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© 2013 Vivid Ngenuity, LLC. All rights reserved. 1
Bio-Link Summer Fellows Forum 2013
Vivian Ngan-Winward, PhD, CMQ/OE
WORKING IN A
REGULATED ENVIRONMENT
– ARE YOUR
BIOTECH STUDENTS
PREPARED?
THIS WORKSHOP COVERS . . .
 Overview of a regulated environment
 Basics of FDA regulations
 How biotech companies comply
 Common FDA inspection observations
 How to prepare students for
 Working in a regulated environment
 Making contributions toward compliance
2
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3
BIOTECHNOLOGY
INDUSTRY
OVERVIEW
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4
BIOTECH PRODUCT LIFE CYCLE
Idea
Research &
Development
[„Proof of
Concept‟]
Prototyping
/ Pilot Plant
[Validation &
Smaller
Scale
Production]
Manufacturing
[Mass / Large
Scale
Production] Consumer
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Business strategy :
 Develop for manufacturability
 Initiate compliance efforts at the idea stage
(identify market)
MARKETING PRODUCTS
 Requires FDA approval / clearance
 Pre-clinical & clinical trials
 Submit application
 Include data to support :
o Product claims
o Product safety
 Approval / clearance given by appropriate
FDA center with oversight for product type
5
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6
WHY THE NEED FOR
REGULATIONS ?
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. . . LESSONS FROM THE PAST
7
1800’s
Poor meat-packing conditions →
Upton Sinclair’s The Jungle
Federal Food and Drug Act →
first regulation of product labeling
1960
Federal Food, Drug, & Cosmetic (FD&C) Act
USDA Bureau of Chemistry →
Food, Drug, and Insecticide Administration (to FDA in 1930)
Misbranding (e.g. labeling is false or misleading) :
food, “tonics”, “elixirs of life”
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1906
1938
1927
Sulfanilamide elixir disaster : 107 deaths !!!1937
Application for Kevadon denied (Frances Kelsey);
thalidomide disaster in Europe (1961-1962)
. . . LESSONS FROM THE PAST
(CONT.)
8
FD&C Act Medical Device Amendments
GXPs
 GMP for Blood & Blood components –
21 CFR 606 (1975)
 GMP for Drugs - 21 CFR 210 & 211 (1978)
 GLP – 21 CFR 58 (1978) for pre-clinical studies
 GMP for Food – 21 CFR 110 (1986)
 GMP for Medical Devices [QSR] – 21 CFR 820 (1996)
 GMP for Dietary Supplements – 21 CFR 111 (2007)
1970’s
- now
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1976
FD&C Act Kefauver-Harris Amendments1962
Dalkon Shield disaster1971
A CLOSER LOOK –
FD&C ACT (1938)
 Extended control to cosmetics and therapeutic devices
 Required new drugs to be shown safe before marketing
 Eliminated Sherley Amendment requirement (to prove
intent to defraud in drug misbranding cases)
 Provided for safe tolerances be set for unavoidable
poisonous substances
 Authorized standards of identity, quality, and fill-of-
container for foods
 Authorized factory inspections
 Added of court injunctions to the penalties
9
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A CLOSER LOOK –
KEFAUVER-HARRIS AMD. (1962)
 Required manufacturers to provide evidence that
proposed drugs were both safe and effective,
demonstrated by adequate and well-controlled clinical
investigations conducted by qualified experts
 Required FDA evaluation of new drug applications (180
days); applications would no longer become
automatically effective
 Required affirmative FDA decision of new drugs before
marketing
 Required manufacturers to maintain records of adverse
drug events and to report these promptly to FDA
10
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BENEFITS OF REGULATIONS
 Sets standards for manufacturers and
expectations for their products
 Protects the public: some assurance of
safety and efficacy
11
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REGULATIONS REFERENCES
12
 FDA : What We Do : History
http://www.fda.gov/AboutFDA/WhatWe
Do/History/default.htm
 Sinclair (1906) The Jungle
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STUDENT PREPARATION IDEAS
13
 Discussion on an aspect of regulations
history
 Research / presentation on one of the
product “disasters”
Goal: orientation to the history and
importance of regulations
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14
THE LAWS &
CODE OF FEDERAL
REGULATIONS
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LAWS → REGULATIONS
15
FDA
United States Code
(U.S.C.) – Title 21
US Federal Government
Code of Federal Regulations
(CFRs) – Title 21, Food & Drugs
Promulgated in
Federal Register
Laws
Codified
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FD&C ACT OVERVIEW
 Chapter I: Short Title
 Chapter II: Definitions
 Chapter III: Prohibited Acts and Penalties
 Chapter IV: Food
 Chapter V: Drugs and Devices
 Chapter VI: Cosmetics
 Chapter VII: General Authority
 Chapter VIII: Imports and Exports
 Chapter IX: Miscellaneous
16
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FD&C ACT OVERVIEW (CONT.)
17
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FD&C Act / U.S.C. section number cross-
reference
http://www.fda.gov/RegulatoryInformation
/Legislation/FederalFoodDrugandCosmeti
cActFDCAct/default.htm
21 CFR OVERVIEW
Parts Covers
100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs
200 & 300 series Pharmaceuticals – 210 & 211 cGMPs
500 series Animal feeds & medications
600 series Biological products – 606 cGMPs
700 series Cosmetics (limited regulations)
800 series Medical devices – 820 cGMPs
900 series Mammography quality requirements
1000 series Radiation emitting device
1200 series Non-FD&C Act rulings
Other GLP – 58; GCP – 50, 54, 56; Electronic Records – 11
18
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21 CFR ?
21 CFR Parts can be viewed at
http://www.ecfr.gov
19
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STUDENT PREPARATION IDEAS
20
 Select several 21 CFR Parts and assign
one to each student to summarize and
present to the class
 Assign students to select and report
on one 21 CFR Part of interest
Goal: exposure to 21 CFRs, and how to
find them
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21
FOOD AND DRUG
ADMINISTRATION
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FDA OVERVIEW
 An agency of Department of Health and
Human Services (as of 1979)
 Mission:
1. “ responsible for protecting the public
health by assuring the safety, efficacy, and
security of human and veterinary drugs,
biological products, medical devices, our
nation’s food supply, cosmetics, and
products that emit radiation ”
22
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FDA OVERVIEW (CONT.)
