Upload
searchtec-consulting-group
View
163
Download
6
Embed Size (px)
DESCRIPTION
Call us for further information and or for future course offeringswww.searchtecgroup.com.Searchtec College InstituteMedical device Management Certificate Program
Citation preview
Good Manufacturing PracticeGMP Training- FDA Regulations
Searchtec Institutewww.Searchtecgroup.com
1
2
Training OverviewThis training course will teach you about the
implementation of Good Manufacturing Practice (GMP) regulations and requirements within the medical devices industry.
3
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
4
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.
5
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
6
GMP Implementation Is Critical For MDX To Maintain Our Dominant Market Position
7
Course AgendaModule 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 4 - Acceptance and Violations Certification Exam
8
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.
9
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
10
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
11
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
12
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
13
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.
14
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.
15
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.
16
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.
17
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.
18
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.
19
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)
20
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
21
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
22
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
23
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
24
25
GMP Training Module 2: Requirements
Course AgendaModule 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 4 - Acceptance and Violations Certification Exam
26
Module 2 OverviewThis module should take approximately one hour
to complete. It will cover the following topics:Quality SystemsIdentification & TraceabilityHandling, Storage, & DistributionRecord Keeping
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes, you may proceed to the 1-hour, 100 question certification exam.
27
28
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
29
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
30
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.
31
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
32
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.
33
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
34
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
35
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
36
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
37
Records KeepingUpon FDA request, manufacturing officials
shall be able at all times to produce records of all:Management reviewsQuality auditsSupplier auditsCorrective actions
38
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
39
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
40
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
41
42
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
43
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
44
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
45
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
46
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
47
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
48
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
49
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
50
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
51
Course AgendaModule 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 4 - Acceptance and Violations Certification Exam
52
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
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.
53
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
documented54
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
55
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:
56
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
57
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
58
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
59
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
60
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
61
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
62
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
63
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.
64
Contamination Control, Buildings, and Equipment To prevent contamination of equipment or product by substances that could have an adverse effect on product quality, each manufacturer shall establish and maintain procedures
Buildings shall be of suitable design and contain sufficient space in order to: Perform necessary operations Prevent mix-ups and assure orderly handling
Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use Schedules for the adjustment, cleaning, and other maintenance of
equipment should be developed to ensure that manufacturing specifications are met
Periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules shall be conducted
Any inherent limitations or allowable tolerances should be visibly posted on or near equipment requiring periodic adjustments or should be readily available to personnel performing adjustments
65
Manufacturing Material and Automated 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
66
Inspection, Measuring, and Test Equipment Each manufacturer shall ensure that all
inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid 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
67
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
68
Process Validation If results of a process cannot be fully verified by subsequent
inspection and test, a process should be validated with a high degree of assurance and approved according to established procedures Any such validation activities and results, the date and signature of the
individual(s) approving the validation should be documented Each manufacturer shall establish and maintain procedures for
monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met Each manufacturer shall ensure that validated processes are
performed by qualified individual(s) For validated processes, the monitoring and control methods and
data, the date performed, and the individual(s) performing the process or the major equipment used shall be documented
When changes or process deviations occur, the manufacturer shall review, evaluate, and document the process and perform revalidation where appropriate
69
Labeling and Packaging 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
70
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
71
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
72
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:
73
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
74
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
76
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
77
Module 3 Questions (1) Which of the following is NOT a reason for conducting quality audits?a) To assure that the quality system is in compliance with the established 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
78
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
79
Module 3 Questions (3) The purpose of design verification is best summarized as:a) Confirming that all manufacturing processes were performed.b) Confirming that the design selected best meets the customer’s needs.c) Confirming that design output meets the design input requirements
What does he acronym DHF stand for?a) Development History 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
80
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
81
Module 3 Questions (5) Control numbers are necessary for identification and traceability under what circumstances:a) The device will be surgically implanted into a 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
82
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
83
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
84
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
85
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
86
87
Course AgendaModule 1 - GMP OverviewModule 2 - Requirements Module 3 - ControlsModule 4 - Acceptance and Violations Certification Exam
88
Module OverviewThis module should take approximately one hour
to complete. It will cover the following topics:Acceptance ActivitiesNonconforming ProductsCorrective and Preventative ActionsGMP ViolationsCase Study
There will be a short 10 question quiz that follows.
Once you have completed all 4 modules and quizzes, you may proceed to the 1-hour, 100 question certification exam.
89
Acceptance 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
90
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
91
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
92
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
93
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
94
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
95
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
96
Corrective &Preventive Action Procedures
Corrective & Preventive Action procedures must include requirements for: Analyzing sources of quality data to identify causes of
nonconforming product, or other quality problems Investigating the cause of nonconformities relating to
product, processes, and the quality system Verifying or validating the corrective and/or preventive
actions Implementing and recording changes in methods and
procedures for correction and prevention of quality problems Ensuring that information related to quality problems or
nonconforming product is disseminated to those directly responsible for assuring product quality or preventing future quality problems
Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review
97
GMP 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
98
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
99
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
100
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!
101
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
102
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
103
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
104
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
105
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
106
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
107
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
108
Module 4 Questions (7)GMP Violations
Which if the following is not one of the most common violations (according to the class)::a) Failure to establish quality control unit 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
109
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
110