gmp training

Good Manufacturing PracticeGMP Training- FDA Regulations

Searchtec Institutewww.Searchtecgroup.com

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Training OverviewThis 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 StructureThis training course is structured around four

learning modules and a final Certification Examination.Module 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 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 ObjectivesGain an understanding of the requirements of

GMPExamine real world case studies involving

GMPDevelop an understanding of how GMP

affects company successComplete Certification Examination

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GMP Implementation Is Critical For MDX To Maintain Our Dominant Market Position

Course AgendaModule 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 4 - Acceptance and Violations Certification Exam

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Module 1 OverviewThis 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 TermsComplaint - 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 (cont)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)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) CIAb) DHSc) DoDd) FDA

What area is not governed by GMP?a) Medical Devicesb) Food Industryc) Drug Industryd) Auto Industry

Why is GMP in place?a) Increase cost of businessb) Make life harderc) Ensure customers receive the best productd) 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 sterilizedTrue / 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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Module 2 OverviewThis module should take approximately one hour

to complete. It will cover the following topics:Quality SystemsIdentification & TraceabilityHandling, Storage, & DistributionRecord Keeping



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Quality System RequirementsThis section covers Subpart B - Quality System

RequirementsQuality 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 RequirementsManufacturer 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 RequirementsExecutives 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 TraceabilityThis section covers Subpart F, Identification

and TraceabilityTo prevent mix-ups, manufacturers must

maintain procedures for properly identifying products during all stages:receiptproductiondistributioninstallation

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Identification and TraceabilityTo ensure the safety of healthcare patients,

manufacturers shall maintain traceability for all devices and componentsMaintain ID proceduresControl number for each unit/lot/batchControl 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, & DistributionThis section covers Subpart L, Handling, Storage,

Distribution, and InstallationProcedures 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 KeepingThis 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 masterDevice historyQuality systemComplaint files

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Records KeepingGeneral requirements for records:

Records shall be kept at manufacturing area or nearby company location

Accessible to company officialsAccessible to FDAShall be properly stored to prevent

deterioration or shall be backed up if stored on company server

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Records KeepingConfidential records shall be properly

marked to aid FDA inspectorsRecords 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 KeepingUpon FDA request, manufacturing officials

shall be able at all times to produce records of all:Management reviewsQuality auditsSupplier auditsCorrective actions

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Records KeepingDevice Master Records (DMR’s) shall be

kept by each manufacturer and shall include the following:Device specs, drawings, compositions, and

formulationsProduction processes: equipment specs,

methods and procedures, and environmental specs

QA procedures and specsPackaging information and specsInstallation and maintenance procedures

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Records KeepingDevice History Records shall be kept and

include the following:Dates of manufacturerQuantities produced and releasedAcceptance recordsIdentification and labeling recordsControl numbers used for devices

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Records KeepingA 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 mannerOral complaints are properly documentedEvaluation to determine whether complaint needs to be

reported to FDAAny complaint concerning product failure is properly

evaluated

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

hit with a letter for multiple GMP ViolationsTwo 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) Organizationb) Establish authorityc) Provide resourcesd) Report earnings

A quality plan should be established which outlines all except:?a) Quality practicesb) Resourcesc) Activitiesd) Hiring goals

FDA CRF 21 is applicable to any furnished device intended for human use in the United States and Commonwealth of ________.a) Costa Ricab) Virgin Islandsc) Monacod) 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) organizationb) authorityc) resourcesd) policy

The company should be ______ and structured to ensure that devices are produced to the design intent.a) politicalb) resourcefulc) full-serviced) organized

________ should be established for those that manage, produce, and review devices.a) intentb) rulesc) awardsd) authority

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Module 2 Questions (3)________ are needed to establish the proper funding for training and quality assessment.

a) plansb) delegationc) serviced) resources

Executives should have management _________ with authority over the quality organization to report and asses the quality system.a) quizzesb) demandsc) oversightd) representatives

