Premarket Testing and Validation

1
Premarket Testing and Validation

• Charles Lankford
• PharmaSys, Inc.
• 216 Towne Village Drive
• Cary, NC. 27513
• charles.lankford_at_pharma-sys.com

2
U S. Food and Drug Administration

• Scientific, regulatory, and public health agency
• oversees items accounting for 25 cents of every
  dollar spent by consumers.

• Jurisdiction
• most food products (other than meat and poultry)
• human and animal drugs
• therapeutic agents of biological origin
• medical devices
• radiation-emitting products for consumer,
  medical, and occupational use
• cosmetics
• animal feed

3
History of the FDA

• single chemist U.S. Department of Agriculture in
  1862
• Regulatory functions added in1906
• The Bureau of Chemistry's name changed to the
  Food, Drug, and Insecticide Administration in
  July 1927,
• nonregulatory research functions of the bureau
  were transferred elsewhere

4
Events Leading to Formation of FDA

• 1905 - Samuel Hopkins Adams 11 articles The
  Great American Fraud in Collier's Weekly.
• analyzed the contents of some of the country's
  most popular medicines.
• argued that many of the companies producing these
  medicines were making false claims about their
  products.
• some cases, these medicines were actually
  damaging the health of those people using them
• 1906 - Upton Sinclair The Jungle
• fictional portrait of life and death of working
  class immigrates in turn-of-the-century Chicago
• filled with page after page of nauseating detail
  he had researched about the meat-packing industry
  
• Public demanded sweeping reforms in the food
  industry
• 30 June 1906 President Roosevelt signed the Food
  and Drugs Act, known simply as the Wiley Act.

5
1906 Food and Drugs Act

• Prohibited interstate transport of unlawful food
  and drugs under penalty of seizure of the
  questionable products and/or prosecution of the
  responsible parties
• Basis on regulation of product labeling rather
  than pre-market approval
• Drugs, defined in accordance with the standards
  of strength, quality, and purity in the United
  States Pharmacopoeia and the National Formulary,
  could not be sold in any other condition unless
  the specific variations from the applicable
  standards were plainly stated on the label

6
1906 Food and Drugs Act

• Foods were not defined according to analogous
  standards, but the law prohibited the addition of
  any ingredients that would substitute for the
  food, conceal damage, pose a health hazard, or
  constitute a filthy or decomposed substance
• If the manufacturer opted to list the weight or
  measure of a food, this had to be done accurately
  
• The food or drug label could not be false or
  misleading in any particular, and the presence
  and amount of eleven dangerous ingredients,
  including alcohol, heroin, and cocaine, had to be
  listed

7
1911

• Supreme Court ruled that the law did not--apply
  to false therapeutic claims.

8
The 1938 Food, Drug, and Cosmetic Act

• A Tennessee drug company marketed a form of the
  new sulfa wonder drug, Sulfanilamide, a drug used
  to treat streptococcal infections, that would
  appeal to pediatric patients, Elixir
  Sulfanilamide.
• 100 people in 15 states died, many were children
• Dissolved in diethylene glycol, a highly toxic
  chemical analogue of antifreeze
• Not tested for toxicity food and drugs law did
  not require safety studies for new drugs

9
The 1938 Food, Drug, and Cosmetic Act

• legally mandated quality and identity standards
  for foods
• prohibition of false therapeutic claims for drugs
  
• coverage of cosmetics and medical devices
• clarification of the FDA's right to conduct
  factory inspections
• control of product advertising, among other items

10
Kefauver-Harris Amendments

• Thalidomide, chiefly sold and prescribed during
  the late 1950s and 1960s to pregnant women, as an
  antiemetic to combat morning sickness and as an
  aid to help them sleep
• Drug stunted the growth of fetal arms and legs,
  10,000 babies affected, never approved in US
• Now approved for the treatment of MULTIPLE
  MYELOMA and ERYTHEMA NODOSUM LEPROSUM
• Resulted in Kefauver-Harris Amendments

