Professional Documents
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Good Manufacturing Practices in A Quality World
Good Manufacturing Practices in A Quality World
PRACTICES
IN A QUALITY WORLD
Gordon Harnack
President, Oracle Consulting Group
Tucson, AZ
1
The Discussion Plan
◼ Definitions
◼ General Discussion
Drugs
Devices
In Vitro Diagnostics
Food
Cosmetics
◼ GMP Specifics – Device GMPs
2
What are Good Manufacturing
Practices (GMP)?
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
6
What FDA Centers deal with
Drug GMPs?
9
Drug GMPs Apply to
10
Drug GMPs
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
17
Cosmetic GMPs – No
Specific GMP Regulations
18
Current Good Food
Manufacturing Practices
◼ 21 CFR 110 – approximately 95 “shalls”
◼ Focus on
Sanitary/Unsanitary conditions
◼ Personnel, Equipment & Buildings
Production/Process Controls
◼ 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
◼ Management responsibility ◼ Labels & Labeling
◼ Quality system controls ◼ Acceptance controls
◼ Training controls ◼ Non-conforming product
controls
◼ Design/Development controls
◼ Corrective & preventive
◼ Document & data controls
action controls
◼ Purchasing controls
◼ Handling, storage, packaging,
◼ Product identification & preservation & delivery
traceability controls controls
◼ Process and manufacturing ◼ Quality record controls
controls
◼ Installation & Servicing
◼ Inspection & testing controls controls
◼ Inspection, measuring, & test ◼ Complaint Handling controls
equipment controls
◼ Statistical technique controls
◼ Process Validation 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
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
Document & Data Controls
29
Purchasing Controls
32
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 33
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…
34
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
35
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 36
Production & Process
Controls (continued)
37
Inspection & Testing
Controls
38
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
39
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
40
Label, Labeling & Packaging
◼ EMP to control labeling activities,
including label:
Integrity
Inspection
Storage
Operations
Control number
41
Packaging
42
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 43
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..
44
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
45
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
46
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
47
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 48
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
49
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
50
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
51
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
52
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
53
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
54
Installation & Servicing
Controls
55
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
56
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 57
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
58
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
59
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 60
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
61
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…
62
Useful Tools in
Understanding GMPs
◼ 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
63
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. 64
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
65
One Final Note (continued)
67
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.” 68
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.” 69
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 70
One Final Note ( continued)
71
Questions
72
Abbreviations Used
§ - Paragraph FDA – Food & Drug Administration
APIs - Active pharmaceutical ingredients FFDC or FFD&C – Federal Food Drug &
CAPA – Corrective Action & Preventive Action Compliance (Act)
CBER – Center for Biologics Research & FMEA – Failure Mode & Effects Analysis
Development EMP – Establish & maintain procedures
CDER – Center for Drug Evaluation & Research GMP – Good Manufacturing Practice
CDRH – Center for Devices & Radiologic Health ID - Identification
CVM – Center for Veterinary Medicine ISO – Acronym for International Standards
CFR – Code of Federal Regulations Organization
cGMP – Current Good Manufacturing Practice OTC – Over the Counter
CPGs – Compliance Policy Guides NCP – Nonconforming Product
CPGM – Compliance Program Guidance Manual QA – Quality Assurance
DHF – Design History File QS – Quality System
DHR – Device History Record QSR – Quality System Regulation
DMR – Device Master Record SOP – Standard Operating Procedure
FDA – Food & Drug Administration UTMD – Utah Medical Device
73