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GOOD MANUFACTURING PRACTICES IN A QUALITY WORLD Gordon Harnack President, Oracle Consulting Group Tucson, AZ – PowerPoint PPT presentation

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  • Gordon Harnack
  • President, Oracle Consulting Group
  • Tucson, AZ
The Discussion Plan
  • Definitions
  • General Discussion
  • Drugs Biologics
  • Devices
  • In Vitro Diagnostics
  • Food
  • Cosmetics
  • GMP Specifics Device GMPs

What are Good Manufacturing Practices (GMP)?
  • Good Manufacturing Practice regulation is a set
    of regulations, codes, and guidelines for the
    manufacture of drugs (known as medicinal products
    in Europe), medical devices, diagnostic products,
    foods products and Active Pharmaceutical
    Ingredients (APIs).
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What are Current Good Manufacturing Practices
  • Good Manufacturing Practice implemented in 1976
    for the manufacture of products that are under
    FDA jurisdiction, including pharmaceuticals,
    biological products and medical devices. Current
    Good Manufacturing Practice ensures that finished
    products have the correct identity, strength,
    quality and purity characteristics they are
    represented to have, and have not been altered
    during processing, packaging, or handling. It
    requires extensive use of documentation and
    strict reconciliation of inventory.

Why GMP Regulations?
  • The Federal Food, Drug Cosmetic Act authorizes
    such regulations
  • Title 21, Chapter 9, FFDC Act has 17 references
    to GMPs
  • FDAs mechanism to implement oversight of any
    manufacturing operation
  • Establishes FDAs minimal manufacturing control
  • Make management the chief jailable officer
  • Absent GMP regulations fall back on FFDC Act!

FDAS ExpectationsRelated to Firm Size
  • The larger the firm the greater FDA expectations
  • However, even the smallest firm MUST address
    every aspect of applicable FDA regulations.

What FDA Centers deal with Drug GMPs?
  • Center for Biologics Evaluation Research (CBER)
  • Center for Drug Evaluation Research (CDER)
  • Center for Veterinary Medicine (CVM)
  • CDER states Useful to manufacturers of
    components used in the manufacture of these

What Types of Firms are Exempt from Drug GMPs?
  • Drug wholesalers, retailers, pharmacies
    hospitals unless engaged in manufacturing
    operations beyond the usual dispensing or selling
    of drugs at retail
  • Compounders of drugs pharmacists physicians
  • Note Compounded drugs must still be composed of
    FDA approved components.
  • Note Some products are exempt from certain
    elements of Drug GMP.

What Types of Firms are Exempt from Drug GMP
Regulations? (cont)
  • Manufacturers of active pharmaceutical
    ingredients (APIs) bulk drugs are exempt from
    cGMP REGULATIONS but NOT cGMP requirements of the
    FFDC Act!
  • FDA cites API manufacturers for violations of the
    ACT, not drug GMP regulations
  • FDAs GMP regulations are used as guidance
    during inspections.
  • FDA claims to be working on specific API GMPs

Drug GMPs Apply to
  • Prescription OTC drugs, including homeopathic
  • Manufacturing facilities of ALL sizes
  • Investigational drugs for clinical trials
  • Foreign produced drugs distributed in the U.S.

Drug GMPs
  • 21 CFR 210 - cGMP in Manufacturing, Processing,
    or Holding of Drugs General
  • 21 CFR 211 - cGMP Practice for Finished
  • 21 CFR 210 211 300 shalls

Drug GMPs (continued)
  • Applicability
  • GMP of s 210 226 s 600 680 supplement
    not supersede each other, unless otherwise
  • Compliance failures ? adulterated drug product

Drug GMPs (continued)
  • Proposed new drug cGMPs will model FDAs intent
    to integrate QS RISK MANAGEMENT to harmonize
    with other non-drug regulatory systems ISO 9000
  • FDA states that a robust modern QS must embrace
    the concept that
  • Quality should be built into the product, and
    testing alone cannot be relied on to ensure
    product quality.

Drug GMPs (continued)
  • GMP Regulations specific to CBER regulated
  • 21 CFR 606 Current GMP for blood blood
  • 21 CFR 610 General biological products
  • 21 CFR 630 General requirements for blood,
    blood components blood derivatives
  • 21 CFR 640 Additional standards for human blood
    and blood products
  • 21 CFR 660 Additional standards for diagnostic
    substances for laboratory tests
  • 21 CFR 680 Additional standards for
    miscellaneous products

Medical Device GMPs
  • 21 CFR 820 - 200 shalls
  • Control each phase of manufacturing
  • Harmonized with ISO 9000
  • Greater emphasis on compliant handling,
    corrective preventive actions, labeling

What Types of Firms are Exempted from Device GMPs?
  • Component manufacturers
  • Note Some individual TYPES of devices are
    exempt from some elements of GMP regulations, for
  • Many Class I devices, like tongue depressors,
    are typically exempted from all GMPs except
    records (820.180) complaint files (820.198).