 Mission (cont.):
2. “ responsible for advancing the public
health by helping to speed innovations that
make medicines and foods more effective,
safer, and more affordable; and helping the
public get the accurate, science-based
information they need to use medicines
and foods to improve their health ”
23
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FDA ORGANIZATION
24
From: www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/default.htm
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FDA ORGANIZATION (CONT.)
25
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Subdivision Responsibility
Office of the Commissioner Program administration
Office of Regulatory Affairs
Enforces FDA regulations, monitors industry
for compliance, recalls
Center for
Biologics
Evaluation &
Research
(CBER)
Assorted biological products/biologics (these
replicate natural human substances):
allergenic extracts for shots, blood & blood
components, gene therapy products,
transplant-related human tissue and cellular
products, vaccines
FDA Subdivisions:
FDA ORGANIZATION (CONT. 2)
26
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Subdivision Responsibility
Center for
Drug
Evaluation &
Research
(CDER)
Drugs (purely chemical substances),
therapeutic biological products (e.g.
monoclonal Abs, cytokines, growth factors,
enzymes, thrombolytics, proteins [natural or
recombinant]) extracted from animals for
therapeutic use, non-vaccine therapeutic
immunotherapies
Center for
Devices &
Radiological
Health
(CDRH)
Medical devices (e.g. catheters, breast
pumps, contact lenses, lab instrumentation),
diagnostic test kits, GMP, compliance,
postmarket tracking, radiological health
screening procedures (mammography, whole
body CT scanning, medical imaging)
FDA Subdivisions (continued):
FDA ORGANIZATION (CONT. 3)
27
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Subdivision Responsibility
Center for
Food Safety &
Applied Nutrition
(CFSAN)
Various food products, GMOs, cosmetics,
dietary supplements, infant formula,
foodborne illness, food labeling & nutrition
Center for
Veterinary Medicine
(CVM)
Food additives and drugs given to animals;
animals from which human foods are derived
FDA Subdivisions (continued):
BIOTECH PRODUCT JURISDICTION
28
Product Type FDA Center
Vaccine and blood product type therapeutic proteins CBER
Some therapeutic biological products (mAbs for in vivo
use, therapeutic proteins, cytokines and growth factors
used as immunomodulators or alterers of cell
production)
Transferred
to CDER
Combination products (e.g. drug/device,
biologic/device, drug/biologic, drug/device/biologic) –
combined, packaged together, packaged separately but
to be used together
CBER, CDER,
or CDRH,
depends on
primary mode
of action
Genetic tests for disease diagnosis or disease
prevention, treatment, or cure
CDRH
Biosimilars (generic biologic, not identical to original) CDER
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REGULATED PRODUCT APPROVALS
Application Type Purpose
Investigational New
Drug (IND)
To request exemption of approved marketing
application for shipping new drug across state
lines for clinical trials
New Drug
Application (NDA)
To request approval to sell and market new drug
in US; submitted with supporting documentation
detailing drug ingredients; how drug is
manufactured, processed, and packaged; results
of animal studies and clinical studies; how the
drug behaves in the body
Abbreviated New
Drug Application
(ANDA)
To request approval to sell and market generic
drug in US; application need not include animal
and clinical studies, but must show evidence that
generic is bioequivalent to innovator drug
29
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Drugs
REGULATED PRODUCT APPROVALS
(CONT.)
Application Type Purpose
Over-the-Counter
Drug (OTC)
Not an application; manufacturer can sell and
market an OTC drug with FDA pre-approval if it
conforms to the FDA-published OTC monograph;
one monograph for each of 80 therapeutic
classes of OTC drugs; monograph contains
acceptable ingredients, doses, formulation, and
labeling, and defines safety and effectiveness
Biologic License
Application (BLA)
To request approval to sell and market biologic
in US; like a NDA but for a biologic
30
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Drugs . . . 2
REGULATED PRODUCT APPROVALS
(CONT. 2)
31
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Medical Devices
Application Type Purpose
Investigational
Device Exemption
(IDE)
To request exemption of approved marketing
application for shipping investigational device
across state lines for clinical trials; clinical trials
typically required to support premarket approvals,
but occasionally needed to support premarket
notifications
Premarket
Notification (PMN) /
510(k) Clearance
To request clearance to sell and market in US non-
exempt Class I device or Class II device that is
substantially equivalent to a legally marketed
(predicate) device
Premarket Approval
(PMA)
To request approval to sell and market non-pre-
amendment Class III or non-510(k) device in US
REGULATED PRODUCT APPROVALS
(CONT. 3)
32
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Medical Devices . . . 2
Application Type Purpose
Humanitarian
Device Exemption
(HDE)
To request exemption of certain requirements to
sell and market humanitarian use device (HUD) in
US that is intended to benefit patients through
treatment or diagnosis of disease or condition
affecting < 4,000 individuals per year; like a PMA
but exempt from proof of effectiveness
requirement
REGULATED PRODUCT APPROVALS
(CONT. 4)
33
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Medical Device Notes
 Device classification:
o Depends on intended use and indications for use
o Over 1,700 distinct devices, grouped into 16
medical specialty panels [per 21 CFR 862-892],
have been classified
o 3 classes: Class I, Class II, and Class III, with
regulatory control increasing from I to III – see:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
Overview/GeneralandSpecialControls/default.htm
REGULATED PRODUCT APPROVALS
(CONT. 5)
34
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Medical Device Notes (cont.)
