An introductory overview of drug regulation in the biotch industry. Provides and intro to cGMP, FDA Inspections and Logistics and Drug Regulation History in the U.S.

1. A cGMP Primer
Chet French
October 2011

2. A cGMP Primer
Agenda
 What is cGMP?
 Basic Principles
 Implications
 Drug Regulation History
 The FDA
Inspectional Methodology
 cGMP Subparts
Summary
A cGMP Primer Chet French Oct 2011

3. Regulated Industries
Nuclear Power Banking
Construction
Utilities
Airlines Minerals & Mining
Pharmaceuticals
Regulations; properly applied confer benefits and protections
A cGMP Primer Chet French Oct 2011
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4. Drug Regulations
How Do We Know the Rules?
 cGMP Regulations
 21CFR 210 & 211
 Proposed Regulations
 FDA Guidelines
 Inspectional Findings
 Best Practices – feasible and valuable
 Changing Technology/Tragedies
 Articles and Presentations by FDA personnel
 ICH Documents
A cGMP Primer Chet French Oct 2011
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5. The cGMPs
21CFR Parts 210 & 211
What are the cGMPs?
A: General Provisions  Federal laws
 Often ambiguous
B: Organization & Personnel
 Establish minimum requirements
C: Buildings and Facilities
D: Equipment
E: Control of Components
F: Production and Process Controls
G: Packaging & Labeling
H: Holding & Distribution
I: Laboratory Controls
J: Records & Reports
K: Returned & Salvaged Drug Products
A cGMP Primer Chet French Oct 2011

6. Drug Regulation History
Patent Medicines 19th Century
A cGMP Primer Chet French Oct 2011

7. Drug Regulation History
Food & Drug Act 1906
“The Jungle”
by Upton Sinclair
The Food and Drug Act (1906)
 Establishment of the FDA
 Prohibited interstate commerce in misbranded
and adulterated foods, drinks, and drugs
A cGMP Primer Chet French Oct 2011

8. Drug Regulation History
Formularies 1920’s
A cGMP Primer Chet French Oct 2011

9. Drug Regulation History
Elixir of Sulfanilamide Tragedy 1937
 Sulfa drugs were a commodity
 Introduction of a liquid syrup to differentiate product
 Used diethylene glycol as solvent
 240 gallons produced and sold
 107 Deaths; Suicide of chemist
A cGMP Primer Chet French Oct 2011

10. Drug Regulation History
Federal Food Drug and Cosmetics Act of 1938
 Must demonstrate scientific proof that new products could be
safely used before putting them on the market.
 Proof of fraud no longer required to stop false claims for
drugs.
 Addition of poisonous substances to foods was prohibited
except where unavoidable in production.
Specific authority conferred for
conducting inspections.
Federal court injunctions against
violations were added to the previous
legal remedies of product seizures and
criminal prosecutions.
A cGMP Primer Chet French Oct 2011

11. Drug Regulation History
Thalidomide Tragedy 1961
Thalidomide
Severe Teratogenic Properties
5,000 Pregnant women ~3,000 affected children
A cGMP Primer Chet French Oct 2011

12. Drug Regulation History
Kefauver Hearings 1960 - 1962
Regulation Amendments
 Tightened control over
prescription drugs
 Safe and effective
 Adverse reaction reporting
 Benefits and risks
 Label changes
Ernst Kefauver
A cGMP Primer Chet French Oct 2011

13. Drug Regulation History
Tylenol Poisoning & Recall 1982
“Raising the
Bar”
Tamper-proof
packaging

14. Drug Regulation History
Barr Laboratories 1993
Supreme Court Decision 1993
 Failure Investigations
 Process Validation
Quality must be built into the product/process
A cGMP Primer Chet French Oct 2011

15. Drug Regulation History
PDUFA 1997
Prescription Drug User Fee Act (1997)
Reduced the legal standard for new drug reviews
Reauthorized user fees
 Fee for Application
 Fee for Establishments
 Renewal Fee for Products
 Promotion of drugs for “off label” use
A cGMP Primer Chet French Oct 2011

