cGMPs
Kim Truttschel, Quality Consultant
Eli Lilly and Company
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So, what is Pharmaceutical
Manufacturing ?
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Heparin Contamination
• February 28, 2008 recall of multi-dose
Heparin due to 785 reports of side effects
and 19 deaths
• A contaminant, over-sulfated chondroitin
sulfate, identified.
• HPLC does not detect since it co-elutes with
heparin.
• Found present in samples at levels of 10% 50%.
• NEJM research linked the contaminant with
the reactions, and deaths
• US House hearing was held on April 29
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Heparin Contamination
Video clip of testimony, April 29, 2008, at
the US House of Representatives,
Energy and Commerce Committee, by
family of Randy Hubley, who died due
to contaminated heparin.
http://energycommerce.house.gov/index.php?option=com_content&vi
ew=article&id=627&catid=31&Itemid=58
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Agenda
• Overview of Regulations
• Overview of U.S. Regulations and
FDA
• cGMP Basics
• Quality
• Data
• Closing
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Major Global Regulations
Canada
European Union
U.S.
Japan
Australia
Countries may have their own local regulations as well
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The global regulations
Whose regulations do we follow?
A product is manufactured in the United States.
It is sold in the US, United Kingdom, France,
Australia and Japan.
Manufacturing must meet the regulatory
requirements of all of these countries.
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U.S. Regulations
Code of Federal Regulations (CFR)
•50 titles covering broad areas subject to
federal regulation
•Title 21- Covers Food and Drug
Parts 1 to 1499
GMP’s Parts 11, 210, 211 & 820
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Global Regulations and Laws
cGMPs
current Good
Manufacturing
Practices
GPPs
Good
Promotional
Practices
GLPs
Good Laboratory
Practices
GCPs
Good Clinical
Practices
GXPs
GRPs
Good
Regulatory
Practices
GDPs
Good
Documentation
Practices
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The cGMPs and the U.S. CFR
Part 11
- Electronic Records; Electronic Signatures
Part 210 - cGMP in Manufacturing, Processing, Packing, or Holding of
Drugs; General
Part 211 - cGMP for Finished Pharmaceuticals
Part 225 - Animal Health Feeds
Part 226 - Premixes/Type A Medicated Articles
Parts 600-610 - General Biologics
Part 620 - Vaccines
Part 640 - Blood Products
Part 680 - Miscellaneous Biotech Products
Part 820 - Quality System Regulation
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The cGMPs and the U.S. CFR
Subparts of Part 211
Subpart A:
General Provisions
Subpart B:
Organization and Personnel
Subpart C:
Buildings and Facilities
Subpart D:
Equipment
Subpart E:
Control of Components and Drug Product
Containers and Closures
Subpart F:
Production and Process Controls
Subpart G:
Packaging and Label Control
Subpart H:
Holding and Distribution
Subpart I:
Laboratory Controls
Subpart J:
Records and Reports
Subpart K:
Returned and Salvaged Drug Products
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The cGMPs
• cGMPs stand for current Good Manufacturing Practices.
• cGMPs are the minimum expectations that regulators
have about how we manufacture our products
• cGMPs are regulations set forth by regulatory agencies
which carry the full weight and force of law.
• cGMPs are approved by regulatory agencies in each
country.
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The cGMPs
Regulators and World Health
Organizations – set regulations
Industry – interprets regulations and
implements regulations
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History of the U.S. Food and
Drug Regulations
1860 - First nationwide food law of modern times
1906 - Pure Food and Drug Act
1906 - FDA (Food and Drug Administration)
1938 - Creation of Food, Drug & Cosmetic Act
1963 - First issue of GMPs
Key Objective of Regulations – Public Health
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Where does the “c” come from?
Industry
Best
Practices
Podium
Speeches
FDA Guidance
Documents
GAMP
CFR – Minimum
GMP Requirements
Industry/ FDA joint
Publications
ASTM
Technology
Advancements
ICH
Global
Efforts and
Organizations
ISO
ISPE
PDA
WHO
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GMP Basics
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GMP Basics: Quality
What areas are affected by the cGMPs?
For Active Pharmaceutical Ingredients (APIs), the cGMPs apply
when starting materials are introduced into the process.
Parenteral Manufacturing
Starting Materials
Distribution
Packaging
APIs
Solid Oral Product Manufacturing
cGMPs apply to ALL finished dose manufacturing activities.
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GMP Basics: Quality
Define What
You Will Do!
Do It Right!
Make It Better!
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GMP Basics: Quality
Define What You Will Do!