Device
Class
Definition
Class I
• Low risk
• Most (~74%) are exempt; non-exempt require PMN / 510(k)
• Exempt manufacturers must still register establishment
and list generic category or classification name
• Exempt devices not exempt from GMP requirements;
however, some are GMP exempt but not from records and
complaint files
• Some exempt devices have limitations to exemption status
• Subject to general controls
REGULATED PRODUCT APPROVALS
(CONT. 6)
35
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Medical Device Notes (cont. 2)
Device
Class
Definition
Class II
• Moderate risk
• Most are not exempt and usually require PMN / 510(k)
• Some are exempt, but not from GMP requirements
• Subject to general controls, and special controls to assure
safety and effectiveness
Class III
• High risk - pose significant risk of illness or injury (devices
usually support or sustain human life); OR
not substantially equivalent to Class I or Class II predicate
• Not exempt and require PMA unless a pre-amendment
(pre May 28, 1976) device
• Subject to general controls with PMA
REGULATED PRODUCT APPROVALS
(CONT. 7)
36
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Medical Device Notes (cont. 3)
 Substantial equivalence: if, in comparison
to predicate . . .
o Has same intended use AND technological
characteristics
o Has same intended use BUT different
technological characteristics that are supported
by data that (1) shows device is at least as safe
and effective as predicate AND (2) does not
raise new safety and effectiveness questions
FDA WEB SITE RESOURCES
 Center–specific information for industry
AND consumers
 About FDA
 Regulatory info & guidance documents
 Science & research
 News
 Recalls & alerts
 Approvals & clearances
37
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STUDENT PREPARATION IDEAS
38
 Invite a local biotech company
representative to speak to your class
about the process required to achieve
a recent product approval / clearance
 Examine and discuss an application for
a recently approved / cleared product
Goal: exposure to FDA submissions
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39
GOOD ? PRACTICES
(GXPS)
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WHAT ARE GXPS ?
GXPs = “best” practices
& FDA mandated
 defines what compliance requires
 does not describe exactly how to do it
40
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21 CFR OVERVIEW
Parts Covers
100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs
200 & 300 series Pharmaceuticals – 210 & 211 cGMPs
500 series Animal feeds & medications
600 series Biological products – 606 cGMPs
700 series Cosmetics (limited regulations)
800 series Medical devices – 820 cGMPs
900 series Mammography quality requirements
1000 series Radiation emitting device
1200 series Non-FD&C Act rulings
Other GLP – 58; GCP – 50, 54, 56; Electronic Records – 11
41
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DIFFERENT GXPS
 Good clinical practices (GCP) :
 Regulates clinical trials involving human
subjects
 Protects human rights
 Provides assurance of safety and efficacy of
developed product
 Good laboratory practices (GLP) :
 Regulates nonclinical laboratory studies that
support FDA approval applications
 Good manufacturing practices (cGMP) :
 Regulates manufacture of products covered by
FD&C Act 42
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GOOD MANUFACTURING
PRACTICES (GMP)
 Most stringently described in 21 CFR Parts
 110 : for food
 111 : for dietary supplements
 210 & 211 : for drugs
 606 : for biologics
 820 : for medical devices (QSRs)
 Provides detailed requirements on how to
operate manufacturing business
 Indirectly impacts R&D
43
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GMP DESIGN CONTROLS
 Design Inputs & Outputs
 Design Verification : Outputs = Inputs
 Design Validation
 Compilation of records:
 Design History File (DHF) : describes design
history of finished product
 Device Master Record (DMR) : contains
procedures and specifications of finished
device/product (“recipe”)
 Device History Record (DHR) : contains
production history of device/product 44
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GMP EXAMPLE
 Medical device cGMP
up close . . .
See also : FDA’s CDRH Learn – Quality
System Regulation 21 CFR 820 Basic
Introduction presentation
http://www.fda.gov/MedicalDevices/ResourcesforYou
/Industry/ucm126252.htm
45
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GXP REFERENCES
 GLP:
o 21 CFR 58
o Lab Compliance GLP tutorial
http://www.labcompliance.com/tutorial/gl
p/default.aspx?sm=d_a
o WHO GLP Handbook (2009)
http://www.who.int/tdr/publications/traini
ng-guideline-publications/good-laboratory-
practice-handbook-ver1/en/
46
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GXP REFERENCES (CONT.)
 GMP FDA guidance documents:
o http://www.fda.gov/Drugs/GuidanceComplian
ceRegulatoryInformation/Guidances/ucm06497
1.htm
o http://www.fda.gov/BiologicsBloodVaccines/G
uidanceComplianceRegulatoryInformation/Gui
dances/General/ucm217665.htm
o http://www.fda.gov/MedicalDevices/DeviceRe
gulationandGuidance/PostmarketRequirements
/QualitySystemsRegulations/MedicalDeviceQua
litySystemsManual/default.htm
47
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STUDENT PREPARATION IDEAS
48
 GXP comparison activity:
Align these 21 CFR Parts:
o GLP (21 CFR 58)
o drug cGMP (21 CFR 210 & 211)
o biologics cGMP (21 CFR 606)
o medical device cGMP (21 CFR 820)
Goal: exposure to details of GXPs and how
they are similar / different
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49
REGULATORY
COMPLIANCE
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THE HIERARCHY
A tight relationship exists
between
 the FDA [regulating body]
 the Laws [US Code]
 the Code of Federal
Regulations (CFRs) - gov’t
agency promulgated
 Good Manufacturing
Practices (GMPs)
 Quality System Regulations
(QSRs)
 Standards / Certifications
(e.g. ISO)
 Quality Management System
50
FDA
Laws (U.S.C.)
Industry-Specific CFRs
GMPs
Quality Management System
GovernmentIndustryCompany
Standards
/ Certif.
(e.g. ISO)
QSRs
ISO
Non-gov‟tOrg
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COMPLYING WITH FDA REGS
How ?
51
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“INTERPRETING REGULATIONS”
52
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What does the sign mean to you ?
How will you ensure compliance ?
COMPLYING WITH FDA REGS . . . 2
By appropriately
interpreting the
regulations
53
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COMPLYING WITH FDA REGS . . . 3
A quality management
system provides a
structure for
the company to
work within and
remain compliant
54
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55
QUALITY
MANAGEMENT
SYSTEM
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QUALITY MANAGEMENT SYSTEM
(QMS) – CHARACTERISTICS
 Required by the FDA (not optional !)
 “Each manufacturer shall establish and
maintain a quality system that is
appropriate for the specific medical
device(s) designed or manufactured, and
that meets the requirements of this part.”
– 21 CFR 820.5
 Designed by each company to align its
operations with the regulations 56
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WHAT IS A QMS ?
