CMC Review and CMC Review and Manufacturing (CGMP) Manufacturing (CGMP)

in Investigational Products in Investigational Products

Chris Joneckis, Ph.D.Chris Joneckis, Ph.D.Senior Advisor For CMC IssuesSenior Advisor For CMC Issues

Center For Biologics Evaluation And Research Center For Biologics Evaluation And Research

Add FDA Bar and

NIAID/ NIHNIAID/ NIHApril 15, 2005April 15, 2005

Presentation Overview• Chemistry Manufacturing and Control (CMC)Chemistry Manufacturing and Control (CMC)

– General Principles & ApproachGeneral Principles & Approach– Information to submit in an INDInformation to submit in an IND

• Good Manufacturing Practices (GMPs)Good Manufacturing Practices (GMPs)– General Principles & ApproachGeneral Principles & Approach– Specific ConsiderationsSpecific Considerations

• Focus mostly on biologics and biotechnology products in early phase Focus mostly on biologics and biotechnology products in early phase of clinical studyof clinical study

• Product class, specific product can influences CMC information to Product class, specific product can influences CMC information to submit and approach to CGMPsubmit and approach to CGMP

• Consult – Guidance & CBER group responsible for review of your Consult – Guidance & CBER group responsible for review of your productproduct

Whole Whole BloodBlood

BloodBloodComponentsComponents

Blood Derivatives and Blood Derivatives and Recombinant AnaloguesRecombinant Analogues

SomaticSomaticCellular & GeneCellular & Gene

TherapiesTherapies

TissuesTissues

Therapeutic VaccinesTherapeutic Vaccines

Allergenic ExtractsAllergenic ExtractsProphylactic VaccinesProphylactic Vaccines

XenotransplantationXenotransplantation TransgenicTransgenic

DevicesDevices

Biologics Regulated by CBEROBRROBRR OVRROVRR

OCTGTOCTGTDevicesDevices

CMC/ CGMP Goals in Clinical Investigation

• Assure safe investigational products Assure safe investigational products – Assure quality of investigational productAssure quality of investigational product

• Ability to reproduce investigational product, Ability to reproduce investigational product, as needed – assure desired quality of as needed – assure desired quality of investigational productinvestigational product– Within a trialWithin a trial– Between trialsBetween trials– Throughout clinical/ product development to Throughout clinical/ product development to

commercial manufacture commercial manufacture

CMC/ CGMP Goals in Clinical Investigation

• Establishing the relationship between the Establishing the relationship between the manufacturing process and resulting product used in manufacturing process and resulting product used in clinical studies (especially pivotal studies - Phase 3) clinical studies (especially pivotal studies - Phase 3) and the process and product to be commercially and the process and product to be commercially marketedmarketed– Process controls and product quality characteristics/ Process controls and product quality characteristics/

attributes attributes

• UltimatelyUltimately, develop an established manufacturing , develop an established manufacturing process assuring consistent production of a process assuring consistent production of a defined quality product for commercial productiondefined quality product for commercial production

Source MaterialSource MaterialComponentsComponentsDescription ofDescription of Manufacturing ProcessManufacturing ProcessSafety-relatedSafety-related Process Controls/ DataProcess Controls/ DataAnalytical Methods/ SpecsAnalytical Methods/ SpecsStabilityStability

Personnel Quality Control FacilitiesEquipment Laboratory Control Component ControlProduction ControlDistribution RecordsLabeling

CGMPCGMPInspectionInspection[21 CFR 210, 211][21 CFR 210, 211]

CMC INDCMC INDReviewReview[21 CFR 312][21 CFR 312]

Control of Investigational ProductControl of Investigational Product

CompanionCompanion

Parameter Considerations

Manufacturing Living sourcesComplex processSensitive to change & environmental influencesLarge amount of variability

Contaminants/ Impurities Subject to contaminationViral/bacteria/fungal/TSE AgentProduct and Process Substances Difficult to define and quantitative

Structure Multiple speciesActive Ingredient Varying Complexity, HeterogeneousCharacterization Ability to be Characterized

Method Limitations

Major Considerations For Biological Products

Implications of Manufacturing a Biologic

–Requires thorough description, characterization, Requires thorough description, characterization, and testing starting with source materials and and testing starting with source materials and components used throughout manufacturingcomponents used throughout manufacturing

–Greater reliance on manufacturing process controlGreater reliance on manufacturing process control–Careful description and evaluation of Careful description and evaluation of

manufacturing changes made during development manufacturing changes made during development for potential product impact - safety and risk for potential product impact - safety and risk assessment assessment

Difficult to distinguish quality change that can Difficult to distinguish quality change that can impact safetyimpact safety

Chemistry Manufacturing and Controls(CMC)

General Principles

“ “FDA’s primary objectives in reviewing an IND FDA’s primary objectives in reviewing an IND are, are, in all phase of the investigationin all phase of the investigation,, to assure to assure the the safetysafety and rights of subjects, … FDA’s and rights of subjects, … FDA’s review of Phase 1 submissions will focus on review of Phase 1 submissions will focus on assessing the safety of Phase 1 assessing the safety of Phase 1 investigationsinvestigations…, …, [21 CFR, 312.22(a)][21 CFR, 312.22(a)]

