Regulatory Compliance in Pharmaceutical Development: GLP & GMP Jeffrey G. Sarver, Ph.D. MBC 3100 March 8, 2016 email questions to: [email protected] * Food and Drug Administration (FDA)Agency of U.S. Department of Health and Human Services (HHS)Protect public health and provide essential public servicesOther HHS agencies include: CDC, NIH, Medicare/MedicaidFDA responsible for assuring safety and efficacy of: Human Drugs - Center for Drug Evaluation and Research (CDER)Veterinary Drugs - Center for Veterinary Medicine (CVM)Biological Agents - Center for Biologic Evaluation and Research (CBER)Medical Devices - Center for Devices and Radiological Health (CDRH)Food/Supplements/Cosmetics - Center for Food Safety and Applied Nutrition (CFSAN) Manufacture Market Drug NDA FDA Review Clinical Trials I, II, III IND FDA Review Preclinical Testing Drug Discovery Drug Development/Approval ProcessIND – Investigational New Drug application (3-6 yr, $5M-$10M)FDA Approval → Proceed into Clinical Trials (~30% from preclinical tests)Clinical Hold → Collect More data or End DevelopmentNDA – New Drug Application (9-12 yr, $500M-$1B)FDA Approval → Drug Enters Market (~8% from preclinical tests)Not Approved → More Data or Adjust Application or End Development Basic Research + Target Discovery Preclinical Testing RequirementsMechanism of Action (in vitro) and Efficacy (in vivo)General Toxicology: Single and Repeated Dose (in vivo)Genotoxicity/Mutagenicity (in vitro/in vivo)Carcinogenicity (in vivo)Reproductive Toxicology/Teratology (in vivo)ADME (in vitro)/Pharmacokinetics (in vivo)Additional Safety TestingCore: Cardiovascular (hERG), Respiratory, CNSOther tests as needed based on structure, mechanism, general tox Additional Information for INDChemistry, Manufacturing, and Controls (CMC)Structure, physical propertiesSynthetic method and scale-upPurity, identification of impuritiesDosage form/route, formulation, preparation, packagingClinical Study ProtocolsPrevious Human Experience (if available) FDA Guidance Documents Information on suggested: testing methods, analyzing and summarizing data Can be found at: http://www.fda.gov/RegulatoryInformation/Guidances/Searching can be difficult/tedious, use appropriate filters:Product → Drugs (or Biologics)FDA Organization → CDER (or CBER)Document Type → Guidance DocumentsExample Guidance Documents available on Blackboard:Genotoxicity TestingCardiotoxicity (hERG) TestingChemistry, Manufacturing, and Controls (CMC) for Phase I DrugMaximum Safe Starting Dose for Clinical Testing International Council on Harmonization (ICH)Harmonize procedures for evaluating/reporting safety, efficacy, CMC in multiple regions/countriesRegulators and industry representatives from participating regions collaborate to generate internationally acceptable guidelinesImprove efficiency of drug testing/reporting requirements for approval in multiple countriesOriginally Europe, Japan, U.S.Other countries adopting IC ...

1. Regulatory Compliance in Pharmaceutical Development:
GLP & GMP
Jeffrey G. Sarver, Ph.D.
MBC 3100
March 8, 2016
email questions to:
[email protected]
*
Food and Drug Administration (FDA)Agency of U.S.
Department of Health and Human Services (HHS)Protect public
health and provide essential public servicesOther HHS agencies
include: CDC, NIH, Medicare/MedicaidFDA responsible for
assuring safety and efficacy of: Human Drugs - Center for Drug
Evaluation and Research (CDER)Veterinary Drugs - Center for
Veterinary Medicine (CVM)Biological Agents - Center for
Biologic Evaluation and Research (CBER)Medical Devices -
Center for Devices and Radiological Health

2. (CDRH)Food/Supplements/Cosmetics - Center for Food Safety
and Applied Nutrition (CFSAN)
Manufacture
Market Drug
NDA
FDA Review
Clinical
Trials
I, II, III
IND
FDA Review
Preclinical
Testing
Drug
Discovery
Drug Development/Approval ProcessIND – Investigational New
Drug application (3-6 yr, $5M-$10M)FDA Approval → Proceed
into Clinical Trials (~30% from preclinical tests)Clinical Hold
→ Collect More data or End DevelopmentNDA – New Drug
Application (9-12 yr, $500M-$1B)FDA Approval → Drug
Enters Market (~8% from preclinical tests)Not Approved →
More Data or Adjust Application or End Development
Basic
Research
+
Target
Discovery

