Lyophilization Processes Jan 05

8/9/2019 Lyophilization Processes Jan 05

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Lyophilization Processes:Lyophilization Processes:

A Compliance/EnforcementA Compliance/Enforcement

PerspectivePerspective

Anne Johnson, Compliance OfficerAnne Johnson, Compliance Officer

Office of Regulatory Affairs/Office of EnforcementOffice of Regulatory Affairs/Office of EnforcementDivision of Compliance Management and OperationsDivision of Compliance Management and Operations

DELAWARE VALLEY CHAPTER MEETING of the

INTERNATIONAL SOCIETY OF LYOPHILIZATION

PLYMOUTH MEETING, PA JANUARY 25, 2005


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OBJECTIVESOBJECTIVES

Organizational Structure of FDA ComplianceOrganizational Structure of FDA Compliance

FDAs Regulatory Options/Enforcement PostureFDAs Regulatory Options/Enforcement Posture

Specific Examples of DeviationsSpecific Examples of Deviations

Written ResponsesWritten Responses

Dispute ResolutionDispute Resolution


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OFFICE OF REGULATORYOFFICE OF REGULATORY

AFFAIRSAFFAIRS


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FDA DISTRICTFDA DISTRICT

ORA DISTRICT INVESTIGATORORA DISTRICT INVESTIGATOR

ORA DISTRICT COMPLIANCE BRANCHORA DISTRICT COMPLIANCE BRANCH

APPROPRIATE CENTER FOR REVIEW ANDAPPROPRIATE CENTER FOR REVIEW ANDCONCURRENCE (CDER)CONCURRENCE (CDER)

OFFICE OF CHIEF COUNSELOFFICE OF CHIEF COUNSEL

ORA OFFICE OF ENFORCEMENT (HIGHERORA OFFICE OF ENFORCEMENT (HIGHERACTIONS SUCH AS INJUNCTIONS, ETC.)ACTIONS SUCH AS INJUNCTIONS, ETC.)


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FDA DISTRICTSFDA DISTRICTS

LETTER ISSUED OR ACTION EXECUTEDLETTER ISSUED OR ACTION EXECUTED

BY ORA DISTRICT STAFFBY ORA DISTRICT STAFF

RESPONSES AND COMMUNICATIONSRESPONSES AND COMMUNICATIONS

COORDINATED WITH DISTRICT STAFFCOORDINATED WITH DISTRICT STAFF


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TEAM BIOLOGICSTEAM BIOLOGICS -- InspectionsInspections

SPECIALIZED GROUP OF ORA INVESTIGATORSSPECIALIZED GROUP OF ORA INVESTIGATORSTHAT REPORT TO ORAs OFFICE OF REGIONALTHAT REPORT TO ORAs OFFICE OF REGIONALOPERATIONSOPERATIONS

PRODUCTS COVERED:PRODUCTS COVERED:

Vaccines, Allergenic Products, Plasma FractionatedVaccines, Allergenic Products, Plasma FractionatedProducts, In Vitro Diagnostic Products, andProducts, In Vitro Diagnostic Products, andTherapeutic Products (CBER and CDER)Therapeutic Products (CBER and CDER)

Domestic and Foreign EstablishmentsDomestic and Foreign Establishments


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TEAM BIOLOGICSTEAM BIOLOGICS -- ComplianceCompliance

SPECIALIZED GROUP OF ORA COMPLIANCE OFFICERSSPECIALIZED GROUP OF ORA COMPLIANCE OFFICERSTHAT REPORT TO ORAS OFFICE OF ENFORCEMENTTHAT REPORT TO ORAS OFFICE OF ENFORCEMENT

REVIEW AND EVALUATE INSPECTIONS PERFORMED BYREVIEW AND EVALUATE INSPECTIONS PERFORMED BYTEAM BIOLOGICS INVESTIGATORSTEAM BIOLOGICS INVESTIGATORS

