GOOD MANUFACTURING
PRACTICES
IN A QUALITY WORLD
Gordon Harnack
President, Oracle Consulting Group
Tucson, AZ
www.fdamaze.com
1
The Discussion Plan


Definitions
General Discussion

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



Drugs & Biologics
Devices
In Vitro Diagnostics
Food
Cosmetics
GMP Specifics – Device GMPs
2
What are Good Manufacturing
Practices (GMP)?


Good Manufacturing Practice regulation is a set
of regulations, codes, and guidelines for the
manufacture of drugs (known as medicinal
products in Europe), medical devices,
diagnostic products, foods products and Active
Pharmaceutical Ingredients (APIs).
http://en.wikipedia.org/wiki/Good_Manufacturing
_Practice
3
What are Current Good
Manufacturing Practices (cGMP)?


Good Manufacturing Practice implemented in
1976 for the manufacture of products that are
under FDA jurisdiction, including
pharmaceuticals, biological products and medical
devices. Current Good Manufacturing Practice
ensures that finished products have the correct
identity, strength, quality and purity
characteristics they are represented to have, and
have not been altered during processing,
packaging, or handling. It requires extensive use
of documentation and strict reconciliation of
inventory.
www.sciteclabs.com/dictionary.html
4
Why GMP Regulations?

The Federal Food, Drug & Cosmetic Act authorizes
such regulations





Title 21, Chapter 9, FFD&C Act has 17 references to GMPs
FDA’s mechanism to implement oversight of any
“manufacturing” operation
Establishes FDA’s “minimal” manufacturing control
expectations
Make management the chief “jailable” officer
Absent GMP regulations – fall back on FFDC Act!
5
FDA’S Expectations
Related to Firm Size


The larger the firm the greater FDA
expectations
However, even the smallest firm MUST
address every aspect of applicable FDA
regulations.
6
What FDA Centers deal with
Drug GMPs?



Center for Biologics Evaluation &
Research (CBER)
Center for Drug Evaluation & Research
(CDER)
Center for Veterinary Medicine (CVM)
CDER states: “Useful to manufacturers of
components used in the manufacture of these
products”
7
What Types of Firms are
Exempt from Drug GMPs?

Drug wholesalers, retailers, pharmacies &
hospitals unless engaged in manufacturing
operations beyond the usual dispensing or
selling of drugs at retail

Compounders of drugs – pharmacists & physicians
Note: Compounded drugs must still be composed of FDA
approved components.
Note: Some products are exempt from certain elements of
Drug GMP.
8
What Types of Firms are Exempt
from Drug GMP Regulations? (cont)

Manufacturers of active pharmaceutical
ingredients (APIs) & bulk drugs are exempt
from cGMP REGULATIONS but NOT cGMP
requirements of the FFDC Act!



FDA cites API manufacturers for violations of the
ACT, not drug GMP regulations
FDA’s GMP regulations are used as “guidance”
during inspections.
FDA claims to be working on specific API GMPs
9
Drug GMPs Apply to




Prescription & OTC drugs, including
homeopathic drugs
Manufacturing facilities of ALL sizes
Investigational drugs for clinical trials
Foreign produced drugs distributed in
the U.S.
10
Drug GMPs



21 CFR § 210 - cGMP in Manufacturing,
Processing, or Holding of Drugs; General
21 CFR 211 - cGMP Practice for Finished
Pharmaceuticals
21 CFR 210 & 211 – 300+ “shalls”
11
Drug GMPs (continued)

Applicability


GMP of §’s 210 – 226 & §’s 600 – 680
supplement – not supersede each other,
unless otherwise directed
Compliance failures  adulterated drug
product
12
Drug GMPs (continued)


Proposed new drug cGMPs will model FDA’s
intent to integrate QS & RISK
MANAGEMENT…& to harmonize with other
non-drug regulatory systems & ISO 9000
FDA states that a robust modern QS must
embrace the concept that:
“Quality should be built into the product, and
testing alone cannot be relied on to ensure
product quality.”
13
Drug GMPs (continued)

GMP Regulations specific to CBER regulated
products






21 CFR 606 – Current GMP for blood & blood
products
21 CFR 610 – General biological products standards
21 CFR 630 – General requirements for blood, blood
components & blood derivatives
21 CFR 640 – Additional standards for human blood
and blood products
21 CFR 660 – Additional standards for diagnostic
substances for laboratory tests
21 CFR 680 – Additional standards for
miscellaneous products
14
Medical Device GMPs





QUALITY SYSTEM REGULATIONS
21 CFR § 820 - 200+ “shalls”
Control each phase of manufacturing
Harmonized with ISO 9000
Greater emphasis on compliant handling,
corrective & preventive actions, &
labeling
15
What Types of Firms are
Exempted from Device GMPs?