 Per 21 CFR 820.3 – “the organizational
structure, responsibilities, procedures,
processes, and resources for implementing
quality management”
 Per Wikipedia – “a set of policies,
processes, and procedures required for
planning and execution of production in
the core business area of an organization”
57
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WHAT IS A QMS ? (CONT.)
 Has a customer focus
 Often designed to meet ISO 9001 standards
– based on 8 principles:
1. Customer focus
2. Leadership
3. Workforce involvement
4. Continuous improvement
5. System approach to management
6. Data-based approach to decision making
7. Positive supplier communication / relationships
8. Total process approach
58
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WHAT IS A QMS ? (CONT. 2)
 Main components
 Management responsibility
 Resource management
 Product realization
 Measurement, analysis, and improvement
 Process-oriented approach to managing
quality
 A framework that directs quality
contributions from all employees
59
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QMS PROCESS MODEL
60
Quality Management System
Continual Improvement
Resource
Management
Process /
Product
Realization
input
Product /
Service
C
U
S
T
O
M
E
R
R
e
q
u
i
r
e
m
e
n
t
s
Measurement,
Analysis, &
Improvement
Management
Responsibility
output
S
a
t
i
s
f
a
c
t
i
o
n
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C
U
S
T
O
M
E
R
WHAT DOES THE QMS COVER ?
 Training & qualifying personnel
 Controlling product design
 Controlling documentation & records
 Controlling purchasing
 Identifying & tracing product at all production
stages
 Defining & controlling production & processes
 Defining & controlling inspection / measuring /
test equipment
61
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WHAT DOES THE QMS COVER ?
(CONT.)
 Validating processes
 Accepting product
 Controlling nonconforming product
 Instituting corrective & preventive actions
 Controlling labeling & packaging
 Servicing production equipment
 Using statistical techniques
62
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COMMON FDA OBSERVATIONS
 Catalogued by the FDA on an annual basis
 Access through:
http://www.fda.gov/ICECI/EnforcementAc
tions/ucm250720.htm
 Examples from FDA inspections during
fiscal year 2012 (Oct 1, 2011 to Sep 30,
2012) – actual observations reported on
Form 483’s
63
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DRUG OBSERVATIONS . . . 1
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Observation Freq Reg Ref
The responsibilities and procedures applicable
to the quality control unit are not [in writing]
[fully followed]. Specifically, ***
169
21 CFR
211.22(d)
There is a failure to thoroughly review [any
unexplained discrepancy] [the failure of a
batch or any of its components to meet any of
its specifications] whether or not the batch has
been already distributed. Specifically, ***
119
21 CFR
211.192
There are no written procedures for production
and process controls designed to assure that
the drug products have the identity, strength,
quality, and purity they purport or are
represented to possess. Specifically, ***
116
21 CFR
211.100(a)
DRUG OBSERVATIONS . . . 2
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Observation Freq Reg Ref
Laboratory controls do not include the
establishment of scientifically sound and
appropriate [specifications] [standards]
[sampling plans] [test procedures] designed to
assure that [components] [drug product
containers] [closures] [in-process materials]
[labeling] [drug products] conform to
appropriate standards of identity, strength,
quality and purity. Specifically, ***
115
21 CFR
211.160(b)
Control procedures are not established which
[monitor the output] [validate the
performance] of those manufacturing processes
that may be responsible for causing variability
in the characteristics of in-process material
and the drug product. Specifically, ***
89
21 CFR
211.110(a)
DRUG OBSERVATIONS . . . 3
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Observation Freq Reg Ref
Written procedures are not [established]
[followed] for the cleaning and maintenance of
equipment, including utensils, used in the
manufacture, processing, packing or holding of
a drug product. Specifically, ***
73
21 CFR
211.67(b)
Routine [calibration] [inspection] [checking] of
[automatic] [mechanical] [electronic]
equipment is not performed according to a
written program designed to assure proper
performance. Specifically, ***
69
21 CFR
211.68(a)
Employees are not given training in [the
particular operations they perform as part of
their function] [current good manufacturing
practices] [written procedures required by
current good manufacturing practice
regulations]. Specifically, ***
65
21 CFR
211.25(a)
DRUG OBSERVATIONS . . . 4
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Observation Freq Reg Ref
Equipment and utensils are not [cleaned]
[maintained] [sanitized] at appropriate
intervals to prevent [malfunctions]
[contamination] that would alter the safety,
identity, strength, quality or purity of the drug
product. Specifically, ***
65
21 CFR
211.67(a)
Written production and process control
procedures are not [followed in the execution
of production and process control functions]
[documented at the time of performance].
Specifically, ***
64
21 CFR
211.100(b)
DRUG OBSERVATIONS . . . 5
© 2013 Vivid Ngenuity, LLC. All rights reserved.
Observation Freq Reg Ref
Testing and release of drug product for
distribution do not include appropriate
laboratory determination of satisfactory
conformance to the [final specifications]
[identity and strength of each active
ingredient] prior to release. Specifically, ***
62
21 CFR
211.165(a)
DEVICE OBSERVATIONS . . . 1
© 2013 Vivid Ngenuity, LLC. All rights reserved.
Observation Freq Reg Ref
Procedures for corrective and preventive
action have not been [adequately] established.
Specifically, ***
372
21 CFR
820.100(a)
Procedures for receiving, reviewing, and
evaluating complaints by a formally designated
unit have not been [adequately] established.
Specifically,***
259
21 CFR
820.198(a)
Written MDR procedures have not been
[developed] [maintained] [implemented].
Specifically, ***
140
21 CFR
803.17
Procedures to ensure that all purchased or
otherwise received product and services
conform to specified requirements have not
been [adequately] established. Specifically, ***
126
21 CFR
820.50
DEVICE OBSERVATIONS . . . 2
© 2013 Vivid Ngenuity, LLC. All rights reserved.
Observation Freq Reg Ref
Corrective and preventive action activities
and/or results have not been [adequately]
documented. Specifically, ***
115
21 CFR
820.100(b)
Procedures have not been [adequately]
established to control product that does not
conform to specified requirements.
Specifically, ***
110
21 CFR
820.90(a)
A process whose results cannot be fully verified
by subsequent inspection and test has not been
[adequately] validated according to
established procedures. Specifically, ***
102
21 CFR
820.75(a)
Procedures for design change have not been
[adequately] established. Specifically,***
101
21 CFR
820.30(i)
DEVICE OBSERVATIONS . . . 3
© 2013 Vivid Ngenuity, LLC. All rights reserved.