WORK CLOSELY WITH CBER AND CDER COMPLIANCEWORK CLOSELY WITH CBER AND CDER COMPLIANCE

SUBJECT TO OCC REVIEW PROCEDURESSUBJECT TO OCC REVIEW PROCEDURES


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CENTER COMPLIANCECENTER COMPLIANCE

CBER OFFICE OFCBER OFFICE OFCOMPLIANCE ANDCOMPLIANCE ANDBIOLOGICS QUALITYBIOLOGICS QUALITY

CDER OFFICE OFCDER OFFICE OFCOMPLIANCECOMPLIANCE


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REGULATORY OPTIONSREGULATORY OPTIONS

ADVISORY ACTIONSADVISORY ACTIONS

UNTITLED LETTERSUNTITLED LETTERS

The agency has a need to communicate withThe agency has a need to communicate withregulated industry about documentedregulated industry about documented

violations that do not meet the threshold ofviolations that do not meet the threshold ofregulatory significanceregulatory significance


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REGULATORY OPTIONSREGULATORY OPTIONS

ADVISORY ACTIONS (contd):ADVISORY ACTIONS (contd):

WARNING LETTERSWARNING LETTERS

A Warning Letter is a written communication from FDAA Warning Letter is a written communication from FDAnotifying an individual or firm that the agency considersnotifying an individual or firm that the agency considersone or more products, practices, processes, or otherone or more products, practices, processes, or otheractivities to be in violation of the Federal FD&C Act, oractivities to be in violation of the Federal FD&C Act, orother acts, and that failure of the responsible party toother acts, and that failure of the responsible party to

take appropriate and prompt action to correct andtake appropriate and prompt action to correct andprevent any future repeat of the violation, may result inprevent any future repeat of the violation, may result inadministrative and/or regulatory enforcement actionadministrative and/or regulatory enforcement actionwithout further notice.without further notice.


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ENFORCEMENT POSTUREENFORCEMENT POSTURE

CONSUMER ACCESS TO SAFE ANDCONSUMER ACCESS TO SAFE AND

EFFECTIVE PRODUCTSEFFECTIVE PRODUCTS

VOLUNTARY CORRECTIONVOLUNTARY CORRECTION


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PRODUCTSPRODUCTS SCOPE AND IMPACTSCOPE AND IMPACT

PRIOR HISTORYPRIOR HISTORY VERY IMPORTANTVERY IMPORTANT PREVIOUS INSPECTIONAL FINDINGSPREVIOUS INSPECTIONAL FINDINGS

RESPONSESRESPONSES

EFFECTIVENESS OF CORRECTIVE ACTIONS ANDEFFECTIVENESS OF CORRECTIVE ACTIONS ANDPREVENTATIVE MEASURESPREVENTATIVE MEASURES

ADVISORY AND ENFORCEMENT ACTIONSADVISORY AND ENFORCEMENT ACTIONS


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IMPORT ACTIVITIESIMPORT ACTIVITIES

ALERTSALERTS

DETENTION OF PRODUCTDETENTION OF PRODUCT

REFUSAL OF ENTRYREFUSAL OF ENTRY


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VIOLATION EXAMPLESVIOLATION EXAMPLES

a temperature distribution study toa temperature distribution study to

assure that all shelves of the lyophilizersassure that all shelves of the lyophilizersobtain and maintain a temperature ofobtain and maintain a temperature of --40C during freeze drying operations has40C during freeze drying operations hasnot been performednot been performed


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The lyophilization cycle for the vialThe lyophilization cycle for the vialconfiguration has not been validated.configuration has not been validated.


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Failure to notify FDAofchanges inFailure to notify FDAofchanges in

equipment and the product process forequipment and the product process foryour productin that:a sixyour productin that:a sixshelflyophilizer was installed and is beingshelflyophilizer was installed and is beingutilized in the freeze drying of yourutilized in the freeze drying of your

product.product.


