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FDA Medical Devices: Auditing the GMPs

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FDA Inspection Results FDA-483 Citations FDA-483 Citations cont. FDA-483 Citations cont. Before the Inspection Are procedures in place? FDA can ... – PowerPoint PPT presentation

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Title: FDA Medical Devices: Auditing the GMPs


1
FDA Medical Devices Auditing the GMPs
2
The Objects Most Feared
  • Very few situations get the same automatic
    negative reaction that the dreaded QA guy
    carrying a clipboard will usually receive
  • Why?

3
Internal Auditors
  • Usually part-time the QA Department borrows
    auditors for a few days when needed on monthly,
    quarterly, or annual schedule
  • Can be full-time in larger organizations
    generally combined with inspection or other QA/QC
    duties
  • Sometimes outsourced consultant is hired to
    perform all or some of the audits

4
You should say YES if asked
  • Increases your value to the company
  • Adds to your resume
  • Good way to get to know other areas of the
    company
  • You will learn to see the Big Picture
  • QA Managers get lonely

5
The Big Picture
  • Sometimes we audit the Trees
  • And sometimes we audit the Forest.
  • Whats the difference?

6

Product Improvement
Supply Management
Sales/ Contract Review
Order Fulfillment
Customer Interface
Project Implementation
Outside Resources
Proposal Generation
Resource Validation
Pre- Sales efforts
Design Review
Current Future Needs
Customers
Delivered Products
7
Continuous Improvement
  • The Three Laws of Statistical Thinking
  • Plan/Do/Check/Act Cycles

8
Three Laws of Statistical Thinking
  • All Work is comprised of interrelated processes
  • All Processes contain variation
  • Success is derived from understanding and
    controlling variation

9
Quality Assurance
  • Everything we do in QA should be designed to
    further the understanding and reduce the
    variation in our work processes.
  • Big honkin binders of procedures are not written
    to please the auditors.
  • Why do we write procedures?

10
Procedures
  • Procedures are written for training and thus
    variation reduction in our processes
  • Why do we audit?

TE009
RFP
11
Auditing
  • Auditing is performed to uncover the difference
    between what we say we do and what we actually do

12
Auditing
  • for both production and management processes.
  • We want Continuous Improvement in all processes.

13
QA Explanation
  • Say What You Do
  • Do What You Say
  • Act on the Differences

14
PDCA Cycles
DO
PLAN
CI
ACT
CHECK
15
DO
CHECK
PLAN
ACT
16
DO
Set objectives and build processes that meet
customer expectations
CHECK
ACT
17
Perform your processes
CHECK
PLAN
ACT
18
DO
Monitor and measure the processes against
policies, objectives and procedures
PLAN
ACT
19
DO
CHECK
PLAN
Take actions based on what youve learned about
the processes
20

Review
  • Why is the Systems Approach important?
  • How would you explain the Three Laws of
    Statistical Thinking to someone else?
  • Auditing belongs to what part of PDCA?

21
FDA Inspection Results
Quality 47 Laboratory 19 Production
11 Facilities/Equipment 8 Materials
6 Packaging/ Labeling 0
22
FDA-483 Citations
21 CFR Primary Reference
Deficiency System
1 211.22(d) The responsibilities procedures applicable to the QC unit are not in writing or fully followed. Quality
2 211.100(b) Written production process control procedures are not followed in the execution of production process control functions /or documented at the time of performance. Production
3 211.25(a) GMP training is not conducted on a continuing basis /or with sufficient frequency to assure employees remain familiar with cGMP requirements applicable to them. Quality
3 211.25(a) Employees are not given training in the particular operations they perform as part of their function, cGMPs, /or written procedures required by cGMPs. Quality

23
FDA-483 Citations cont.
21CFR Reference
Deficiency Primary System
4 211.110(a) Control procedures are not established which monitor the output /or validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of IP material the drug product. Quality
5 211.188 Batch production control records are not prepared for each batch of drug product produced /or do not include complete information relating to the production control of each batch. Production
24
FDA-483 Citations cont.
21 CFR Primary Reference
Deficiency System
6 211.160(b) Lab. controls do not include the establishment of scientifically sound appropriate specs., standards, sampling plans, /or test procedures designed to assure that components, containers, closures, in-process materials, labeling /or drug products conform to appropriate standards of identity, strength, quality purity. Laboratory
7 211.165(a) Testing release of drug products for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specs. /or identity strength of each AI prior to release. Laboratory
8 211.100(a) There are no written procedures for production process controls designed to assure that the drug products have the identity, strength, quality, purity they purport or are represented to possess. Quality

