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Regulatory Compliance in Pharmaceutical Development: GLP & GMP Jeffrey G. Sarver, Ph.D. MBC 3100 March 8, 2016 email questions to:

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Presentation on theme: "Regulatory Compliance in Pharmaceutical Development: GLP & GMP Jeffrey G. Sarver, Ph.D. MBC 3100 March 8, 2016 email questions to:"— Presentation transcript:

1 Regulatory Compliance in Pharmaceutical Development: GLP & GMP Jeffrey G. Sarver, Ph.D. MBC 3100 March 8, questions to:

2 Food and Drug Administration (FDA)
Agency of U.S. Department of Health and Human Services (HHS) Protect public health and provide essential public services Other HHS agencies include: CDC, NIH, Medicare/Medicaid FDA 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)

3 Drug Development/Approval Process
Basic Research + Target Discovery Drug Discovery Preclinical Testing IND FDA Review Clinical Trials I, II, III NDA FDA Review Manufacture Market Drug IND – 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 Development NDA – 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

4 Preclinical Testing Requirements
Mechanism 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 Testing Core: Cardiovascular (hERG), Respiratory, CNS Other tests as needed based on structure, mechanism, general tox

5 Additional Information for IND
Chemistry, Manufacturing, and Controls (CMC) Structure, physical properties Synthetic method and scale-up Purity, identification of impurities Dosage form/route, formulation, preparation, packaging Clinical Study Protocols Previous Human Experience (if available)

6 FDA Guidance Documents
Information on suggested: testing methods, analyzing and summarizing data Can be found at: Searching can be difficult/tedious, use appropriate filters: Product → Drugs (or Biologics) FDA Organization → CDER (or CBER) Document Type → Guidance Documents Example Guidance Documents available on Blackboard: Genotoxicity Testing Cardiotoxicity (hERG) Testing Chemistry, Manufacturing, and Controls (CMC) for Phase I Drug Maximum Safe Starting Dose for Clinical Testing

7 International Council on Harmonization (ICH)
Harmonize procedures for evaluating/reporting safety, efficacy, CMC in multiple regions/countries Regulators and industry representatives from participating regions collaborate to generate internationally acceptable guidelines Improve efficiency of drug testing/reporting requirements for approval in multiple countries Originally Europe, Japan, U.S. Other countries adopting ICH standards

8 Clinical Trials Phase 1: Phase 0: Phase 2: Phase 3: $0.3M-$0.5M
PK and Biomarkers at microdoses Generally 7-15 subjects Optional, helps other phases Phase 1: Safety and PK Generally 20 to ~80 subjects $0.3M-$0.5M $2M-$5M Phase 2: Efficacy and safety Several hundred subjects Phase 3: Efficacy and safety Several hundred to several thousand subjects $5M-$20M $12M-$50M

9 Information Required for NDA
Clinical safety/efficacy/PK data Preclinical pharmacology/toxicology data Chemistry/Manufacturing information Package Labeling Additional information as appropriate Patent Information, Licensing Rights Approval/Marketing/Usage in other countries

10 FDA “Good Practice” Regulations
Response to malpractice/unreliable results from pharmaceutical companies and contract research organizations (CROs) Basic Research + Target Discovery Drug Discovery Preclinical Testing IND FDA Review Clinical Trials I, II, III NDA FDA Review Manufacture Market Drug Not Regulated Good Laboratory Practice (GLP) Good Clinical Practice (GCP) Good Manufacturing Practice (GMP) Drug Synthesis GMP Drug Synthesis GMP Sample Analysis GLP

11 Good Laboratory Practice (GLP)
Legally mandated guidelines for proper design, performance, 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)

12 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!

13 GLP Fundamentals - Resources
Organization and Personnel Defined and Appropriate Organization (Organization Chart) Management / Study Director and Qualifications Personnel Duties and Qualifications Curriculum Vitae for everyone involved Facilities and Equipment Buildings Pharmaceutical Dose Preparation Area Construction Arrangement Animal Facility Equipment (maintenance/calibration)

14 GLP Fundamentals – Study Protocol
Title and statement of purpose Identification of test / control items Name of Sponsor and address of facility Name of Study Director / Responsible Person Proposed Dates Justification for selection of test systems (cells, animals) Description of test systems Experimental Design Quality Assurance Approval of protocol Circulation of protocol Protocol Amendments Storage plans for all records after study ends

15 GLP Fundamental - SOPs Standard Operating Procedures (SOPs)
Total integration in master documentation system Comprehensive coverage of all phases Readability Usability and traceability Understanding by staff Responsibility for each SOP Formal change control system Centralized organization of formatting, number, issuance, modification, removal Immediate availability Archiving of older versions SOP examples on Blackboard -SOP – writing-managing SOPs -SOP - NMR Sample Prep

16 GLP Fundamentals – Agent Prep/Dosing
Test/Control Agents Receipt Storage Usage Disposal Preparation of Dose Formulation Initial preparation and planning Formulating the test / control item Sampling and quality control of dose formulation Formulation records Dosing Detailed records of dosing Staff must be well trained Dose volume is calculated and verified Dosing procedure performed in fixed order

17 GLP Fundamentals – Test Systems
Animals, cell lines, bacteria, isolated biochemical used in testing procedures Must match quality and quantity specified in protocol Suppliers, ordering, transport, and receiving Verification of appropriateness for testing procedures Assignment and transfer to groups for testing Control and monitoring of environmental variables

18 GLP Fundamentals – Quality Assurance
Independent review of entire process Protocol review SOP review Planning (Master Schedule, Inspection Plan) Internal Inspections and Audits Study based inspections / audits System or facility based inspection / audits Process based inspections Final Report / Raw Data Quality Assurance Statement Inspections of suppliers and contractors Distribution/archiving of QA files/reports

19 GLP Fundamentals – Documentation
Final Report Name and address of test facility Dates of start and finish Name of Study Director Objectives Details of test / control substances and vehicles Description of test system Details of dosing, route and duration Statistics Discussion References GLP Compliance Statement from Study Director QA Statement of Inspections/Audits Signed/dated reports from scientists

20 FDA Inspection of GLP Facility
Four kinds of FDA inspections of GLP laboratories: Periodic/routine evaluation of GLP compliance (every 2 years) Data audit to verify information in final report submitted to FDA is accurate/reflected by raw data Directed 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 taken Inspection Outcomes Facility 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!

21 GLP in Academic Research
Research/facilities in academia rarely comply with GLP Pediatric Department Clinical Sample GLP Laboratory Wesley Gray, Dr. Bruce Levison, HEB 2nd floor DLAR has made efforts to become GLP compliant GLP compliance is expensive and time-consuming GLP is not needed to publish research results GLP is not followed in most academic laboratories

22 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

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

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