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lyophilizerdid not achieve the specifiedlyophilizerdid not achieve the specified

pressure during primary dryingPartiallypressure during primary dryingPartiallystoppered product vials were storedforstoppered product vials were storedfor62 hours inside lyophilizerno62 hours inside lyophilizernodocumentation that the impactwasdocumentation that the impactwas

evaluatedevaluated


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the lyophilization cyclethe lyophilization cycle currentlycurrently ininusehas not been validatedusehas not been validated


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process validation was performed using

process validation was performed usingdata from eight lyophilization runs. Threedata from eight lyophilization runs. Three

lots were rejected, and one lot was notlots were rejected, and one lot was notreleasedreleased


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Failure to validate processes which can notFailure to validate processes which can notbe verified by subsequent inspection inbe verified by subsequent inspection inthat the lyophilization process has notthat the lyophilization process has notbeen validated.been validated.


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RESPONSESRESPONSES

1.1. Clear understanding of the deviation/violationClear understanding of the deviation/violation

2.2. If you dont agree, then say so. Explain yourIf you dont agree, then say so. Explain your

reasoningreasoning

How and when???How and when???

-- During the inspection,During the inspection,

-- At the closeout,At the closeout,

-- In your written response.In your written response.


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RESPONSESRESPONSES

An evaluation of the deviation/violation thatAn evaluation of the deviation/violation thatincludes:includes:

-- the specific incident(s) citedthe specific incident(s) cited

-- impact on product(s) or process(es)impact on product(s) or process(es)

-- specific corrective actions for thatspecific corrective actions for thatincidentincident


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RESPONSESRESPONSES

-- possibility of other affected lots, products,possibility of other affected lots, products,

processes, manufacturing locationsprocesses, manufacturing locations

-- affected marketed lots/productsaffected marketed lots/products

-- global corrective actions, employeeglobal corrective actions, employeetraining, SOP revisions, etc.training, SOP revisions, etc.


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Dispute ResolutionDispute Resolution

Policies and procedures that would allowPolicies and procedures that would allow

rapidrapid,, objectiveobjective resolution ofresolution ofscientificscientificandand technicaltechnicalquestions and issues thatquestions and issues thatmay arise either during an inspection or asmay arise either during an inspection or asthe result of an inspection.the result of an inspection.


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WHO MAY DISPUTE?WHO MAY DISPUTE?

The Manufacturer or Establishment thatThe Manufacturer or Establishment thatwas inspected.was inspected.

Domestic or International EntityDomestic or International Entity

Human and Veterinary DrugsHuman and Veterinary Drugs

Human Biological DrugsHuman Biological Drugs


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WHY WOULD YOU DISPUTE?WHY WOULD YOU DISPUTE?

A SATISFACTORY RESOLUTION COULDA SATISFACTORY RESOLUTION COULDNOT BE OBTAINED DURING THENOT BE OBTAINED DURING THEINSPECTION(complexity, etc)INSPECTION(complexity, etc)

-- ANDAND --

THE FDATHE FDA--483 HAS BEEN ISSUED483 HAS BEEN ISSUED


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What May Be Disputed?What May Be Disputed?

A Scientific or Technical Issue related toA Scientific or Technical Issue related toGood Manufacturing PracticesGood Manufacturing Practices AdequacyAdequacy

AppropriatenessAppropriateness InterpretationInterpretation

A Scientific or Technical Issue RaisedA Scientific or Technical Issue Raised

During an InspectionDuring an InspectionGMP [CBER/CDER/CVM] orGMP [CBER/CDER/CVM] or

PAIPAI [CDER/CVM][CDER/CVM]


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What May Not Be Disputed?What May Not Be Disputed?

Precise Requirements of the regulationsPrecise Requirements of the regulationsor in an Approved Applicationor in an Approved Application

Issues Not Raised During An InspectionIssues Not Raised During An Inspection

Procedural or Administrative IssuesProcedural or Administrative Issues

Writing style/wording differencesWriting style/wording differences


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WHEN CAN YOU DISPUTE?WHEN CAN YOU DISPUTE?