11
Kefauver-Harris Amendments

• mandates efficacy safety before a drug could be
  marketed
• requires FDA to assess the efficacy of all drugs
  introduced since 1938,
• institutes stricter agency control over drug
  trials (including a requirement that patients
  involved must give their informed consent)
• transferred from the Federal Trade Commission to
  the FDA regulation of prescription drug
  advertising,
• established good manufacturing practices by the
  drug industry
• granted the FDA greater powers to access company
  production and control records to verify those
  practices

12
Drug or Device Deemed Adulterated if

• If it consists in whole or in part of any filthy,
  putrid, or decomposed substance

13
Drug or Device Deemed Adulterated if

• prepared, packed, or held under insanitary
  conditions
• do not conform to or are not operated or
  administered in conformity with current good
  manufacturing practice
• are not operated or administered in conformity
  with the positron emission tomography compounding
  standards and the official monographs of the
  United States Pharmacopoeia

14
Drug or Device Deemed Adulterated if

• composed, in whole or in part, of any poisonous
  or deleterious substance
• a color additive which is unsafe
• animal feed bearing or containing a new animal
  drug, and such animal feed is unsafe

15
Drug or Device Deemed Adulterated if

• strength differs from, or its quality or purity
  falls below, the standards
• strength, quality, or purity shall be made in
  accordance with the tests or methods of assay set
  forth in such compendium

16
Drug or Device Deemed Adulterated if

• mixed or packed therewith so as to reduce its
  quality or strength or
• substituted wholly or in part

17
PART 211 DRUG GMP

• A--General Provisions    
• B--Organization and Personnel    
• C--Buildings and Facilities
• D--Equipment
• E--Control of Components and Drug Product
  Containers and Closures    
• F--Production and Process Controls

• G--Packaging and Labeling Control
• H--Holding and Distribution    
• I--Laboratory Controls
• Subpart J--Records and Reports
• K--Returned and Salvaged Drug Products

18
Part 820 Device QSR

• A--General Provisions
• B--Quality System Requirements    
• C--Design Controls    
• D--Document Controls    
• E--Purchasing Controls

•  F--Identification and Traceability    
• G--Production and Process Controls  
• H--Acceptance Activities    

19
Part 820 Device QSR

• I--Nonconforming Product    
• J--Corrective and Preventive Action    
• K--Labeling and Packaging Control
• K--Labeling and Packaging Control   

•  L--Handling, Storage, Distribution, and
  Installation    
• MRecords    
• NServicing   
• O--Statistical Techniques

20
FDA Documentation

• Regulation Codified and Law
• Preamble Dialog of FDAs thinking when reg was
  codified
• Guidance - FDAs current thinking about reg

21
GCP and Clinical Trials

• Electronic Records Electronic Signatures (21 CFR
  Part 11)
• Human Subject Protection (Informed Consent) (21
  CFR Part 50)
• Additional Safeguards for Children in Clinical
  Investigations of FDA-Regulated Products (Interim
  Rule) (21 CFR Part 50, subpart D)
• Financial Disclosure by Clinical Investigators
  (21 CFR Part 54)
• Institutional Review Boards (21 CFR Part 56)

22
GCP and Clinical Trials

• Forms 1571 (Investigational New Drug Application)
  and 1572 (Statement of Investigator)
• Applications for FDA Approval to Market a New
  Drug (21 CFR Part 314)
• Applications for FDA Approval of a Biologic
  License (21 CFR Part 601)
• Investigational Device Exemptions (21 CFR Part
  812)
• Premarket Approval of Medical Devices (21 CFR
  Part 814

23
Drug Approval Process
24
Drug Development and Approval Process

• U.S. system most rigorous in the world
• On average, it costs a company 360 million to
  get one new medicine from the laboratory to the
  pharmacist's shelf
• It takes 12 years on average for an experimental
  drug to travel from lab to medicine chest.
• Only five in 5,000 compounds that enter
  preclinical testing make it to human testing.
• One of these five tested in people is approved.

25
Biological Screening and Pharmacological Testing

• Studies to explore the pharmacological activity
  and therapeutic potential of compounds.
• animals, isolated cell cultures and tissues,
  enzymes and cloned receptor sites as well as
  computer models.

