CGMP for Phase 1 Mar09

8/8/2019 CGMP for Phase 1 Mar09

1/19

Guidance for IndustryGuidance for Industry

CGMP for Phase 1CGMP for Phase 1Investigational DrugsInvestigational Drugs

July 2008July 2008

Center for Drug Evaluation and Research (CDER)Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)Center for Biologics Evaluation and Research (CBER)

Office of Regulatory Affairs (ORA)Office of Regulatory Affairs (ORA)


2/19

Overview: cGMP for Phase 1Overview: cGMP for Phase 1

Past: Applied same standard to all drugs thatPast: Applied same standard to all drugs thatwere be administered to humanswere be administered to humans

July 2008: The manufacture of mostJuly 2008: The manufacture of most

investigational new drugs (IND) used in phase 1investigational new drugs (IND) used in phase 1clinical trials are exempt from complying with 21clinical trials are exempt from complying with 21CFR part 211CFR part 211

Improve the quality of phase 1 investigationalImprove the quality of phase 1 investigationaldrugs and facilitate the initiate of clinical trials indrugs and facilitate the initiate of clinical trials inhumanshumans


3/19

Overview: cGMP for Phase 1Overview: cGMP for Phase 1

Other guidance from FDA:Other guidance from FDA:

INDsINDs------Approaches to Complying with CGMPApproaches to Complying with CGMPDuring Phase 1 dated January 2006 is being issuedDuring Phase 1 dated January 2006 is being issuedconcurrently with a final rule that specifies that 21concurrently with a final rule that specifies that 21CFR part 211 no longer applies for mostCFR part 211 no longer applies for mostinvestigational products, including exploratoryinvestigational products, including exploratoryproducts that are manufactured for use in phase 1products that are manufactured for use in phase 1

Preamble to 21 CFR 210 and 211Preamble to 21 CFR 210 and 211

505(i) of the FD&C Act505(i) of the FD&C Act


4/19

Overview: cGMP for Phase 1Overview: cGMP for Phase 1 Included:Included:

Recombinant and nonRecombinant and non--recombinant productsrecombinant products VaccinesVaccines

Allergenic productsAllergenic products

In vivo diagnosticsIn vivo diagnostics Plasma derivatives Blood and blood components (but mustPlasma derivatives Blood and blood components (but must

comply with 21 CFR 600comply with 21 CFR 600--660)660)

Gene therapy and somatic cellular therapyGene therapy and somatic cellular therapy APIs used in phase 1APIs used in phase 1

Excluded:Excluded: Human cell or tissue productsHuman cell or tissue products

Clinical trials for device approvalClinical trials for device approval

Products manufactured for phase 1 and 2 clinical trialsProducts manufactured for phase 1 and 2 clinical trials

Already approved productsAlready approved products

PET drugs (21 CFR 212)PET drugs (21 CFR 212)


5/19

Overview: CGMP for Phase 1Overview: CGMP for Phase 1 General Points throughout the guideline:General Points throughout the guideline:

Quality and safety maintained by appropriate QCQuality and safety maintained by appropriate QCprocedures, Good scientific and QC principlesprocedures, Good scientific and QC principles

WellWell--defined, written proceduresdefined, written proceduresAdequately controlled equipment and manufacturingAdequately controlled equipment and manufacturing

environmentenvironment

Accurate and consistently recorded data fromAccurate and consistently recorded data from

manufacturing and testingmanufacturing and testing

Drugs must meet appropriate standards ofDrugs must meet appropriate standards ofsafety,safety,identity, strength, quality, and purityidentity, strength, quality, and purity

Use of the wordU

se of the word appropriateappropriate ~ 35 times~ 35 times


6/19

FacilitiesFacilities Can use laboratories that are not expressly or solelyCan use laboratories that are not expressly or solely

designed for their manufacture, can use shareddesigned for their manufacture, can use sharedfacilities, academic institutionsfacilities, academic institutions

Need to conduct a comprehensive and systematicNeed to conduct a comprehensive and systematic

evaluation of the manufacturing setting to identifyevaluation of the manufacturing setting to identifypotential hazardspotential hazards

Focus on contamination and crossFocus on contamination and cross--contamination withcontamination withother substancesother substances

Identify appropriate actions prior to and duringIdentify appropriate actions prior to and duringmanufacturing that eliminate or mitigate those hazardsmanufacturing that eliminate or mitigate those hazards

Assess contract facilities to ensure effective qualityAssess contract facilities to ensure effective qualitycontrol functionscontrol functions How will we document these assessments?How will we document these assessments?