25
Before the Inspection
  • Are procedures in place? FDA can request copies
    of high-level documents and procedures the
    organization is not required to provide.
  • Do the procedures meet the requirements?
  • Review records
  • Pre-notification for quality system audits when
    company has a clean record, but surprise
    inspections are always possible

26
FDA Inspection/ Audit 4 Major Subsystems
  • Management Controls
  • Design Controls
  • Corrective Preventive Action (CAPA)
  • Medical Device Reporting
  • Corrections and Removals
  • Medical Device Tracking
  • Production Process Controls
  • Sterilization Controls

27
FDA Inspectional Objectives 4 Major Subsystems
  • Management Controls (7 Objectives)
  • Design Controls (15 Objectives)
  • Corrective Preventive Action (10 Objectives)
  • Medical Device Reporting (4 Objectives)
  • Corrections and Removals (3 Objectives)
  • Medical Device Tracking (3 Objectives)
  • Production Process Controls (6 Objectives)
  • Sterilization Controls (5 Objectives)

28
First Major Subsystem Management Controls
  • Interview of the Management Representative
  • Does management have a good understanding of what
    is required under this section?

29
Management Controls
The purpose of the management control subsystem
is to provide adequate resources for device
design, manufacturing, quality assurance,
distribution, installation, and servicing
activities assure the quality system is
functioning properly monitor the quality system
and make necessary adjustments. A quality system
that has been implemented effectively and is
monitored to identify and address problems is
more likely to produce devices that function as
intended. A primary purpose of the inspection is
to determine whether management with executive
responsibility ensures that an adequate and
effective quality system has been established
(defined, documented and implemented) at the
firm. Because of this, each inspection should
begin and end with an evaluation of this
subsystem.
30
ISO 13485 5.5.2 Management Representative CFR
Title 21 Part 820 Subpart B Section 820.20
Management Responsibility
  • The Code of Federal Regulations Part 820 is
    referred to as the Quality System Regulation
    (QSR)
  • It is harmonized with ISO 13485, meaning that
    they cover the same requirements and share much
    of the same language.
  • ISO, in common usage, refers to the International
    Organization for Standardization.
  • The organization registers to the Standard, and
    complies with the law

31
ISO 13485 5.5.2 Management Representative CFR
Title 21 Part 820 Subpart B Section 820.20
Management Responsibility
  • Top Management shall appoint a Representative
    with RA that includes
  • Ensuring QMS processes are established and
    maintained
  • Reporting to Top Management on performance and
    improvement needs
  • Ensuring the promotion of regulatory and customer
    requirements throughout the Organization

32
Inspectional Objective 1
  • Verify that a quality policy, management review
    and quality audit procedures, quality plan, and
    quality system procedures and instructions have
    been defined and documented.

33
Inspectional Objective 2
  • Verify that a quality policy and objectives have
    been implemented.
  • What is the difference between documented and
    implemented to an auditor?

34
ISO 13485 5.3 Quality Policy CFR 820.20 (a)
  • Top Management must establish a written policy
    appropriate to the organization that includes
  • a statement of commitment to comply with the
    regulatory requirements and to maintain the
    effectiveness of the quality management system
    and
  • provides a framework for establishing and
    reviewing the quality objectives
  • Management must communicate the policy
    throughout the organization and continually
    review the policy for its suitability

35
Inspectional Objective 3
  • Review the firm's established organizational
    structure to confirm that it includes provisions
    for responsibilities, authorities and necessary
    resources.

36
Inspectional Objective 4
  • Confirm that a management representative has
    been appointed. Evaluate the purview of the
    management representative.

37
Inspectional Objective 5
  • Verify that management reviews, including a
    review of the suitability and effectiveness of
    the quality system, are being conducted

38
ISO 13485 5.6.1 Management Review
  • At planned intervals, Top Management shall
    review the QMS for suitability and effectiveness,
    which shall include assessment of opportunities
    for improvement and the need for changes to the
    QMS including the Quality Policy and Objectives.
  • Records shall be maintained.
  • Requirements are established for Review of
    Inputs and Outputs including

39
5.6.2 Review Input
  • Results of Audits
  • Customer Feedback
  • Process Performance/ Product Conformity
  • Preventive/Corrective Actions
  • Follow ups to Action Items
  • Changes affecting the QMS
  • Recommendations for Improvement
  • Changes to regulations

40
Planned Intervals
  • Monthly Project Reviews
  • Quarterly or Annual System Reviews
  • Annual Procedure and Manual Reviews
  • Other?
  • Whats appropriate?