26
Pharmaceutical Dosage Formulation and Stability
Testing

• The process of turning an active compound into a
  form and strength suitable for human use .

27
Toxicology and Safety Testing

• Tests to determine the potential risk a compound
  poses to man and the environment
• These studies involve the use of animals, tissue
  cultures, and other test systems to examine the
  relationship between factors such as dose level,
  frequency of administration, and duration of
  exposure to both the short- and long-term
  survival of living organisms.
• LD50

28
Regulatory Review Investigational New Drug (IND)
Application

• An application filed with the U.S. FDA prior to
  human testing.
• The IND application is a compilation of all known
  information about the compound. It also includes
  a description of the clinical research plan for
  the product and the specific protocol for phase I
  study.
• Unless the FDA says no, the IND is automatically
  approved after 30 days and clinical tests can
  begin.

29
Phase I Clinical Evaluation

• The first testing of a new compound in human
  subjects, for the purpose of establishing the
  tolerance of healthy human subjects at different
  doses
• defining its pharmacologic effects at anticipated
  therapeutic levels
• studying its absorption, distribution,
  metabolism, and excretion patterns in humans

30
Phase II Clinical Evaluation

• Controlled clinical trials of a compound's
  potential usefulness and short term risks.
• A relatively small number of patients, usually no
  more than several hundred subjects, enrolled in
  phase II studies.

31
Phase III Clinical Evaluation

• Controlled and uncontrolled clinical trials of a
  drug's safety and effectiveness in hospital and
  outpatient settings.
• gather precise information on the drug's
  effectiveness
• determine adverse effects
• identify the best way of administering and using
• phase III studies can involve several hundred to
  several thousand subjects.

32
Institutional Review Boards

• used to ensure the rights and welfare of people
  participating in clinical trials both before and
  during their trial participation.
• make sure that participants are fully informed
  and have given their written consent before
  studies ever begin.
• monitored by the FDA to protect and ensure the
  safety of participants in medical research.
• An IRB must be composed of no less than five
  experts and lay people with varying backgrounds
  to ensure a complete and adequate review of
  activities commonly conducted by research
  institutions.
• In addition to possessing the professional
  competence needed to review specific activities,
  an IRB must be able to ascertain the
  acceptability of applications and proposals in
  terms of institutional commitments and
  regulations, applicable law, standards of
  professional conduct and practice, and community
  attitudes.
• Therefore, IRBs must be composed of people whose
  concerns are in relevant areas.

33
Bioavailability Studies

• The use of healthy volunteers to document the
  rate of absorption and excretion from the body of
  a compound's active ingredients.
• Companies conduct bioavailability studies both at
  the beginning of human testing and just prior to
  marketing to show that the formulation used to
  demonstrate safety and efficacy in clinical
  trials is equivalent to the product that will be
  distributed for sale.
• Companies also conduct bioavailability studies on
  marketed products whenever they change the method
  used to administer the drug (e.g., from injection
  or oral dose form), the composition of the drug,
  the concentration of the active ingredient, or
  the manufacturing process used to produce the
  drug.

34
Process Development for Manufacturing and Quality
Control (CMC)

• Engineering and manufacturing design activities
  to establish a company's capacity to produce a
  product in large volume and development of
  procedures to ensure chemical stability,
  batch-to-batch uniformity, and overall product
  quality.

35
Regulatory Review New Drug Application (NDA)

• An application to the FDA for approval to market
  a new drug. All information about the drug
  gathered during the drug discovery and
  development process is assembled in the NDA.
• During the review period, the FDA may ask the
  company for additional information about the
  product or seek clarification of the data
  contained in the application.

36
Postapproval Research

• Adverse events must be reported
• Additional indications

37
Basic Regulatory Requirements for Medical Devices

• Premarket Notification 510(k), unless exempt, or
  Premarket Approval (PMA)
• Establishment registration on form FDA-2891
• Medical Device Listing on form FDA-2892
• Quality System (QS) regulation
• Labeling requirements
• Medical Device Reporting (MDR)

38
Premarket Notification 510(k) - 21 CFR Part 807
Subpart E

• If device requires the submission,
• can not commercially distribute until you
  receive a letter of substantial equivalence from
  FDA authorizing you to do so.