General Principles

“ “The amount of information on a particular drug The amount of information on a particular drug that must be submitted in an IND to assure the that must be submitted in an IND to assure the accomplishments of the objectives… accomplishments of the objectives… {safety & {safety & quality}quality} …depends upon such factors as the …depends upon such factors as the novelty of the drugnovelty of the drug, , the extent to which it has the extent to which it has been studied previouslybeen studied previously, , the known or the known or suspected riskssuspected risks and the and the developmental phase of developmental phase of the drugthe drug.”.” [21 CFR, 312.22(b)][21 CFR, 312.22(b)]

General Principles “ “ Although in each phase of the investigation Although in each phase of the investigation sufficient informationsufficient information is required to be is required to be submitted to assure the proper identification, submitted to assure the proper identification, quality, purity, and strength of the quality, purity, and strength of the investigational drug, investigational drug, the amount of the amount of informationinformation needed to make that assurance needed to make that assurance will will vary with the phase of the investigation, vary with the phase of the investigation, the dosage form, and the amount of the dosage form, and the amount of information otherwise availableinformation otherwise available.”.” [21 CFR 312.23 [21 CFR 312.23 (a)(7)(i)](a)(7)(i)]

Phase 1 Considerations• CMC safety issues as they relate to the quality CMC safety issues as they relate to the quality

aspects of productaspects of product• What is the risk for human subjects? Are there any What is the risk for human subjects? Are there any

signals from preclinical studies?signals from preclinical studies?• The product class and the individual product affect, The product class and the individual product affect,

to some extent, the type and extent of information to some extent, the type and extent of information needed to assess safetyneeded to assess safety– Often novel and complex products require additional Often novel and complex products require additional

information to address unknowns and added complexity information to address unknowns and added complexity (e.g., transgenic, xenotransplantation)(e.g., transgenic, xenotransplantation)

Source MaterialSource MaterialComponentsComponentsDescription ofDescription of Manufacturing ProcessManufacturing ProcessSafety-relatedSafety-related Process Controls/ DataProcess Controls/ DataAnalytical Methods/ Analytical Methods/ SpecificationsSpecificationsStabilityStability

CMC INDCMC INDReviewReview

Control of Investigational ProductControl of Investigational Product

CMC Content – Source Material• Cells, Viruses, Banking Systems Cells, Viruses, Banking Systems

– Origin/ Method of collectionOrigin/ Method of collection– History (potential exposure)History (potential exposure)– Manipulation, establishment of banks, cryopreservation Manipulation, establishment of banks, cryopreservation – Testing – Source/ source materialTesting – Source/ source material

(e.g., Microbiology, endogenous/ adventitious agents, (bovine/ porcine), (e.g., Microbiology, endogenous/ adventitious agents, (bovine/ porcine), identity, purity, activity, replication competent viruses)identity, purity, activity, replication competent viruses)

• Genetic materialGenetic material– OriginOrigin– Gene modification, construction of vector, purification Gene modification, construction of vector, purification – Testing (e.g., sequencing) Testing (e.g., sequencing)

CMC Content Source Material

• Evaluation Evaluation – Risk assessment of parent cells - history, potential exposure to viral Risk assessment of parent cells - history, potential exposure to viral

agents agents – Screening donors for risk factors, absence of disease markers Screening donors for risk factors, absence of disease markers

• Testing for viruses Testing for viruses – Endogenous virus testing Endogenous virus testing – Donors, animals, host cells, cell banks, EPCDonors, animals, host cells, cell banks, EPC– General and Species specific testsGeneral and Species specific tests– FDA-approved tests if available FDA-approved tests if available

• Control Control – Establishing & maintaining cell banks, viral seeds under cGMP’sEstablishing & maintaining cell banks, viral seeds under cGMP’s– Establishing plasma donor deferral roles for unsuitable donorsEstablishing plasma donor deferral roles for unsuitable donors– Closed herds & flocks, sentinel animalsClosed herds & flocks, sentinel animals– Quarantine until testing and control assures and establishes safetyQuarantine until testing and control assures and establishes safety

CMC Contents - Components• All components (e.g., raw materials, excipients, reagents, All components (e.g., raw materials, excipients, reagents,

ancillary products) used in productionancillary products) used in production– Safety and quality of materialSafety and quality of material– Source, screening, testing Source, screening, testing – Use in process, (evaluated in context of use)Use in process, (evaluated in context of use)– Known/ potential toxicitiesKnown/ potential toxicities

Penicillin, MTX, residual chemicalsPenicillin, MTX, residual chemicals What is the amount in final product? Consider testing, qualification study What is the amount in final product? Consider testing, qualification study

– FDA-approved products (e.g., albumin) preferredFDA-approved products (e.g., albumin) preferred– Clinical-grade reagents preferredClinical-grade reagents preferred

• Combination products (biologic, drug, device)Combination products (biologic, drug, device)• Develop qualification program during development Develop qualification program during development

TSE’s• Ruminant-derived materials (e.g., bovine origin)Ruminant-derived materials (e.g., bovine origin)

– Avoidance of animal (human) derived materials, if at all Avoidance of animal (human) derived materials, if at all possiblepossible

– Assure material from BSE-free country “The list” Assure material from BSE-free country “The list” [USDA 9 CFR [USDA 9 CFR 94.18]94.18]

– Identify country of origin, tissue source, supplier, stage of Identify country of origin, tissue source, supplier, stage of manufacture manufacture

– Maintain traceable recordsMaintain traceable records– Don’t forget to test for viral agents [e.g., 9 CFR] provides Don’t forget to test for viral agents [e.g., 9 CFR] provides

useful thoughts for assessment – not a requirementuseful thoughts for assessment – not a requirement• What about the next country to make the list ?What about the next country to make the list ?

