importing countries as applicable to their products. The developed countries have their own guidelines .e.g.:EU guidelines to Good Manufacturing Practice (Medicinal Products for Human and Veterinary use) October 2005



21 CFR Part 211, Current Good Manufacturing Practice for Finished PharmaceuticalsHowever, the good news is that there has been an attempt of harmonization of the cGMP regulations world wide.

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US FDA under its Pharmaceutical CGMPsfor the 21st Century initiative saw the need to harmonize CGMPS with the globally followed Quality Systems.

As a result of this initiative, FDA has issued a guidance for the industry ‘Quality Systems Approach to Pharmaceutical CGMP Regulations’

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Guidelines of quite a few countries are similar in terms of their expectations for GMP compliance .

While the rest of the world countries have their own guidelines, most of the countries follow WHO GMP guidelines for carrying out the audits.

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PREPARATION FOR THE AUDITS


The first requirement is to have a Management Team working under a well-defined organization chartThe individual identified to lead the inspection is usually the Head of QA and the other key members are:

Head of ProductionHead of Quality Control

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Head of Engineering Services Head of Formulation DevelopmentHead of Regulatory Affairs

Secondly, it should be ensured that the Manufacturing Facility is GMP-compliant

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The basic documents which are required to be kept ready before the audit are:A Site Master File (PIC/S,WHO requirements)Quality ManualOther documents of level 2,3 and 4 of the documentation system

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Documentation for Quality SystemLevel 1:Quality ManualLevel 2:Quality Assurance

ProceduresLevel 3:Work Instructions

(SOP’s)Level4: Forms and Records

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QUALITY MANUAL

Quality Assurance Procedures

(Quality System Procedures) Site Master FileValidation Master Plan

Qualification Protocols & Reports

Validation Protocols & Reports Master Documents Operating

Procedures

Master Formula Record

Batch Manufacturing & Packing Record

Specification & Test Procedures

Stores Procedures Production Procedures

Quality Control Procedures

Maintenance Procedures

Human Resources Procedures

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Product Design & Development Document Design & Development

CAPA

Handling of Discrepancies

Self Inspection

Quality Control

Production & Process Control

Materials Control

Facility / Equipment QUalifcation

Management Organization

Quality Policy

QAP : 001 Management OrganizationQAP : 005 Training of Personnel

Classification of Quality System Procedures

QAP : 006 Procedure for Launch of New ProductsQAP : 007 Product Design and Technology TransferQAP : 008 Product Development for Regulated MarketQAP : 026 Creation and Approval of ArtworksQAP : 031 Stability Studies of Drug ProductsQAP : 034 Handling of Materials for Product

DevelopmentQAP : 035 Process ValidationQAP : 036 Cleaning ValidationQAP : 037 Validation of Analytical MethodQAP : 053 Preparation & Submission of Technical

Dossier for Regulated Markets

QAP : 002 Design & Control of DocumentsQAP : 003 Design of Master DocumentsQAP : 021 Design of Validation DocumentsQAP : 044 Preparation of Site Master FileQAP : 004 Change Control

QAP : 018 Maintenance of EquipmentQAP : 025 CalibrationQAP : 040 Qualification of EquipmentQAP : 041 Handling of Service Contracts

QAP : 009 Item Codification SystemQAP : 010 Vendor ApprovalQAP : 054 Indent and Purchase of Raw

and Packing MaterialQAP : 011 Receipt, Storage & Handling

of Raw & Packing Materials

QAP : 051 Production Planning and ControlQAP : 012 Export Order Review QAP : 038 Post Approval Manufacture of Commercial Scale BatchesQAP : 013 Creation and Completion of BMR & BPRQAP : 014 Manufacturing of Bulk ProductQAP : 015 Packing of Bulk ProductQAP : 017 Receipt, Storage and Handling of Finished Products

QAP : 023 Quality Control of Raw & Packing MaterialQAP : 024 Quality Control of Bulk & Finished ProductsQAP : 045 Handling of Stability Samples for Domestic Market & Reporting Results of AnalysisQAP : 052 Handling of Laboratory MaterialsQAP : 022 Testing of Samples & Reporting of Results of Analysis

QAP : 032 Self - InspectionQAP : 033 Product Quality Review

QAO : 016 Handling of DeviationsQAP : 019 Control of Non-Conforming ProductsQAP : 042 Incident Reporting and Investigation QAP : 027 Handling of Out of Specification (OOS) Test Results QAP : 039 Product RecoveryQAP : 028 Handling of Market ComplaintsQAP : 029 Handling of Adverse Drug Reaction ComplaintsQAP : 030 Product RecallQAP : 020 Handling of Returned Products

QAP : 0043 Corrective and Preventive Action (CAPA)

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Trained ManpowerOperators: For performing the jobs in accordance with written instructionsMiddle Level Managers:To implement the Company’s System ProceduresTop level Managers: To design documents consistent with the regulatory requirements



Conduct mock audits and resolve the

deficienciesSelect a conference room as the meeting placePrior to the inspection bring or have ready to bring all pertinent documentation

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Do a rehearsal with role playingAsk yourselves problem questionsIdentify and clearly archive all GMP/non-GMP documentation

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SCOPE OF THE AUDIT


Opening Meeting

Company Presentation

Production Facility Tour

Utility Visit

On-line Documentation Review19

SCOPE OF THE AUDIT


Quality System Documentation Review

Closing Meeting

Audit Report

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SCOPE OF THE AUDIT


Basic observations during the facility tour are aimed at finding out:Whether the products are being manufactured in a Qualified Facility (Qualified Building, Qualified Production Equipment, Qualified Utilities) using Validated Processes to ensure that products of required quality are manufactured consistently.