39
Premarket Notification 510(k) - 21 CFR Part 807
Subpart E

• A 510(k) must demonstrate that the device is
  substantially equivalent to one legally in
  commercial distribution
• Application fee applies to Traditional,
  Abbreviated, and Special 510(k)s. Small
  businesses may pay smaller fee.

40
Premarket Notification 510(k) - 21 CFR Part 807
Subpart E

• Most Class I devices and some Class II devices
  are exempt
• A list of exempt devices is located at
  http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
  cfpcd/315.cfm

41
Premarket Approval (PMA) - 21 CFR Part 814

• Product requiring PMAs
• Class III devices, high risk devices, pose a
  significant risk of illness or injury
• devices found not substantially equivalent to
  Class I and II predicate

42
Premarket Approval (PMA) - 21 CFR Part 814

• PMA process is more involved
• includes the submission of clinical data to
  support claims made for the device.
• The PMA is an actual approval of the device by
  FDA.
• Medical device user fees apply to original PMAs
  and certain types of PMA supplements.

43
Investigational Device Exemption (IDE) - 21CFR
Part 812

• Clinical studies with devices of significant risk
  must be approved by FDA and by an Institutional
  Review Board (IRB) before the study can begin.
• Studies with devices of nonsignificant risk must
  be approved by the IRB only

44
Establishment Registration form FDA-2891 - 21 CFR
Part 807

• Manufacturers must register their establishments
  with the FDA
• Once a year, FDA sends the registration form
  FDA-2891(a) to all registered firms to be
  verified, corrected, and returned by the firm as
  a yearly registration
• foreign manufacturers must also designate a U.S.
  Agent

45
Medical Device Listing form FDA-2892 - 21CFR Part
807

• All medical devices are required to be listed
  with the
• Firms that are required to list their devices are
  those that
• manufacture,
• repackage and relabel,
• develop specifications,
• reprocess single-use devices,
• remanufacture
• manufacture accessories and components sold
  directly to the end user

46
Labeling - 21 CFR Part 801

• Labeling includes labels on the device as well as
  descriptive and informational literature that
  accompanies the device. Labeling requirements can
  be accessed on the web at http//www.fda.gov/cdrh
  /devadvice/33.html

47
Medical Device Reporting - 21 CFR Part 803

• Incidents in which a device may have caused or
  contributed to a death or serious injury must to
  be reported to FDA under the Medical Device
  Reporting program.
• The MDR regulation is a mechanism for FDA and
  manufacturers to identify and monitor significant
  adverse events involving medical devices. The
  goals of the regulation are to detect and correct
  problems in a timely manner.

48
Medical Device Classification

• classifications for approximately 1,700 different
  generic types of devices
• three regulatory classes based on the level of
  control necessary to assure the safety and
  effectiveness of the device.

49
Device Class and Regulatory Controls

• Class I General Controls
• With Exemptions
• Without Exemptions
• Class II General Controls and Special Controls
• With Exemptions
• Without Exemptions
• Class III General Controls and Premarket Approval

50
Class I Devices

• Class I devices are subject to the least
  regulatory control.
• They present minimal potential for harm to the
  user and are often simpler in design than Class
  II or Class III devices.
• Most Class I devices are exempt from the
  premarket notification and/or good manufacturing
  practices regulation. Information on Class I
  exempt devices is located under the heading What
  are Class I/II Exemptions?.

51
Class I - General Controls

• Class I devices are subject to "General Controls
• Establishment Registration (
• Medical Device Listing
• Manufactured s in accordance with GMP
• Labeled in accordance with labeling regulations
  (21 CFR Part 801 or 809)
• Submission of a premarket notification 510(k)
• Examples of Class I devices include elastic
  bandages, examination gloves, and hand-held
  surgical instruments.