– Emphasis on avoidance Emphasis on avoidance – Secondly, risk assessment of material Secondly, risk assessment of material

CMC Content - Manufacturing Process & Process Controls

• Description of the manufacturing process - Drug Description of the manufacturing process - Drug Substance & Drug Product Substance & Drug Product – Method of preparation, including:Method of preparation, including:

complete complete description covering source, expression description covering source, expression methods, production, materials and components, culture, methods, production, materials and components, culture, purification, formulation, finishing, storage periods and purification, formulation, finishing, storage periods and conditionsconditions

description of differences in manufacturing for DS & DP in description of differences in manufacturing for DS & DP in preclinical studies vs. clinical studies (if performed)preclinical studies vs. clinical studies (if performed)

– Adequate description of process controls for process steps Adequate description of process controls for process steps especially those that directly affect safety (e.g., virus especially those that directly affect safety (e.g., virus inactivation, vaccine attenuation, cell irradiation)inactivation, vaccine attenuation, cell irradiation)

– Data demonstrating that safety–related processes are Data demonstrating that safety–related processes are effective when operated within manufacturing controlseffective when operated within manufacturing controls

CMC Content - Analytical Procedures• Appropriate testingAppropriate testing

– Description of tests, analytical procedures & acceptance Description of tests, analytical procedures & acceptance criteria (Specification) criteria (Specification)

– Testing throughout manufacturing - source material, Testing throughout manufacturing - source material, components, intermediates, in–process manufacturing, DS & components, intermediates, in–process manufacturing, DS & DP, stability DP, stability

• Appropriate acceptance criteria may not be known for all Appropriate acceptance criteria may not be known for all materials and all testsmaterials and all tests– May have “report results, “broader criteria”May have “report results, “broader criteria”– Establish acceptance criteria for known (suspected) safety-Establish acceptance criteria for known (suspected) safety-

related tests (e.g., source materials, components, lot release related tests (e.g., source materials, components, lot release DS/DP)DS/DP)

CMC Content - Analytical Procedures• Appropriate description- Drug Substance, Drug ProductAppropriate description- Drug Substance, Drug Product

– Characterization Testing (structural, physiochemical, immunological) Characterization Testing (structural, physiochemical, immunological) – Release TestingRelease Testing

Identity, Identity, Purity - process and product Purity - process and product Potency – bioactivity – representative of mechanism of action, Potency – bioactivity – representative of mechanism of action, Strength - concentration Strength - concentration Microbiological, Microbiological,

– Sterility – (modified USP method – alternate microbial methods) methodsSterility – (modified USP method – alternate microbial methods) methods– Mycoplasma -Mycoplasma -– EndotoxinEndotoxin

• Submission of test results on preliminary/ available lots (e.g., Submission of test results on preliminary/ available lots (e.g., preclinical studies/ lots used in clinical studies) - dependspreclinical studies/ lots used in clinical studies) - depends

CMC Content -Testing - SterilityCMC Content -Testing - Sterility

• Sterility of the Cell Banks, Product, and Sterility of the Cell Banks, Product, and Placebo must be demonstrated by testing for Placebo must be demonstrated by testing for viable organisms (bacteria & fungi)viable organisms (bacteria & fungi)

• Recommend following 21CFR 610.12 Recommend following 21CFR 610.12 (modified USP method)(modified USP method)– Suitability for Use - Interference from Test Article Suitability for Use - Interference from Test Article

• What about short-lived biologics, other What about short-lived biologics, other situations (e.g., cell therapies)?situations (e.g., cell therapies)?

CMC Content - Testing - SterilityCMC Content - Testing - Sterility

• Possible exceptions for cellular therapies, Possible exceptions for cellular therapies, (discuss options with CBER):(discuss options with CBER):

• Cell therapiesCell therapies– Gram-stain/ Follow-up with culture testGram-stain/ Follow-up with culture test– Action plan-based upon subsequent positive Action plan-based upon subsequent positive

contamination in sterility test after cell contamination in sterility test after cell administrationadministration

Patient/physician notification, investigation, speciation Patient/physician notification, investigation, speciation

• Rapid Microbial MethodsRapid Microbial Methods

Testing - MycoplasmaTesting - Mycoplasma

• Mycoplasma - test for cultivable and Mycoplasma - test for cultivable and non-cultivablenon-cultivable

• Options for non-culture test:Options for non-culture test:– Hoechst stainHoechst stain– PCRPCR– Newer methodsNewer methods

CMC – Content Testing Endotoxin CMC – Content Testing Endotoxin (pyrogenicity)(pyrogenicity)

• OptionsOptions– Limulus Amebocyte Lysate (LAL) test orLimulus Amebocyte Lysate (LAL) test or– Rabbit-pyrogenicity test (21CFR 610.13(b)) Rabbit-pyrogenicity test (21CFR 610.13(b))

• Final products - acceptable levels (LAL)Final products - acceptable levels (LAL)– 5 Endotoxin units (EU) per kg body weight per hour for parenteral administration5 Endotoxin units (EU) per kg body weight per hour for parenteral administration– 0.2 EU per kg body weight per hour for intrathecal administration0.2 EU per kg body weight per hour for intrathecal administration

