Good Manufacturing Practice

GMP Training- FDA Regulations

Searchtec Institute
www.Searchtecgroup.com

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Training Overview
This training course will teach you about the
implementation of Good Manufacturing Practice
(GMP) regulations and requirements within the
medical devices industry.

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Training Structure
This training course is structured around four
learning modules and a final Certification
Examination.
Module 1 - GMP Overview
Module 2 - Requirements
Module 3 - Controls
Module 4 - Acceptance and Violations
Certification Exam

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Module Questions
(instructions for Web site designer)

 Each module will have 25 questions attached. Correct answers are shown last,
and in Bold.
 The question selection and order will be randomized for each quiz or test
session.
 The module quiz will contain 10 module questions, randomly chosen and randomly
ordered.
 The test will contain all 100 module questions from all modules, randomly ordered.
 The order of possible answers for each question will be randomized, except for “All
of the above” answers which are always last.
 A 90% score (90 of 100 questions) will be required to pass the final test. There
is no pass/fail criteria for the module quiz.
 The score and missed questions of each quiz and the test will be immediately
reported upon completion. Correct answers for missed questions will not be
reported.
 The quiz may be retaken as many times as desired, but the module must be
reviewed from the start in order to retake the quiz.
 The final test may be taken as many times as needed, without having to
review any of the material.

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GMP Training Objectives
Gain an understanding of the requirements of GMP
Examine real world case studies involving GMP
Develop an understanding of how GMP affects
company success
Complete Certification Examination

GMP Implementation Is Critical For MDX To Maintain Our

Dominant Market Position

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Course Agenda
Module 1 - GMP Overview
Module 2 - Requirements
Module 3 - Controls
Module 4 - Acceptance and Violations
Certification Exam

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Module 1 Overview
This module should take approximately one hour to
complete. It will cover the following topics:
What is GMP?
Why GMP?
Key Terms and Definitions
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes,
you may proceed to the 1-hour, 100 question
certification exam.

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What Is GMP?
GMP refers to the Good Manufacturing Practice
Regulations developed by the US Food and Drug
Administration under the authority of the Federal Food,
Drug, and Cosmetic Act
GMP regulations require a quality approach to
manufacturing that help companies minimize or eliminate
instances of contamination, mix-ups, and errors 

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What Is GMP? (cont)
 GMP practices govern a number of different areas
as outlined below
 21 CFR 210-211 Pharmacy & Veterinarian Products
 21 CFR 600 Biomedical Products
 21 CFR 820 Medical Device QSR
 21 CFR 100 Food Products
 This course will focus on the Medical Device GMP
requirements

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Why GMP?
GMP is intended to protect consumers from
purchasing a product which is not effective or even
dangerous
Failure of firms to comply with GMP regulations can
result in very serious consequences including
recall, seizure, fines, and jail time

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21 CFR 820 Medical Device QSR
Overview
The GMP requirements for Medical Devices are outlined
on the FDA website under Subchapter H of the GMP
regulations
This subchapter outlines the specific FDA GMP
requirements for implementation and regulation

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GMP Terms
 Complaint - Any written, electronic, or oral communication that
alleges deficiencies related to the identity, quality, durability,
reliability, safety, effectiveness, or performance of a device after it is
released for distribution.
 Component - Any raw material, substance, piece, part, software,
firmware, labeling, or assembly which is intended to be included as
part of the finished, packaged, and labeled device.
 Control number - Any distinctive symbols, such as a distinctive
combination of letters or numbers, or both, from which the history of
the manufacturing, packaging, labeling, and distribution of a unit, lot,
or batch of finished devices can be determined.

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GMP Terms (cont)
 Design history file (DHF) - A compilation of records which
describes the design history of a finished device.
 Design input - Means the physical and performance requirements of
a device that are used as a basis for device design.
 Design output - The results of a design effort at each design phase
and at the end of the total design effort. The finished design output is
the basis for the device master record.
 Design review - A documented, comprehensive, systematic
examination of a design to evaluate the adequacy of the design
requirements, to evaluate the capability of the design to meet these
requirements, and to identify problems.

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GMP Terms (cont)
 Device history record (DHR) - A compilation of records containing
the production history of a finished device.
 Device master record (DMR) - A compilation of records containing
the procedures and specifications for a finished device.
 Establish - Define, document (in writing or electronically), and
implement.
 Finished device - Any device or accessory to any device that is
suitable for use or capable of functioning, whether or not it is
packaged, labeled, or sterilized.
 Lot or batch - One or more components or finished devices that
consist of a single type, model, class, size, composition, or software
version that are manufactured under essentially the same conditions
and that are intended to have uniform characteristics and quality
within specified limits.

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GMP
 Terms
Management (cont)
with executive responsibility - Those senior
employees of a manufacturer who have the authority to establish or
make changes to the manufacturer's quality policy and quality system.
 Manufacturer - Any person who designs, manufactures, fabricates,
assembles, or processes a finished device.
 Manufacturing material - Any material or substance used in or used
to facilitate the manufacturing process, a concomitant constituent, or
a byproduct constituent produced during the manufacturing process.
 Nonconformity - The nonfulfillment of a specified requirement.
 Product - Components, manufacturing materials, in- process devices,
finished devices, and returned devices.

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GMP Terms (cont)
 Quality - The totality of features and characteristics that bear on the
ability of a device to satisfy fitness-for-use, including safety and
performance.
 Quality audit - A systematic, independent examination of a
manufacturer's quality system that is performed at defined intervals
and at sufficient frequency.
 Quality policy - Means the overall intentions and direction of an
organization with respect to quality, as established by management
with executive responsibility.
 Quality system - The organizational structure, responsibilities,
procedures, processes, and resources for implementing quality
management.

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GMP Terms (cont)
 Remanufacturer - Any person who processes, conditions, renovates,
repackages, restores, or does any other act to a finished device that
significantly changes the finished device's performance or safety
specifications, or intended use.
 Rework - Action taken on a nonconforming product so that it will
fulfill the specified DMR requirements before it is released for
distribution.
 Specification - Any requirement with which a product, process,
service, or other activity must conform.

