Good Manufacturing Practice

y GMP Training- FDA Regulations

Searchtec Institute www.Searchtecgroup.com

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

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Module Questions
(instructions for Web site designer)

y Each module will have 25 questions attached. Correct answers are shown last, and in Bold. y The question selection and order will be randomized for each quiz or test session.
y The module quiz will contain 10 module questions, randomly chosen and randomly

ordered. y The test will contain all 100 module questions from all modules, randomly ordered. y The order of possible answers for each question will be randomized, except for All of the above answers which are always last.

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

GMP Implementation Is Critical For MDX To Maintain Our Dominant Market Position
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Course Agenda
y Module 1 - GMP Overview y Module 2 - Requirements y Module 3 - Controls y Module 4 - Acceptance and Violations y Certification Exam

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Module 1 Overview
y This module should take approximately one hour to complete. It will cover the following topics: y What is GMP? y Why GMP? y Key Terms and Definitions y There will be a short 10 question quiz that follows. y 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?
y 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 y 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)
y
y y y y

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

y

This course will focus on the Medical Device GMP requirements

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Why GMP?
y GMP is intended to protect consumers from purchasing a product which is not effective or even dangerous y 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
y The GMP requirements for Medical Devices are outlined

on the FDA website under Subchapter H of the GMP regulations y This subchapter outlines the specific FDA GMP requirements for implementation and regulation

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GMP Terms
y 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. y 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. y 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)
y Design history file (DHF) - A compilation of records which describes

the design history of a finished device. y Design input - Means the physical and performance requirements of a device that are used as a basis for device design. y 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. y 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)
y Device history record (DHR) - A compilation of records containing y y y

y

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 (cont)
y y y y

y Management 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)
y Quality - The totality of features and characteristics that bear on the

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

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GMP Terms (cont)
y 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. y Rework - Action taken on a nonconforming product so that it will fulfill the specified DMR requirements before it is released for distribution. y Specification - Any requirement with which a product, process, service, or other activity must conform.

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GMP Terms (cont)
y Validation - Confirmation by examination and provision of objective

evidence that the particular requirements for a specific intended use can be consistently fulfilled. y Process validation - Establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications. y Design validation - Establishing by objective evidence that device specifications conform with user needs and intended use(s). y 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
y Module 1 - GMP Overview y Module 2 - Requirements y Module 3 - Controls y Module 4 - Acceptance and Violations y Certification Exam

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Module 2 Overview
y This module should take approximately one hour to

complete. It will cover the following topics: y Quality Systems y Identification & Traceability y Handling, Storage, & Distribution y Record Keeping y There will be a short 10 question quiz that follows. y 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
y This section covers Subpart B - Quality System Requirements y Quality System is the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management y Key requirement: FDA CRF 21 (US) & ISO13485 (Global, EU) y 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
y Manufacturer requirements and responsibilities: y Policy management must establish objectives and commitments to pursue and implement best practices. y Organization company should be structured to ensure that devices are produced to the design intent. y Authority should be established for those that manage, produce, and review devices y Resources proper funding for training and quality assessment shall be established

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Quality System Requirements
y Executives should have management representatives with authority

over the quality organization to report and asses the quality system. y Established procedures should call for management reviews of the quality system based on requirements outlined in the quality policy. y A quality plan should be established which outlines quality practices, resources, and activities. y Procedure outlines should be established and followed throughout the quality system.

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

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Identification and Traceability
y To ensure the safety of healthcare patients, manufacturers shall maintain traceability for all devices and components y Maintain ID procedures y Control number for each unit/lot/batch y 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
y This section covers Subpart L, Handling, Storage, Distribution, and

Installation y Procedures need to be established and maintained to ensure that mix-ups, damage, or contamination do not alter products during handling and storage y 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 y 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
y This section covers Subpart M, Records y Records are documents that detail the specifications of a device, its history, or its quality processes followed during production y Types of records include: y Device master y Device history y Quality system y Complaint files

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

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Records Keeping
y Confidential records shall be properly marked to aid FDA inspectors y 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
y Upon FDA request, manufacturing officials shall be able at all times to produce records of all: y Management reviews y Quality audits y Supplier audits y Corrective actions