41
5.6.3 Review Output
  • Improvements needed to maintain effectiveness of
    the QMS and its processes
  • Improvement of product relative to the customer
  • Resource Needs

42
8.2.2 Internal Audit
  • The organization shall conduct internal audits
    at planned intervals to determine whether the
    QMS
  • Conforms to planned arrangements (7.1)
  • Requirements of the standard
  • Requirements of the organization

43
8.2.2 Internal Audit
  • The organization shall conduct internal audits
    at planned intervals to determine whether the
    QMS
  • Is effectively implemented and maintained

44
8.2.2 Internal Audit PLAN
An audit program shall be planned, taking into
consideration the status and importance of the
processes and areas to be audited, as well as the
results of previous audits. The audit criteria,
scope, frequency and methods shall be defined.
Selection of auditors and conduct of audits shall
ensure objectivity and impartiality of the audit
process. Auditors shall not audit their own work.
45
ISO 8.2.2 Auditors shall not audit their own
work. CFR 820.22 Quality audits shall be
conducted by individuals who do not have direct
responsibility for the matters being
audited. Can the Manager of Product Engineering
be an internal auditor?
46
8.2.2 Internal Audit DO
The responsibilities and requirements for
planning and conducting audits, and for reporting
results and maintaining records shall be defined
in a documented procedure. The management
responsible for the area being audited shall
ensure that actions are taken without undue delay
to eliminate detected nonconformities and their
causes.
47
8.2.2 Internal Audit ACT
Actions must be taken or planned ASAP after the
audit finding or observation is reported
Corrective Action
48
Inspectional Objective 7
  • Evaluate whether management with executive
    responsibility ensures that an adequate and
    effective quality system has been established and
    maintained.

49

Review
  • Why does FDA look at the high-level documents
    before beginning the inspection?
  • Why is the Quality Policy required?
  • Explain Management Review.

50
Major Subsystem 2 Design Controls
  • In 1990 FDA published a study showing that 44 of
    device failures leading to recalls (1983-1989)
    were due to design failures that could have been
    prevented.
  • For software failures, that number was over 90.

51
Design Controls
The purpose of the design control subsystem is to
control the design process to assure that devices
meet user needs, intended uses, and specified
requirements. Attention to design and
development planning, identifying design inputs,
developing design outputs, verifying that design
outputs meet design inputs, validating the
design, controlling design changes, reviewing
design results, transferring the design to
production, and compiling a design history file
help assure that resulting designs will meet user
needs, intended uses and requirements.
52
Inspectional Objective 12
  • 1. Select a single design project.
  • 2. For the design project selected, verify that
    design control procedures that address the
    requirements of Section 820.30 of the regulation
    have been defined and documented.

53
Inspectional Objective 3
  • Review the design plan for the selected project
    to understand the layout of the design and
    development activities including assigned
    responsibilities and interfaces.

54
Inspectional Objective 5
  • Verify that the design outputs that are essential
    for the proper functioning of the device were
    identified.
  • The total finished design output consists of the
    device, its packaging and labeling, and the
    device master record.

55
CFR 820.120 Device Labeling
  • Procedures must be written
  • Labels must be legible and remain attached
  • Information must be validated and released by
    signature
  • Storage and handling procedures to prevent
    mix-ups

56
Inspectional Objective 6
  • Confirm that acceptance criteria were established
    prior to the performance of verification and
    validation activities.
  • What is the difference between these terms?

57
Inspectional Objective 13
  • Confirm that changes were controlled including
    validation or where appropriate verification.

58
7.3.5 Design and Development Verification
  • Verification shall be performed with planned
    arrangements (7.3.1) to ensure that the design
    and development have met the input requirements.
    Records shall be maintained.

7.3.6 Design and Development Validation
  • Validation shall be performed with planned
    arrangements to ensure that the resulting product
    have met the requirements for the application or
    intended use. Validation will be performed prior
    to delivery. Records shall be maintained.

7.3.7 Design and Development Changes
  • Changes shall be identified and records
    maintained. Changes shall be reviewed, verified
    and validated, and approved. Review shall include
    evaluation of effects on completed work.

59

Review
  • T/F Design problems with software in devices are
    a minor concern to the FDA
  • T/F Product acceptance criteria are established
    by the verification and validation processes
  • T/F Validation studies are completed years after
    the product is on the market

60
Major Subsystem 3 Corrective Preventive Action
  • Requires procedure(s)
  • Problem Analysis
  • Investigation
  • Identify actions
  • Verify Validate planned actions
  • Maintain documentation changes
  • Notify responsible parties
  • Submit to management review
  • Document entire process

CFR 820.100
61
Corrective Preventive Actions
The purpose of the corrective and preventive
action subsystem is to collect information,
analyze information, identify and investigate
product and quality problems, and take
appropriate and effective corrective and/or
preventive action to prevent their recurrence.
Verifying or validating corrective and preventive
actions, communicating corrective and preventive
action activities to responsible people,
providing relevant information for management
review, and documenting these activities are
essential in dealing effectively with product and
quality problems, preventing their recurrence,
and preventing or minimizing device failures.
62
Inspectional Objective 2
  • 2. Determine if appropriate sources of product
    and quality problems have been identified.
    Confirm that data from these sources are analyzed
    to identify corrective action.
  • 3. Determine if sources of product and quality
    information that may show unfavorable trends have
    been identified. Confirm that data from these
    sources are analyzed to identify preventive
    action.