3. Preclinical Testing RequirementsMechanism of Action (in vitro)
and Efficacy (in vivo)General Toxicology: Single and Repeated
Dose (in vivo)Genotoxicity/Mutagenicity (in vitro/in
vivo)Carcinogenicity (in vivo)Reproductive
Toxicology/Teratology (in vivo)ADME (in
vitro)/Pharmacokinetics (in vivo)Additional Safety TestingCore:
Cardiovascular (hERG), Respiratory, CNSOther tests as needed
based on structure, mechanism, general tox
Additional Information for INDChemistry, Manufacturing, and
Controls (CMC)Structure, physical propertiesSynthetic method
and scale-upPurity, identification of impuritiesDosage
form/route, formulation, preparation, packagingClinical Study
ProtocolsPrevious Human Experience (if available)
FDA Guidance Documents
Information on suggested: testing methods, analyzing and
summarizing data
Can be found at:
http://www.fda.gov/RegulatoryInformation/Guidances/Searchin
g can be difficult/tedious, use appropriate filters:Product →
Drugs (or Biologics)FDA Organization → CDER (or
CBER)Document Type → Guidance DocumentsExample
Guidance Documents available on Blackboard:Genotoxicity
TestingCardiotoxicity (hERG) TestingChemistry,
Manufacturing, and Controls (CMC) for Phase I DrugMaximum
Safe Starting Dose for Clinical Testing

4. International Council on Harmonization (ICH)Harmonize
procedures for evaluating/reporting safety, efficacy, CMC in
multiple regions/countriesRegulators and industry
representatives from participating regions collaborate to
generate internationally acceptable guidelinesImprove
efficiency of drug testing/reporting requirements for approval in
multiple countriesOriginally Europe, Japan, U.S.Other countries
adopting ICH standards
Clinical Trials
Phase 1: Safety and PK Generally 20 to ~80 subjects
Phase 3: Efficacy and safety Several hundred to several
thousand subjects
Phase 2: Efficacy and safety Several hundred subjects
Phase 0: PK and Biomarkers at microdoses Generally 7-15
subjects Optional, helps other phases

5. $2M-$5M
$5M-$20M
$12M-$50M
$0.3M-$0.5M
*
Information Required for NDAClinical safety/efficacy/PK
dataPreclinical pharmacology/toxicology
dataChemistry/Manufacturing informationPackage
LabelingAdditional information as appropriatePatent
Information, Licensing RightsApproval/Marketing/Usage in
other countries
Manufacture
Market Drug
NDA
FDA Review
Clinical
Trials
I, II, III
IND
FDA Review

6. Preclinical
Testing
Drug
Discovery
FDA “Good Practice” RegulationsResponse to
malpractice/unreliable results from pharmaceutical companies
and contract research organizations (CROs)
Basic
Research
+
Target
Discovery
Not Regulated
Good
Laboratory
Practice
(GLP)
Good
Clinical
Practice
(GCP)
Good
Manufacturing
Practice
(GMP)
Drug Synthesis
GMP
Drug Synthesis
GMP
Sample Analysis
GLP
GOOD LABORATORY PRACTICE (GLP)
Legally mandated guidelines for proper design, performance,

7. and record keeping of preclinical testing
See 21 CFR 58 GLP Regulations on Blackboard
See Guidance – GLP FAQs on Blackboard
Proper management/organization of research team, equipment
operation/maintenance, Quality Assurance (QA) review
Helps ensure consistent/repeatable results that can be trusted
Allows full review and audit of everything that is done for FDA
drug approval
GLP employed in a similar manner for testing used in other
regulatory decisions (eg, EPA Pesticide Licensing)
GLP PRINCIPLES
Only follow the instructions that you have read, not those that
someone told you! Everything done according
to written SOPs!
If it isn’t written down, it didn’t happen! Keep
records of everything!
Document actions as they occur, not afterwards! Live
record keeping with full documentation!
Check, double check and check again!
Verify everything!
Plan ahead to minimize unexpected events! Ensure all
procedures provide reliable results!
GLP FUNDAMENTALS - RESOURCESOrganization and
PersonnelDefined and Appropriate Organization (Organization
Chart)Management / Study Director and
QualificationsPersonnel Duties and QualificationsCurriculum
Vitae for everyone involved
Facilities and EquipmentBuildingsPharmaceutical Dose
Preparation AreaConstructionArrangementAnimal
FacilityEquipment (maintenance/calibration)