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GMP Terms (cont)
 Validation - Confirmation by examination and provision of objective
evidence that the particular requirements for a specific intended use
can be consistently fulfilled.
 Process validation - Establishing by objective evidence that a
process consistently produces a result or product meeting its
predetermined specifications.
 Design validation - Establishing by objective evidence that device
specifications conform with user needs and intended use(s).
 Verification - Confirmation by examination and provision of
objective evidence that specified requirements have been fulfilled.
(Source: http://www.gmp1st.com/gmp.htm)

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Module 1 Questions (1)
What organization governs GMP implementation?
a) CIA
b) DHS
c) DoD
d) FDA

What area is not governed by GMP?

a) Medical Devices
b) Food Industry
c) Drug Industry
d) Auto Industry

Why is GMP in place?

a) Increase cost of business
b) Make life harder
c) Ensure customers receive the best product
d) Ensure customers receive products that are not dangerous

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Module 1 Questions (2)
True or False: Violating GMP standards can result in legal action by the
government and consumers.
True / False

True or False: Quality Audit means the totality of features and characteristics
that bear on the ability of a device to satisfy fitness-for-use, including safety
and performance.
True / False

True or False: Rework means action taken on a nonconforming product so that

it will fulfill the specified DMR requirements before it is released for
distribution.
True / False

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Module 1 Questions (3)
True or False: Manufacturer means any person who designs, manufactures,
fabricates, assembles, or processes a finished device.
True / False

True or False: Lot means define, document (in writing or electronically), and
implement.
True / False

True or False: Finished device means any device or accessory to any device that is
suitable for use or capable of functioning, whether or not it is packaged,
labeled, or sterilized
True / False

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Module 1 Questions (4)
True or False: Design validation means establishing by objective evidence that a process
consistently produces a result or product meeting its predetermined specifications.
True / False

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GMP Training
Module 2:
Requirements

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Course Agenda
Module 1 - GMP Overview
Module 2 - Requirements
Module 3 - Controls
Module 4 - Acceptance and Violations
Certification Exam

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Module 2 Overview
This module should take approximately one hour to
complete. It will cover the following topics:
Quality Systems
Identification & Traceability
Handling, Storage, & Distribution
Record Keeping
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes, you
may proceed to the 1-hour, 100 question certification
exam.

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Quality System Requirements
This section covers Subpart B - Quality System
Requirements
Quality System is the organizational structure,
responsibilities, procedures, processes, and resources
for implementing quality management
Key requirement: FDA CRF 21 (US) & ISO13485
(Global, EU)
FDA CRF 21 - Applicable to any furnished device
intended for human use in the United States and
Commonwealth of Puerto Rico

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Quality System Requirements
Manufacturer requirements and responsibilities:
Policy – management must establish objectives and
commitments to pursue and implement best practices.
Organization – company should be structured to
ensure that devices are produced to the design intent.
Authority – should be established for those that
manage, produce, and review devices
Resources – proper funding for training and quality
assessment shall be established

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Quality System Requirements
 Executives should have management representatives with
authority over the quality organization to report and asses the quality
system.
 Established procedures should call for management reviews of the
quality system based on requirements outlined in the quality policy.
 A quality plan should be established which outlines quality practices,
resources, and activities.
 Procedure outlines should be established and followed throughout
the quality system.

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Identification and Traceability
This section covers Subpart F, Identification and
Traceability
To prevent mix-ups, manufacturers must maintain
procedures for properly identifying products during
all stages:
receipt
production
distribution
installation

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Identification and Traceability
To ensure the safety of healthcare patients,
manufacturers shall maintain traceability for all
devices and components
Maintain ID procedures
Control number for each unit/lot/batch
Control number for components

* These requirements are for all products whose failure to perform

properly could result in significant injury.

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Handling, Storage, &
Distribution
 This section covers Subpart L, Handling, Storage, Distribution, and
Installation
 Procedures need to be established and maintained to ensure that
mix-ups, damage, or contamination do not alter products during
handling and storage
 Manufacturers shall maintain procedures for control and
distribution of finished devices to make sure that each product
purchase order is free of error. Distribution records shall be
kept for all such products
 Procedures established by the manufacturer should be followed
during the installation of any device. Adequate installation and
inspection instructions shall be maintained and followed at all
times

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Records Keeping
This section covers Subpart M, Records
Records are documents that detail the specifications
of a device, its history, or its quality processes
followed during production
Types of records include:
Device master
Device history
Quality system
Complaint files

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Records Keeping
General requirements for records:
Records shall be kept at manufacturing area or
nearby company location
Accessible to company officials
Accessible to FDA
Shall be properly stored to prevent deterioration or
shall be backed up if stored on company server

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Records Keeping
Confidential records shall be properly marked to
aid FDA inspectors
Records shall be kept through the design period
and expected product life of all devices. A
minimum of two years is required from the device
distribution date

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Records Keeping
Upon FDA request, manufacturing officials shall be
able at all times to produce records of all:
Management reviews
Quality audits
Supplier audits
Corrective actions

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Records Keeping
Device Master Records (DMR’s) shall be kept by
each manufacturer and shall include the following:
Device specs, drawings, compositions, and formulations
Production processes: equipment specs, methods and
procedures, and environmental specs
QA procedures and specs
Packaging information and specs
Installation and maintenance procedures

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Records Keeping
Device History Records shall be kept and include
the following:
Dates of manufacturer
Quantities produced and released
Acceptance records
Identification and labeling records
Control numbers used for devices

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Records Keeping
A Quality System Record (QSR) shall be kept and
contain procedures and documentation of all activities
specific to a device
A complaint file shall be kept. Procedures shall be
established for the receiving, reviewing, and evaluating of
all formal complaints. Procedures shall ensure that:
 Complaints are processed in timely manner
 Oral complaints are properly documented
 Evaluation to determine whether complaint needs to be reported
to FDA
 Any complaint concerning product failure is properly evaluated