In Vitro Devices GMPs
  • 21 CFR 809 In vitro diagnostic products for
    human use - approximately 25 shalls

Cosmetic GMPs No Specific GMP Regulations
  • Regulated under the FFDC Act for
  • Labeling
  • Ingredients
  • Contaminants
  • Processing
  • Packaging, or
  • Shipping and handling

Current Good Food Manufacturing Practices
  • 21 CFR 110 approximately 95 shalls
  • Focus on
  • Sanitary/Unsanitary conditions
  • Personnel, Equipment Buildings
  • Production/Process Controls
  • Raw materials
  • Water
  • Storage
  • Warehousing distribution

Now a Close Examination of Medical Device GMPs
What Types of Firms are Subject to Device GMPs?
  • Remanufacturers
  • Custom Device Manufacturers
  • Contract Manufacturers
  • Contract Testing Labs
  • Repackagers, Relabelers Specification
  • Manufacturers of Accessories
  • Initial Distributors

Medical Device GMP20 Elements
  • Labels Labeling
  • Acceptance controls
  • Non-conforming product controls
  • Corrective preventive action controls
  • Handling, storage, packaging, preservation
    delivery controls
  • Quality record controls
  • Installation Servicing controls
  • Complaint Handling controls
  • Statistical technique controls
  • Management responsibility
  • Quality system controls
  • Training controls
  • Design/Development controls
  • Document data controls
  • Purchasing controls
  • Product identification traceability controls
  • Process and manufacturing controls
  • Inspection testing controls
  • Inspection, measuring, test equipment controls
  • Process Validation

Management Controls
  • Management shall
  • Establish its policy and objectives for, and
    commitment to quality
  • Policy is understood
  • Implemented
  • Maintained at all levels
  • Establish maintain adequate organizational
    structure ensuring that devices are designed
    produced in regulatory compliance
  • Establish maintain appropriate responsibility,
    authority interrelations of all personnel
  • Provide adequate resources
  • Appoint a Management Representative

Management Controls (continued)
  • Management shall
  • Require the Management Representative to review
    the suitability effectiveness of the QS at
    defined intervals to ensure
  • Establish a quality plan that defines quality
    practices, resources activities
  • Establish how requirements for quality are met.
  • Establish maintain QS procedures

Quality System Controls
  • Establish procedures for quality audits
  • Sufficient personnel with necessary education,
    background, training experience to

Training Controls
  • Establish procedures to identify training needs
    ensure all personnel are trained to adequately
    perform their assigned responsibilities
  • Personnel shall be made aware of device defects
    which may occur from improper performance
  • Personnel performing verification/validation
    activities shall be made aware of defects
    errors that may be encountered

Design Controls
  • Planning
  • Requirements
  • Specifications
  • Verification
  • Validation
  • Change Control
  • Review
  • Transfer
  • Design History File (DHF)

Design Risk Analysis
  • Safety requirements should be commensurate with
    the hazards that can result from a system
  • FDA expects that all individual hazards,
    including SW, be identified and either eliminated
    or reduced to acceptable levels during the
    devices design development
  • FMEAs Fault Trees

Human Factors in Device Design
  • FDA's site on human factors
  • See Fitting Human Factors in the Product
    Development Process published in the January
    2006 Medical Device Diagnostic Industry
    magazine available as a pdf

What are Human Factors?
  • Human factors (HF) is the study of how people use
    technology. The interaction of human abilities,
    expectations, and limitations, with work
    environments and system design.
  • The term human factors engineering (HFE) refers
    to the application of human factors principles to
    the design of devices and systems. It is often
    interchanged with the terms "human engineering,"
    "usability engineering," or "ergonomics."
  • The goal of HFE is to design devices that users
    accept willingly and operate safely in realistic
    conditions. In medical applications, HFE helps
    improve human performance and reduce the risks
    associated with use error.
  • In many cases, HFE focuses on the device user
    interface (also called the UI or the man-machine
    interface). The user interface includes all
    components and accessories necessary to operate
    and properly maintain the device, including the
    controls, displays, software, logic of operation,
    labels, and instructions.