Observation Freq Reg Ref
Complaints involving the possible failure of [a
device] [labeling] [packaging] to meet any of
its specifications were not [reviewed]
[evaluated] [investigated] where necessary.
Specifically, ***
96
21 CFR
820.198(c)
Procedures for quality audits have not been
[adequately] established. Specifically, ***
91
21 CFR
820.22
A device master record has not been
[adequately] maintained. Specifically, ***
91
21 CFR
820.181
COMMONALITY
 Procedures for XXX not [adequately]
established / followed
© 2013 Vivid Ngenuity, LLC. All rights reserved.
STUDENT PREPARATION IDEAS
73
 Review and discuss these common
observations with students
 Case studies – select Form 483’s for class
review and discussion (RE: local
companies have more relevance)
http://www.fda.gov/AboutFDA/CentersOffices/Offi
ceofGlobalRegulatoryOperationsandPolicy/ORA/ORA
ElectronicReadingRoom/default.htm
Goal: understand common mistakes to
better contribute toward compliance
© 2013 Vivid Ngenuity, LLC. All rights reserved.
QUESTIONS ?
74
Vivian Ngan-Winward
vivian.ngan-winward@slcc.edu
801-957-6210
© 2013 Vivid Ngenuity, LLC. All rights reserved.

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Working in a_regulated_environment_presentation_ngan-winward

  • 1. © 2013 Vivid Ngenuity, LLC. All rights reserved. 1 Bio-Link Summer Fellows Forum 2013 Vivian Ngan-Winward, PhD, CMQ/OE WORKING IN A REGULATED ENVIRONMENT – ARE YOUR BIOTECH STUDENTS PREPARED?
  • 2. THIS WORKSHOP COVERS . . .  Overview of a regulated environment  Basics of FDA regulations  How biotech companies comply  Common FDA inspection observations  How to prepare students for  Working in a regulated environment  Making contributions toward compliance 2 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 3. 3 BIOTECHNOLOGY INDUSTRY OVERVIEW © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 4. 4 BIOTECH PRODUCT LIFE CYCLE Idea Research & Development [„Proof of Concept‟] Prototyping / Pilot Plant [Validation & Smaller Scale Production] Manufacturing [Mass / Large Scale Production] Consumer © 2013 Vivid Ngenuity, LLC. All rights reserved. Business strategy :  Develop for manufacturability  Initiate compliance efforts at the idea stage (identify market)
  • 5. MARKETING PRODUCTS  Requires FDA approval / clearance  Pre-clinical & clinical trials  Submit application  Include data to support : o Product claims o Product safety  Approval / clearance given by appropriate FDA center with oversight for product type 5 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 6. 6 WHY THE NEED FOR REGULATIONS ? © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 7. . . . LESSONS FROM THE PAST 7 1800’s Poor meat-packing conditions → Upton Sinclair’s The Jungle Federal Food and Drug Act → first regulation of product labeling 1960 Federal Food, Drug, & Cosmetic (FD&C) Act USDA Bureau of Chemistry → Food, Drug, and Insecticide Administration (to FDA in 1930) Misbranding (e.g. labeling is false or misleading) : food, “tonics”, “elixirs of life” © 2013 Vivid Ngenuity, LLC. All rights reserved. 1906 1938 1927 Sulfanilamide elixir disaster : 107 deaths !!!1937 Application for Kevadon denied (Frances Kelsey); thalidomide disaster in Europe (1961-1962)
  • 8. . . . LESSONS FROM THE PAST (CONT.) 8 FD&C Act Medical Device Amendments GXPs  GMP for Blood & Blood components – 21 CFR 606 (1975)  GMP for Drugs - 21 CFR 210 & 211 (1978)  GLP – 21 CFR 58 (1978) for pre-clinical studies  GMP for Food – 21 CFR 110 (1986)  GMP for Medical Devices [QSR] – 21 CFR 820 (1996)  GMP for Dietary Supplements – 21 CFR 111 (2007) 1970’s - now © 2013 Vivid Ngenuity, LLC. All rights reserved. 1976 FD&C Act Kefauver-Harris Amendments1962 Dalkon Shield disaster1971
  • 9. A CLOSER LOOK – FD&C ACT (1938)  Extended control to cosmetics and therapeutic devices  Required new drugs to be shown safe before marketing  Eliminated Sherley Amendment requirement (to prove intent to defraud in drug misbranding cases)  Provided for safe tolerances be set for unavoidable poisonous substances  Authorized standards of identity, quality, and fill-of- container for foods  Authorized factory inspections  Added of court injunctions to the penalties 9 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 10. A CLOSER LOOK – KEFAUVER-HARRIS AMD. (1962)  Required manufacturers to provide evidence that proposed drugs were both safe and effective, demonstrated by adequate and well-controlled clinical investigations conducted by qualified experts  Required FDA evaluation of new drug applications (180 days); applications would no longer become automatically effective  Required affirmative FDA decision of new drugs before marketing  Required manufacturers to maintain records of adverse drug events and to report these promptly to FDA 10 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 11. BENEFITS OF REGULATIONS  Sets standards for manufacturers and expectations for their products  Protects the public: some assurance of safety and efficacy 11 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 12. REGULATIONS REFERENCES 12  FDA : What We Do : History http://www.fda.gov/AboutFDA/WhatWe Do/History/default.htm  Sinclair (1906) The Jungle © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 13. STUDENT PREPARATION IDEAS 13  Discussion on an aspect of regulations history  Research / presentation on one of the product “disasters” Goal: orientation to the history and importance of regulations © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 14. 14 THE LAWS & CODE OF FEDERAL REGULATIONS © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 15. LAWS → REGULATIONS 15 FDA United States Code (U.S.C.) – Title 21 US Federal Government Code of Federal Regulations (CFRs) – Title 21, Food & Drugs Promulgated in Federal Register Laws Codified © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 16. FD&C ACT OVERVIEW  Chapter I: Short Title  Chapter II: Definitions  Chapter III: Prohibited Acts and Penalties  Chapter IV: Food  Chapter V: Drugs and Devices  Chapter VI: Cosmetics  Chapter VII: General Authority  Chapter VIII: Imports and Exports  Chapter IX: Miscellaneous 16 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 17. FD&C ACT OVERVIEW (CONT.) 17 © 2013 Vivid Ngenuity, LLC. All rights reserved. FD&C Act / U.S.C. section number cross- reference http://www.fda.gov/RegulatoryInformation /Legislation/FederalFoodDrugandCosmeti cActFDCAct/default.htm