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Cody
Case Labs (drug maker in Wyoming): 2006
Study
 Following a two week FDA investigation Cody Labs was hit with a
letter for multiple GMP Violations
 Two finished drug products were adulterated by company’s
lack of GMP compliance
 Water system used on finished products did not have installation and
operational qualifications
 Company’s own quality procedures for the water system were not
followed for two years
 Air-handling system was not qualified to show that dry powders in the
air would not alter drug products
 Failed to date and sign master production and control records
These GMP failures will keep Cody Labs in the hurt box
until these violations are explained or resolved

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Module 2 Questions (1)
Which of the following is not a quality system manufacturing responsibility?
a) Organization
b) Establish authority
c) Provide resources
d) Report earnings

A quality plan should be established which outlines all except:?

a) Quality practices
b) Resources
c) Activities
d) Hiring goals

FDA CRF 21 is applicable to any furnished device intended for human use in the United States and
Commonwealth of ________.
a) Costa Rica
b) Virgin Islands
c) Monaco
d) Puerto Rico

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Module 2 Questions (2)
Management must establish a _____ so objectives and commitments are pursued and best practices are
implemented.
a) organization
b) authority
c) resources
d) policy

The company should be ______ and structured to ensure that devices are produced to the design intent.
a) political
b) resourceful
c) full-service
d) organized

________ should be established for those that manage, produce, and review devices.
a) intent
b) rules
c) awards
d) authority

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Module 2 Questions (3)
________ are needed to establish the proper funding for training and quality assessment.
a) plans
b) delegation
c) service
d) resources

Executives should have management _________ with authority over the quality organization to report
and asses the quality system.
a) quizzes
b) demands
c) oversight
d) representatives

Established procedures should call for management _______of the quality system based on
requirements outlined in the quality policy.
a) authority
b) direction
c) help
d) reviews

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Module 2 Questions (4)
True or False: To ensure the safety of healthcare patients, manufacturers shall maintain traceability for
all devices and components.
True / False

True or False: Manufacturers must maintain procedures for properly identifying products during all of
these stages: receipt, production, distribution, & installation.
True / False

Procedures need to be established and maintained to ensure that mix-ups, damage, or contamination do
not alter products during _______.
a) reviews
b) inspection
c) assembly
d) handing and storage

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Module 2 Questions (5)
Manufacturers shall maintain procedures for control and ________of finished devices to make sure that
each product purchase order is free of error.
a) process
b) inspection
c) handling
d) distribution

Procedures established by the manufacturer should be followed during the ________ of any device.
a) planning
b) distribution
c) inspection
d) installation

Manufacturers shall create procedures for:

a) Handling & Storage
b) Distribution
c) Installation
d) All of the above

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Module 2 Questions (6)
Types of _____ include: Device master, Device history, Quality system, and Complaint files
a) Communication
b) Distribution
c) Processes
d) Records

Records shall be kept at the _______ area or nearby company location.

a) office
b) executive
c) planners
d) manufacturing

Confidential Records shall be properly marked to aid _____inspectors.

a) CIA
b) FAD
c) LDS
d) FDA

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Module 2 Questions (7)
A __________Record shall be kept and contain procedures and documentation of all activities specific to
a device
a) Master
b) Planning
c) Product
d) Quality System

Device__________ shall contain the control numbers used for devices.

a) reports
b) instructions
c) user manuals
d) history records

True or False: Device history records contain information on quantities produced and released
True / False

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Module 2 Questions (8)
Which is not a general requirement for Records:
a) Records shall be kept at manufacturing area or nearby company location
b) Accessible to company officials
c) Accessible to FDA
d) Accessible to all company employees

Records shall be kept through the design period and expected product life of all devices. A minimum of
____years is required from the device distribution date.
a) 4
b) 3
c) 1
d) 2

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Module 2 Questions (9)
Device History Records shall be kept and include the following:
a) Dates of manufacturer
b) Quantities produced and released
c) Acceptance records
d) All of the above

Any voiced concern about a products failure should be documented in a:

a) Database
b) Quality Report
c) Engineering Order
d) Complaint File

True or False: Records should be accessible to company officials

True / False

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Course Agenda
Module 1 - GMP Overview
Module 2 - Requirements
Module 3 - Controls
Module 4 - Acceptance and Violations
Certification Exam

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Module 3 Overview
This module should take approximately one hour to
complete. It will cover the following topics:
 Quality Audits
 Design, Document, and Purchasing Controls
 Production and Process Control
 Environmental Control and Clean Rooms
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes, you
may proceed to the 1-hour, 100 question certification
exam.

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Quality Audits
 This section covers Subpart B, Quality Audits
 Each manufacturer shall establish procedures for quality audits and
conduct such audits in order to:
 Assure that the quality system is in compliance with the established
requirements
 Determine the effectiveness of the quality system
 Audits should be conducted by individuals who do not have direct
responsibility for the matters being audited
 Corrective action(s), including a re-audit of deficient matters, shall
be taken when necessary
 A report of the results of each quality audit/re-audit shall be made.
 Such reports shall be reviewed by management responsible for the matters
audited
 Dates and results of quality audits/re-audits are to be documented

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Personnel
This section covers Subpart B, Personnel
Each manufacturer shall:
 Have sufficient personnel with the necessary education,
background, training, and experience to assure that all
activities required by this part are correctly performed
 Establish procedures for identifying training needs and ensure
that all personnel are trained to adequately perform their
assigned responsibilities. Training shall be documented
 Personnel shall be made aware of device defects which may occur
from the improper performance of their specific jobs
 Personnel who perform verification and validation activities shall be
made aware of defects and errors that may be encountered as part of
their job functions

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Design Controls
This section covers Subpart C, Design Controls
Each manufacturer of any class III or class II device, and
the class I devices listed below, shall establish and
maintain procedures to control the design of the device
in order to ensure that specified design requirements are
met
The following class I devices are subject to design
controls:
 Devices automated with computer software; and
 The devices listed in the following chart:
Section Device
868.681 Catheter, Tracheobronchial Suction.
878.446 Glove, Surgeon's.
880.676 Restraint, Protective.
System, Applicator, Radionuclide,
892.565 Manual.
892.574 Source, Radionuclide Teletherapy.
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Design Development Planning and
Input
 Each manufacturer shall establish and maintain plans that describe or
reference the design and development activities and define
responsibility for implementation
 The plans shall identify and describe the interfaces with different
groups or activities that provide, or result in, input to the design and
development process
 As design and development evolve, the plans shall be reviewed, updated,
and approved
 Each manufacturer shall establish and maintain procedures to ensure
that the design requirements relating to a device are appropriate and
address the intended use of the device, including the needs of the
user and patient
 The procedures shall include a mechanism for addressing incomplete,
ambiguous, or conflicting requirements
 The design input requirements shall be documented and shall be reviewed
and approved by a designated individual(s)
 The approval, including the date and signature of the individual(s)
approving the requirements, shall be documented

