2. Role of FDA
FDA was designed to promote and protect the public’s health
Food and Drug Cosmetic Act first passed in 1906 to prevent the sale of unacceptable food and drugs

3. Role of FDA
Minimum requirement for release of a drug is that it has to safe and effective
There are always risks and side effects
The FDA has to determine when the benefits out weigh the risks
Vaccines and life threatening diseases
Clinical trials: when is enough enough?
Thalidomide incident

4. Center for Drug Evaluation & Research
CDER
Group which assures the safety and effectiveness of drugs available in the U.S.
Monitors for adulterated or contaminated drugs
Adulterated: drug or food produced by methods which do not conform to cGMP

5. Center for Biologics Evaluation and Research
CBER
Reviews applications for new biologics produced from microbes and viruses
Examples: vaccines, allergens, monoclonal antibodies
Regulates all aspects of the process from mfg. to QC, to labeling and advertising

6. Center for Devices & Radiologic Health
CDRH
Regulates medical devices and some in vitro diagnostic kits
Examples of devices:
Pace maker, ultrasonic cleaners for cleaning medical instruments, insulin monitors, thermometers
Examples of in vitro diagnostic kits
CK-MB kits

7. Center for Food Safety & Applied Nutrition
Protects and promotes health & economic interests by ensuring that foods are safe, nutritious, and honestly labeled
Also oversees cosmetics

8. FDA Actions Facility Inspections
483: inspector’s note documenting a deficiency
Not following procedure
Incomplete records
Warning letter: written letter citing cGMP violations. Requires a written response of corrective actions to be implemented.

9. FDA Actions
If a company does not comply with FDA requests the FDA can do any and all of the following:
Take the product(s) off of the market
Sue and or arrest executives
Detain imports / exports
FDA cannot do nothing when they know there are issues at a company

10. Product Development: Ideas to Market
Computer Modeling
In vitro studies
Pre-clinical Animal studies
Investigation New Drug Application
Clinical studies
New Drug Application and Approval
Manufacturing
Marketing and Sales

11. GLP Good Laboratory Practices
Prescribes practices for conducting non clinical lab studies that support or are intended to support applications for research or marketing of regulated products.
Required for research applications to be submitted to the FDA
Intended to assure the quality and integrity of safety data filed
Does not include human studies or clinical studies

12. Examples of what’s included
Good lab practices
Labeling reagent bottles w/ proper info.
Reagent name, date, initials or name of who prepared it
Equipment monitoring
Calibrated, cleaned and verification logs
Written procedures
Filled out, reviewed by QA, and maintained
Personnel should be qualified or at least knowledgeable

13. Standard Operating Procedures: SOPs
Procedures for the following:
Manufacture the product
Test and release the product
Train personnel
Label and packaging the product
How to handle non conforming product
How to design new products

14. Standard Operating Procedures
Good SOPs contain the following:
Purpose or scope
Materials
Procedure
Must be written in proper order
Must include sufficient detail for operator to follow
Should include “checkers” for calculations
Must include initials and signature of operator
Must have Supervisors review and sign off\
Should be reviewed and updated as needed

15. Clinical Investigation
Definition: any experiment that involves a test article and one or more human subjects and that is either subject to requirements for submission to FDA or is not subject for submission but results are intended to be submitted later.

16. Phases of Clinical Trials
Phase 1: small number of patients, (10-20)
Can take 9-18 months to complete
May continue with animal studies for long term data
Phase 2: continues to test safety and evaluates how well the new drug is working. More patients enrolled ( )
May take 1-2 years to complete
Phase 3: most extensive study,1-3 years
Fully assess safety and effectiveness of drug
patients involved, diverse group, multiple sites
May compare old and new drug treatments
Evaluating side effects
Phase 4: long term side effects and effectiveness

17. Single and Double Blinded Study
Single-Blind study: clinical trial study in which the human subjects do not know if they are receiving the active product or a placebo.
Double-Blind study: study in which neither the subject nor the investigator knows the treatment assigned. (usually subjects, investigators, monitors and data analysts are unaware)