Component manufacturers
Note: Some individual TYPES of devices are
exempt from some elements of GMP
regulations, for example:
Many Class I devices, like tongue
depressors, are typically exempted from all
GMPs except records (820.180) & complaint
files (820.198).
16
In Vitro Devices GMPs

21 CFR 809 – In vitro diagnostic products
for human use - approximately 25
“shalls”
17
Cosmetic GMPs – No
Specific GMP Regulations

Regulated under the FFDC Act for:






Labeling
Ingredients
Contaminants
Processing
Packaging, or
Shipping and handling
18
Current Good Food
Manufacturing Practices


21 CFR 110 – approximately 95 “shalls”
Focus on

Sanitary/Unsanitary conditions


Production/Process Controls




Personnel, Equipment & Buildings
Raw materials
Water
Storage
Warehousing & distribution
19
Now a Close Examination of
Medical Device GMPs
20
What Types of Firms are
Subject to Device GMPs?







Remanufacturers
Custom Device Manufacturers
Contract Manufacturers
Contract Testing Labs
Repackagers, Relabelers & Specification
Developers
Manufacturers of Accessories
Initial Distributors
21
Medical Device GMP
20 Elements

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
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




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Management responsibility
Quality system controls
Training controls
Design/Development controls
Document & data controls
Purchasing controls
Product identification &
traceability controls
Process and manufacturing
controls
Inspection & testing controls
Inspection, measuring, & test
equipment controls
Process Validation






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

Labels & Labeling
Acceptance controls
Non-conforming product
controls
Corrective & preventive
action controls
Handling, storage, packaging,
preservation & delivery
controls
Quality record controls
Installation & Servicing
controls
Complaint Handling controls
Statistical technique controls
22
Management Controls

Management shall:

Establish its policy and objectives for, and
commitment to quality…







Policy is understood
Implemented
Maintained at all levels
Establish & maintain adequate organizational
structure – ensuring that devices are designed &
produced in regulatory compliance
Establish & maintain appropriate responsibility,
authority & interrelations of all personnel…
Provide adequate resources…
Appoint a Management Representative…
23
Management Controls
(continued)

Management shall:




Require the Management Representative to
review the suitability & effectiveness of the
QS at defined intervals to ensure…
Establish a quality plan that defines quality
practices, resources & activities…
Establish how requirements for quality are
met.
Establish & maintain QS procedures…
24
Quality System Controls


Establish procedures for quality audits …
Sufficient personnel with necessary education,
background, training & experience to…
25
Training Controls

Establish procedures to identify training needs
& ensure all personnel are trained to
adequately perform their assigned
responsibilities…
 Personnel shall be made aware of device
defects which may occur from improper
performance…
 Personnel performing verification/validation
activities shall be made aware of defects &
errors that may be encountered…
26
Design Controls





Planning
Requirements
Specifications
Verification
Validation




Change Control
Review
Transfer
Design History File
(DHF)
27
Design Risk Analysis


“Safety requirements should be
commensurate with the hazards that can
result from a system failure.”
FDA expects that all individual hazards,
including SW, be identified and either
eliminated or reduced to acceptable
levels during the device’s design &
development

FMEAs & Fault Trees
28
“Human Factors” in
Device Design
FDA's site on human factors
www.fda.gov/cdrh/humanfactors
 See “Fitting Human Factors in the Product
Development Process” published in the
January 2006 Medical Device & Diagnostic
Industry magazine – available as a “pdf”…
www.agilisconsulting.com/pdf/HumanFactor
sandtheProductDevelopmentProcess.pdf

29
What are Human Factors?




Human factors (HF) is the study of how people use technology. The
interaction of human abilities, expectations, and limitations, with
work environments and system design.
The term “human factors engineering” (HFE) refers to the
application of human factors principles to the design of devices and
systems. It is often interchanged with the terms "human
engineering," "usability engineering," or "ergonomics."
The goal of HFE is to design devices that users accept willingly and
operate safely in realistic conditions. In medical applications, HFE
helps improve human performance and reduce the risks associated
with use error.
In many cases, HFE focuses on the device user interface (also
called the UI or the man-machine interface). The user interface
includes all components and accessories necessary to operate and
properly maintain the device, including the controls, displays,
software, logic of operation, labels, and instructions.
30
Document & Data Controls