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Design
defining andOutput and Review
 Each manufacturer shall establish and maintain procedures for
documenting design output in terms that allow an
adequate evaluation of conformance to design input requirements
 Design output procedures shall contain or make reference to
acceptance criteria and shall ensure that those design outputs that are
essential for the proper functioning of the device are identified
 Output shall be documented, reviewed, and approved before release.
Approvals, including the date and signature of the approving individual(s),
shall be documented
 Each manufacturer shall establish and maintain procedures to ensure
that formal documented reviews of the design results are planned and
conducted at appropriate stages of the device's design development
 The procedures shall ensure that participants at each design review
include representatives of all functions concerned with the design
stage being reviewed and an individual(s) who does not have direct
responsibility for the design stage being reviewed, as well as any
specialists needed
 Results, including identification of the design, the date, and the
individual(s) performing the review, shall be documented in the DHF

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Design Verification and Validation
 Each manufacturer shall establish and maintain procedures for
verifying the device design
 Verification shall confirm that the design output meets the design
input requirements
 Results of the verification, including identification of the design,
method(s), the date, and the individual(s) performing the verification,
shall be documented in the DHF
 Each manufacturer shall establish and maintain procedures for
validating the device design
 Design validation shall be performed under defined operating
conditions on initial production units, lots, or batches, or their
equivalents
 Design validation shall ensure that devices conform to defined user
needs and intended uses and shall include testing of production units
under actual or simulated use conditions
 Design validation shall include software validation and risk analysis,
where appropriate
 The results of the design validation, including identification of the design,
method(s), the date, and the individual(s) performing the validation, shall
be documented in the DHF
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Design Transfer, Changes, and the Design History File
(DHF)
Each manufacturer shall establish and maintain
procedures to ensure that the device design is correctly
translated into production specifications
Each manufacturer shall establish and maintain
procedures for the identification, documentation,
validation or where appropriate verification, review, and
approval of design changes before their
implementation
Each manufacturer shall establish and maintain a DHF for
each type of device. The DHF shall contain or reference
the records necessary to demonstrate that the design
was developed in accordance with the approved
design plan and the requirements of this part

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Document Controls
 This section covers Subpart D, Document Controls
 Each manufacturer shall establish and maintain procedures to control all
documents required by this part, providing for the following:
 Individual(s) should be designated to review for adequacy and approve prior to
issuance all documents established to meet the requirements of this part
 Approvals should be documented, including the date and signature of the approving
individual(s)
 Documents shall be available at all locations for which they are designated, used, or
otherwise necessary, and all obsolete documents shall be promptly removed from all
points of use or otherwise prevented from unintended use
 Unless specifically designated otherwise ,changes to documents shall be reviewed
and approved by an individual(s) in the same function or organization that
performed the original review and approval
 Approved changes shall be communicated to the appropriate personnel in a timely
manner
 Each manufacturer shall maintain records of changes to documents including; a
description of the change, identification of affected documents, signature of the approving
individual(s), approval date, and when the change becomes effective

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Purchasing Controls
 This section covers Subpart E, Purchasing Controls
 Each manufacturer is required to establish and maintain procedures to ensure that all
purchased or received product/services conform to specified requirements.
 Such requirements must also be met by any suppliers, contractors, and consultants. It is
the manufacturer’s responsibility to:
 Evaluate and document the selection process of potential suppliers, contractors, and
consultants on the basis of their ability to meet specified requirements
 Define the type and extent of control to be exercised over the product, services, suppliers,
contractors, and consultants
 Establish and maintain records of acceptable suppliers, contractors, and consultants.
 Maintain data that clearly describe or reference the specified requirements for
purchased or received product and services. Where possible, purchase documents should
include an agreement that the suppliers, contractors, and consultants agree to notify the
manufacturer of changes in the product/service that may affect the quality of a finished
device. Any such purchasing data shall be approved in accordance with 820.40

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Production and Process Controls
 This section covers Subpart G, Production and Process Controls
 To ensure that a device conforms to its specifications, each manufacturer
shall develop, conduct, control, and monitor production processes
 Where deviations from specifications could occur as a result of the
manufacturing process, the manufacturer shall establish and maintain process
control procedures that describe process controls necessary to ensure
conformance to specifications. Such process controls should include:
 Documented instructions, standard operating procedures (SOP's), and methods
that define and control the manner of production
 Monitoring and control of process parameters and component and device
characteristics during production
 Compliance with specified reference standards or codes
 The approval of processes and process equipment
 Criteria for workmanship which shall be expressed in documented standards or
by means of identified and approved representative samples

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Process Change, Environmental Control, and Personnel
 Each manufacturer shall establish and maintain procedures for changes to a
specification, method, process, or procedure.
 Prior to implementation, any changes shall be verified or validated according to 820.75, and
these activities should be documented.
 Changes shall be approved in accordance with 820.40.
 Where environmental conditions could reasonably be expected to have an adverse
effect on product quality, procedures to adequately control the environmental
conditions should be established and maintained.
 Environmental control system(s) should be periodically inspected to verify that the system is
adequate and functioning properly.
 These activities shall be documented and reviewed.
 Requirements for the health, cleanliness, personal practices, and clothing of
personnel should be established and maintained if contact between personnel and
product or environment could reasonably be expected to have an adverse effect on
product quality.
 Maintenance and other personnel who are required to only work temporarily under special
environmental conditions should be appropriately trained or supervised by a trained
individual.