CMC Content - Stability Studies• Investigational product should be stable during planned duration of Investigational product should be stable during planned duration of

clinical studies – need to conduct stability in all phases clinical studies – need to conduct stability in all phases [21 CFR [21 CFR 312.23(a)(7)(ii)]312.23(a)(7)(ii)]

• Recommended to submit information to support stability - dependsRecommended to submit information to support stability - depends– Knowledge of product class and stability Knowledge of product class and stability – Unusual situation, labile product, unknown product class Unusual situation, labile product, unknown product class – Preliminary stability test results may be acceptablePreliminary stability test results may be acceptable

• Description of stability testingDescription of stability testing– Typically, a subset of release testing Typically, a subset of release testing – For some products consider accelerated stability for major changes in For some products consider accelerated stability for major changes in

(Phase 2/ 3)(Phase 2/ 3)– Establish a real-time, real-condition stability protocolEstablish a real-time, real-condition stability protocol

Phase 1 Considerations

• How some information is reported may influence How some information is reported may influence the type and extent of other information that the type and extent of other information that should be provided should be provided

• Issues associated with specific productsIssues associated with specific products– Known labile productKnown labile product– Substantial time elapsed from manufacture and testingSubstantial time elapsed from manufacture and testing– Product used in preclinical studies different from that in Product used in preclinical studies different from that in

clinical studies clinical studies – Combination products (drug, device, biologic)Combination products (drug, device, biologic)

IND Clinical Hold

“ “Human subjects are or would be exposed to Human subjects are or would be exposed to an unreasonable and significant risk of illness an unreasonable and significant risk of illness or injuryor injury.” .” [21 CFR 312.42 (b) (1) (i)][21 CFR 312.42 (b) (1) (i)]

““The IND does not contain The IND does not contain sufficient information sufficient information required under 312.23 to assess the risks to required under 312.23 to assess the risks to subjectssubjects of the proposed studies.” of the proposed studies.” [21 CFR 312.42 [21 CFR 312.42

(b) (1) (iv)] (b) (1) (iv)]

• Absent, inadequate or incomplete informationAbsent, inadequate or incomplete information– Variety of CMC content information described, including Variety of CMC content information described, including

Incomplete description of the manufacturing processIncomplete description of the manufacturing process Information on animal-derived components not providedInformation on animal-derived components not provided Sourcing and history information - “Source Material” Sourcing and history information - “Source Material” Description and results of adventitious agent safety testing Description and results of adventitious agent safety testing

information - componentsinformation - components Lack of detailed testing procedure – in- process and final productLack of detailed testing procedure – in- process and final product Inadequate product release testing Inadequate product release testing Sponsor does not perform test (e.g., endotoxin, sterility) at Sponsor does not perform test (e.g., endotoxin, sterility) at

appropriate manufacturing stage - after final manipulation, or with appropriate manufacturing stage - after final manipulation, or with appropriate test article (e.g, mycoplasma)appropriate test article (e.g, mycoplasma)

Inadequate demonstration of viral clearance Inadequate demonstration of viral clearance

Phase 1- Hold Items

General Principles

• “ “ {FDA’s primary objectives in reviewing {FDA’s primary objectives in reviewing an IND are}an IND are} …and in …and in Phase 2 and 3Phase 2 and 3, to , to help assure that the help assure that the quality of the quality of the scientific evaluation of drugs is scientific evaluation of drugs is adequateadequate to permit an evaluation of the to permit an evaluation of the drug’s effectiveness and safety….” drug’s effectiveness and safety….” [21 [21 CFR, 312.22(a)]CFR, 312.22(a)]

CMC DevelopmentSAFETY INFORMATION

Source characterization

Components info.

DS/DP Characterization

Testing/Qualification/ Clearance of impurities, contaminants

Process control esp. for safety processes (e.g., sterilization, virus clearance)

Pre-clinicalPre-clinicalDiscoveryDiscovery

BLABLA

Incremental Approach - CMCIncremental Approach - CMC

Phase 1Phase 1

Phase 3Phase 3Phase 2Phase 2

DEVELOPMENT ACTIVITIES

DS & DP Characterization

Formulation Development

Component Characterization

Assay Development/ Validation

Specification Development

Stability Studies

Manufacturing Process

Control & Validation

Major Developmental Issues• Critical Assays - validated, reproducible, Critical Assays - validated, reproducible,

quantitative sensitive, specific and biologically quantitative sensitive, specific and biologically relevantrelevant– Potency (Bioassay) – multiple products Potency (Bioassay) – multiple products – Identity – Cell Therapy Identity – Cell Therapy – Other critical assaysOther critical assays

• Comparability AssessmentsComparability Assessments– Need to demonstrate comparability of a vector GT Need to demonstrate comparability of a vector GT

product and a cell therapy product product and a cell therapy product – Difficulties in establishing comparability (Cell Therapy)Difficulties in establishing comparability (Cell Therapy)

Expectations For Analytical Methods During Development

• Ensure safety of the productEnsure safety of the product• Assurance that analytical information gained Assurance that analytical information gained

in development can be reliability related to in development can be reliability related to commercial manufacturingcommercial manufacturing

• Provides sufficient foundation for process Provides sufficient foundation for process validation, determining acceptance criteria validation, determining acceptance criteria etc., by submission of marketing applicationetc., by submission of marketing application

