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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
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
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
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
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
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
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.
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
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
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
Examples of what’s included
Good lab practices
Labeling reagent bottles w/ proper info.
Equipment monitoring
Calibrated, cleaned and verification logs
Written procedures
Reagent name, date, initials or name of who prepared it
Filled out, reviewed by QA, and maintained
Personnel should be qualified or at least
knowledgeable
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
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
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.
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 (100-300)
May take 1-2 years to complete
Phase 3: most extensive study,1-3 years
Fully assess safety and effectiveness of drug
100-1000 patients involved, diverse group, multiple sites
May compare old and new drug treatments
Evaluating side effects
Phase 4: long term side effects and effectiveness
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)
Participants in clinical trials
Investigator
Sponsor
Sponsor Investigator
Human Subject
Institution
Institution Review Board
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
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.
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
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
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
Operations responsibilities
This is where cGMP
comes into play
General Provisions
cGMP should apply to activities associated with
manufacturing
packaging
holding
distributing
Manufacturer would need to comply with requirements
applicable to operations performed
Components of a cGMP
Personnel
Physical plant internal environment
Equipment and utensils
Production and process controls
Records and Recordkeeping
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
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
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
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.
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
Label Text
Fixed 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
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
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
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