Establish & Maintain procedures (EMP) to
control ALL documents required by
regulations…including


Document review, approval & distribution
Document changes…
31
Purchasing Controls

EMP to ensure that ALL purchased or
otherwise received product & services
conform to SPECIFIED
REQUIREMENTS…including


Evaluation of suppliers, contractors &
consultants
Establish & maintain data that clearly
describe or reference SPECIFIED
REQUIREMENTS…including quality
requirements
32
Product ID & Traceability
Controls


EMP for identifying product during ALL
stages of receipt, production, distribution
& installation
Devices intended for surgical implant, life
sustaining or supporting…whose failure
when properly used can be expected to
result in significant injury shall be
identified with a control number…
33
Process & Manufacturing
Controls


Manufacturer shall develop, conduct,
control & monitor production processes
to ensure that a device conforms
specifications…
Establish & maintain process control
procedures that describe all necessary
controls…
34
Production & Process
Controls (continued)

Process controls shall include:





Documented instructions, SOPs, & methods
that define & control production
Monitoring & control of process parameters,
component & device characteristics
Compliance with specified standards or
codes
Approval of processes & equipment
Criteria for workmanship expressed in
documented standards or by identified &
approved samples
35
Production & Process
Controls (continued)



EMP to control ALL changes to
specifications, methods, processes or
procedures…
Where environmental conditions can
have any adverse effect on product
quality…EMP to adequately control those
conditions…
EMP for health, cleanliness, personnel
practices & clothing of personnel…
36
Production & Process
Controls (continued)


EMP to prevent contamination of
equipment or product…
Provide buildings of suitable design &
with sufficient space to perform
necessary operations, prevent mix-ups &
assure orderly handling
37
Production & Process
Controls (continued)


Ensure that ALL equipment used in
manufacturing process meets its
specified requirements…
Equipment is properly installed,
maintained, adjusted, cleaned & used



Establish & maintain schedules for
equipment adjustment, cleaning or other
maintenance…
Conduct periodic inspections
Ensure limitations/tolerances are posted
38
Production & Process
Controls (continued)


Where manufacturing material could be
expected to have adverse effects…EMP
for the use & removal of those
materials…
Validate any computers or automated
data processing systems used
39
Inspection & Testing
Controls


Manufacturers shall ensure that ALL
inspection, measuring & test equipment
is suitable & is capable of producing
valid results…
EMP to ensure equipment is routinely
calibrated, inspected, checked &
maintained…
40
Inspection, Measuring &
Test Equipment Controls


Calibration procedures shall include specific
directions & limits for accuracy & precision…
Accuracy & precision failures shall require
remedial action to reestablish the limits &
assess adverse effect(s) on product quality…


Calibration standards used shall be traceable…
Calibration records shall include equipment ID,
dates, individuals, & the next calibration date
41
Process Validation


Where the results of processes cannot be
FULLY verified by inspection & test, the
process shall be validated according to
established procedures
EMP to monitor & control validated
process parameters, controlling:

Personnel, records & changes
42
Label, Labeling & Packaging

EMP to control labeling activities,
including label:





Integrity
Inspection
Storage
Operations
Control number
43
Packaging

Manufacturer shall ensure that packaging
& shipping containers are designed &
constructed to protect the device from
alteration or damage…
44
Acceptance Controls

EMP for inspections, tests or other
verifications as acceptance of:
 Incoming product against specified
requirements
 In-process product against specified
requirements
 Finished devices to ensure EACH
production run, lot or batch meets
acceptance criteria
45
Acceptance Controls
(continued)

Manufacturer shall:

Document acceptance activities, including:






Activities performed
Dates
Results
Signatures of individuals
If appropriate, equipment used
Identify acceptance status throughout the
processes..
46
Non-conforming Product
Controls



EMP to control non-conforming product
(NCP)
Procedures shall control ID,
documentation, evaluation, segregation
& disposition of NCP
Evaluation shall include determining any
need for an investigation & the
persons/organizations responsible for
the NCP
47
NCP Controls (continued)


EMP that define the responsibility for
review & the authority for the disposition
of NCP
Procedures shall control:



Reviews & dispositions
Records shall document any justification for
use of NCP & signatures of authorizers
Rework shall include appropriate retesting,
reevaluation & adverse effects assessment
to ensure the product meets specifications
48
Corrective & Preventive
Action Controls

EMP for implementing CAPAs, including:




Analyzing processes, work ops,
concessions, audits, records, complaints,
returns, & other sources of quality data
Use of appropriate statistical methods
Investigating nonconformances to product
processes & the QS
Identifying action(s) needed to correct or
prevent recurrence of nonconformances
49
CAPA Controls (continued)

