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Role of FDA
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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
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Minimum requirement for release of a drug is
that it has to safe and effective
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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?
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Thalidomide incident
Center for Drug Evaluation &
Research
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CDER
Group which assures the safety and
effectiveness of drugs available in the U.S.
Monitors for adulterated or contaminated drugs
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Adulterated: drug or food produced by methods
which do not conform to cGMP
Center for Biologics Evaluation and
Research
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CBER
Reviews applications for new biologics produced
from microbes and viruses
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Examples: vaccines, allergens, monoclonal antibodies
Regulates all aspects of the process from mfg. to
QC, to labeling and advertising
Center for Devices & Radiologic
Health
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CDRH
Regulates medical devices and some in vitro
diagnostic kits
Examples of devices:
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Pace maker, ultrasonic cleaners for cleaning medical
instruments, insulin monitors, thermometers
Examples of in vitro diagnostic kits
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CK-MB kits
Center for Food Safety & Applied
Nutrition
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Protects and promotes health & economic
interests by ensuring that foods are safe,
nutritious, and honestly labeled
Also oversees cosmetics
FDA Actions
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Facility Inspections
483: inspector’s note documenting a deficiency
Not following procedure
 Incomplete records
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Warning letter: written letter citing cGMP
violations. Requires a written response of
corrective actions to be implemented.
FDA Actions
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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
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FDA cannot do nothing when they know there
are issues at a company
Product Development:
Ideas to Market
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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
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Good Laboratory Practices
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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
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Examples of what’s included
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Good lab practices
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Labeling reagent bottles w/ proper info.
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Equipment monitoring
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Calibrated, cleaned and verification logs
Written procedures
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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
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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
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Standard Operating Procedures
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Good SOPs contain the following:
Purpose or scope
 Materials
 Procedure
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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\
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Should be reviewed and updated as needed
Clinical Investigation
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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
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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
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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
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Investigator
Sponsor
Sponsor Investigator
Human Subject
Institution
Institution Review Board
Clinical Trial Data Analysis
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Data analyzed by Statistics or Biostatistics
group
Use well defined, accepted and pre-determined
data analysis formulas and methods.
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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?
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Outlier: data point outside of the average range
and is usually larger or smaller than the rest of
the points
Clinical Trial Data Analysis
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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
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Definition: any board, committee or group
formally designated by an institution to
review biomedical research involving human
subjects
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IRB approval MUST be obtained before
an investigator can begin a study
Institutional Review Board
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Usually comprised of medical and lay persons (at
least 5 members, no conflict of interest)
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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?
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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
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cGMP should apply to activities associated with
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manufacturing
packaging
holding
distributing
Manufacturer would need to comply with requirements
applicable to operations performed
Components of a cGMP
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Personnel
Physical plant internal environment
Equipment and utensils
Production and process controls
Records and Recordkeeping
QSR
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QSR: Quality System Regulations
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Standard produced by the FDA which companies
MUST follow
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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
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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
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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
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Label Approval and Control
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Regulatory, Quality Assurance and Marketing are
the groups who “approve” the final label
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Materials, QA, QC, and Mfg. “control” the label
from receipt, through inspection to application
to product, through finished product inspection.
Labeling and Packaging Control
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Why would this be an area to be audited?
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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
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Fixed Text
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Text that does not change with each lot
Company name, address,
 Product Name, storage temp, ingredients
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Variable Text
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Text that does change with each lot
Lot number and or serial number
 Expiration Date
 Concentration or Potency
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Marketing Information
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Labels and Package inserts are highly controlled
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Marketing information such as product
informational flyer
Approved by Regulatory and Marketing
 Marketing distributes w/out control
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Audits
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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
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Meeting to review process and timing
Tour of company
Ask for records
Review records
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Ask for interviewees if necessary
Write preliminary report
Review prelim report w/mgmt