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Contamination Control, Buildings, and Equipment
 To prevent contamination of equipment or product by substances that could
have an adverse effect on product quality, each manufacturer shall establish and
maintain procedures
 Buildings shall be of suitable design and contain sufficient space in order to:
 Perform necessary operations
 Prevent mix-ups and assure orderly handling
 Each manufacturer shall ensure that all equipment used in the
manufacturing process meets specified requirements and is appropriately
designed, constructed, placed, and installed to facilitate maintenance,
adjustment, cleaning, and use
 Schedules for the adjustment, cleaning, and other maintenance of equipment
should be developed to ensure that manufacturing specifications are met
 Periodic inspections in accordance with established procedures to ensure adherence
to applicable equipment maintenance schedules shall be conducted
 Any inherent limitations or allowable tolerances should be visibly posted on or
near equipment requiring periodic adjustments or should be readily available to
personnel performing adjustments

65
Manufacturing Material and Automated Processes
 When a manufacturing material could have an adverse effect on
product quality:
 Procedures should be developed for both the use and removal of such
material to ensure either that it is removed or limited to an amount that
does not adversely affect the device's quality
 Any such removal or reduction should be documented
 When computers or automated data processing systems are used
as part of production or the quality system:
 Computer software should be validated for its intended use according to
established protocol
 Software changes should be validated before approval and issuance
 These validation activities and results shall be documented

66
Inspection, Measuring, and Test Equipment
Each manufacturer shall ensure that all inspection,
measuring, and test equipment, including mechanical,
automated, or electronic inspection and test equipment, is
suitable for its intended purposes and is capable of
producing valid results
 Each manufacturer shall establish and maintain procedures to
ensure that equipment is routinely calibrated, inspected,
checked, and maintained
 The procedures shall include provisions for handling, preservation, and
storage of equipment, so that its accuracy and fitness for use are
maintained
 These activities shall be documented

67
Calibration of Equipment
 Calibration procedures shall include specific directions and limits
for accuracy and precision
 When accuracy and precision limits are not met, there shall be provisions
for remedial action to reestablish the limits and to evaluate whether
there was any adverse effect on the device's quality
 These activities shall be documented
 Calibration standards used for inspection, measuring, and test equipment shall
be traceable to national or international standards. A manufacturer shall
establish and maintain an in-house standards if national or international
standards are not practical
 The equipment identification, calibration dates, the individual performing each
calibration, and the next calibration date shall be documented and displayed on
or near each piece of equipment or readily available to the personnel using
such equipment and to the individuals responsible for calibrating the equipment

68
Process Validation
 If results of a process cannot be fully verified by subsequent inspection
and test, a process should be validated with a high degree of assurance
and approved according to established procedures
 Any such validation activities and results, the date and signature of the individual(s)
approving the validation should be documented
 Each manufacturer shall establish and maintain procedures for monitoring
and control of process parameters for validated processes to ensure that the
specified requirements continue to be met
 Each manufacturer shall ensure that validated processes are performed by
qualified individual(s)
 For validated processes, the monitoring and control methods and data, the date
performed, and the individual(s) performing the process or the major equipment
used shall be documented
 When changes or process deviations occur, the manufacturer shall review,
evaluate, and document the process and perform revalidation where
appropriate

69
Labeling and Packaging Controls
 This section covers Subpart K, Labeling and Packaging Controls
 Each manufacturer shall establish and maintain procedures to control
labeling activities
 Labels shall be printed and applied so as to remain legible and
affixed during the customary conditions of processing, storage,
handling, distribution, and where appropriate use
 Labeling shall not be released for storage or use until a designated
individual(s) has examined the labeling for accuracy including, where
applicable, the correct expiration date, control number, storage
instructions, handling instructions, and any additional processing
instructions
 The release, including the date and signature of the individual(s)
performing the examination, shall be documented in the DHR
 Each manufacturer shall store labeling in a manner that provides
proper identification and is designed to prevent mix-ups

70
Labeling and Packaging
Each manufacturer shall control labeling and
packaging operations to prevent labeling mix-ups
 The label and labeling used for each production unit, lot, or batch
shall be documented in the DHR
Where a control number is required, that control
number shall be on or shall accompany the device
through distribution
Each manufacturer shall ensure that device packaging and
shipping containers are designed and constructed to
protect the device from alteration or damage during
the customary conditions of processing, storage,
handling, and distribution

71
Clean Room Controls /
Contamination
The following guidance is intended to help manufacturers
meet the good manufacturing practice requirement
regulations of 2l CFR parts 210 and 211
To maintain product sterility, it is essential that the
environment in which aseptic operations (e.g.,
equipment setup, filling) are conducted be controlled
and maintained at an appropriate quality
 One aspect of environmental quality is the particle content of
the air. Particles are significant because they can enter a product
as an extraneous contaminant, and can also contaminate it
biologically by acting as a vehicle for microorganisms
 Appropriately designed air handling systems can be used to
establish a clean room, in order to minimize particle content
of a critical area

72
Clean
 Room Classes
Various classes of clean rooms have been established. A lower
classification or designation indicates tighter environmental
requirements. The following table summarizes classes of clean
rooms:

73
Important Classes of Clean Rooms
Two clean areas are of particular importance:
 A critical area, Class 100 (ISO 5), is one in which the sterilized
product, containers, and closures are exposed to environmental
conditions that must be designed to maintain product sterility
 Activities conducted in such areas include manipulations (e.g., aseptic
connections, sterile ingredient additions) of sterile materials prior to
and during filling and closing operations
 This area is critical because an exposed product is vulnerable to
contamination and will not be subsequently sterilized in its
immediate container
 Supporting clean areas, at minimum Class 10,000 (ISO 7), can
have various classifications and functions. Many support areas
function as zones in which nonsterile components, formulated
products, in-process materials, equipment, and container/closures
are prepared, held, or transferred

74
Clean Room Gowning
 Only personnel who are qualified and appropriately gowned
should be permitted access a clean room manufacturing area
 The gown should provide a barrier between the body and exposed
sterilized materials and prevent contamination from particles
generated by, and microorganisms shed from, the body
 It’s recommended that gowns are sterilized and nonshedding, and
cover the skin and hair (face-masks, hoods, beard/moustache covers,
protective goggles, and elastic gloves are examples of common
elements of gowns)
 Written procedures should detail the methods used to don each
gown component in an aseptic manner
 An adequate barrier should be created by the overlapping of gown
components (e.g., gloves overlapping sleeves).
 If an element of a gown is found to be torn or defective, it should
be changed immediately
 Gloves should be sanitized frequently