CAPA procedures shall require:




Verification or validation of CAPAs to ensure
their effectiveness & that they do not
adversely affect the finished device
Implementing & recording changes in
methods & procedures needed to correct &
prevent quality problems
Ensuring information identified is
disseminated to all appropriate individuals
Submitting records for management review
50
Handling, Storage, Preservation
& Delivery Controls

EMP to:



Control storage areas to prevent mix-ups,
damage, deterioration, contamination or
other adverse effects
Control product requiring stock rotation
Control receipt from & dispatch to storage
areas
51
Delivery Controls

EMP to:




Ensure only approved devices are released
POs are reviewed to ensure ambiguities &
errors are resolved…
Ensure stock that deteriorates over time is
properly controlled & expired devices are
not distributed
Maintain distribution records that ID



Name & address of initial consignee
Date, ID & quantity of devices shipped
Any control numbers used
52
Quality Record Controls



All required records shall be maintained
at the manufacturing location or other
location that is reasonably accessible for
FDA inspection, review & copying
Records deemed confidential may be so
marked
All required records shall be retained for
the device’s expected life – but in no case
less than 2 years from the date of release
53
Quality Records – Quality
System Records (QSR)

Manufacturers shall maintain a quality
system record (QSR) that includes

Procedures and records of activities
required by FDA regulation that are not
specific to a particular type of device,
including:




SOP creation & numbering SOPs
Training SOPs and records
Purchasing SOPs and records
Supplier assessment SOPs and records
54
Quality Records – Device
Master Record (DMR)

Maintain an approved DMR, including:





Device specifications – drawings,
composition, formulation, component
specifications & SW specifications
Product process specifications – equipment
specs, production methods, production
SOPs & environmental specs
QA SOPs, QA specs, acceptance criteria &
QA equipment
Packaging & labeling specs, & methods
Installation, maintenance & servicing SOPs
55
Quality Records – Device
History Record (DHR)

EMP that ensure the DHR documents
devices were manufactured in
accordance with the DMR & FDA
regulations, the DHR includes:





Date(s) & quantity of manufactured devices
Quantity released for distribution
Acceptance records
Primary ID label & labeling
Any device ID & control number(s) used
56
Installation & Servicing
Controls



EMP for adequate installation, inspection
instructions & any needed test activities
Procedures shall ensure proper
installation & device performance after
installation
Installation SOPs shall be distributed
appropriately
57
Installation & Servicing
Controls

Procedures shall require:



Installation personnel perform any required
testing in accordance with manufacturers
instructions & document the inspection &
testing to demonstrate proper installation
Specified servicing requirements follow
established & maintained SOPs that require
servicing meets specified requirements
Service reports are analyzed with
appropriate statistical methods
58
Servicing Controls


Service reports that represent an event
that must be reported to FDA under MDR
regulations shall automatically be
considered a complaint & handled in
accordance with FDA complaint handling
regulations
Reports shall include:



Name, date, ID & any control # of devices serviced
Individual performing service & service performed
Any test & inspection data
59
Complaint Handling
Controls

EMP for:


Receiving, reviewing & evaluating
complaints by a FORMALLY DESIGNATED
UNIT
Complaints shall be



Processed in a uniform & timely manner
Oral (complaints) documented upon receipt
Evaluated to determine if complaint
represents an MDR event requiring reporting
60
Complaint Handling
Controls (continued)

Manufacturers shall:


Review & evaluate all complaints to
determine if an investigation is necessary
If a determination is made that no
investigation is required, a record of shall be
made that IDs the reason & the individual
making the decision
61
Complaint Handling
Controls (continued)

Complaints involving device failures to
meet ANY specification shall be:


Reviewed, evaluated & investigated – unless
such investigation has already been
performed for a similar complaint & another
investigation is unnecessary
Documented to show a determination of:



Whether the device failed to meet specifications
Whether the device was being used for treatment or
diagnosis
Any relationship to any device to any reported incident
or adverse event
62
Complaint Handling
Controls (continued)

Complaint investigation records shall
include:







Device name & date complaint received
Device ID & control #s used
Name, address & phone # of complainant
Nature & details of complaint
Dates & results of investigation
Any corrective action taken
Any reply to complainant
63
Statistical Technique
Controls

Where appropriate, EMP for:



Identifying valid statistical techniques
required for establishing, controlling &
verifying the acceptability of process
capability and product characteristics
Sampling plans, when used, shall be written
& based on valid rationale
Ensuring sampling methods are adequate
for their intended use…
64
Useful Tools in
Understanding GMPs