7/19

EquipmentEquipment E

quipment: Disposables, Prepackaged Materials, Closed SystemsE

quipment: Disposables, Prepackaged Materials, Closed Systems Appropriate space, lighting, cooling, ventilation, cooling,Appropriate space, lighting, cooling, ventilation, cooling,

heating, plumbing, washing, and sanitationheating, plumbing, washing, and sanitation

Identify all equipment used for a particular process andIdentify all equipment used for a particular process anddocument it in the recorddocument it in the record

Equipment that will not react with, add to, or be absorbed by theE

quipment that will not react with, add to, or be absorbed by thephase 1 drugphase 1 drug Equipment properly maintained, cleaned, calibrated and sanitizedEquipment properly maintained, cleaned, calibrated and sanitized

following written proceduresfollowing written procedures Procedural controls to prevent contamination and crossProcedural controls to prevent contamination and cross

contaminationcontamination

Air cleanliness suitable to the operationsAir cleanliness suitable to the operations

Use of procedural controls in a facility promotes orderlyUse of procedural controls in a facility promotes orderlymanufacturing and aids in preventing contaminationmanufacturing and aids in preventing contamination


8/19

Personnel and the QC FunctionPersonnel and the QC Function

Personnel need education, experience and trainingPersonnel need education, experience and training Need a written plan that describes the role and responsibilities ofNeed a written plan that describes the role and responsibilities of

the QC functionthe QC function

Examine materials and componentsExamine materials and components Review and approval of manufacturing and testingReview and approval of manufacturing and testing

procedures and acceptance criteriaprocedures and acceptance criteria Releasing or rejecting batchesReleasing or rejecting batches Investigating unexpected results or errorsInvestigating unexpected results or errors

Recommends assigning an individual independent ofRecommends assigning an individual independent ofmanufacturing, howeveradmits thatmanufacturing, howeveradmits that in some small in some smalloperations it may be necessary to have the same individualoperations it may be necessary to have the same individual

perform the manufacturing and the QC functionsperform the manufacturing and the QC functions

Another qualified individual independent of manufacturingAnother qualified individual independent of manufacturing

must conduct periodic reviewsmust conduct periodic reviews


9/19

MaterialsMaterials

Traceable to each batchTraceable to each batch

Records need: receipt date, quantity of shipment.Records need: receipt date, quantity of shipment.

suppliers name, lot number, storage conditions,suppliers name, lot number, storage conditions,and expiration dateand expiration date

Establish criteria and examine certificate ofEstablish criteria and examine certificate of

analysis (COA)analysis (COA)

Identity testing for APIIdentity testing for API


10/19

DocumentationDocumentation

General Records:General Records:

Equipment maintenance and calibrationEquipment maintenance and calibration

Manufacturing records and analytical test recordsManufacturing records and analytical test records Distribution recordsDistribution records

QC Function PlanQC Function Plan

Component recordsComponent records

Deviations and investigationsDeviations and investigations

ComplaintsComplaints


11/19

DocumentationDocumentation

Sufficient records to replicate manufacturing:Sufficient records to replicate manufacturing:

MaterialsMaterials

EquipmentEquipment

Procedures usedProcedures used

Any problems encountered in manufacturingAny problems encountered in manufacturing

Record of changesRecord of changes

Record of microbial controlsRecord of microbial controls


12/19

Laboratory ControlsLaboratory Controls

Scientifically sound: specific, sensitive andScientifically sound: specific, sensitive andaccurateaccurate (but does not use the word(but does not use the wordqualification)qualification)

Specifications for known safetySpecifications for known safety--related concernsrelated concernsshould be established and metshould be established and met

Personnel verify that equipment is in goodPersonnel verify that equipment is in good

working condition (e.g. system suitability)working condition (e.g. system suitability) Stability from date of manufacture through dateStability from date of manufacture through date

of last administrationof last administration


13/19

Packaging, Labeling andPackaging, Labeling and

DistributionDistribution Procedures for product segregation, labelProcedures for product segregation, label

reconciliation, verification of operations by areconciliation, verification of operations by asecond person,second person, confirmatory laboratory testingconfirmatory laboratory testing

and QC reviewand QC review

Distribution record sufficiently detailed to allowDistribution record sufficiently detailed to allow

traceability and facilitate recall.traceability and facilitate recall.