52
Class II - Special Controls

• Special controls may include special labeling
  requirements, mandatory performance standards and
  postmarket surveillance.
• Examples of Class II devices include sterilizers,
  LIMS, powered wheelchairs, infusion pumps, and
  surgical drapes.

53
Class III - Premarket Approval

• Class III is the most stringent regulatory
  category for devices.
• insufficient information exists to assure safety
  and effectiveness
• Class III devices are usually those that support
  or sustain human life
• Premarket approval is required
• Not all Class III devices require an approved
  PMA.
• Class III devices which are equivalent to devices
  legally marketed before May 28, 1976

54
Class III Devices Requiring an Approved Premarket
Approval Application

• Examples of Class III devices which require a
  premarket approval include replacement heart
  valves, silicone gel-filled breast implants, and
  implanted cerebella stimulators, pacemaker.

55
DESIGN VERIFICATION AND VALIDATION
56
DESIGN VERIFICATION AND VALIDATION

• Establish and maintain procedures for verifying
  device design
• Confirm design output meets the design input
  requirements
• Results documented in the DHF

57
DESIGN VERIFICATION AND VALIDATION

• Performed under defined operating conditions on
  initial production units, lots, or batches, or
  their equivalents
• Include testing of production units under actual
  or simulated use conditions
• Include software validation and risk analysis,
  where appropriate

58
DEFINITIONS

• Specification - any requirement with which a
  product, process, service, or other activity must
  conform
• Validation - confirmation by examination and
  provision of objective evidence that the
  particular requirements for a specific intended
  use can be consistently fulfilled

59
DEFINITIONS

• Process Validation - objective evidence that a
  process consistently produces a result or product
  meeting specifications
• Design Validation - 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

60
DESIGN VERIFICATION AND VALIDATION

• Always done versus specifications
• Control of specifications increases probability
  of achieving desired results
• Specifications reviewed before as development
  procedes.
• As designs evolve, they should be evaluated
  versus their current specifications.

61
DESIGN VERIFICATION AND VALIDATION

• Always done versus specifications
• Control of specifications increases probability
  of achieving desired results
• Specifications reviewed before as development
  procedes.
• As designs evolve, they should be evaluated
  versus their current specifications.

62
DESIGN VERIFICATION AND VALIDATION

• Should be done with test equipment calibrated and
  controlled according to quality system
  requirements.

63
DESIGN VERIFICATION AND VALIDATION

• Performed according to a written protocol(s)
• Include defined conditions for the testing
• Approved before being used.

64
DESIGN VERIFICATION AND VALIDATION

• Test protocol(s) are not perfect
• annotate ongoing changes to a protocol
• record technical comments about any deviations or
  other events that occurred during testing
• The slightest problem should not be ignored

65
SOFTWARE VALIDATION

• Ongoing development - evaluated and reviewed
  versus the software specifications
• Final" prototype(s) - software and hardware are
  validated

66
SOFTWARE VALIDATION

• Before testing detailed code should be visually
  reviewed versus flow charts and specifications.
• All cases, especially decision points and
  error/limit handling, should be reviewed and the
  results documented.

67
SOFTWARE VALIDATION

• Code visually reviewed versus flow charts and
  specifications
• All cases decision points and error/limit
  handling, reviewed and the results documented

68
SOFTWARE VALIDATION

• Algorithms should checked for accuracy.
• Recalls have occurred because algorithms were
  incorrectly copied from a source and, in other
  cases, because the source algorithm was
  incorrect.

69
SOFTWARE VALIDATION

• Testing includes normal operation of the complete
  device
• Combined system of hardware and software should
  be challenged with abnormal inputs and
  conditions. As appropriate, these inputs and
  conditions include such items as

70
Inputs and Conditions

• exposure to static electricity
• power loss and restart
• simultaneous inputs or interrupts
• limit testing

• operator errors
• induced failure of sensors and cables or other
  interconnects
• induced failure of output equipment

71
SOFTWARE VALIDATION

• Testing includes normal operation of the complete
  device
• Combined system of hardware and software should
  be challenged with abnormal inputs and
  conditions. As appropriate, these inputs and
  conditions include such items as

72
LABELING VERIFICATION

• Exercised such that all labeling, displays, and
  outputs are generated, reviewed, and the results
  documented.
• All displayed prompts and instructions are
  checked versus the manufacturer's and FDA's
  labeling requirements and operator manual.