Established procedures should call for management _______of the quality system based on requirements outlined in the quality policy.a) authorityb) directionc) helpd) 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) reviewsb) inspectionc) assemblyd) 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) processb) inspectionc) handlingd) distribution

Procedures established by the manufacturer should be followed during the ________ of any device. a) planningb) distributionc) inspectiond) installation

Manufacturers shall create procedures for:a) Handling & Storageb) Distributionc) Installationd) 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) Communicationb) Distributionc) Processesd) Records

Records shall be kept at the _______ area or nearby company location.a) officeb) executivec) plannersd) manufacturing

Confidential Records shall be properly marked to aid _____inspectors.a) CIAb) FADc) LDSd) 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 devicea) Masterb) Planningc) Productd) Quality System

Device__________ shall contain the control numbers used for devices.a) reportsb) instructionsc) user manualsd) history records

True or False: Device history records contain information on quantities produced and releasedTrue / 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 locationb) Accessible to company officialsc) Accessible to FDAd) 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) 4b) 3c) 1d) 2

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Module 2 Questions (9)Device History Records shall be kept and include the following:

a) Dates of manufacturerb) Quantities produced and releasedc) Acceptance recordsd) All of the above

Any voiced concern about a products failure should be documented in a:a) Databaseb) Quality Reportc) Engineering Orderd) Complaint File

True or False: Records should be accessible to company officialsTrue / False


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Module 3 OverviewThis module should take approximately one hour

to complete. It will cover the following topics:Quality AuditsDesign, Document, and Purchasing ControlsProduction and Process ControlEnvironmental Control and Clean Rooms



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Quality AuditsThis section covers Subpart B, Quality AuditsEach 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 auditedDates and results of quality audits/re-audits are to be

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PersonnelThis 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 ControlsThis 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:

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Section Device868.681 Catheter, Tracheobronchial Suction.878.446 Glove, Surgeon's.880.676 Restraint, Protective.

892.565System, Applicator, Radionuclide, Manual.

892.574 Source, Radionuclide Teletherapy.

Design Development Planning and InputEach 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 Output and ReviewEach 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 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 ValidationEach 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

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Manufacturing Material and Automated ProcessesWhen 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 documentedWhen 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

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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 resultsEach 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

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Calibration of EquipmentCalibration 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

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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

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Labeling and Packaging ControlsThis section covers Subpart K, Labeling and Packaging

ControlsEach manufacturer shall establish and maintain procedures to

control labeling activitiesLabels 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 DHREach manufacturer shall store labeling in a manner that

provides proper identification and is designed to prevent mix-ups

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Labeling and PackagingEach manufacturer shall control labeling and

packaging operations to prevent labeling mix-upsThe label and labeling used for each production unit, lot, or

batch shall be documented in the DHRWhere 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

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Clean Room Controls / ContaminationThe 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 qualityOne 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

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Clean Room ClassesVarious 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 RoomsTwo 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

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Clean Room GowningOnly 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 frequently75

Clean Room Rules of ConductEmployees 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

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

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Case StudyFlu vaccination contamination: 2004Chiron 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 lotsChiron 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

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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 requirementsb) To determine the effectiveness of the quality systemc) To fix a known inefficiency in the manufacturing process

Who should conduct a quality audit?a) Employees directly responsible for the matters being auditedb) Managers directly responsible for the matters being auditedc) 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 overrunsb) Schedule changesc) Difficult personneld) 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 thefollowing?a) Some Class I devicesb) Class II devicesc) Class III devicesd) 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) Incompleteb) Ambiguousc) Conflictingd) 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 reviewedb) Needed Specialistsc) Individuals who do not have direct responsibility for the design stage being reviewedd) 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 Folderb) Designated Holding Fixturec) Design History Filterd) 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

fromunintended useb) Approved changes should be communicated to the appropriate personal in a timely mannerc) Each manufacturer should maintain records of changes to documentsd) 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 changeb) Identification of affected documentsc) Date that change request was initiatedd) Answers a and ce) Answers a and b