16. The Food & Drug Administration
Mission: “Protect the Public”
An enforcement agency
$39 BL
Enforces the Federal Food Drug
and Cosmetic Act of 1938
$350 BL
Determines the state of $487 BL
compliance by conducting site $102 BL
inspections
Under Fire for Unsafe Drug Approvals*
Inspections Behind Schedule Annual Commerce = $1,000,000,000,000+
Resource Constraints - High Staff Turnover
*Outlook: Likely much greater safety vigilance
A cGMP Primer *Source: Institute of Medicine Report 2006 French Oct 2011
Chet

17. The Regulatory Environment
Drug Safety Under Scrutiny
BEXTRA®
(Arthritis)
Heart Attack
Stroke
Stevens Johnson
Syndrome
TYSABRI®
(MS)
PML
AVANDIA® MERIDIA®
(Diabetes) (Obesity)
VIOXX® Heart Attack Heart Failure
(Acute Pain) Renal Failure
Heart Attack
Stroke
A cGMP Primer Chet French Oct 2011

18. Drug Regulation
Safety Data – Risks vs. Benefits
Do the Risks
Outweigh the
Benefits?
?
Safety Profile
Cumulative
Clinical Approval
Identified Risks
Safety Data Collected
A cGMP Primer Chet French Oct 2011

19. Drug Regulation
Patient Safety Takes “Center Stage”
What Clinical Trials Do Well
Determine with some certainty that the product is effective and
that the common serious adverse events are identified
Limitations of Clinical Trials
 Seldom more than 3,000 patients
 Patients with complicated medical conditions often excluded
 Patients receiving certain concurrent meds are often excluded
 Pediatric and elderly populations may be excluded
 Trials often last only weeks to months; identification of reactions due
to long- term use or latent effects is difficult
A cGMP Primer Chet French Oct 2011

20. Drug Development and Commercialization
Stakeholders - Competing Interests
 Thorough Reviews
 Safe & Effective
 Accessible  Quick Review
 Inexpensive  Quick to Market
 “Latest & Greatest”
Greatest”  First-in-Class
 Safe & Effective  Profitable
 Preserve Status Quo
 Balance Competing Interests
 Allocate Resources Judiciously
A cGMP Primer Chet French Oct 2011

21. FDA
Partial Organization Structure
U.S. Dept of Health & Human Services
FDA
CDER CBER ORA
Biennial
Preapproval
Inspections
Inspections
Team Biologics
A cGMP Primer Chet French Oct 2011

22. FDA Inspections
Types
Licensure/Surveillance Inspections (Planned)
 Pre-Approval Inspection for Licensure (BLA)
 Prior Approval Supplement (PAS)
 GMP or Compliance Inspection (Biennial)
For-Cause Inspections (Unplanned):
 Product Complaint
 Adverse Event
 Industry “Triggered” event
 Market Withdrawal
Legal Authority for Inspections
 Sec. 704 of the Federal Food, Drug and Cosmetic Act of 1938
 Sec. 351(c) of the Public Health Service Act (licensed biologics)
 21 CFR 600.22 (licensed biologics)
A cGMP Primer Chet French Oct 2011

23. The Inspection
Goals & Objectives
Goal of the Investigators:
1. Verify the integrity of information
supporting the application (PAS)
2. Determine conformance to
cGMPs at the facility used for
manufacturing, processing,
packaging, and holding of the
drug product.
Goal of the Inspected:
“A favorable outcome”

24. Facility and Product Licensure
The Stakes
Consequences of failure are extreme:
 Loss of Revenue
 Business Viability - Time
 Jobs
 Company’s Reputation
 Credibility
 More Rigorous Future Scrutiny
Drug-to-market costs: $800 million -$1.7 BBL*
*Source: Tufts Center for the Study of Drug Development 2001

25. Inspection Preparation
Relevant Documentation
Documents compiled for review:
 Deviations/OOS/CAPAs
 Validation/Revalidation Data/Trending
 Logbooks
 P&ID
 Material Review Board Minutes
 Critical Systems
Systems Review – (examples)
 Cleaning Validations (Equipment and Facilities)
 Change Management
 Environmental Monitoring
 Stability Program
 HVAC/Water/Utilities
 Shipping/Receiving/Warehousing
 Raw Material In-Process Testing & Release
A cGMP Primer Interested in assessing capabilities Chet French Oct 2011

26. The FDA Investigators
Inspectional Experts
Civil Servants - Strong belief in purpose
Specialized training (frequent and recurring):
 Human Psychology
 Interview Techniques
Inspection Team
 1-5 Investigators with Lead
 CDER Office of Compliance
 Office of Biotechnology Products
 CDER District Office
 Mix and Match
 1- 3 weeks duration
 No vested interest in organizations’ success…
Application for approval must stand on own merits!!