  • 18. 21 CFR OVERVIEW Parts Covers 100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs 200 & 300 series Pharmaceuticals – 210 & 211 cGMPs 500 series Animal feeds & medications 600 series Biological products – 606 cGMPs 700 series Cosmetics (limited regulations) 800 series Medical devices – 820 cGMPs 900 series Mammography quality requirements 1000 series Radiation emitting device 1200 series Non-FD&C Act rulings Other GLP – 58; GCP – 50, 54, 56; Electronic Records – 11 18 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 19. 21 CFR ? 21 CFR Parts can be viewed at http://www.ecfr.gov 19 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 20. STUDENT PREPARATION IDEAS 20  Select several 21 CFR Parts and assign one to each student to summarize and present to the class  Assign students to select and report on one 21 CFR Part of interest Goal: exposure to 21 CFRs, and how to find them © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 21. 21 FOOD AND DRUG ADMINISTRATION © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 22. FDA OVERVIEW  An agency of Department of Health and Human Services (as of 1979)  Mission: 1. “ responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation ” 22 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 23. FDA OVERVIEW (CONT.)  Mission (cont.): 2. “ responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health ” 23 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 25. FDA ORGANIZATION (CONT.) 25 © 2013 Vivid Ngenuity, LLC. All rights reserved. Subdivision Responsibility Office of the Commissioner Program administration Office of Regulatory Affairs Enforces FDA regulations, monitors industry for compliance, recalls Center for Biologics Evaluation & Research (CBER) Assorted biological products/biologics (these replicate natural human substances): allergenic extracts for shots, blood & blood components, gene therapy products, transplant-related human tissue and cellular products, vaccines FDA Subdivisions:
  • 26. FDA ORGANIZATION (CONT. 2) 26 © 2013 Vivid Ngenuity, LLC. All rights reserved. Subdivision Responsibility Center for Drug Evaluation & Research (CDER) Drugs (purely chemical substances), therapeutic biological products (e.g. monoclonal Abs, cytokines, growth factors, enzymes, thrombolytics, proteins [natural or recombinant]) extracted from animals for therapeutic use, non-vaccine therapeutic immunotherapies Center for Devices & Radiological Health (CDRH) Medical devices (e.g. catheters, breast pumps, contact lenses, lab instrumentation), diagnostic test kits, GMP, compliance, postmarket tracking, radiological health screening procedures (mammography, whole body CT scanning, medical imaging) FDA Subdivisions (continued):
  • 27. FDA ORGANIZATION (CONT. 3) 27 © 2013 Vivid Ngenuity, LLC. All rights reserved. Subdivision Responsibility Center for Food Safety & Applied Nutrition (CFSAN) Various food products, GMOs, cosmetics, dietary supplements, infant formula, foodborne illness, food labeling & nutrition Center for Veterinary Medicine (CVM) Food additives and drugs given to animals; animals from which human foods are derived FDA Subdivisions (continued):
  • 28. BIOTECH PRODUCT JURISDICTION 28 Product Type FDA Center Vaccine and blood product type therapeutic proteins CBER Some therapeutic biological products (mAbs for in vivo use, therapeutic proteins, cytokines and growth factors used as immunomodulators or alterers of cell production) Transferred to CDER Combination products (e.g. drug/device, biologic/device, drug/biologic, drug/device/biologic) – combined, packaged together, packaged separately but to be used together CBER, CDER, or CDRH, depends on primary mode of action Genetic tests for disease diagnosis or disease prevention, treatment, or cure CDRH Biosimilars (generic biologic, not identical to original) CDER © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 29. REGULATED PRODUCT APPROVALS Application Type Purpose Investigational New Drug (IND) To request exemption of approved marketing application for shipping new drug across state lines for clinical trials New Drug Application (NDA) To request approval to sell and market new drug in US; submitted with supporting documentation detailing drug ingredients; how drug is manufactured, processed, and packaged; results of animal studies and clinical studies; how the drug behaves in the body Abbreviated New Drug Application (ANDA) To request approval to sell and market generic drug in US; application need not include animal and clinical studies, but must show evidence that generic is bioequivalent to innovator drug 29 © 2013 Vivid Ngenuity, LLC. All rights reserved. Drugs
  • 30. REGULATED PRODUCT APPROVALS (CONT.) Application Type Purpose Over-the-Counter Drug (OTC) Not an application; manufacturer can sell and market an OTC drug with FDA pre-approval if it conforms to the FDA-published OTC monograph; one monograph for each of 80 therapeutic classes of OTC drugs; monograph contains acceptable ingredients, doses, formulation, and labeling, and defines safety and effectiveness Biologic License Application (BLA) To request approval to sell and market biologic in US; like a NDA but for a biologic 30 © 2013 Vivid Ngenuity, LLC. All rights reserved. Drugs . . . 2
  • 31. REGULATED PRODUCT APPROVALS (CONT. 2) 31 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Devices Application Type Purpose Investigational Device Exemption (IDE) To request exemption of approved marketing application for shipping investigational device across state lines for clinical trials; clinical trials typically required to support premarket approvals, but occasionally needed to support premarket notifications Premarket Notification (PMN) / 510(k) Clearance To request clearance to sell and market in US non- exempt Class I device or Class II device that is substantially equivalent to a legally marketed (predicate) device Premarket Approval (PMA) To request approval to sell and market non-pre- amendment Class III or non-510(k) device in US
  • 32. REGULATED PRODUCT APPROVALS (CONT. 3) 32 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Devices . . . 2 Application Type Purpose Humanitarian Device Exemption (HDE) To request exemption of certain requirements to sell and market humanitarian use device (HUD) in US that is intended to benefit patients through treatment or diagnosis of disease or condition affecting < 4,000 individuals per year; like a PMA but exempt from proof of effectiveness requirement
  • 33. REGULATED PRODUCT APPROVALS (CONT. 4) 33 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes  Device classification: o Depends on intended use and indications for use o Over 1,700 distinct devices, grouped into 16 medical specialty panels [per 21 CFR 862-892], have been classified o 3 classes: Class I, Class II, and Class III, with regulatory control increasing from I to III – see: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Overview/GeneralandSpecialControls/default.htm