73
LABELING VERIFICATION

• Printed labeling and screen displays should be
  checked to see if they are directed to the user
  and not to the system designer
• Data, identifications, or other key information
  displayed should be current, complete,
  unambiguous, and accurate

74
LABELING VERIFICATION

• Printouts should undergo a verification similar
  to that performed for the screen or other
  displays
• Annotated copies of verified labeling, printouts,
  etc. and associated notes and any checklists
  should be placed in the design history file

75
820.30(h) Design Transfer

• Each manufacturer shall establish and maintain
  procedures to ensure that the device design is
  correctly translated into production
  specifications.
• Production specifications must ensure that
  manufactured devices are repeatedly and reliably
  produced within product and process capabilities.
  
• The process of encapsulating knowledge about the
  device into production specifications is critical
  to device quality.

76
820.30(j) Design history file

• Each manufacturer shall establish and maintain a
  DHF for each type of device.
• Other national regulations require some form of
  documentation and records. Product documentation
  required by Canada, Europe, and Japan contain
  certain elements of the U. S. FDA design history
  file requirements without requiring all the
  elements to be compiled in a file.
• Virtually every section of the design control
  requirements specifies information which should
  be recorded. The compilation of these records is
  sometimes referred to as the design history file.

77
Typical DHF

• Detailed design and development plan specifying
  design tasks and deliverables.
• Copies of approved design input documents and
  design output documents.
• Documentation of design reviews.
• Validation documentation.
• When applicable, copies of controlled design
  documents and change control records.

78
Design changes

• establish and maintain procedures for design
  changes before their implementation.
• Document control
• Change control

79
Production Testing is not Verification

• Some manufacturers erroneously equate production
  testing with verification.
• Verification testing establishes conformance of
  design output with design input
• Production testing is to determine whether the
  unit under test has been correctly manufactured
  screen out manufacturing process errors and
  detect infant mortality failures
• Typically, a small subset of functional and
  performance tests accomplish this objective with
  a high degree of accuracy.
• Production testing is rarely, if ever,
  comprehensive enough to verify the design.

80
Example

• A leakage test may be used during production to
  ensure that a hermetically-sealed enclosure was
  properly assembled may not be sensitive enough
  to detect long-term diffusion of gas through the
  packaging material.
• Permeability of the packaging material is an
  intrinsic property of the material rather than an
  assembly issue likely be verified using a more
  specialized test than is used during production.

81
Environmental Conditions

• Validation should include simulation of the
  expected environmental conditions

82
VALIDATION DOCUMENTATION

• Validation is a compilation of the results of all
  validation activities.
• For a complex design, the detailed results may be
  contained in a variety of separate documents and
  summarized in a validation report.
• Supporting test articles should be explicitly
  referenced in the validation report and either
  included as an appendix or available in the
  design history file.

83
WHAT PROCESSES SHOULD BE VALIDATED

• Routine end-product tests have insufficient
  sensitivity to verify the desired safety and
  efficacy of the finished devices
• Clinical or destructive testing would be required
  to show that the manufacturing process has
  produced the desired result or product
• Routine end-product tests do not reveal all
  variations in safety and efficacy that may occur
  in the finished devices.
• The process capability is unknown, or it is
  suspected that the process is barely capable of
  meeting the device specifications.

84
820.75 PROCESS VALIDATION

• (a) Where the results of a process cannot be
  fully verified by subsequent inspection and test,
  the process shall be validated with a high degree
  of assurance and approved according to
  established procedures.
• The validation activities and results, including
  the date and signature of the individual(s)
  approving the validation and where appropriate
  the major equipment validated, shall be
  documented.
• (b) 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.
• (1) Each manufacturer shall ensure that validated
  processes are performed by qualified
  individual(s).
• (2) For validated processes, the monitoring and
  control methods and data, the date performed,
  and, where appropriate, the individual(s)
  performing the process or the major equipment
  used shall be documented.
• (c) When changes or process deviations occur, the
  manufacturer shall review and evaluate the
  process and perform revalidation where
  appropriate. These activities shall be
  documented.