75
Clean
Employees Room Rules training
shall receive fundamental of Conduct
on topics that should
include aseptic technique, cleanroom behavior, microbiology,
hygiene, gowning, patient safety hazards posed by a nonsterile drug
product, and the specific written procedures covering aseptic
manufacturing area operations
 After initial training, personnel should participate regularly in an
ongoing training program
 Supervisory personnel should routinely evaluate each operator’s
conformance to written procedures during actual operations
 Some of the techniques aimed at maintaining sterility of sterile items
and surfaces include:
 Contact sterile materials only with sterile instruments
 After initial gowning, sterile gloves should be regularly sanitized or
changed, as appropriate, to minimize the risk of contamination
 Move slowly and deliberately
 Keep the entire body out of the path of unidirectional airflow
 Approach a necessary manipulation in a manner that does not
compromise sterility of the product
76
FluStudy
Case vaccination contamination: 2004
 Chiron manufacturing plant shut down by regulators due to failure
to follow GMP
 Chiron was to supply nearly half of the US vaccine supply for 2004-2005
 Serratia bacteria discovered in nine of its 100 flu vaccine lots
 Inadequate environmental controls and record keeping
 FDA documented 20 separate problems with manufacturing and record
keeping
 Because company did not keep adequate records, it could not
trace/isolate the problem, and had to destroy all 100 lots
 Chiron company adversely affected and public put at risk
 Chiron suspended for five month
 Stock plunged, and Chiron suffered $22.9 million net loss in 4th quarter
of 2004
 Loss of half of the US flu shot vaccinations and 20% of UK doses

77
Module 3 Questions (1)
Which of the following is NOT a reason for conducting quality audits?
a) To assure that the quality system is in compliance with the established requirements
b) To determine the effectiveness of the quality system
c) To fix a known inefficiency in the manufacturing process

Who should conduct a quality audit?

a) Employees directly responsible for the matters being audited
b) Managers directly responsible for the matters being audited
c) Individuals who do not have direct responsibility for the matter being audited

Personnel who perform verification and validation activities shall be made aware of _____________
that may be encountered as part of their job functions.
a) Cost overruns
b) Schedule changes
c) Difficult personnel
d) Defects and errors

78
Module 3 Questions (2)
Procedures to control the design of devices shall be established and maintained for which of the
following?
a) Some Class I devices
b) Class II devices
c) Class III devices
d) All of the above

Procedures developed for the purpose of design input requirements should have mechanisms to address all of the
following problems with requirements EXCEPT requirements that are:
a) Incomplete
b) Ambiguous
c) Conflicting
d) Excessive

Which of the following groups need to be represented at a design review?

a) Representatives of all functions concerned with the design stage being reviewed
b) Needed Specialists
c) Individuals who do not have direct responsibility for the design stage being reviewed
d) All of the above

79
Module 3 Questions (3)
The purpose of design verification is best summarized as:
a) Confirming that all manufacturing processes were performed.
b) Confirming that the design selected best meets the customer’s needs.
c) Confirming that design output meets the design input requirements

What does he acronym DHF stand for?

a) Development History Folder
b) Designated Holding Fixture
c) Design History Filter
d) Design History File

Which of the following is NOT true of document control?

a) All obsolete documents shall be promptly removed from all points of use or otherwise prevented from
unintended use
b) Approved changes should be communicated to the appropriate personal in a timely manner
c) Each manufacturer should maintain records of changes to documents
d) Documents shall be available at some of the locations for which they are designated,
used, or otherwise necessary

80
Module 3 Questions (4)
Manufacturers shall maintain records of changes to documents that should include which of the following:
a) Description of change
b) Identification of affected documents
c) Date that change request was initiated
d) Answers a and c
e) Answers a and b

When purchasing materials or services, manufacturers only need to document the selection of:
a) Suppliers
b) Contractors
c) Consultants
d) All of the above

The main objective for traceability and identification requirements is to:

a) Monitor inventory
b) Forecast material shortages
c) Ensure prompt delivery
d) Prevent mix-ups

81
Module 3 Questions (5)
Control numbers are necessary for identification and traceability under what circumstances:
a) The device will be surgically implanted into a body
b) The device has a high probability of being misplaced
c) The device will be used to support/sustain life
d) All of the above
e) Answers a and c

Which of the following is NOT a production of process control that needs to be documented:
a) Documented instructions, standard operating procedures (SOP's), and methods that define and control the manner
of production
b) Monitoring and control of process parameters and component and device characteristics during production
c) Compliance with specified reference standards or codes
d) The rejection of processes and process equipment

Which of the following is true of the control of environmental conditions:

a) Environmental control systems should be periodically inspected for system adequacy and proper functionality
b) Inspection activities should be documented and reviewed
c) Environmental controls should be open-loop as approved by the FDA
d) All of the above
e) Answers a and b

82
Module 3 Questions (6)
Because certain types of personnel (such as maintenance) are only required to work temporarily under special
environmental conditions:
a) They do not need to receive appropriate training
b) They can work unsupervised
c) They are not expected to meet any special health, cleanliness, and clothing requirements
d) They should be appropriately trained or supervised by a trained individual

Buildings shall be of suitable design and contain sufficient space in order to:
a) Achieve the appropriate air particle count
b) Accommodate several work areas
c) Ensure that clean rooms are located far away from sources of contamination
d) Perform necessary operations and prevent mix-ups

Which of the following is NOT true of the display of inherent limitations or allowable tolerances of
equipment:
a) It can be posted near the equipment
b) It merely needs to be readily available to personnel performing adjustments
d) It can only be posted on the equipment

83
Module 3 Questions (7)
Which of the following is NOT true of the use of computers or automated data processing systems as
part of the production or quality system:
a) Computer software should be validated for its intended use according to established protocol
b) Software changes should always be validated before approval and issuance
c) Validation activities and results do not need to be documented as long as all parties involved agree that the
change is needed.