18. Participants in clinical trials
Investigator
Sponsor
Sponsor Investigator
Human Subject
Institution
Institution Review Board

19. Clinical Trial Data Analysis
Data analyzed by Statistics or Biostatistics group
Use well defined, accepted and pre-determined data analysis formulas and methods.
Looking for levels of significance 99% still means 1% error possible of 1/100 (0.01).
Is that good enough?
How do you balance the data with the delay in releasing a product?
Outlier: data point outside of the average range and is usually larger or smaller than the rest of the points

20. Clinical Trial Data Analysis
INCLUSION/EXCLUSION CRITERIA: The medical or social standards determining whether a person may or may not be allowed to enter a clinical trial. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. It is important to note that inclusion and exclusion criteria are not used to reject people personally, but rather to identify appropriate participants and keep them safe.

21. Institutional Review Board
Definition: any board, committee or group formally designated by an institution to review biomedical research involving human subjects
IRB approval MUST be obtained before an investigator can begin a study

22. Institutional Review Board
Usually comprised of medical and lay persons (at least 5 members, no conflict of interest)
Established to protect the human subjects and ensure fair enrollment
Review and Approve Informed Consent
Conduct periodic reviews to ensure integrity of the study

23. What are cGMP’s Designed To Do?
Protect consumers from adulterated product
Protect consumers from products that do not contain what is claimed on the label
Provide consistent industry-wide requirements
Ensure quality of product not safety or efficacy of dietary ingredients

24. Operations responsibilities
This is where cGMP comes into play

25. General Provisions cGMP should apply to activities associated with
manufacturing
packaging
holding
distributing
Manufacturer would need to comply with requirements applicable to operations performed

26. Components of a cGMP Personnel Physical plant internal environment
Equipment and utensils
Production and process controls
Records and Recordkeeping

27. QSR QSR: Quality System Regulations
Standard produced by the FDA which companies MUST follow
Include standards such as training, document control, process control, design control
cGMP and QSR are essentially the same
Mandated by FDA; only in US

28. ISO Similar to QSR International standard Voluntary
Provides marketing edge and is well received by customers
Risks: failure or loss of certification, add’tl expense
ISO 9001

29. Batch Records FDA Requirement cGMP requirement QSR requirement
ISO requirement
Failing to do so can get you into a heap of trouble!
Used to ensure consistent product

30. Batch Record: Record Keeping
What are some record keeping requirements?
Black ink
No white out
Single line, date, initial
No blanks, N/A any lines which do not apply
Legible

31. Label Approval and Control
Regulatory, Quality Assurance and Marketing are the groups who “approve” the final label
Materials, QA, QC, and Mfg. “control” the label from receipt, through inspection to application to product, through finished product inspection.

32. Labeling and Packaging Control
Why would this be an area to be audited?
Label text: pre-approved and inspected
Label adhesion: pre-approved and inspected
Label accountability: verified at every step
Package insert content: pre-approved and inspected
Package insert accountability: verified at every step
CONTROLLED TO PREVENT MIXUPS

33. Label Text Fixed Text Variable Text
Text that does not change with each lot
Company name, address,
Product Name, storage temp, ingredients
Variable Text
Text that does change with each lot
Lot number and or serial number
Expiration Date
Concentration or Potency

34. Marketing Information
Labels and Package inserts are highly controlled
Marketing information such as product informational flyer
Approved by Regulatory and Marketing
Marketing distributes w/out control

35. Audits
The evaluation of the company, the process, and the product to assure quality and reliability
Management Responsibility
Auditing (internal and external)
Design Control
Document Control
Purchasing Control
Identification and Traceability

36. Process of Auditing Meeting to review process and timing
Tour of company
Ask for records
Review records
Ask for interviewees if necessary
Write preliminary report
Review prelim report w/mgmt