85
Planning the Process Validation Study

• The plan should include design reviews.
• The plan for the validation study is documented
  in the validation protocol.
• A copy of the protocol and validation results are
  placed in the Design History File (DHF) 820.30
  (j) or quality system record file (820.186).
• The operational, monitoring, and other
  production-related procedures are part of the
  device master record (DMR) (820.181).

86
Typical Elements of Process Validation Study

• any special controls or conditions to be placed
  on preceding processes during the validation
• process parameters to be controlled and
  monitored, and methods for controlling and
  monitoring 820.70(a) 820.75(b)(2)
• product characteristics to be monitored and
  method for monitoring 820.70(a)(2)
  820.75(b)(2) 820.80(c)
• any subjective criteria used to evaluate the
  product
• definition of what constitutes nonconformance for
  both measurable and subjective criteria
• statistical methods for data collection and
  analysis (820.250)
• consideration of maintenance and repairs
  820.72(a)
• conditions that may indicate that the process
  should be revalidated 820.75(c)
• stages of the study where design review is
  required and
• approval(s) of the protocol.

• identification of the process
• identification of device(s) to be manufactured
  using the process
• criteria for a successful study
• length and duration of the study
• assumptions (shifts, operators, equipment,
  components
• identification of equipment to be used in the
  process 820.75(b)(2)
• identification of utilities for the process
  equipment
• identification of operators and required operator
  qualifications 820.75(b)(2)
• complete description of the process may
  reference the DMR 820.181(b)
• relevant specifications including those for the
  product, components, manufacturing materials, the
  environment, etc. may reference the DMR and
  quality system files 820.181(a) and (b)
  820.186

87
Installation and Operation Qualification

• Process equipment should be installed, reviewed,
  calibrated, challenged, and evaluated to ensure
  that it is capable of operating within
  established limits and tolerances as well as
  throughout all anticipated operating ranges.
• examining equipment design and supplied
  documentation
• determining installation requirements
• establishing any needed environmental controls
  and procedures
• assuring that the work area has sufficient space
  to perform the processing and associated
  activities
• installing the equipment
• verifying correct installation
• establishing manufacturing procedures for the
  monitoring, operation, and control of the
  equipment including the minimum number of
  operators
• determining calibration, cleaning, maintenance,
  adjustment, and expected repair requirements
• identifying important elements of the equipment
  that could affect the output or finished device
• verifying that the system or subsystem performs
  as intended throughout all anticipated operating
  ranges and
• documenting the above information.

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Process Performance Qualification

• The purpose of process performance qualification
  is to rigorously test the process to determine
  whether it is capable of consistently producing
  an output or in-process or finished devices which
  meet specifications. In entering the process
  performance qualification phase of validation, it
  is understood that the
• device, packaging, and process specifications
  have been established, documented, and
  essentially proven acceptable through
  engineering, laboratory or other verification
  methods 820.30 820.70(a) and
• process and ancillary equipment and the
  environment have been judged acceptable on the
  basis of installation and operation qualification
  studies 820.70(g).

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Product Performance Qualification

• Demonstrate that the process has not adversely
  affected the finished product and that the
  product meets its predetermined specifications
  and quality attributes.
• Products used for design validation should be
  manufactured using the same production equipment,
  methods and procedures that will be used in
  routine production.
• Design validation can be conducted using finished
  products made during process validation studies
  and will satisfy the need for product performance
  qualification.
• Design validation shall ensure that devices
  conform to defined user needs and intended uses
  and shall include testing production units under
  actual or simulated use conditions 820.30(g).
• Original designs and design changes are subject
  to design control requirements 820.30(i). The
  results of design validation are subject to
  review under the design control review
  requirements 820.30(e).

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Questions Answers

• Charles Lankford
• PharmaSys, Inc.
• 216 Towne Village Drive
• Cary, NC. 27513
• charles.lankford_at_pharma-sys.com

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