Analytical Methods Validation

• ““Methods validation is the Methods validation is the processprocess of of demonstrating that analytical demonstrating that analytical procedures are procedures are suitable for their suitable for their intended useintended use.” .” [FDA Draft Guidance on Analytical [FDA Draft Guidance on Analytical Procedures…]Procedures…]

• Analytical procedure:Analytical procedure:– Does what it is intended to doDoes what it is intended to do– Yields data to answer a questionYields data to answer a question– Provides confidence in resultsProvides confidence in results– Is reproducibleIs reproducible

Analytical Method Validation

• Methods used in IND studies should be:Methods used in IND studies should be:– Scientifically sound, yield reproducible results and have sufficient Scientifically sound, yield reproducible results and have sufficient

sensitivity, specificity, and accuracy for the specified purpose. sensitivity, specificity, and accuracy for the specified purpose. – Conducted following established written procedures under controlled Conducted following established written procedures under controlled

conditions that may include use of reference materials, standards, conditions that may include use of reference materials, standards, positive, and negative controls or other appropriate controls. positive, and negative controls or other appropriate controls.

• For pivotal investigational trials – validation should be For pivotal investigational trials – validation should be strongly considered, may be needed for some assays (e.g., strongly considered, may be needed for some assays (e.g., potency) potency) – Understand risk to product if assays are not validated by pivotal Understand risk to product if assays are not validated by pivotal

trials.trials.

CH, CH, CH, CHANGES

“ “ FDA recognizes that modifications to the method FDA recognizes that modifications to the method of preparation of the new drug substance and of preparation of the new drug substance and dosage forms…are likely as the investigation dosage forms…are likely as the investigation progresses” progresses” [21 CFR 312.23 (a)(7)(i)][21 CFR 312.23 (a)(7)(i)]

“ “ As drug development proceeds …the sponsor As drug development proceeds …the sponsor should submit should submit information amendmentsinformation amendments to to supplement the initial information submitted on supplement the initial information submitted on the CMC with information appropriate to the the CMC with information appropriate to the expanded scope of the investigation.” expanded scope of the investigation.” [21 CFR 312.23 [21 CFR 312.23 (a)(7)(iii)](a)(7)(iii)]

Reporting Changes • Intended or Unintended - Change Happens!Intended or Unintended - Change Happens!• Evaluate the change(s) for potential to impact the Evaluate the change(s) for potential to impact the

DS & DP product quality with regard to safety DS & DP product quality with regard to safety and and efficacyefficacy

• Comparability Study Comparability Study • Report in an Report in an information amendmentinformation amendment

– Significant/ most manufacturing changes Significant/ most manufacturing changes – Changes that are likely to affect safety Changes that are likely to affect safety and efficacyand efficacy prior prior

to use in clinical studiesto use in clinical studies How to determine potential ?How to determine potential ?

– Supporting studies and dataSupporting studies and data

CMC Summary

• CBER - Flexible regulatory approach CBER - Flexible regulatory approach – Different information (type and extent) is sometimes Different information (type and extent) is sometimes

necessary for addressing specific IND CMC issues for necessary for addressing specific IND CMC issues for different biologic product classes and even individual different biologic product classes and even individual products within a classproducts within a class

• Newer therapies/ technologies generally result in a Newer therapies/ technologies generally result in a greater number and different hold/ product greater number and different hold/ product development issues than more established biologics development issues than more established biologics

• Sponsors with minimal regulatory experience & Sponsors with minimal regulatory experience & product/ process understanding generally product/ process understanding generally experience greater delays in product approvalexperience greater delays in product approval

CGMP’s For Clinical Trials, March 1, 2005CGMP’s For Clinical Trials, March 1, 2005http://www.fda.gov/cber/summaries/pda030105cj.pdfhttp://www.fda.gov/cber/summaries/pda030105cj.pdf

Current Good Manufacturing PracticesCurrent Good Manufacturing Practices(CGMP)(CGMP)

What are CGMPs?

• CGMPs cover a broad range of CGMPs cover a broad range of methods, practices and principles that methods, practices and principles that are implemented and documented are implemented and documented during product development to ensure during product development to ensure consistent manufacture of quality consistent manufacture of quality productsproducts

Regulatory Basis• Drugs and biologics Drugs and biologics including investigational including investigational

productsproducts are required to be manufactured in are required to be manufactured in accordance with CGMPs accordance with CGMPs – if not, considered adulterated if not, considered adulterated [501(a)(2)(B) Food, Drug [501(a)(2)(B) Food, Drug

and Cosmetic Act]and Cosmetic Act]– Compliance with Compliance with 21 CFR 210, 211 Current Good 21 CFR 210, 211 Current Good

Manufacturing Practices for Finished Pharmaceuticals Manufacturing Practices for Finished Pharmaceuticals Regulations [1978]Regulations [1978]

– No specific regulations for Drug Substance (Active No specific regulations for Drug Substance (Active Pharmaceutical Ingredient) ProductionPharmaceutical Ingredient) Production

Investigational Studies & cGMP

• Not always possibly to fully comply with CGMP Not always possibly to fully comply with CGMP regulations (i.e., 21 CFR 211)regulations (i.e., 21 CFR 211)

• Some CGMP regulations designed for Some CGMP regulations designed for repetitive, repetitive, commercial manufacture of an approved productcommercial manufacture of an approved product– Defined product quality attributesDefined product quality attributes– Uses an established manufacturing processUses an established manufacturing process