Document Data Controls
  • Establish Maintain procedures (EMP) to control
    ALL documents required by regulationsincluding
  • Document review, approval distribution
  • Document changes

Purchasing Controls
  • EMP to ensure that ALL purchased or otherwise
    received product services conform to SPECIFIED
  • Evaluation of suppliers, contractors
  • Establish maintain data that clearly describe
    or reference SPECIFIED REQUIREMENTSincluding
    quality requirements

Product ID Traceability Controls
  • EMP for identifying product during ALL stages of
    receipt, production, distribution installation
  • Devices intended for surgical implant, life
    sustaining or supportingwhose failure when
    properly used can be expected to result in
    significant injury shall be identified with a
    control number

Process Manufacturing Controls
  • Manufacturer shall develop, conduct, control
    monitor production processes to ensure that a
    device conforms specifications
  • Establish maintain process control procedures
    that describe all necessary controls

Production Process Controls (continued)
  • Process controls shall include
  • Documented instructions, SOPs, methods that
    define control production
  • Monitoring control of process parameters,
    component device characteristics
  • Compliance with specified standards or codes
  • Approval of processes equipment
  • Criteria for workmanship expressed in documented
    standards or by identified approved samples

Production Process Controls (continued)
  • EMP to control ALL changes to specifications,
    methods, processes or procedures
  • Where environmental conditions can have any
    adverse effect on product qualityEMP to
    adequately control those conditions
  • EMP for health, cleanliness, personnel practices
    clothing of personnel

Production Process Controls (continued)
  • EMP to prevent contamination of equipment or
  • Provide buildings of suitable design with
    sufficient space to perform necessary operations,
    prevent mix-ups assure orderly handling

Production Process Controls (continued)
  • Ensure that ALL equipment used in manufacturing
    process meets its specified requirements
  • Equipment is properly installed, maintained,
    adjusted, cleaned used
  • Establish maintain schedules for equipment
    adjustment, cleaning or other maintenance
  • Conduct periodic inspections
  • Ensure limitations/tolerances are posted

Production Process Controls (continued)
  • Where manufacturing material could be expected to
    have adverse effectsEMP for the use removal of
    those materials
  • Validate any computers or automated data
    processing systems used

Inspection Testing Controls
  • Manufacturers shall ensure that ALL inspection,
    measuring test equipment is suitable is
    capable of producing valid results
  • EMP to ensure equipment is routinely calibrated,
    inspected, checked maintained

Inspection, Measuring Test Equipment Controls
  • Calibration procedures shall include specific
    directions limits for accuracy precision
  • Accuracy precision failures shall require
    remedial action to reestablish the limits
    assess adverse effect(s) on product quality
  • Calibration standards used shall be traceable
  • Calibration records shall include equipment ID,
    dates, individuals, the next calibration date

Process Validation
  • Where the results of processes cannot be FULLY
    verified by inspection test, the process shall
    be validated according to established procedures
  • EMP to monitor control validated process
    parameters, controlling
  • Personnel, records changes

Label, Labeling Packaging
  • EMP to control labeling activities, including
  • Integrity
  • Inspection
  • Storage
  • Operations
  • Control number

  • Manufacturer shall ensure that packaging
    shipping containers are designed constructed to
    protect the device from alteration or damage

Acceptance Controls
  • EMP for inspections, tests or other verifications
    as acceptance of
  • Incoming product against specified requirements
  • In-process product against specified requirements
  • Finished devices to ensure EACH production run,
    lot or batch meets acceptance criteria

Acceptance Controls (continued)
  • Manufacturer shall
  • Document acceptance activities, including
  • Activities performed
  • Dates
  • Results
  • Signatures of individuals
  • If appropriate, equipment used
  • Identify acceptance status throughout the

Non-conforming Product Controls
  • EMP to control non-conforming product (NCP)
  • Procedures shall control ID, documentation,
    evaluation, segregation disposition of NCP
  • Evaluation shall include determining any need for
    an investigation the persons/organizations
    responsible for the NCP

NCP Controls (continued)
  • EMP that define the responsibility for review
    the authority for the disposition of NCP
  • Procedures shall control
  • Reviews dispositions
  • Records shall document any justification for use
    of NCP signatures of authorizers
  • Rework shall include appropriate retesting,
    reevaluation adverse effects assessment to
    ensure the product meets specifications

Corrective Preventive Action Controls
  • EMP for implementing CAPAs, including
  • Analyzing processes, work ops, concessions,
    audits, records, complaints, returns, other
    sources of quality data
  • Use of appropriate statistical methods
  • Investigating nonconformances to product
    processes the QS
  • Identifying action(s) needed to correct or
    prevent recurrence of nonconformances