8. GLP FUNDAMENTALS – STUDY PROTOCOLStudy
ProtocolTitle and statement of purposeIdentification of test /
control itemsName of Sponsor and address of facilityName of
Study Director / Responsible PersonProposed DatesJustification
for selection of test systems (cells, animals)Description of test
systemsExperimental DesignQuality AssuranceApproval of
protocolCirculation of protocolProtocol AmendmentsStorage
plans for all records after study ends
GLP FUNDAMENTAL - SOPSStandard Operating Procedures
(SOPs)Total integration in master documentation
systemComprehensive coverage of all
phasesReadabilityUsability and traceabilityUnderstanding by
staffResponsibility for each SOPFormal change control
systemCentralized organization of formatting, number, issuance,
modification, removalImmediate availabilityArchiving of older
versions
SOP examples on Blackboard
-SOP – writing-managing SOPs
-SOP - NMR Sample Prep
GLP FUNDAMENTALS – AGENT PREP/DOSINGTest/Control
AgentsReceiptStorageUsageDisposalPreparation of Dose
FormulationInitial preparation and planningFormulating the test
/ control itemSampling and quality control of dose
formulationFormulation records DosingDetailed records of
dosingStaff must be well trainedDose volume is calculated and
verifiedDosing procedure performed in fixed order

9. GLP FUNDAMENTALS – TEST SYSTEMSTest
SystemsAnimals, cell lines, bacteria, isolated biochemical used
in testing proceduresMust match quality and quantity specified
in protocolSuppliers, ordering, transport, and
receivingVerification of appropriateness for testing
proceduresAssignment and transfer to groups for testingControl
and monitoring of environmental variables
GLP FUNDAMENTALS – QUALITY ASSURANCEIndependent
review of entire processProtocol reviewSOP reviewPlanning
(Master Schedule, Inspection Plan)Internal Inspections and
AuditsStudy based inspections / auditsSystem or facility based
inspection / auditsProcess based inspectionsFinal Report / Raw
DataQuality Assurance StatementInspections of suppliers and
contractorsDistribution/archiving of QA files/reports
GLP FUNDAMENTALS – DOCUMENTATIONFinal
ReportName and address of test facilityDates of start and
finishName of Study DirectorObjectivesDetails of test / control
substances and vehiclesDescription of test systemDetails of
dosing, route and durationStatisticsDiscussionReferencesGLP
Compliance Statement from Study DirectorQA Statement of
Inspections/AuditsSigned/dated reports from scientists
FDA INSPECTION OF GLP FACILITYFour kinds of FDA
inspections of GLP laboratories:Periodic/routine evaluation of
GLP compliance (every 2 years) Data audit to verify

10. information in final report submitted to FDA is
accurate/reflected by raw dataDirected inspection conducted for
various compelling reasons (eg, questionable data in final
report, tips from informants)Follow-up inspection after earlier
inspection revealed objectionable practices/conditions, assure
proper corrective actions takenInspection OutcomesFacility in
compliance with all GLP regulations → Yay, party on!Facility
failed one or more GLP regulations → Warning, shape-
up!Noncompliance adversely affected study validity → Data
rejected!
GLP in Academic Research
Research/facilities in academia rarely comply with
GLPPediatric Department Clinical Sample GLP Laboratory
Wesley Gray, Dr. Bruce Levison, HEB 2nd floorDLAR has
made efforts to become GLP compliantGLP compliance is
expensive and time-consumingGLP is not needed to publish
research resultsGLP is not followed in most academic
laboratories
GOOD MANUFACTURING PRACTICE (CGMP)
Legally mandated guidelines for proper manufacture and quality
control verification of pharmaceutical products
See 21 CFR 211 GMP Regulations on Blackboard
See Guidance – GMP for Drug Products on Blackboard
Proper management/organization of manufacturing team,
equipment operation/maintenance, QC review
Helps ensure consistent/safe production of drug products
Allows full review and audit of all production runs for product
Overall very similar to GLP procedures but for drug product

11. Some materials adapted from slides authored by:
Dr. Hanan Ghantous, PhD (FDA)
Merle J. Heineke (former DLAR Associate Dir)