Develop a Robust Process
Qualify Equipment to Run the Process
Write Protocols, Procedures and Tickets
Validate the Process
Do we understand
what is critical to
Is the equipment adequate
the product?
to run the process? Does
the equipment work
properly?
How should this
process be run?
Assurance that the
process works –
every time.
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Qualify the Equipment
Is the equipment adequate
to run the process? Does
the equipment work
properly?
• Is the equipment adequate to run
the process?
• Does it meet what we need?
• Can the mixing blade spin at the rate(s)
needed to produce the product?
• Does the equipment work
properly?
• At various rate settings, does the agitator
actually spin at that rate?
• Does it meet an acceptable range?
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GMP Basics: Quality
Do It Right!
Qualified People
Maintain Equipment
Do personnel know
what they are
doing and why?
What if something
goes wrong?
Follow tickets and procedures
Document appropriately
Right Environment
Clean and safe
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Maintain the Equipment
motors
gages
finish
gaskets
• Where is the most likely failure
for the equipment and what is
the impact to the product?
• What is the plan to prevent
critical failures?
• How often does the equipment
need maintenance?
• How often does it need
replaced?
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GMP Basics: Quality
Make It Better!
Proactively
investigate
trends.
Assure that all
aspects of the
change are
understood so that
impact is managed.
Monitor the process (testing, observations,
trending)
Investigate Deviations, find Root Cause,
Prevent Reoccurrences
Make Changes in a Controlled Manner
React Quickly to Indicators (customer
complaints, stability)
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Assure that all aspects
of the change are
understood so that
impact is managed.
Make Changes in a
Controlled Manner
• If a better agitator is found,
consideration has to be given
to:
• Operation of the new agitator –
does it meet the needs of the
product?
• Materials of construction – is it compatible with the
product?
• Equipment qualification – does the new agitator work
properly?
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GMP Basics: Quality Unit
• Firms must have a quality unit
independent of production.
• Oversee manufacturing
• Perform testing
• Old thinking:
“Quality Unit is responsible for Quality”
• New Thinking:
Every employee is responsible for Quality.
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Quality Basics
The actual dose of any
prescription drug you
take cannot be tested
because it would have
to be broken down for
analysis--after which it
could never be used by
a patient.
This means that you depend on
the manufacturer for assurance
that the dose you take is identical
to the ones which have been
tested every time it is
manufactured.
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GMP Basics: Data
Products
Manufacturing
Data
Integrity of our products depends on the integrity
of the data…
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GMP Basics: Data
What is data?
Factual information, especially information
organized for analysis or used to reason or make
decisions.
What is raw data?
Data recorded on/in its original paper or
electronic form to support the safety,
identity, strength, purity and/or quality of a product.
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GMP Basics: Data
Data Integrity is basically the
assurance that information is:
•
•
•
•
•
•
true
accurate
complete
retrievable
honest
easily located and verified
Also, the information must lead us to reproducible and
equitable results.
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GMP Basics: Data
How to ensure data integrity?
• good documentation practices
• appropriate handling of raw data
• record retention
• electronic files
• electronic signatures
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Summary
•
•
•
•
cGMPs Protect Public Health
Many countries have regulations
FDA governs pharmaceutical manufacturing in the U.S.
cGMP basics – Quality Manufacturing
Design a capable
process
•
Execute in the
state of control
Continuously improve
cGMP basics – Data Integrity
true
retrievable
honest
accurate
complete
easily located and verified
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Thank you for your attention!
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Acknowledgements
• Thanks to the following for content:
• Jamie Steinmetz
• Nikki Mehringer
• Thanks to the following for supporting
presentation:
• Tracy Wilson
• Sarah Langan
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Back up Information
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Basics of Quality – Batch Release
Monitor
Deviation
Execute
Validated
Process
Procedures
Test
Change
Release the Batch
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FDA
Health and Human Services
Administration for
Children and Families
•Centers for Medicare &
Medicaid Services
Administration on Aging
•Food & Drug Administration
Agency for Healthcare
Research and Quality
•Health Resources &
Services Administration
•Agency for Toxic Substances
& Disease Registry
•Indian Health Service
•Centers for Disease
Control & Prevention
•National Institutes of Health
•Substance Abuse & Mental Health
Services Administration
•Office of the Inspector General
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GMP Basics: Data
Good Documentation Practices
What are the expectations for documentation?
Documentation must be:
Permanent
Clear
Legible
Truthful
Accurate
Complete
Timely
Consistent
If you don't
sign in ....
you weren't
here!
If you don’t
document it …. it
wasn’t done!
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