DURING THE INSPECTION, FDADURING THE INSPECTION, FDA

STRONGLY ENCOURAGES OPENSTRONGLY ENCOURAGES OPENDIALOGUE ON ALL ISSUES BY AND WITHDIALOGUE ON ALL ISSUES BY AND WITHTHE INSPECTION TEAM IN HOPES TOTHE INSPECTION TEAM IN HOPES TOHAVE ALL ISSUES UNDERSTOOD ANDHAVE ALL ISSUES UNDERSTOOD AND

RESOLVED, IN THE MOST EFFICIENTRESOLVED, IN THE MOST EFFICIENTMANNER.MANNER.


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WHEN?WHEN?

TIERTIER--1: WITHIN 10 BUSINESS DAYS OF1: WITHIN 10 BUSINESS DAYS OFTHE ISSUANCE OF THE 483THE ISSUANCE OF THE 483

TIERTIER--2: WITHIN 60 DAYS OF RECEIPT2: WITHIN 60 DAYS OF RECEIPTOF THE TIEROF THE TIER--1 DECISION1 DECISION

Failure to adhere to these time frames couldFailure to adhere to these time frames couldresultinarefusalto considerresultinarefusalto consider


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TIERTIER--1: Initial Request For Resolution1: Initial Request For Resolution

1.1. Nature of dispute in written formatNature of dispute in written format

2.2. Include supporting documentationInclude supporting documentation **

*This should not include any information that was not*This should not include any information that was notpresented to the Inspection Team during thepresented to the Inspection Team during theinspection.inspection.


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TIERTIER--1 Process1 Process

ORA Review and EvaluationORA Review and Evaluation

Written response within 30 days:Written response within 30 days:

We agree with youWe agree with you

We disagree with youWe disagree with youYou request does not qualify orYou request does not qualify or

additional review time is neededadditional review time is needed


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TIERTIER--22 APPEAL INITIAL DECISIONAPPEAL INITIAL DECISION

1.1. Must be in written formatMust be in written format

2.2. Request resolution by D.R. PanelRequest resolution by D.R. Panel

3.3. Nature of continuing disputeNature of continuing dispute

4.4. Include supporting documentsInclude supporting documents


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Dispute Resolution PanelDispute Resolution Panel

Panel Membership (integrated and neutralPanel Membership (integrated and neutral nonopreviously involved decision makers)previously involved decision makers)

Decide to accept, review, and evaluateDecide to accept, review, and evaluate

Dispute is reviewed during Panel MeetingsDispute is reviewed during Panel Meetings


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D.R. Panel Review and EvaluationD.R. Panel Review and Evaluation

Written response within 30 days:Written response within 30 days:

We agree with youWe agree with you

We disagree with youWe disagree with youYou request does not qualify orYou request does not qualify or

additional review time is neededadditional review time is needed


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FINAL DECISIONSFINAL DECISIONS

TIERTIER--1 and TIER1 and TIER--22

The Program Center is notified and makesThe Program Center is notified and makesdecision available for public dissemination,decision available for public dissemination,to promote consistency of application andto promote consistency of application andinterpretation.interpretation.


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ReferencesReferences

Warning Letters are posted at:Warning Letters are posted at: www.fda.govwww.fda.gov

Inspectional Guidances:Inspectional Guidances:

www.fda.gov/ora/inspect_refwww.fda.gov/ora/inspect_ref

Title 21 Code of Federal Regulations (CFR)Title 21 Code of Federal Regulations (CFR)

Draft Dispute Resolution Procedures:Draft Dispute Resolution Procedures:www.fda.gov/cder/guidance/5804dft.htmwww.fda.gov/cder/guidance/5804dft.htm

Lyophilization Processes Jan 05

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