27. The FDA Inspection
Systems-Based Approach
Production
Facilities &
System
Equipment
System
Quality
Laboratory
System
Control
Materials
System
System
Packaging
and
Labeling
System
One System out of control = Noncompliance

28. FDA Inspections
Receiving the Investigators
 Credentials – Agency represented
 Visitor badge issued; seated in lobby
 Contact list notified in order
 Responsible Head is presented the Notice
of Inspection (FDA 482 Form)
 Escorted and Sequestered in Room(s)
(Controlled Environment)
Ms.
Investigator

29. Inspection Logistics
Day One
 Introductions
 Review FDA 482
 Establish & Negotiate Agenda
 Inventory of Controlled Docs
 Prepared Overview Presentations
(SMEs)
 CAPAs, Deviations, Failure
Investigations, Prior Inspection
Corrective Actions
Alert: Conduct Walkthroughs of Potential Inspection Touring Areas
A cGMP Primer Chet French Oct 2011

30. Inspection Logistics
Inside the Inspection Room
Host SME
Scribe
Front Room
Manager
FDA
Investigators
Runners
SMEs
Scribe
Host
SME
A “well-choreographed dance”

31. The Inspection
Day-by-Day
 What do they do?
 Ask lots of questions
 Review lots of documents
 Make copies
 Talk to lots of employees
 Tour the facility (Start → End)
 Observe processes/equipment &
people
 Collect Samples

32. The Inspection
Day-by-Day
What do they find?
 Recordkeeping Errors
 Documentation Inconsistencies
 Logsbooks, BRs, Validation Protocols
Logsbooks, BRs,
 Procedures not followed
 Timeliness
 Responsibilities
 Electronic Issues BATCH RECORD
 Systems Issues

33. The Inspection
Day-by-Day
Daily Wrap-up Sessions FDA 483*
 Chaired by Senior Quality Host
 Convey trends and anticipate next areas of focus
 Push for spot corrections
 Annotated 483s
FDA 483 Final Day
Observation 1…….
Observation 2
 FDA 483 Form – List of Observations
Observation 3**
 Most significant listed first
 Type important; not number
 Final Wrap-up Session
A cGMP Primer Chet French Oct 2011

34. FDA 483 Observations Biologics 2010
by Category
108 (27%)
68 (17%)
55 (14%)
31 (8%)
Number of FDA 483 Observations
Source: BioQuality May 2010
A cGMP Primer Chet French Oct 2011

35. FDA Inspectional Outcomes
Preapproval Inspection (PAI)
Withold Approval
FDA 483 Form
Reinspection Inadequate
or Late
Corrective Actions
Adequate
Conditional Approval
Approval
A cGMP Primer Chet French Oct 2011

36. FDA Inspectional Outcomes
Compliance or Biennial Inspection
FDA 483 Form
Warning Letter
Establishment Official Action
Inspection Report Indicated (OAI)
NOIR
Action Indicated
Consent Decree
No Official
Corrective
Actions
Criminal Charges
Continued
Operation
A cGMP Primer Chet French Oct 2011

37. Regulatory Inspection Trends
Enforcement Statistics
Civil Money Penalties* 1 Trend is to focus on more
Seizures* 6 (-44%) serious violations
Injunctions* 12
Convictions 344
Warning Letters 471 (-39%)
Recalls* 5,585
FDA 483 Observations 5,100 (-1%)
Inspections* 15,581
Import Refusals 49,988
Fines/Restitutions* $1.92 BBL
(*)= Voluntary
Searchable Database at the FDA Website
www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm
A cGMP Primer Chet French Oct 2011
Source: FDA PDUFA Goals Report 2008