14/19

Special Manufacturing SituationsSpecial Manufacturing Situations

MultiMulti--Product Facilities: Periodically evaluate theProduct Facilities: Periodically evaluate theimplemented procedural control for their effectivenessimplemented procedural control for their effectiveness

Biologics:Biologics:

Testing to reproduce a comparable phase 1 drug, inTesting to reproduce a comparable phase 1 drug, in--processprocessand final product retains for comparisonand final product retains for comparison

Equipment and controls for safetyEquipment and controls for safety--related functions (e.g. viralrelated functions (e.g. viralclearance)clearance)

Testing for safetyTesting for safety--related purposes (viral loads, bioburden,related purposes (viral loads, bioburden,removal of residual substances, etc.)removal of residual substances, etc.)

Adventitious agent controlAdventitious agent control

Alternate approaches allowed for gene therapy (e.g. one batchAlternate approaches allowed for gene therapy (e.g. one batchper patient)per patient)


15/19

Aseptic ProcessingAseptic Processing

References FDA Guidance for Industry: SterileReferences FDA Guidance for Industry: Sterile

Drugs Produced by Aseptic ProcessingDrugs Produced by Aseptic Processing--CurrentCurrentGood Manufacturing Practices.Good Manufacturing Practices.


16/19

cGMPs for Phase 1cGMPs for Phase 1

Other ConsiderationsOther Considerations Where is the clinical trial?Where is the clinical trial?

ICH Q7AICH Q7A EMEAEMEA

Raw material identity testingRaw material identity testing

Quality AgreementsQuality Agreements

QualityUnitQualityUnit FacilityFacility

QP Audits, release of lots, and stability extensionsQP Audits, release of lots, and stability extensions

Expectations of other territoriesExpectations of other territories Expectations of potential partnersExpectations of potential partners

What else will the material be used for?What else will the material be used for? Is it a phase 1/phase 2 trialIs it a phase 1/phase 2 trial


17/19

cGMPs for Phase 1 OthercGMPs for Phase 1 Other

ConsiderationsConsiderations Drug device combination productsDrug device combination products

Need to follow QSR and Design ControlsNeed to follow QSR and Design Controls

Quality Systems and documentation:Quality Systems and documentation:

Use same or different Quality System for Phase 1Use same or different Quality System for Phase 1

Separate Training for Phase 1Separate Training for Phase 1 Assay QualificationAssay Qualification Audit ProgramAudit Program

Document ReviewDocument Review

StaffingStaffing

Additional requirements such as QC plan, hazard assessment,Additional requirements such as QC plan, hazard assessment,multimulti--product use periodic assessment of procedural control,product use periodic assessment of procedural control,

Documentation of scientific rationalDocumentation of scientific rational Where will phase 2 work be done? Is there enough informationWhere will phase 2 work be done? Is there enough information

to ensure an efficient and successful tech transfer?to ensure an efficient and successful tech transfer?


18/19

Contract Manufacturing and TestingContract Manufacturing and Testing

Different Quality Agreement for phase 1contractors, orDifferent Quality Agreement for phase 1contractors, orDevelopment Agreement or Scope of Work?Development Agreement or Scope of Work?

Can you use the pilot or nonCan you use the pilot or non--GMP facility atGMP facility at

contractors? (less $$$ and time constraints)contractors? (less $$$ and time constraints) Documentation practices at contractorDocumentation practices at contractor

Deviation and Change approval practicesDeviation and Change approval practices

Assessment or AuditAssessment or Audit

Use sites you may have not used previouslyUse sites you may have not used previously

New facilities specific to Phase 1New facilities specific to Phase 1


19/19

Impact to Timeline?Impact to Timeline?

Flexibility in facilities uses for manufacturing,Flexibility in facilities uses for manufacturing,

internal and for contract manufacturinginternal and for contract manufacturing

Flexibility in staffingFlexibility in staffing Disposable equipment, less cleaning validationDisposable equipment, less cleaning validation

and change over time for facilitiesand change over time for facilities

Assay qualificationAssay qualification Documentation in the guideline is similar, butDocumentation in the guideline is similar, but

more specific in some areas than 21CFR 211more specific in some areas than 21CFR 211

Documents

CGMP for Phase 1 Mar09