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

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

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Records Keeping
y A Quality System Record (QSR) shall be kept and contain

procedures and documentation of all activities specific to a device y A complaint file shall be kept. Procedures shall be established for the receiving, reviewing, and evaluating of all formal complaints. Procedures shall ensure that:
y Complaints are processed in timely manner y Oral complaints are properly documented y Evaluation to determine whether complaint needs to be reported to

FDA y Any complaint concerning product failure is properly evaluated

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y Cody Labs Case Study (drug maker in Wyoming): 2006
y Following a two week FDA investigation Cody Labs was hit

letter for multiple GMP Violations y Two finished drug products were adulterated by lack of GMP compliance
y y y y

with a

company s

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
y Module 1 - GMP Overview y Module 2 - Requirements y Module 3 - Controls y Module 4 - Acceptance and Violations y Certification Exam

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Module 3 Overview
y This module should take approximately one hour to

complete. It will cover the following topics:
y Quality Audits y Design, Document, and Purchasing Controls y Production and Process Control y Environmental Control and Clean Rooms

y There will be a short 10 question quiz that follows. y 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
y This section covers Subpart B, Quality Audits y Each manufacturer shall establish procedures for quality audits and

conduct such audits in order to:

y Assure that the quality system is in compliance with the established

requirements y Determine the effectiveness of the quality system

y Audits should be conducted by individuals who do not have direct

responsibility for the matters being audited y Corrective action(s), including a re-audit of deficient matters, shall be taken when necessary y A report of the results of each quality audit/re-audit shall be made.
y Such reports shall be reviewed by management responsible for the matters

audited

y Dates and results of quality audits/re-audits are to be documented
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Personnel
y This section covers Subpart B, Personnel y Each manufacturer shall:
y Have sufficient personnel with the necessary education,

background, training, and experience to assure that all activities required by this part are correctly performed y Establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities. Training shall be documented
y

y

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 C, y This secti c vers Subpart

si C tr ls y Each a fact rer f a y class III or class II evice, a the class I ic s list elow, shall esta lish a ai tai roce res to c tr l t si ft ic i or er to e s re that s ecifie esig re ire e ts are et y The followi g class I evices are s ject to esig controls:
y evices aut at it c put r s ft ar ; and y 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 y Each manufacturer shall establish and maintain plans that describe or
reference the design and development activities and define responsibility for implementation
y 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 y As design and development evolve, the plans shall be reviewed, updated, and approved

y 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

y The procedures shall include a mechanism for addressing incomplete,

ambiguous, or conflicting requirements y The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s) y The approval, including the date and signature of the individual(s) approving the requirements, shall be documented
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Design Output and Review

y Each manufacturer shall establish and maintain procedures for

defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements
y 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 y Output shall be documented, reviewed, and approved before release. Approvals, including the date and signature of the approving individual(s), shall be documented

y Each manufacturer shall establish and maintain procedures to ensure
y The procedures shall ensure that participants at each design review

that formal documented reviews of the design results are planned and conducted at appropriate stages of the device's design development
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 y 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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y Each manufacturer shall establish Designthe device design andand Validation Verification maintain procedures for verifying
y Verification shall confirm that the design output meets the design input

requirements y 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

y Each manufacturer shall establish and maintain procedures for

validating the device design

y Design validation shall be performed under defined operating

conditions on initial production units, lots, or batches, or their equivalents y 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 y Design validation shall include software validation and risk analysis, where appropriate y 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)
y Each manufacturer shall establish and maintain procedures

to ensure that the device design is correctly translated into production specifications y 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 y 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
y y

y This section covers Subpart D, Document Controls y Each manufacturer shall establish and maintain procedures to control all documents required by this part, providing for the following:
y 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

y 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
y y

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
y This section covers Subpart E, Purchasing Controls y Each manufacturer is required to establish and maintain procedures to ensure that all

purchased or received product/services conform to specified requirements. y 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 y Define the type and extent of control to be exercised over the product, services, suppliers, contractors, and consultants y Establish and maintain records of acceptable suppliers, contractors, and consultants. y 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
y

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Production and Process Controls
y This section covers Subpart G, Production and Process Controls y To ensure that a device conforms to its specifications, each manufacturer shall develop, conduct, control, and monitor production processes y 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:
y Documented instructions, standard operating procedures (SOP's), and methods y y y y

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
y Each manufacturer shall establish and maintain procedures for changes to a

specification, method, process, or procedure.
y

Prior to implementation, any changes shall be verified or validated according to 820.75, and these activities should be documented. y Changes shall be approved in accordance with 820.40.