• However, CGMPs (principles) are clearly applicable However, CGMPs (principles) are clearly applicable to manufacture of investigational productsto manufacture of investigational products

• Types and extent of control may differ due to stage of Types and extent of control may differ due to stage of development development

CGMP in Clinical Investigation

Phase III

Pre-clinicalDiscovery

BLA

Phase 2Phase 2Phase 3Phase 3

Incremental CGMPIncremental CGMP

Incremental CMCIncremental CMC

Phase 1Phase 1

Analytical ValidationAnalytical Validation

ProcessProcess ValidationValidationProcess ControlsProcess Controls

Component QualificationComponent Qualification

Achieving CGMP Compliance

• Effective quality control standards for Phase 1Effective quality control standards for Phase 1– Well defined written proceduresWell defined written procedures– Adequately controlled equipmentAdequately controlled equipment– Accurate and consistent recording of data Accurate and consistent recording of data

(manufacturing and testing)(manufacturing and testing)• Implement CGMP consistent with good Implement CGMP consistent with good

scientific methodology, product development scientific methodology, product development and quality (control) principlesand quality (control) principles

Achieving CGMP Compliance• CGMP are written to allow flexibility, however, this has potential CGMP are written to allow flexibility, however, this has potential

for subjective interpretation by producer & investigator - for subjective interpretation by producer & investigator - Alternative ???Alternative ???

• CGMP are minimum requirements/ expectationsCGMP are minimum requirements/ expectations• Develop control measures specifically tailored to the product, Develop control measures specifically tailored to the product,

manufacturing process and facilitymanufacturing process and facility• How to determine CGMPs that are appropriate for my process, How to determine CGMPs that are appropriate for my process,

product and stage of clinical trial? product and stage of clinical trial? • Risk AssessmentRisk Assessment - justify your rationale and document - justify your rationale and document

– For example, formal evaluation of production environment For example, formal evaluation of production environment – Apply safeguards before, during and after manufactureApply safeguards before, during and after manufacture

Achieving CGMP Compliance

• Implement controls - shown to be both feasible Implement controls - shown to be both feasible and valuable in assuring drug qualityand valuable in assuring drug quality

Not an excuse for inadequate controls !Not an excuse for inadequate controls !• SSpecific product and manufacturing process may pecific product and manufacturing process may

impact ability to comply – decide and document impact ability to comply – decide and document • Not possible to follow comply with CGMPNot possible to follow comply with CGMP

– Include rationale for approaches followed in records for Include rationale for approaches followed in records for investigational productinvestigational product

– Include reasons not follow obvious recommendationsInclude reasons not follow obvious recommendations

Utilize Technology & Resources

• FacilitateFacilitate– CGMP complianceCGMP compliance– Product development (streamline)Product development (streamline)

• For example, consider utilizingFor example, consider utilizing– Disposable equipment and process aidsDisposable equipment and process aids– Prepackaged WFI & sterilized containersPrepackaged WFI & sterilized containers– Closed process equipment Closed process equipment – Contract or shared production & testing facilitiesContract or shared production & testing facilities

Inspection of Clinical Sites

• Manufacturing (that includes testing Manufacturing (that includes testing sites) are subject to CGMP inspection sites) are subject to CGMP inspection

• No formal inspection prerequisite No formal inspection prerequisite requirement for sites manufacturing requirement for sites manufacturing clinical investigational drugs clinical investigational drugs

Source MaterialSource MaterialComponentsComponentsDescription ofDescription of Manufacturing ProcessManufacturing ProcessSafety-relatedSafety-related Process Controls/ DataProcess Controls/ DataAnalytical Methods/ SpecsAnalytical Methods/ SpecsStabilityStability

Personnel Quality Control FacilitiesEquipment Laboratory Control Component ControlProduction ControlDistribution RecordsLabeling

CGMPCGMPInspectionInspection

CMC INDCMC INDReviewReview

Quality

• Quality Control - function Quality Control - function • Quality is the responsibility of all staff Quality is the responsibility of all staff

involved in production involved in production • Quality should be built into the product, Quality should be built into the product,

and testing alone cannot be relied on to and testing alone cannot be relied on to ensure product qualityensure product quality

Quality Control• Written quality control (QC) plan – responsibilitiesWritten quality control (QC) plan – responsibilities

– Review and release components Review and release components – Review and approval of production procedures, testing Review and approval of production procedures, testing

procedures & acceptance criteriaprocedures & acceptance criteria– Release or reject each batch upon cumulative review Release or reject each batch upon cumulative review – Investigate errors and initiate corrective actions Investigate errors and initiate corrective actions

• Responsibilities are performed independently Responsibilities are performed independently from productionfrom production

• Appropriately trained individual(s) – sufficient to Appropriately trained individual(s) – sufficient to perform QC functionperform QC function

Facilities• Adequate and appropriate - HVAC, light, Adequate and appropriate - HVAC, light,

water, plumbing, space etc. water, plumbing, space etc. – Maybe dependent upon product and processMaybe dependent upon product and process