CAPA Controls (continued)
  • CAPA procedures shall require
  • Verification or validation of CAPAs to ensure
    their effectiveness that they do not adversely
    affect the finished device
  • Implementing recording changes in methods
    procedures needed to correct prevent quality
  • Ensuring information identified is disseminated
    to all appropriate individuals
  • Submitting records for management review

Handling, Storage, Preservation Delivery
  • EMP to
  • Control storage areas to prevent mix-ups, damage,
    deterioration, contamination or other adverse
  • Control product requiring stock rotation
  • Control receipt from dispatch to storage areas

Delivery Controls
  • EMP to
  • Ensure only approved devices are released
  • POs are reviewed to ensure ambiguities errors
    are resolved
  • Ensure stock that deteriorates over time is
    properly controlled expired devices are not
  • Maintain distribution records that ID
  • Name address of initial consignee
  • Date, ID quantity of devices shipped
  • Any control numbers used

Quality Record Controls
  • All required records shall be maintained at the
    manufacturing location or other location that is
    reasonably accessible for FDA inspection, review
  • Records deemed confidential may be so marked
  • All required records shall be retained for the
    devices expected life but in no case less than
    2 years from the date of release

Quality Records Quality System Records (QSR)
  • Manufacturers shall maintain a quality system
    record (QSR) that includes
  • Procedures and records of activities required by
    FDA regulation that are not specific to a
    particular type of device, including
  • SOP creation numbering SOPs
  • Training SOPs and records
  • Purchasing SOPs and records
  • Supplier assessment SOPs and records

Quality Records Device Master Record (DMR)
  • Maintain an approved DMR, including
  • Device specifications drawings, composition,
    formulation, component specifications SW
  • Product process specifications equipment specs,
    production methods, production SOPs
    environmental specs
  • QA SOPs, QA specs, acceptance criteria QA
  • Packaging labeling specs, methods
  • Installation, maintenance servicing SOPs

Quality Records Device History Record (DHR)
  • EMP that ensure the DHR documents devices were
    manufactured in accordance with the DMR FDA
    regulations, the DHR includes
  • Date(s) quantity of manufactured devices
  • Quantity released for distribution
  • Acceptance records
  • Primary ID label labeling
  • Any device ID control number(s) used

Installation Servicing Controls
  • EMP for adequate installation, inspection
    instructions any needed test activities
  • Procedures shall ensure proper installation
    device performance after installation
  • Installation SOPs shall be distributed

Installation Servicing Controls
  • Procedures shall require
  • Installation personnel perform any required
    testing in accordance with manufacturers
    instructions document the inspection testing
    to demonstrate proper installation
  • Specified servicing requirements follow
    established maintained SOPs that require
    servicing meets specified requirements
  • Service reports are analyzed with appropriate
    statistical methods

Servicing Controls
  • Service reports that represent an event that must
    be reported to FDA under MDR regulations shall
    automatically be considered a complaint handled
    in accordance with FDA complaint handling
  • Reports shall include
  • Name, date, ID any control of devices
  • Individual performing service service performed
  • Any test inspection data

Complaint Handling Controls
  • EMP for
  • Receiving, reviewing evaluating complaints by a
  • Complaints shall be
  • Processed in a uniform timely manner
  • Oral (complaints) documented upon receipt
  • Evaluated to determine if complaint represents an
    MDR event requiring reporting

Complaint Handling Controls (continued)
  • Manufacturers shall
  • Review evaluate all complaints to determine if
    an investigation is necessary
  • If a determination is made that no investigation
    is required, a record of shall be made that IDs
    the reason the individual making the decision

Complaint Handling Controls (continued)
  • Complaints involving device failures to meet ANY
    specification shall be
  • Reviewed, evaluated investigated unless such
    investigation has already been performed for a
    similar complaint another investigation is
  • Documented to show a determination of
  • Whether the device failed to meet specifications
  • Whether the device was being used for treatment
    or diagnosis
  • Any relationship to any device to any reported
    incident or adverse event

Complaint Handling Controls (continued)
  • Complaint investigation records shall include
  • Device name date complaint received
  • Device ID control s used
  • Name, address phone of complainant
  • Nature details of complaint
  • Dates results of investigation
  • Any corrective action taken
  • Any reply to complainant

Statistical Technique Controls
  • Where appropriate, EMP for
  • Identifying valid statistical techniques required
    for establishing, controlling verifying the
    acceptability of process capability and product
  • Sampling plans, when used, shall be written
    based on valid rationale
  • Ensuring sampling methods are adequate for their
    intended use