  • 34. REGULATED PRODUCT APPROVALS (CONT. 5) 34 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont.) Device Class Definition Class I • Low risk • Most (~74%) are exempt; non-exempt require PMN / 510(k) • Exempt manufacturers must still register establishment and list generic category or classification name • Exempt devices not exempt from GMP requirements; however, some are GMP exempt but not from records and complaint files • Some exempt devices have limitations to exemption status • Subject to general controls
  • 35. REGULATED PRODUCT APPROVALS (CONT. 6) 35 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont. 2) Device Class Definition Class II • Moderate risk • Most are not exempt and usually require PMN / 510(k) • Some are exempt, but not from GMP requirements • Subject to general controls, and special controls to assure safety and effectiveness Class III • High risk - pose significant risk of illness or injury (devices usually support or sustain human life); OR not substantially equivalent to Class I or Class II predicate • Not exempt and require PMA unless a pre-amendment (pre May 28, 1976) device • Subject to general controls with PMA
  • 36. REGULATED PRODUCT APPROVALS (CONT. 7) 36 © 2013 Vivid Ngenuity, LLC. All rights reserved. Medical Device Notes (cont. 3)  Substantial equivalence: if, in comparison to predicate . . . o Has same intended use AND technological characteristics o Has same intended use BUT different technological characteristics that are supported by data that (1) shows device is at least as safe and effective as predicate AND (2) does not raise new safety and effectiveness questions
  • 37. FDA WEB SITE RESOURCES  Center–specific information for industry AND consumers  About FDA  Regulatory info & guidance documents  Science & research  News  Recalls & alerts  Approvals & clearances 37 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 38. STUDENT PREPARATION IDEAS 38  Invite a local biotech company representative to speak to your class about the process required to achieve a recent product approval / clearance  Examine and discuss an application for a recently approved / cleared product Goal: exposure to FDA submissions © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 39. 39 GOOD ? PRACTICES (GXPS) © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 40. WHAT ARE GXPS ? GXPs = “best” practices & FDA mandated  defines what compliance requires  does not describe exactly how to do it 40 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 41. 21 CFR OVERVIEW Parts Covers 100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs 200 & 300 series Pharmaceuticals – 210 & 211 cGMPs 500 series Animal feeds & medications 600 series Biological products – 606 cGMPs 700 series Cosmetics (limited regulations) 800 series Medical devices – 820 cGMPs 900 series Mammography quality requirements 1000 series Radiation emitting device 1200 series Non-FD&C Act rulings Other GLP – 58; GCP – 50, 54, 56; Electronic Records – 11 41 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 42. DIFFERENT GXPS  Good clinical practices (GCP) :  Regulates clinical trials involving human subjects  Protects human rights  Provides assurance of safety and efficacy of developed product  Good laboratory practices (GLP) :  Regulates nonclinical laboratory studies that support FDA approval applications  Good manufacturing practices (cGMP) :  Regulates manufacture of products covered by FD&C Act 42 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 43. GOOD MANUFACTURING PRACTICES (GMP)  Most stringently described in 21 CFR Parts  110 : for food  111 : for dietary supplements  210 & 211 : for drugs  606 : for biologics  820 : for medical devices (QSRs)  Provides detailed requirements on how to operate manufacturing business  Indirectly impacts R&D 43 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 44. GMP DESIGN CONTROLS  Design Inputs & Outputs  Design Verification : Outputs = Inputs  Design Validation  Compilation of records:  Design History File (DHF) : describes design history of finished product  Device Master Record (DMR) : contains procedures and specifications of finished device/product (“recipe”)  Device History Record (DHR) : contains production history of device/product 44 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 45. GMP EXAMPLE  Medical device cGMP up close . . . See also : FDA’s CDRH Learn – Quality System Regulation 21 CFR 820 Basic Introduction presentation http://www.fda.gov/MedicalDevices/ResourcesforYou /Industry/ucm126252.htm 45 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 46. GXP REFERENCES  GLP: o 21 CFR 58 o Lab Compliance GLP tutorial http://www.labcompliance.com/tutorial/gl p/default.aspx?sm=d_a o WHO GLP Handbook (2009) http://www.who.int/tdr/publications/traini ng-guideline-publications/good-laboratory- practice-handbook-ver1/en/ 46 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 47. GXP REFERENCES (CONT.)  GMP FDA guidance documents: o http://www.fda.gov/Drugs/GuidanceComplian ceRegulatoryInformation/Guidances/ucm06497 1.htm o http://www.fda.gov/BiologicsBloodVaccines/G uidanceComplianceRegulatoryInformation/Gui dances/General/ucm217665.htm o http://www.fda.gov/MedicalDevices/DeviceRe gulationandGuidance/PostmarketRequirements /QualitySystemsRegulations/MedicalDeviceQua litySystemsManual/default.htm 47 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 48. STUDENT PREPARATION IDEAS 48  GXP comparison activity: Align these 21 CFR Parts: o GLP (21 CFR 58) o drug cGMP (21 CFR 210 & 211) o biologics cGMP (21 CFR 606) o medical device cGMP (21 CFR 820) Goal: exposure to details of GXPs and how they are similar / different © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 49. 49 REGULATORY COMPLIANCE © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 50. THE HIERARCHY A tight relationship exists between  the FDA [regulating body]  the Laws [US Code]  the Code of Federal Regulations (CFRs) - gov’t agency promulgated  Good Manufacturing Practices (GMPs)  Quality System Regulations (QSRs)  Standards / Certifications (e.g. ISO)  Quality Management System 50 FDA Laws (U.S.C.) Industry-Specific CFRs GMPs Quality Management System GovernmentIndustryCompany Standards / Certif. (e.g. ISO) QSRs ISO Non-gov‟tOrg © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 51. COMPLYING WITH FDA REGS How ? 51 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 52. “INTERPRETING REGULATIONS” 52 © 2013 Vivid Ngenuity, LLC. All rights reserved. What does the sign mean to you ? How will you ensure compliance ?