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

Warning Letters & Recall postings
Guidance Documents
Compliance Policy Guides (CPGs)
Compliance Program Guidance Manual (CPGM)
Guidance Documents for Regulated Industry
Regulatory Procedures Manual (RPM)
Investigations Operations Manual
Laboratory Information Bulletins
Laboratory Procedures Manual
65
One Final Note




FDA is NOT ALWAYS RIGHT!
The Agency is made up of PEOPLE,
people with strong convictions & egos
The Agency is a bureaucracy &
bureaucracies over-reach, over-state,
over-react & almost NEVER admit they
are wrong
The following is an example of a
bureaucratic mis-step.
66
One Final Note (continued)



Between 2001 – 2004 Utah Medical was cited
by FDA for a number of GMP violations
August 2004 FDA sought a Permanent
Injunction to stop the firm from manufacturing
& distributing medical devices UNTIL the firm
DEMONSTRATED corrections in deviations
from GMPs
"FDA will not tolerate manufacturing practices
that can potentially put patients at risk," said
FDA Acting Commissioner Dr. Lester M.
Crawford
67
One Final Note (continued)


FDA’s injunction followed three years of FDA
inspections that FDA claimed “revealed a
pattern of significant deviations from the
Quality System regulation at Utah Medical's
Midvale facility.”
FDA claimed “Utah Medical has consistently
failed to ensure that its products are
manufactured in accordance with the Quality
System regulation.”
68
One Final Note (continued)

On Oct 21, 2005 Federal Judge Bruce Jenkins
found & stated “This is an unusual case. The
safety of the products manufactured by Utah
Medical has never been at issue.”
69
One Final Note (continued)

The judge noted that “Even though product
safety is a non-issue, the relief originally
sought by the United States was to stop Utah
Medical’s products from entering commerce
because of alleged persistent deficiencies of
Utah Medical in complying with the applicable
quality system regulations (21 CFR § 820), and
asserting that a failure to comply by definition
produced an adulterated product and
subjected the product and the persons
responsible for the product to regulatory
action.”
70
One Final Note (continued)


Judge Jenkins went on to state “In short, the
United States asked that Utah Medical be
ordered to stop the sale of product until Utah
Medical complies with the regulation 21 CFR §
820 and in a manner that has been found
acceptable to FDA.”
Further he stated “The court has been
impressed as well by Utah Medical’s design of
product, its record-keeping of each step along
the way, the acceptance in the market of its
products, the Company’s uniform processing
of complaints, and the manner in which change
is made in practice and procedure as a result
of complaint handling.”
71
One Final Note (continued)


Judge Jenkins concluded “It makes no sense
for the court to order Utah Medical to do
something they are already doing.”
The Court disagreed with all allegations by the
FDA, and dismissed the lawsuit filed in August
2004 that sought to shut down UTMD, without
any evidence of unsafe, ineffective, or
defective products or products causing any
patient harm, until UTMD complied with the
FDA’s interpretation of the QSR, an
interpretation that was never provided to UTMD
until after the lawsuit was filed
72
One Final Note ( continued)

The U.S. Federal District Court in Salt
Lake City confirmed that UTMD is
operating in compliance with 21 CFR §
820, the U.S. Food & Drug Administration
(FDA) Quality System Regulation (QSR).
73
Questions
?
74
Abbreviations Used
§ - Paragraph
APIs - Active pharmaceutical ingredients
CAPA – Corrective Action & Preventive Action
CBER – Center for Biologics Research &
Development
CDER – Center for Drug Evaluation & Research
CDRH – Center for Devices & Radiologic Health
CVM – Center for Veterinary Medicine
CFR – Code of Federal Regulations
cGMP – Current Good Manufacturing Practice
CPGs – Compliance Policy Guides
CPGM – Compliance Program Guidance Manual
DHF – Design History File
DHR – Device History Record
DMR – Device Master Record
FDA – Food & Drug Administration
FFDC or FFD&C – Federal Food Drug &
Compliance (Act)
FMEA – Failure Mode & Effects Analysis
EMP – Establish & maintain procedures
GMP – Good Manufacturing Practice
ID - Identification
ISO – Acronym for International Standards
Organization
IQ – Installation Qualification
OC – Operational Qualification
OTC – Over the Counter
NCP – Nonconforming Product
PQ – Performance Qualification
QA – Quality Assurance
QS – Quality System
QSR – Quality System Regulation
SOP – Standard Operating Procedure
UTMD – Utah Medical Device
75