38. Quality by Design
A Model for cGMP Compliance
FDA assigns quality oversight to the Quality division
211.22 The quality control unit shall have the
responsibility and authority to review production records
to assure that no errors have occurred or, if errors have
occurred, that they have been fully investigated.
QA
Oversight
Product Mfg, Processing,
Holding, Testing,
Packaging, Labeling
A cGMP Primer Chet French Oct 2011
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39. Records and Reports - Good Documentation
Subpart J
Logbooks
Re
co
ch rd
at sM
M atc
rds h
co
Re
Labels All cGMP records must be:
• Accurate
• Legible
• Complete
• Timely
• Truthful
and… reconcilable
Records Match Batch Records & Systems
A cGMP Primer Chet French Oct 2011
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40. FDA’s View on Documentation/Recordkeeping
How data is entered into cGMP
documents is important because this is
the documented evidence of GMP
activities.
The drug regulatory program
depends on the reliability,
truthfulness, completeness and
accuracy of data and information
on record.
“If it wasn’t documented; then it wasn’t
performed”
A cGMP Primer Chet French Oct 2011
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41. Organization & Personnel
Subpart B
 … shall have the education, experience
and training or any combination thereof to
enable each individual to perform their
assigned function.
 Training on cGMPs
 Training ongoing and current
Be knowledgeable about:
cGMP Regulations
Policies, Procedures and Guidelines
Stay current on:
Regulatory inspectional activity
Changing technology
A cGMP Primer Chet French Oct 2011
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42. Building and Facilities - Design Implications
Subpart C
Linear Facility: Parenterals and API  Process Drives Design
 Separation of Operations Essential
 Reduced Heating and Cooling Costs Compact Facility
 Shorter Pipe and Process Flows
 Gravity Feed
 Reduced Construction Costs
A cGMP Primer Chet French Oct 2011
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43. Components of an HVAC System:
Building and Facilities
Subpart C Terminal Diffusers
Controlled Cleanroom Airflow
 Appropriate for intended purpose
 Adequate space & layout
HEPA Filter  Ensure a state of control
A cGMP Primer Chet French Oct 2011

44. Equipment
Subpart D
HPLC - Analytical Scale
Equipment adequate and
appropriate for state of
control*
Chromatography Very Large Scale
Source: FDA Guidance for Industry cGMP for Phase 1 Investigational Drugs 2008
A cGMP Primer Chet French Oct 2011

45. Production & Process Controls
Subpart F
A Typical Biopharmaceutical Process:
 Raw Material Storage/Handling
 Weigh/Dispense
 Media/Buffer/Component Preparation & Hold
 Inoculum Preparation
 Fermentation/Cell Culture
 Recovery/Harvest
 Purification
 Bulk Filling
 CIP/SIP
 Biowaste Deactivation
A cGMP Primer Chet French Oct 2011

46. Production & Process Controls
Subpart F
Host Cells Personnel
Raw
Materials
Common Conduits of Contamination
Bacteria
MMV (Parvovirus) Saprolegnia Mold Mycoplasma
A cGMP Primer Chet French Oct 2011

47. Production & Process Controls - Cleaning Validation
Subpart F
Spore Dots
Riboflavin Surface Studies
Validation: Scientifically and statistical
verification of a state of control of
process and equipment
TOC Swabbing
A cGMP Primer Chet French Oct 2011
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48. Packaging & Labeling
Subpart G
 QA Line Clearance
 Critical Step
 100% Reconciliation of closures containers and labels
Labeling: #1 root cause for recalls
A cGMP Primer Chet French Oct 2011

49. Summary
 The FDA regulates the drug industry
The FDA is required by law to periodically conduct site
inspections to assess our level of compliance with the
regulations.
 GMP regulations are the intent of the law
 GMP expectations are the spirit of the law
 FDA focusing attention on quality systems approach to
inspections to assure a sustained state of control
 Robust quality systems are the centerpiece to compliance
with the cGMPs
A cGMP Primer Chet French Oct 2011

50. Q&A
?
Questions/Comments
A cGMP Primer Chet French Oct 2011