When purchasing materials or services, manufacturers only need to document the selection of:a) Suppliersb) Contractorsc) Consultantsd) All of the above

The main objective for traceability and identification requirements is to:a) Monitor inventoryb) Forecast material shortagesc) Ensure prompt deliveryd) 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 bodyb) The device has a high probability of being misplaced c) The device will be used to support/sustain lifed) All of the abovee) 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 mannerof productionb) Monitoring and control of process parameters and component and device characteristics during

productionc) Compliance with specified reference standards or codesd) 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

functionalityb) Inspection activities should be documented and reviewedc) Environmental controls should be open-loop as approved by the FDAd) All of the abovee) 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

specialenvironmental conditions:a) They do not need to receive appropriate trainingb) They can work unsupervisedc) 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 countb) Accommodate several work areasc) Ensure that clean rooms are located far away from sources of contaminationd) Perform necessary operations and prevent mix-ups

Which of the following is NOT true of the display of inherent limitations or allowable tolerances ofequipment:a) It can be posted near the equipmentb) It merely needs to be readily available to personnel performing adjustmentsd) 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 aspart of the production or quality system:a) Computer software should be validated for its intended use according to established protocolb) Software changes should always be validated before approval and issuancec) 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 thefollowing EXCEPT:a) Routinely calibratedb) Routinely inspectedc) Routinely maintainedd) Routinely operated

Which of the following is an item that should be documented and displayed after equipment is calibrated:

a) Original purchase dateb) Equipment manufacturerc) Allowable tolerancesd) 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 indefinitelyb) Accepted conditionallyc) Redesigned until inspection and test can be used for verificationd) 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 thelabeling for all of the following information EXCEPT:a) Correct expiration dateb) Control numberc) Storage instructionsd) Content

Air particles are significant because they can:a) Make the reading of instrumentation difficultb) Enter a product as an extraneous contaminantc) Act as a vehicle for microorganismsd) Answers a and be) 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 countb) A higher Clean Air Classification, lower air particle countc) A higher Clean Air Classification, higher air particle count

d) A lower Clean Air Classification, lower air particle count

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Module OverviewThis module should take approximately one hour

to complete. It will cover the following topics:Acceptance ActivitiesNonconforming ProductsCorrective and Preventative ActionsGMP ViolationsCase Study



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Acceptance ActivitiesThis section covers Subpart H, Acceptance

ActivitiesAcceptance 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

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Types of Acceptance ActivitiesAcceptance activities fall into 3 types,

corresponding to the manufacturing stageManufacturers must establish and maintain

acceptance procedures, and document activities and results, for each typeReceiving: 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

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Acceptance Records and StatusManufacturers 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 DHRManufacturers 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

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Nonconforming ProductThis section covers Subpart I, Nonconforming

ProductA product is nonconforming if it fails

acceptance criteria at any stageManufacturers must establish and maintain

procedures for control, review, disposition, and rework of non-conforming products

Procedures must address non-conforming productIdentificationDocumentationEvaluationSegregationDisposition

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Nonconforming Product Evaluation and DispositionNonconformance evaluation must include

Determination of need for investigationIdentification of person(s) responsible for the

noncomplianceNonconformance evaluation and any

investigation must be documentedDisposition procedures are required if the

nonconforming product is to be used or reworked

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Nonconforming Product DispositionDisposition procedures must define

Responsibility for nonconformance reviewAuthority for disposition

Disposition must be documentedJustification for use of productSignature 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

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Corrective & Preventive ActionThis section covers Subpart J, Corrective and

Preventive ActionManufacturers must establish and maintain

procedures for implementing corrective and preventive actionCorrective action means tasks undertaken to fix

current nonconformitiesPreventive action means tasks undertaken to predict

and forestall future nonconformitiesAll corrective and preventive activities and

results must be documented

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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

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GMP Violations21 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

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Most Common ViolationsHere is a list of the seven most common types of

GMP violations (courtesy Robert McClure):1. Failure to establish quality control unit procedures2. Failure to establish an adequate training program3. Failure to perform finished product testing4. Failure to properly calibrate testing equipment5. Failure to establish adequate written procedures for

production and process control6. Failure to establish adequate batch production records7. Failure to establish adequate labeling procedures

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FDA GMP InvestigationsHere 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

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Improve Company CultureCompany culture is critical for preventing

violations (courtesy MasterControl)Don’t wait for FDA to tell you what to doHave a defensible system for making decisions and

developing processes, based on good scienceImplement a continuous improvement processDaily mode of preparednessPredict and eliminate underlying systemic causes,

don’t focus on symptomsPreventive is better than corrective!