• Adequate work areas for intended tasksAdequate work areas for intended tasks• Water of appropriate source and qualityWater of appropriate source and quality• Adequate air handling to prevent Adequate air handling to prevent

contamination and cross-contaminationcontamination and cross-contamination• Procedural controls to avoid Procedural controls to avoid

contamination and mix-upscontamination and mix-ups

Equipment

• Appropriate for intended functionAppropriate for intended function• Properly maintained, calibrated, cleaned Properly maintained, calibrated, cleaned

and sanitized following written and sanitized following written procedures and at appropriate intervalsprocedures and at appropriate intervals

• Should not contaminate or be reactive Should not contaminate or be reactive additive or absorptive with product additive or absorptive with product

• Identified and documented in production Identified and documented in production recordsrecords

Multiproduct• Multi-productMulti-product

– Generally, only one product manufactured in an area/ Generally, only one product manufactured in an area/ room at a timeroom at a time

– Same area/ room may be used for multiple purposes, if: Same area/ room may be used for multiple purposes, if: Appropriate design & procedural controls allow for orderly Appropriate design & procedural controls allow for orderly

handling of materials & equipment – prevent contamination/ handling of materials & equipment – prevent contamination/ cross contamination, mix-upscross contamination, mix-ups

Effective Cleaning and change over procedures Effective Cleaning and change over procedures

• Multi-product aspects – potential impact on other Multi-product aspects – potential impact on other productproduct– How to consider unknowns?How to consider unknowns?

Laboratory • Production testsProduction tests

– Specified quality attributes monitored – appropriate Specified quality attributes monitored – appropriate acceptance criteria applied (e.g., known safety-acceptance criteria applied (e.g., known safety-related and other tests as appropriate)related and other tests as appropriate)

– Scientifically sound analytical procedures (e.g., Scientifically sound analytical procedures (e.g., specificity, sensitivity, accuracy)specificity, sensitivity, accuracy)

– Tests conducted using written procedures under Tests conducted using written procedures under controlled conditions controlled conditions

– Periodic calibration and maintenance of laboratory Periodic calibration and maintenance of laboratory equipment equipment

Consider systems suitabilityConsider systems suitability

Laboratory

• Retain representative sample for Retain representative sample for additional release testingadditional release testing

• Initiate stability study to support use in Initiate stability study to support use in clinical trialsclinical trials

Sterile/ Aseptic Processing• Can be challenging to control and assure in Can be challenging to control and assure in

early investigational phasesearly investigational phases• Take special precautionsTake special precautions• Appropriate training Appropriate training • Aseptic manipulation conducted under Aseptic manipulation conducted under

appropriate conditions (e.g., Class 100 appropriate conditions (e.g., Class 100 conditions - laminar flow hood) -conditions - laminar flow hood) -

• Document and follow all procedures intended to Document and follow all procedures intended to maintain the sterility of the components, in-maintain the sterility of the components, in-process materials, components and final product process materials, components and final product

Biotechnology and Biological Products• Appropriate equipment qualification and controls in Appropriate equipment qualification and controls in

production needed to assure safety related function (e.g., production needed to assure safety related function (e.g., viral clearance, viral toxin inactivation, pasteurization) will viral clearance, viral toxin inactivation, pasteurization) will perform as intendedperform as intended– Accompanying testing for safety-related functions Accompanying testing for safety-related functions

• Difficulties to distinguish changes in quality attributes or Difficulties to distinguish changes in quality attributes or predict impact of observed changes on safety predict impact of observed changes on safety

• Difficulties in assessing “Comparability” suggest Difficulties in assessing “Comparability” suggest – Comprehensive documentationComprehensive documentation– Controls and documentation Controls and documentation – Sufficient product retainsSufficient product retains

Multiple Batches

• Produces of multiple batches (e.g., Produces of multiple batches (e.g., therapeutic vaccines, cell therapies)therapeutic vaccines, cell therapies)– Consistency among batches is important Consistency among batches is important – Accelerated accumulation of data than typical Accelerated accumulation of data than typical

manufacturemanufacture– Periodic review and modification to control Periodic review and modification to control

procedures and production operationsprocedures and production operations

CGMP Overall Summary• cGMP need to be in place for products used in cGMP need to be in place for products used in

clinical IND studiesclinical IND studies• CGMP reflect and are consistent with good CGMP reflect and are consistent with good

product developmentproduct development• Follow general approaches and principles that Follow general approaches and principles that

are broadly applicableare broadly applicable• Tailor CGMP application to product, process and Tailor CGMP application to product, process and

facilityfacility– Assess risks and take appropriate actions Assess risks and take appropriate actions

• Emphasize Product Quality Emphasize Product Quality

CGMPCGMPInspectionInspection[21 CFR 210, 211][21 CFR 210, 211]

CMC INDCMC INDReviewReview[21 CFR 312][21 CFR 312]

Review and Inspection Activities

cGMPcGMP

CMCCMC

Control of Investigational Clinical TrialsControl of Investigational Clinical Trials

CompanionCompanion

Quality Unit DescriptionQuality Unit DescriptionSegregation and Tracking Segregation and Tracking of Autologous cellsof Autologous cells

Product Development and Regulation - CBER Philosophy

• Regulation Goal: Balanced, Flexible, Regulation Goal: Balanced, Flexible, ResponsiveResponsive – Assure the safety and rights of subjectsAssure the safety and rights of subjects– Protect the public healthProtect the public health– Not impede technological innovation & Not impede technological innovation &

product development product development • InfluencesInfluences

– Available scientific knowledge, pre-clinical, Available scientific knowledge, pre-clinical, clinical knowledge & experienceclinical knowledge & experience