Each manufacturer shall establish and maintain procedures to ensure that equipment is all of the
following EXCEPT:
a) Routinely calibrated
b) Routinely inspected
c) Routinely maintained
d) Routinely operated

Which of the following is an item that should be documented and displayed after equipment is calibrated:
a) Original purchase date
b) Equipment manufacturer
c) Allowable tolerances
d) Individual who performed calibration

84
Module 3 Questions (8)
If process cannot be fully verified by subsequent inspection and test, a process should be:
a) Discontinued indefinitely
b) Accepted conditionally
c) Redesigned until inspection and test can be used for verification
d) Validated with a high degree of assurance, and approved to established procedures

Labeling shall not be released for storage or use until a designated individual has examined the
labeling for all of the following information EXCEPT:
a) Correct expiration date
b) Control number
c) Storage instructions
d) Content

Air particles are significant because they can:

a) Make the reading of instrumentation difficult
b) Enter a product as an extraneous contaminant
c) Act as a vehicle for microorganisms
d) Answers a and b
e) Answers b and c

85
Module 3 Questions (9)
A lower ISO designation of a clean room
corresponds to:
a) A lower Clean Air Classification, higher air particle count
b) A higher Clean Air Classification, lower air particle count
c) A higher Clean Air Classification, higher air particle count
d) A lower Clean Air Classification, lower air particle count

86
87
Course Agenda
Module 1 - GMP Overview
Module 2 - Requirements
Module 3 - Controls
Module 4 - Acceptance and Violations
Certification Exam

88
Module Overview
This module should take approximately one hour to
complete. It will cover the following topics:
 Acceptance Activities
 Nonconforming Products
 Corrective and Preventative Actions
 GMP Violations
 Case Study
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes, you
may proceed to the 1-hour, 100 question certification
exam.

89
Acceptance Activities
This section covers Subpart H, Acceptance Activities
Acceptance activities include inspections, tests, and
other verification activities demonstrating that GMP
has been followed, applicable acceptance criteria have
been met, and appropriate requirements have been met
Manufacturers are required to establish and maintain
acceptance activity procedures. Acceptance activities
must be documented throughout the manufacturing
process
Results (including acceptance or rejection) must be
documented and maintained, allowing the acceptance
status of a product to be determined at any time

90
Types of Acceptance Activities
Acceptance activities fall into 3 types, corresponding to
the manufacturing stage
Manufacturers must establish and maintain acceptance
procedures, and document activities and results, for each
type
 Receiving: Incoming product
 In-process: Where appropriate, product is controlled until final
acceptance or necessary approvals are obtained and documented
 Final: Every lot or batch of finished product is quarantined or
otherwise controlled until all of the following criteria are met:
 Acceptance activities documented in DMR are completed
 Associated data and documentation is reviewed
 Release is authorized by signature of a designated individual
 Release authorization is dated

91
Acceptance

Records and Status
Manufacturers must document acceptance activities, including:
 Activities performed
 Dates
 Results
 Signature of the conducting individual
 Equipment used, where appropriate. Equipment information must also be
kept in the DHR
 Manufacturers must identify (document) the acceptance status of a
product to indicate whether it has met acceptance criteria. The
identification must be maintained throughout the product life:
 Manufacturing
 Packaging
 Labeling
 Installation
 Servicing

92
Nonconforming Product
This section covers Subpart I, Nonconforming Product
A product is nonconforming if it fails acceptance criteria
at any stage
Manufacturers must establish and maintain procedures
for control, review, disposition, and rework of non-
conforming products
Procedures must address non-conforming product
 Identification
 Documentation
 Evaluation
 Segregation
 Disposition

93
Nonconforming Product Evaluation and Disposition
Nonconformance evaluation must include
Determination of need for investigation
Identification of person(s) responsible for the
noncompliance
Nonconformance evaluation and any investigation
must be documented
Disposition procedures are required if the
nonconforming product is to be used or reworked

94
Nonconforming Product Disposition
Disposition procedures must define
 Responsibility for nonconformance review
 Authority for disposition
Disposition must be documented
 Justification for use of product
 Signature of individual(s) authorizing use
Rework procedures must include reevaluation and
retesting after rework
Rework, reevaluation, and determination of adverse
effects on product due to rework must all be documented
in the DHR

95
Corrective & Preventive Action
This section covers Subpart J, Corrective and Preventive
Action
Manufacturers must establish and maintain procedures
for implementing corrective and preventive action
 Corrective action means tasks undertaken to fix current
nonconformities
 Preventive action means tasks undertaken to predict and
forestall future nonconformities
All corrective and preventive activities and results must be
documented

96
Corrective &
Preventive Action Procedures
 Corrective & Preventive Action procedures must include requirements
for:
 Analyzing sources of quality data to identify causes of nonconforming
product, or other quality problems
 Investigating the cause of nonconformities relating to product, processes,
and the quality system
 Verifying or validating the corrective and/or preventive actions
 Implementing and recording changes in methods and procedures for
correction and prevention of quality problems
 Ensuring that information related to quality problems or nonconforming
product is disseminated to those directly responsible for assuring product
quality or preventing future quality problems
 Submitting relevant information on identified quality problems, as well
as corrective and preventive actions, for management review

97
GMP
Violations
21 CFR 820 does not contain a list of violations. If any requirement of
the law is not met, it can be considered a violation
 Violations have varying civil and/or criminal penalties, please refer to
your compliance officer for details
 It is critical that manufacturers have internal processes in place to
predict and prevent violations. If a violation does occur, it must be
documented and reported to your immediate supervisor. Your
management will determine how to report the violation to the FDA
 Once the situation is corrected, make sure to create a list of lessons
learned. Use these lessons to change current procedures and prevent
future similar violations

98
Most Common Violations
Here is a list of the seven most common types of GMP
violations (courtesy Robert McClure):
 1. Failure to establish quality control unit procedures
 2. Failure to establish an adequate training program
 3. Failure to perform finished product testing
 4. Failure to properly calibrate testing equipment
 5. Failure to establish adequate written procedures for production and
process control
 6. Failure to establish adequate batch production records
 7. Failure to establish adequate labeling procedures

