GOOD MANUFACTURING PRACTICES IN A QUALITY WORLD

1
GOOD MANUFACTURING PRACTICESIN A QUALITY WORLD

• Gordon Harnack
• President, Oracle Consulting Group
• Tucson, AZ

www.fdamaze.com
2
The Discussion Plan

• Definitions
• General Discussion
• Drugs Biologics
• Devices
• In Vitro Diagnostics
• Food
• Cosmetics
• GMP Specifics Device GMPs

3
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).
• http//en.wikipedia.org/wiki/Good_Manufacturing_Pr
  actice

4
What are Current Good Manufacturing Practices
(cGMP)?

• 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.
• www.sciteclabs.com/dictionary.html

5
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
  expectations
• Make management the chief jailable officer
• Absent GMP regulations fall back on FFDC Act!

6
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.

7
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
  products

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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.

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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

10
Drug GMPs Apply to

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

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Drug GMPs

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

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Drug GMPs (continued)

• Applicability
• GMP of s 210 226 s 600 680 supplement
  not supersede each other, unless otherwise
  directed
• Compliance failures ? adulterated drug product

13
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.

14
Drug GMPs (continued)

• GMP Regulations specific to CBER regulated
  products
• 21 CFR 606 Current GMP for blood blood
  products
• 21 CFR 610 General biological products
  standards
• 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

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Medical Device GMPs

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

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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
  example
• Many Class I devices, like tongue depressors,
  are typically exempted from all GMPs except
  records (820.180) complaint files (820.198).

17
In Vitro Devices GMPs

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

18
Cosmetic GMPs No Specific GMP Regulations

• Regulated under the FFDC Act for
• Labeling
• Ingredients
• Contaminants
• Processing
• Packaging, or
• Shipping and handling

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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

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Now a Close Examination of Medical Device GMPs
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What Types of Firms are Subject to Device GMPs?

• Remanufacturers
• Custom Device Manufacturers
• Contract Manufacturers
• Contract Testing Labs
• Repackagers, Relabelers Specification
  Developers
• Manufacturers of Accessories
• Initial Distributors

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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

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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

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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

25
Quality System Controls

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

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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

27
Design Controls

• Planning
• Requirements
• Specifications
• Verification
• Validation

• Change Control
• Review
• Transfer
• Design History File (DHF)

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Design Risk Analysis

• Safety requirements should be commensurate with
  the hazards that can result from a system
  failure.
• 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

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Human Factors in Device Design

• FDA's site on human factors www.fda.gov/cdrh/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
• www.agilisconsulting.com/pdf/HumanFactorsandthePro
  ductDevelopmentProcess.pdf

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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.

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Document Data Controls

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

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Purchasing Controls

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

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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

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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

35
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

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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

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Production Process Controls (continued)

• EMP to prevent contamination of equipment or
  product
• Provide buildings of suitable design with
  sufficient space to perform necessary operations,
  prevent mix-ups assure orderly handling

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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

39
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

40
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

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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

42
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

43
Label, Labeling Packaging

• EMP to control labeling activities, including
  label
• Integrity
• Inspection
• Storage
• Operations
• Control number

44
Packaging

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

45
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

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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
  processes..

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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

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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

49
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

50
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
  problems
• Ensuring information identified is disseminated
  to all appropriate individuals
• Submitting records for management review

51
Handling, Storage, Preservation Delivery
Controls

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

52
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
  distributed
• Maintain distribution records that ID
• Name address of initial consignee
• Date, ID quantity of devices shipped
• Any control numbers used

53
Quality Record Controls

• All required records shall be maintained at the
  manufacturing location or other location that is
  reasonably accessible for FDA inspection, review
  copying
• 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

54
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

55
Quality Records Device Master Record (DMR)

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

56
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

57
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
  appropriately

58
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

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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
  regulations
• Reports shall include
• Name, date, ID any control of devices
  serviced
• Individual performing service service performed
• Any test inspection data

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Complaint Handling Controls

• EMP for
• Receiving, reviewing evaluating complaints by a
  FORMALLY DESIGNATED UNIT
• 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

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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

62
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
  unnecessary
• 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

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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

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Statistical Technique Controls

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

65
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

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One Final Note

• FDA is NOT ALWAYS RIGHT!
• 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
  mis-step.

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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

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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.

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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.

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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.

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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.

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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

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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
  (QSR).

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Questions

• ?

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Abbreviations Used

• - Paragraph
• APIs - Active pharmaceutical ingredients
• CAPA Corrective Action Preventive Action
• CBER Center for Biologics Research
  Development
• 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
  (Act)
• FMEA Failure Mode Effects Analysis
• EMP Establish maintain procedures
• GMP Good Manufacturing Practice
• ID - Identification
• ISO Acronym for International Standards
  Organization
• 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