y Where environmental conditions could reasonably be expected to have an adverse
y

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. y These activities shall be documented and reviewed.

y 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.
y

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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y 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 y Buildings shall be of suitable design and contain sufficient space in order to:
y Perform necessary operations y Prevent mix-ups and assure orderly handling

Contamination Control, Buildings, and Equipment

y 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
y Schedules for the adjustment, cleaning, and other maintenance of equipment

should be developed to ensure that manufacturing specifications are met y Periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules shall be conducted y 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

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Manufacturing Material and Automated Processes
y When a manufacturing material could have an adverse effect on

product quality:

y 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 y Any such removal or reduction should be documented

y When computers or automated data processing systems are used

as part of production or the quality system:

y Computer software should be validated for its intended use according to

established protocol y Software changes should be validated before approval and issuance y These validation activities and results shall be documented

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Inspection, Measuring, and Test Equipment
y 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
y Each manufacturer shall establish and maintain procedures to

ensure that equipment is routinely calibrated, inspected, checked, and maintained
y

The procedures shall include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained

y These activities shall be documented

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Calibration of Equipment
y Calibration procedures shall include specific directions and limits

for accuracy and precision

y 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 y These activities shall be documented
y

y

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

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Process Validation
y 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
y Any such validation activities and results, the date and signature of the individual(s)

approving the validation should be documented

y 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
y Each manufacturer shall ensure that validated processes are performed by

qualified individual(s) y 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 y When changes or process deviations occur, the manufacturer shall review, evaluate, and document the process and perform revalidation where appropriate

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Labeling and Packaging Controls
y This section covers Subpart K, Labeling and Packaging Controls y Each manufacturer shall establish and maintain procedures to control

labeling activities y 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 y 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
y The release, including the date and signature of the individual(s)

performing the examination, shall be documented in the DHR

y Each manufacturer shall store labeling in a manner that provides

proper identification and is designed to prevent mix-ups

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Labeling and Packaging
y Each manufacturer shall control labeling and packaging

operations to prevent labeling mix-ups
shall be documented in the DHR

y The label and labeling used for each production unit, lot, or batch

y Where a control number is required, that control number

shall be on or shall accompany the device through distribution y 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

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Clean Room Controls / Contamination
y The following guidance is intended to help manufacturers

meet the good manufacturing practice requirement regulations of 2l CFR parts 210 and 211 y 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
y 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 y Appropriately designed air handling systems can be used to establish a clean room, in order to minimize particle content of a critical area

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Clean Room Classes

y 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:

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Important Classes of Clean Rooms
y Two clean areas are of particular importance:
y 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
y

y

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

y 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
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Clean Room Gowning
y Only personnel who are qualified and appropriately gowned should y y

y y y y

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

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Clean Room Rules of Conduct

y Employees shall receive fundamental training 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 y After initial training, personnel should participate regularly in an ongoing training program y Supervisory personnel should routinely evaluate each operator s conformance to written procedures during actual operations y Some of the techniques aimed at maintaining sterility of sterile items and surfaces include:
y Contact sterile materials only with sterile instruments y After initial gowning, sterile gloves should be regularly sanitized or

changed, as appropriate, to minimize the risk of contamination y Move slowly and deliberately y Keep the entire body out of the path of unidirectional airflow y Approach a necessary manipulation in a manner that does not compromise sterility of the product

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y Flu vaccination contamination: 2004 Case Study
y Chiron manufacturing plant shut down by regulators due to failure

to follow GMP
y y

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

y Inadequate environmental controls and record keeping y FDA documented 20 separate problems with manufacturing and record keeping y Because company did not keep adequate records, it could not trace/isolate the problem, and had to destroy all 100 lots y Chiron company adversely affected and public put at risk y Chiron suspended for five month y Stock plunged, and Chiron suffered $22.9 million net loss in 4th quarter of 2004 y Loss of half of the US flu shot vaccinations and 20% of UK doses

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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

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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

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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

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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

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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

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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

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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

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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

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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

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

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Module Overview
y This module should take approximately one hour to

complete. It will cover the following topics:
y y y y y

Acceptance Activities Nonconforming Products Corrective and Preventative Actions GMP Violations Case Study

y There will be a short 10 question quiz that follows. y Once you have completed all 4 modules and quizzes, you

may proceed to the 1-hour, 100 question certification exam.