99
FDA GMP Investigations
 Here are the top items an FDA investigator looks for when a violation
occurs (courtesy MasterControl)
 Process understanding and control
 companies must be able to demonstrate process validity at any time
 consistency of product quality
 extensive documentation including test results, process deviations, complaints,
etc.
 Reaction to violations
 investigation of full scope of violation
 for example, have other batches been affected
 corrective and preventive measures
 Laboratory operations
 sample accountability
 control and validation – are processes well-defined and routinely followed
 reaction to out-of-spec laboratory results (see above)
 GMP Training (initial and continuing)
 training level and adequate number of trained personnel

100
Improve Company Culture
Company culture is critical for preventing violations
(courtesy MasterControl)
 Don’t wait for FDA to tell you what to do
 Have a defensible system for making decisions and developing
processes, based on good science
 Implement a continuous improvement process
 Daily mode of preparedness
 Predict and eliminate underlying systemic causes, don’t focus on
symptoms
 Preventive is better than corrective!

101
 The Spring 2008 heparin contamination problem demonstrates the
Case Studyof these topics
importance
 Neither US distributor nor China supplier performed proper Acceptance Activities
 Distributor blames manufacturer
 FDA believes manufacturer did not monitor suppliers properly
 Manufacturer blames suppliers, not itself
 China upstream suppliers are small and unregistered
 Because of this, there was no detection of Nonconforming Product
 Neither individual testing nor investigation full scope of problem was conducted, therefore
there was no opportunity to reject product or rework supply chain
 This resulted in a Violation...but where/how did it occur?
 There was a cultural and regulatory disconnect between US and Chinese regulators and
supply chains
 The exact cause and starting point of problem is still under investigation
 Moral: All parties in supply chain must proactively strive to meet GMP
requirements to prevent problems, and must test and verify at every stage of
product development to quickly correct problems that do occur
 International, global industry makes this even more critical

102
Module 4 Questions (1)
Acceptance Activities
Which of the following is NOT a type of acceptance activity?
a) Final
b) In-Process
c) Receiving
d) Prototype

Which of the following is required for completion of In-Process acceptance?

a) Production manager signoff
b) Analysis of possible side effects
c) Labor union approval
d) Cost-benefit report
e) Final acceptance

Which of the following acceptance criteria is NOT required for product release?
a) Release is authorized by signature of a designated individual
b) Associated data and documentation is reviewed
c) Release authorization is dated
d) Acceptance activities documented in DMR are completed
e) FDA inspection

103
Module 4 Questions (2)
Acceptance Activities
Which of these is a product life stage that requires identification of acceptance activities?
a) Prototyping
b) Operation
c) Disposal
d) Design
e) Packaging

Which of the following does NOT have to be included in acceptance documentation?

a) Activities performed
b) Dates
c) Results
d) Signature of the conducting individual
e) Training record of conducting individual

Which of the following is NOT a project life stage requiring acceptance status?
a) Manufacturing
b) Packaging
c) Labeling
d) Servicing
e) Marketing

104
Module 4 Questions (3)
Nonconforming Products
Which acceptance procedures for nonconforming products are NOT required?
a) Review
b) Control
c) Disposition
d) Rework
e) User identification

Acceptance procedures do NOT need to address nonconforming product:

a) Identification
b) Documentation
c) Evaluation
d) Disposition
e) Design

Nonconformance evaluation must include:

a) Determination of need for investigation
b) Identification of person(s) responsible for noncompliance
c) Documentation of evaluation procedure
d) Documentation of any investigation
e) All of the above

105
Module 4 Questions (4)
Nonconforming Products
Nonconforming product disposition procedures do NOT have to define:
a) Authority for disposition
b) Responsibility for nonconformance review
c) Authorizing individual(s)
d) Justification for use of product
e) Reason for nonconformance

Rework procedures do NOT have to define:

a) Identification
b) Documentation
c) Evaluation
d) Disposition
e) Design

The following procedures do not have to be documented in the DHR:

a) Rework
b) Reevaluation after rework
c) Determination of adverse effects due to rework
d) Destruction of reworked product

106
Module 4 Questions (5)
Corrective and Preventative Actions

Manufacturers must establish and maintain procedures for preventive as well as corrective actions.
True
False

Preventive actions must predict and forestall current nonconformities.

True
False

Corrective actions must fix current nonconformities.

True
False

107
Module 4 Questions (6)
Corrective and Preventative Actions
Which of the following must always be documented:
a) Corrective action activities
b) Corrective action results
c) Preventive action activities
d) Preventive action results
e) All of the above

Corrective and preventive action procedures must include:

a) Analyzing sources of quality data
b) Investigating the cause of nonconformities
c) Verifying/validating actions
d) Implementing changes in procedures
e) All of the above

Identified quality problems, as well as actions taken, must be submitted for management review:
True
False

108
Module 4 Questions (7)
GMP Violations

Which if the following is not one of the most common violations (according to the class)::
a) Failure to establish quality control unit procedures
b) Failure to establish an adequate training program
c) Failure to perform finished product testing
d) Failure to properly calibrate testing equipment
e) Failure to properly evaluate product after rework

Which if the following is NOT one of the most important issues for an FDA investigator to address after a violation occurs
(according to the class)?
a) Process understanding and control
b) Reaction to violations (scope of investigation)
c) Laboratory operations
d) GMP Training (initial and continuing)
e) Environmental and pollution controls

What is not part of a constructive corporate culture for preventing violations?

a) Defensible system for making decisions and developing processes, based on good science
b) “Continuous improvement” process
c) Daily mode of preparedness
d) Predict and eliminate underlying systemic causes, don’t focus on symptoms
e) Document only noncompliance events, not routine processes

109
Module 4 Questions (8)
GMP Violations
All GMP violations are specifically listed in 21 CFR 820.
True
False

Manufacturers must be able to demonstrate process validity only during FDA inspections.
True
False

All GMP violations are specifically listed in 21 CFR 820.

True
False

Upon discovery of a GMP violation, its full scope must always be investigated.
True
False

110