1

GOOD MANUFACTURING
PRACTICES
IN A QUALITY WORLD
MANISH JOSHI
MANAGER QUALITY ASURANCE
D.P.I
 2
The Discussion Plan

 Definitions
 General Discussion
 Drugs
 Devices
 In Vitro Diagnostics
 Food
 Cosmetics
 GMP Specifics – Device GMPs
 3
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).
 4
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.
 5
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!
 6
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.
 7
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”
 8
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.
 9
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
 10
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.
Drug GMPs 11

 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”
 Drug GMPs (continued) 12

 Applicability
 GMP of §’s 210 – 226 & §’s 600 – 680 supplement – not supersede each other, unless
otherwise directed
 Compliance failures  adulterated drug product
 13
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.”
 14
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
 15
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
 16
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).
 17
In Vitro Devices GMPs

 21 CFR 809 – In vitro diagnostic products for human use -

approximately 25 “shalls”
 18
Cosmetic GMPs – No Specific GMP
Regulations

 Regulated under the FFDC Act for:

 Labeling
 Ingredients
 Contaminants
 Processing
 Packaging, or
 Shipping and handling
 19
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
 20
Now a Close Examination of
Medical Device GMPs
 21
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
 22
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 action
 Document & data controls controls
  Handling, storage, packaging,
Purchasing controls
preservation & delivery controls
 Product identification & traceability
controls  Quality record controls
  Installation & Servicing controls
Process and manufacturing controls
  Complaint Handling controls
Inspection & testing controls
  Statistical technique controls
Inspection, measuring, & test
equipment controls
 Process Validation
 23
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…
 24
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…
 Quality System Controls 25

 Establish procedures for quality audits …

 Sufficient
personnel with necessary education,
background, training & experience to…
Training Controls 26

 Establishprocedures 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…
 Design Controls 27

 Planning  Change Control

 Requirements  Review
 Specifications  Transfer
 Verification  Design History File
 Validation (DHF)
 Design Risk Analysis 28

 “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
 29
Document & Data Controls

 Establish & Maintain procedures (EMP) to control ALL

documents required by regulations…including
 Document review, approval & distribution
 Document changes…
 Purchasing Controls
30

 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
 31
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…
 32
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…
 33
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
 34
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…
 35
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
 36
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
 37
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
 38
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…
 39
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
 40
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
 41
Label, Labeling & Packaging

 EMP to control labeling activities, including label:

 Integrity
 Inspection
 Storage
 Operations
 Control number
Packaging 42

 Manufacturer shall ensure that packaging & shipping

containers are designed & constructed to protect the device
from alteration or damage…
 43
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
 44
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..
 45
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
 NCP Controls (continued) 46

 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
 47
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
 48
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
Handling, Storage, Preservation
49
& 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
 Delivery Controls 50

 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
 51
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
 52
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
 53
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
 54
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
 55
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
 56
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
 57
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
 58
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
 59
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
 60
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
 61
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
 62
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…
 63
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
 64
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.
 65
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
 66
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.”
 67
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.”
 One Final Note (continued) 68

 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.”
 One Final Note (continued) 69

 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.”
 One Final Note (continued) 70

 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
One Final Note ( continued) 71

 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).
 72
Questions
?

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
73
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
OTC – Over the Counter
NCP – Nonconforming Product
QA – Quality Assurance
QS – Quality System
QSR – Quality System Regulation
SOP – Standard Operating Procedure
UTMD – Utah Medical Device