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AcceptanceSubpart H, Acceptance Activities Activities y This section covers
y 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 y Manufacturers are required to establish and maintain acceptance activity procedures. Acceptance activities must be documented throughout the manufacturing process y Results (including acceptance or rejection) must be documented and maintained, allowing the acceptance status of a product to be determined at any time

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Types of Acceptance corresponding to the Activities y Acceptance activities fall into 3 types,
manufacturing stage y Manufacturers must establish and maintain acceptance procedures, and document activities and results, for each type
y Receiving: Incoming product y In-process: Where appropriate, product is controlled until final

acceptance or necessary approvals are obtained and documented y Final: Every lot or batch of finished product is quarantined or otherwise controlled until all of the following criteria are met:
y y y y

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

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Acceptance Records and Status
y Manufacturers must document acceptance activities, including:
y y y y y

Activities performed Dates Results Signature of the conducting individual Equipment used, where appropriate. Equipment information must also be kept in the DHR

y 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:
y y y y y

Manufacturing Packaging Labeling Installation Servicing

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Nonconforming Product Product y This section covers Subpart I, Nonconforming
y A product is nonconforming if it fails acceptance criteria

at any stage y Manufacturers must establish and maintain procedures for control, review, disposition, and rework of nonconforming products y Procedures must address non-conforming product
y y y y y

Identification Documentation Evaluation Segregation Disposition

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

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Nonconforming Product Disposition
y Disposition procedures must define
y Responsibility for nonconformance review y Authority for disposition

y Disposition must be documented
y Justification for use of product y Signature of individual(s) authorizing use

y Rework procedures must include reevaluation and

retesting after rework y Rework, reevaluation, and determination of adverse effects on product due to rework must all be documented in the DHR

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Corrective & Preventive Action
y This section covers Subpart J, Corrective and Preventive

Action y Manufacturers must establish and maintain procedures for implementing corrective and preventive action
y Corrective action means tasks undertaken to fix current

nonconformities y Preventive action means tasks undertaken to predict and forestall future nonconformities

y All corrective and preventive activities and results must be

documented

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Corrective & Preventive Action Procedures
y Corrective & Preventive Action procedures must include requirements

for:
y y y y

y Analyzing sources of quality data to identify causes of nonconforming

y

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

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GMP Violations

y 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 y Violations have varying civil and/or criminal penalties, please refer to your compliance officer for details y 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 y 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

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Mostlist of the seven mostViolationsGMP Common common types of y Here is a
violations (courtesy Robert McClure):
y 1. Failure to establish quality control unit procedures y 2. Failure to establish an adequate training program y 3. Failure to perform finished product testing y 4. Failure to properly calibrate testing equipment y 5. Failure to establish adequate written procedures for production and

process control y 6. Failure to establish adequate batch production records y 7. Failure to establish adequate labeling procedures

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FDA GMP Investigations
y Here are the top items an FDA investigator looks for when a violation

occurs (courtesy MasterControl)

y Process understanding and control y companies must be able to demonstrate process validity at any time y consistency of product quality y extensive documentation including test results, process deviations, complaints, etc. y Reaction to violations y investigation of full scope of violation
y

for example, have other batches been affected

y

corrective and preventive measures

y Laboratory operations y sample accountability y control and validation are processes well-defined and routinely followed y reaction to out-of-spec laboratory results (see above) y GMP Training (initial and continuing) y training level and adequate number of trained personnel

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Improve Company Culture
y Company culture is critical for preventing violations

(courtesy MasterControl)
y Don t wait for FDA to tell you what to do y Have a defensible system for making decisions and developing y y y y

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!

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y The Spring Case Study2008 heparin contamination problem demonstrates the importance of these topics
y Neither US distributor nor China supplier performed proper Acceptance Activities y Distributor blames manufacturer y FDA believes manufacturer did not monitor suppliers properly y Manufacturer blames suppliers, not itself y China upstream suppliers are small and unregistered y Because of this, there was no detection of Nonconforming Product y Neither individual testing nor investigation full scope of problem was conducted, therefore there was no opportunity to reject product or rework supply chain y This resulted in a Violation...but where/how did it occur? y There was a cultural and regulatory disconnect between US and Chinese regulators and supply chains y The exact cause and starting point of problem is still under investigation y 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
y

International, global industry makes this even more critical

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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

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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

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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

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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

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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

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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

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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

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