SCOPE OF THE AUDIT


Basic observations during the facility tour are aimed at finding out:Possibility of mix-ups of the materials during storage and handling and products during manufacture and handlingPossibility of Cross-Contamination (Important in multi-product facilities)

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SCOPE OF THE AUDIT


Areas of focus during the tour:Personnel and Materials FlowAuditors normally follow the flow of materials and product- in- process. Some start with an external round of the siteWhether entry procedures and gowning practices are adequate

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Whether the Facility finishes are state-of-the artFacility Housekeeping/Sanitation is of high standardsHousekeeping equipment is separately stored and cleaned

SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Whether the men and material entries are well protected from external contamination and Pest Control is in placeReceiving and dispatch bays are provided

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Are all components, raw materials, etc. properly identified?Status Labelling of the Stored Materials Area in Use, Equipment In Use, Materials in Process , Bulk Product , Packed Product is correct?

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Access control for restricted areas are providedSecured storage of raw materials, printed packing materials, intermediate product and finished product is ensured

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Do the instruments and equipment look clean and labelled and stored properly?Calibration Status of Measuring Devices is indicated on the equipmentDaily check on Weighing Balances is performed

SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Standard calibrated weights traceable to national standards are used Is there a preventive maintenance program for:

All processing and packing equipmentAll utilities

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Whether maintenance records are availableEnvironmental Conditions are appropriate to the activities carried outEnvironmental Conditions are monitored and recorded

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?All Activities are carried out in accordance with the authorized written instructionsBatch records used are verified and approved by QA to confirm that they are based on the current approved versions of the Master Formula Records

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?On-line recording of the activities performed is done in the Batch Manufacturing Record (BMR) and signed and dated by the operator and the supervisorIs data in the BMR adequate to demonstrate compliance with the GMP requirements.

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Cursory data in the BMR and reference to many additional records/logs is not appreciated Deviations from the instructions are reported and investigatedNon-standard batch sizes are not accepted

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?Receipt and verification of all materials and product- in-process is done and recordedAll in-process controls are performed and recorded in the BMR

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SCOPE OF THE AUDIT


Areas of focus during the tour:What is looked at?In Quality Control Laboratory reliability of the data is verified:All instruments are calibratedVolumetric solutions are prepared and used correctlyCurrent specifications and work records are used for analyzing the samples

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SCOPE OF THE AUDIT


Review of documentsCurrent Authorized Versions of Documents are under useDo the SOPs describe what is to be done?Do you follow what the SOPs describe?Are the SOPs clear and precise?Are the SOPs available to all manufacturing and support personnel?

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SCOPE OF THE AUDIT


Review of documentsHave the personnel been trained on the pertinent SOPs?Are the training records up-to-dateArea and equipment usage logs are maintained at the place of useEnvironmental monitoring logs are available

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SCOPE OF THE AUDIT


Review of documentsQuality System Documents dealing with the following are checked:

DeviationsChange controlNon-Conforming ProductMarket ComplaintsProduct Recall

SCOPE OF THE AUDIT


Review of documentsQuality System Documents dealing with the following are checked:

Incident ReportingCAPA (Corrective and Preventive Actions)

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INTERACTION WITH THE INSPECTORS


Business-like, Normal ( not under pressure, not too friendly), PoliteCheck and confirm correct name, pronunciation of the name, how he/she would like to be addressedAvoid first names.Form of address as Mr. or Ms. before the surname / family name

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INTERACTION WITH THE INSPECTORS


Do not stand behind the auditor .Do not see over his/her shoulderDo not talk / chat with others during the auditOne nominated person should accompany and deal with the inspector who should be either the Head of Q A or the unit head but not certainly any administrative /marketing executive

HOW TO ANSWER THE QUESTIONS ?


Understand the question and ask politely to repeat the question, if not followedDo not panic !Be honestAnswer the questionDo not volunteer information

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Identify the problem clearlyWas anything done earlierWhat can be done nowWhat is to be done in the near futureWhat can be done to prevent a recurrenceTry not to react to the situation with aimmediate corrective action

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Identify “confidential” documentsMake two copies of every document that is requested and retain one copyTake good notes of the observations made / discussions heldEnsure that the context of the observations is clearly understood and explained



What arouses suspicion?Batch production records look neatEvasive or nebulous answersSeveral SOPs revised on same dateConfusion among employees

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What arouses suspicion?Not clear on dates started or stopped for productionHold times not justifiedEye contact or body language

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POST AUDIT ACTIONS


During the exit meetingAssemble a pertinent teamListenTake notesAsk questionsClarify observationsDiscussIf corrected state as such

POST AUDIT ACTIONS


Do not make commitments that can not be keptAgree to reasonable timelinesManagement can challenge observationsProvide supporting documentation

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POST AUDIT ACTIONS


Reconvene to discuss observationsPrepare response to deficienciesAddress promised/agreed to corrective actionsPrepare strategies to close out inspectionCommunicate with agencyCommunicate proactively!

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DO’S AND DONT’S


DO’S:Follow the instructions given in this presentationBe SincereShow keenness in respondingAccept suggestions Honestly accept if something is not done

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DO’S AND DONT’S


DONT’S:Never argueNever engage in discussion on unrelated matters during the auditDo not try to cover upDo not show- offDo not justify any point by being defensive

HOW TO FACE OVERSEAS AUDITSA final word:

Do not consider audits as a burden but an opportunity to learn and improve

Be proud to show your facility, documentation and demonstrate your commitment to CGMP

Be positive and enjoy the experience

If you follow this approach the approval of your facility is in your hands

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THANK YOU FOR YOUR ATTENTION

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