  • 53. COMPLYING WITH FDA REGS . . . 2 By appropriately interpreting the regulations 53 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 54. COMPLYING WITH FDA REGS . . . 3 A quality management system provides a structure for the company to work within and remain compliant 54 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 55. 55 QUALITY MANAGEMENT SYSTEM © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 56. QUALITY MANAGEMENT SYSTEM (QMS) – CHARACTERISTICS  Required by the FDA (not optional !)  “Each manufacturer shall establish and maintain a quality system that is appropriate for the specific medical device(s) designed or manufactured, and that meets the requirements of this part.” – 21 CFR 820.5  Designed by each company to align its operations with the regulations 56 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 57. WHAT IS A QMS ?  Per 21 CFR 820.3 – “the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management”  Per Wikipedia – “a set of policies, processes, and procedures required for planning and execution of production in the core business area of an organization” 57 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 58. WHAT IS A QMS ? (CONT.)  Has a customer focus  Often designed to meet ISO 9001 standards – based on 8 principles: 1. Customer focus 2. Leadership 3. Workforce involvement 4. Continuous improvement 5. System approach to management 6. Data-based approach to decision making 7. Positive supplier communication / relationships 8. Total process approach 58 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 59. WHAT IS A QMS ? (CONT. 2)  Main components  Management responsibility  Resource management  Product realization  Measurement, analysis, and improvement  Process-oriented approach to managing quality  A framework that directs quality contributions from all employees 59 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 60. QMS PROCESS MODEL 60 Quality Management System Continual Improvement Resource Management Process / Product Realization input Product / Service C U S T O M E R R e q u i r e m e n t s Measurement, Analysis, & Improvement Management Responsibility output S a t i s f a c t i o n © 2013 Vivid Ngenuity, LLC. All rights reserved. C U S T O M E R
  • 61. WHAT DOES THE QMS COVER ?  Training & qualifying personnel  Controlling product design  Controlling documentation & records  Controlling purchasing  Identifying & tracing product at all production stages  Defining & controlling production & processes  Defining & controlling inspection / measuring / test equipment 61 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 62. WHAT DOES THE QMS COVER ? (CONT.)  Validating processes  Accepting product  Controlling nonconforming product  Instituting corrective & preventive actions  Controlling labeling & packaging  Servicing production equipment  Using statistical techniques 62 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 63. COMMON FDA OBSERVATIONS  Catalogued by the FDA on an annual basis  Access through: http://www.fda.gov/ICECI/EnforcementAc tions/ucm250720.htm  Examples from FDA inspections during fiscal year 2012 (Oct 1, 2011 to Sep 30, 2012) – actual observations reported on Form 483’s 63 © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 64. DRUG OBSERVATIONS . . . 1 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. Specifically, *** 169 21 CFR 211.22(d) There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. Specifically, *** 119 21 CFR 211.192 There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, *** 116 21 CFR 211.100(a)
  • 65. DRUG OBSERVATIONS . . . 2 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. Specifically, *** 115 21 CFR 211.160(b) Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Specifically, *** 89 21 CFR 211.110(a)
  • 66. DRUG OBSERVATIONS . . . 3 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, *** 73 21 CFR 211.67(b) Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, *** 69 21 CFR 211.68(a) Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations]. Specifically, *** 65 21 CFR 211.25(a)
  • 67. DRUG OBSERVATIONS . . . 4 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, *** 65 21 CFR 211.67(a) Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance]. Specifically, *** 64 21 CFR 211.100(b)
  • 68. DRUG OBSERVATIONS . . . 5 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release. Specifically, *** 62 21 CFR 211.165(a)
  • 69. DEVICE OBSERVATIONS . . . 1 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Procedures for corrective and preventive action have not been [adequately] established. Specifically, *** 372 21 CFR 820.100(a) Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established. Specifically,*** 259 21 CFR 820.198(a) Written MDR procedures have not been [developed] [maintained] [implemented]. Specifically, *** 140 21 CFR 803.17 Procedures to ensure that all purchased or otherwise received product and services conform to specified requirements have not been [adequately] established. Specifically, *** 126 21 CFR 820.50
  • 70. DEVICE OBSERVATIONS . . . 2 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Corrective and preventive action activities and/or results have not been [adequately] documented. Specifically, *** 115 21 CFR 820.100(b) Procedures have not been [adequately] established to control product that does not conform to specified requirements. Specifically, *** 110 21 CFR 820.90(a) A process whose results cannot be fully verified by subsequent inspection and test has not been [adequately] validated according to established procedures. Specifically, *** 102 21 CFR 820.75(a) Procedures for design change have not been [adequately] established. Specifically,*** 101 21 CFR 820.30(i)
  • 71. DEVICE OBSERVATIONS . . . 3 © 2013 Vivid Ngenuity, LLC. All rights reserved. Observation Freq Reg Ref Complaints involving the possible failure of [a device] [labeling] [packaging] to meet any of its specifications were not [reviewed] [evaluated] [investigated] where necessary. Specifically, *** 96 21 CFR 820.198(c) Procedures for quality audits have not been [adequately] established. Specifically, *** 91 21 CFR 820.22 A device master record has not been [adequately] maintained. Specifically, *** 91 21 CFR 820.181
  • 72. COMMONALITY  Procedures for XXX not [adequately] established / followed © 2013 Vivid Ngenuity, LLC. All rights reserved.
  • 73. STUDENT PREPARATION IDEAS 73  Review and discuss these common observations with students  Case studies – select Form 483’s for class review and discussion (RE: local companies have more relevance) http://www.fda.gov/AboutFDA/CentersOffices/Offi ceofGlobalRegulatoryOperationsandPolicy/ORA/ORA ElectronicReadingRoom/default.htm Goal: understand common mistakes to better contribute toward compliance © 2013 Vivid Ngenuity, LLC. All rights reserved.