– Scientific researchScientific research– Crises/ tragic eventsCrises/ tragic events

• Appropriate Risk ManagementAppropriate Risk Management

Suggestions• ““Know thy process and thy product”Know thy process and thy product”• Reserve sufficient DS & DP retain samples Reserve sufficient DS & DP retain samples • Document appropriately (integral part of cGMP’s)Document appropriately (integral part of cGMP’s)• Consult CBER guidance (not a be all/ end all)Consult CBER guidance (not a be all/ end all)• Take advantage of the opportunity to interact and Take advantage of the opportunity to interact and

meet with CBER – use time productivelymeet with CBER – use time productively• Listen and respond to CBER’s commentsListen and respond to CBER’s comments

– Included non-hold CMC comments for further development Included non-hold CMC comments for further development • Sponsors should proactively address issues that may Sponsors should proactively address issues that may

arise.arise.

CBER CMC Guidances• Draft Guidance for FDA Review Staff and Sponsors: Draft Guidance for FDA Review Staff and Sponsors:

Content and Review of Chemistry, Manufacturing, and Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) Investigational New Drug Applications (INDs) [November 2004][November 2004]

• Draft Guidance for Reviewers: Instructions and Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, and Control Template for Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Somatic Cell Therapy (CMC) Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications (INDs) Investigational New Drug Applications (INDs) [August [August 2003]2003]

• Draft Considerations for Plasmid DNA Vaccines For Draft Considerations for Plasmid DNA Vaccines For Infections Disease IndicationsInfections Disease Indications [February 2005][February 2005]

FDA CGMP Guidance• FDA Guidance aimed at fostering compliance with CGMP, FDA Guidance aimed at fostering compliance with CGMP,

however few directly address issue related to CGMP in however few directly address issue related to CGMP in clinical investigationclinical investigation

• Section 19, Q7A GMP Guidance For Active Section 19, Q7A GMP Guidance For Active Pharmaceutical Ingredients Pharmaceutical Ingredients [FDA adopted September 2001][FDA adopted September 2001]

• Developing Draft guidance “Approaches to Complying with Developing Draft guidance “Approaches to Complying with CGMP During Phase 1” CGMP During Phase 1”

• Draft guidance discussed at Office of Pharmaceutical Draft guidance discussed at Office of Pharmaceutical Science Advisory Committee – July 21, 2004 Science Advisory Committee – July 21, 2004 www.fda.gov/ohrms/dockets/ac/cder04.html#PharmSciencewww.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience

• Cell and Gene Therapy Facilities [in development]Cell and Gene Therapy Facilities [in development]

Acknowledgements/ ContactsAndrew Chang, Ph.D.Andrew Chang, Ph.D.Division of Hematology, OBRR, CBER (Recombinant blood factors;Division of Hematology, OBRR, CBER (Recombinant blood factors;Plasma-derivatives)Plasma-derivatives)

Kimberly Benton, Ph.D.Kimberly Benton, Ph.D.Division of Cell and Gene Therapy, OCTGT, CBER (Cellular Products)Division of Cell and Gene Therapy, OCTGT, CBER (Cellular Products)

Eda Bloom, M.D.Eda Bloom, M.D.Division of Cell and Gene Therapy, OCTG, CBER (Xenotransplantation)Division of Cell and Gene Therapy, OCTG, CBER (Xenotransplantation)

Stephanie Simek, Ph.D.Stephanie Simek, Ph.D. Division of Cell and Gene Therapy, OCTGT, CBER (Gene Therapy Division of Cell and Gene Therapy, OCTGT, CBER (Gene Therapy

Products)Products)

Acknowledgements/ ContactsLoris McVittie, Ph.D. Loris McVittie, Ph.D. Division of Vaccines and Related-Products, OVRR, CBER (Viral-Division of Vaccines and Related-Products, OVRR, CBER (Viral-

vaccines)vaccines)

Paul Richman, Ph.D.Paul Richman, Ph.D.Division of Vaccines and Related Products, OVRR, CBER Division of Vaccines and Related Products, OVRR, CBER

(Bacterial vaccines)(Bacterial vaccines)

Laurie Norwood Laurie Norwood Division of Manufacturing and Product Quality, OCBQ, CBER Division of Manufacturing and Product Quality, OCBQ, CBER

(Facilities) (Facilities)

Chiang Syin, Ph.D.Chiang Syin, Ph.D. Division of Manufacturing and Product Quality, OCBQ (Facilities)Division of Manufacturing and Product Quality, OCBQ (Facilities)

CBER Available Information• Internet Internet www.fda.gov/cber/www.fda.gov/cber/• Fax Information SystemFax Information System

– In US toll-free: 1-888-CBER-FAX (1-888-223-7329)In US toll-free: 1-888-CBER-FAX (1-888-223-7329)– Outside US: 301-827-3844Outside US: 301-827-3844

• Email -Email -Manufacturers assistance: MATT@CBER.FDA.GOVManufacturers assistance: MATT@CBER.FDA.GOV• CBER Voice Information System at:CBER Voice Information System at:

– 1-800-835-4709 or 301-827-18001-800-835-4709 or 301-827-1800Chris Joneckis, Ph.D., Chris Joneckis, Ph.D., Office of the Director, CBEROffice of the Director, CBERJoneckis@cber.fda.govJoneckis@cber.fda.gov