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Case Study The Spring 2008 heparin contamination problem demonstrates the importance of these topics 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

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Module 4 Questions (1)Acceptance ActivitiesWhich of the following is NOT a type of acceptance activity?

a) Finalb) In-Processc) Receivingd) Prototype

Which of the following is required for completion of In-Process acceptance?a) Production manager signoffb) Analysis of possible side effectsc) Labor union approvald) Cost-benefit reporte) Final acceptance

Which of the following acceptance criteria is NOT required for product release?a) Release is authorized by signature of a designated individualb) Associated data and documentation is reviewedc) Release authorization is datedd) Acceptance activities documented in DMR are completede) FDA inspection

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Module 4 Questions (2) Acceptance ActivitiesWhich of these is a product life stage that requires identification of acceptance activities?

a) Prototypingb) Operationc) Disposald) Designe) Packaging

Which of the following does NOT have to be included in acceptance documentation?a) Activities performedb) Datesc) Resultsd) Signature of the conducting individuale) Training record of conducting individual

Which of the following is NOT a project life stage requiring acceptance status?a) Manufacturingb) Packagingc) Labelingd) Servicinge) Marketing

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Module 4 Questions (3) Nonconforming ProductsWhich acceptance procedures for nonconforming products are NOT required?

a) Reviewb) Controlc) Dispositiond) Reworke) User identification

Acceptance procedures do NOT need to address nonconforming product:a) Identificationb) Documentationc) Evaluationd) Dispositione) Design

Nonconformance evaluation must include:a) Determination of need for investigationb) Identification of person(s) responsible for noncompliancec) Documentation of evaluation procedured) Documentation of any investigatione) All of the above

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Module 4 Questions (4) Nonconforming ProductsNonconforming product disposition procedures do NOT have to define:

a) Authority for dispositionb) Responsibility for nonconformance reviewc) Authorizing individual(s)d) Justification for use of producte) Reason for nonconformance

Rework procedures do NOT have to define:a) Identificationb) Documentationc) Evaluationd) Dispositione) Design

The following procedures do not have to be documented in the DHR:a) Reworkb) Reevaluation after reworkc) Determination of adverse effects due to reworkd) Destruction of reworked product

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Module 4 Questions (5)Corrective and Preventative Actions

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

Preventive actions must predict and forestall current nonconformities.TrueFalse

Corrective actions must fix current nonconformities.TrueFalse

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Module 4 Questions (6) Corrective and Preventative ActionsWhich of the following must always be documented:

a) Corrective action activitiesb) Corrective action resultsc) Preventive action activitiesd) Preventive action resultse) All of the above

Corrective and preventive action procedures must include:a) Analyzing sources of quality datab) Investigating the cause of nonconformitiesc) Verifying/validating actionsd) Implementing changes in procedurese) All of the above

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

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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 proceduresb) Failure to establish an adequate training programc) Failure to perform finished product testingd) Failure to properly calibrate testing equipmente) 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 controlb) Reaction to violations (scope of investigation)c) Laboratory operationsd) 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 scienceb) “Continuous improvement” processc) Daily mode of preparednessd) Predict and eliminate underlying systemic causes, don’t focus on symptomse) Document only noncompliance events, not routine processes

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Module 4 Questions (8)GMP ViolationsAll GMP violations are specifically listed in 21 CFR 820.

TrueFalse

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

All GMP violations are specifically listed in 21 CFR 820.TrueFalse

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

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