Useful Tools in Understanding GMPs
  • Warning Letters Recall postings
  • Guidance Documents
  • Compliance Policy Guides (CPGs)
  • Compliance Program Guidance Manual (CPGM)
  • Guidance Documents for Regulated Industry
  • Regulatory Procedures Manual (RPM)
  • Investigations Operations Manual
  • Laboratory Information Bulletins
  • Laboratory Procedures Manual

One Final Note
  • The Agency is made up of PEOPLE, people with
    strong convictions egos
  • The Agency is a bureaucracy bureaucracies
    over-reach, over-state, over-react almost NEVER
    admit they are wrong
  • The following is an example of a bureaucratic

One Final Note (continued)
  • Between 2001 2004 Utah Medical was cited by FDA
    for a number of GMP violations
  • August 2004 FDA sought a Permanent Injunction to
    stop the firm from manufacturing distributing
    medical devices UNTIL the firm DEMONSTRATED
    corrections in deviations from GMPs
  • "FDA will not tolerate manufacturing practices
    that can potentially put patients at risk," said
    FDA Acting Commissioner Dr. Lester M. Crawford

One Final Note (continued)
  • FDAs injunction followed three years of FDA
    inspections that FDA claimed revealed a pattern
    of significant deviations from the Quality System
    regulation at Utah Medical's Midvale facility.
  • FDA claimed Utah Medical has consistently failed
    to ensure that its products are manufactured in
    accordance with the Quality System regulation.

One Final Note (continued)
  • On Oct 21, 2005 Federal Judge Bruce Jenkins found
    stated This is an unusual case. The safety of
    the products manufactured by Utah Medical has
    never been at issue.

One Final Note (continued)
  • The judge noted that Even though product safety
    is a non-issue, the relief originally sought by
    the United States was to stop Utah Medicals
    products from entering commerce because of
    alleged persistent deficiencies of Utah Medical
    in complying with the applicable quality system
    regulations (21 CFR 820), and asserting that a
    failure to comply by definition produced an
    adulterated product and subjected the product and
    the persons responsible for the product to
    regulatory action.

One Final Note (continued)
  • Judge Jenkins went on to state In short, the
    United States asked that Utah Medical be ordered
    to stop the sale of product until Utah Medical
    complies with the regulation 21 CFR 820 and in
    a manner that has been found acceptable to FDA.
  • Further he stated The court has been impressed
    as well by Utah Medicals design of product, its
    record-keeping of each step along the way, the
    acceptance in the market of its products, the
    Companys uniform processing of complaints, and
    the manner in which change is made in practice
    and procedure as a result of complaint handling.

One Final Note (continued)
  • Judge Jenkins concluded It makes no sense for
    the court to order Utah Medical to do something
    they are already doing.
  • The Court disagreed with all allegations by the
    FDA, and dismissed the lawsuit filed in August
    2004 that sought to shut down UTMD, without any
    evidence of unsafe, ineffective, or defective
    products or products causing any patient harm,
    until UTMD complied with the FDAs interpretation
    of the QSR, an interpretation that was never
    provided to UTMD until after the lawsuit was filed

One Final Note ( continued)
  • The U.S. Federal District Court in Salt Lake City
    confirmed that UTMD is operating in compliance
    with 21 CFR 820, the U.S. Food Drug
    Administration (FDA) Quality System Regulation

  • ?

Abbreviations Used
  • - Paragraph
  • APIs - Active pharmaceutical ingredients
  • CAPA Corrective Action Preventive Action
  • CBER Center for Biologics Research
  • CDER Center for Drug Evaluation Research
  • CDRH Center for Devices Radiologic Health
  • CVM Center for Veterinary Medicine
  • CFR Code of Federal Regulations
  • cGMP Current Good Manufacturing Practice
  • CPGs Compliance Policy Guides
  • CPGM Compliance Program Guidance Manual
  • DHF Design History File
  • DHR Device History Record
  • DMR Device Master Record
  • FDA Food Drug Administration
  • FFDC or FFDC Federal Food Drug Compliance
  • FMEA Failure Mode Effects Analysis
  • EMP Establish maintain procedures
  • GMP Good Manufacturing Practice
  • ID - Identification
  • ISO Acronym for International Standards
  • IQ Installation Qualification
  • OC Operational Qualification
  • OTC Over the Counter
  • NCP Nonconforming Product
  • PQ Performance Qualification
  • QA Quality Assurance
  • QS Quality System
  • QSR Quality System Regulation
  • SOP Standard Operating Procedure
  • UTMD Utah Medical Device
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