63
Inspectional Objective 6
  • Determine if failure investigation procedures are
    followed. Determine if the degree to which a
    quality problem or nonconforming product is
    investigated is commensurate with the
    significance and risk of the nonconformity.
    Determine if failure investigations are conducted
    to determine root cause (where possible). Verify
    that there is control for preventing distribution
    of nonconforming product.

64
CFR 820.90 Nonconforming Product
  • NCP must be controlled including
  • Identification
  • Documentation
  • Evaluation
  • Segregation
  • Disposition
  • NCP can be authorized for use provided
  • Documentation of the review
  • Justification for release
  • Signature of person authorizing the release

65
Inspectional Objective 10
  • Determine if information regarding nonconforming
    product and quality problems and corrective and
    preventive actions has been properly
    disseminated, including dissemination for
    management review.

66
3 Subsystems to CAPA Subsystem
  • Medical Device Reporting Confirm that the firm
    follows their procedures and they are effective
    in identifying MDR reportable deaths, serious
    injuries and malfunctions.
  • Corrections Removals Determine if corrections
    or removals of a device were initiated by the
    manufacturer.
  • Medical Device Tracking Determine if the firm
    manufactures or imports a tracked device.

67

Review
  • What must be done with Nonconforming product?
  • What is the difference between corrective and
    preventive actions?
  • What is required to release nonconforming
    product?

68
Major Subsystem 4 Production Process Controls
CFR 820.70
  • Develop, conduct, control and monitor production
    processes
  • Environment, personnel, contamination, buildings,
    and equipment monitoring and changes.
  • Calibration and process validation issues

69
Production Process Controls
The purpose of the production and process control
subsystem is to manufacture products that meet
specifications. Developing processes that are
adequate to produce devices that meet
specifications, validating (or fully verifying
the results of) those processes, and monitoring
and controlling the processes are all steps that
help assure the result will be devices that meet
specifications.
70
Inspectional Objective 1
  • Select a process for review based on a. CAPA
    indicators of process problems b. Use of the
    process for manufacturing higher risk devices c.
    Degree of risk of the process to cause device
    failures d. The firms lack of familiarity and
    experience with the process e. Use of the
    process in manufacturing multiple devices f.
    Variety in process technologies and profile
    classes g. Processes not covered during previous
    inspections h. Any other appropriate criterion
    as dictated by the assignment

71
Inspectional Objective 6
  • Verify that personnel have been appropriately
    qualified to implement validated processes or
    appropriately trained to implement processes
    which yield results that can be fully verified.

72
Sterilization Process Controls Subsystem of
Production and Process Controls
  • Inspectional Objective 3 If review of the
    Device History Records (including process control
    and monitoring records, acceptance activity
    records, etc.) reveals that the sterilization
    process is outside the firms tolerance for
    operating or performance parameters
  • a. Determine whether the nonconformances were
    handled appropriately and
  • b. Review the equipment adjustment, calibration
    and maintenance

73
Part II Auditing
  • Sampling Plan for Records
  • The Audit Process
  • Plan
  • Do
  • Check
  • Act

74
Luck of the Auditor Sampling
Audits are often samples. We cant look at
every record or inspect every device. Formal
sampling plans provide statistical assurance
provided that every item has equal chance of
being selected and that item is chosen randomly.
75
Sampling Plan for Records
  • Assumptions
  • Record not critical
  • 10 Defective is my threshold of pain
  • 90 Detection desirable

76
Sampling Plan for Records
  • Simplicity Rules!
  • Zero Acceptance Sampling
  • (Fail on single nonconformance)
  • Constant Sample Size
  • Randomize by taking every nth record

77
Sampling Plan for Records
Records Sx Size Reject on (Lot
Size) 50 10 1 defect 100 10 1
defect 10,000 10 1 defect
78
Sampling Plan for Records
Records Sx Size Reject on Probability (Lot
Size) Of Correct Rejection 50 10 1
defect 81 100 10 1 defect 80 10,000 10 1
defect 78
79
Sampling Plan for Records
Records Sx Size Reject on Probability (Lot
Size) Of Correct Rejection 50 20 1
defect 91 100 20 1 defect 90 10,000 20 1
defect 86
80
The Audit Process
  • Planning
  • Doing
  • Checking
  • Acting on What Weve Learned

81
Planning the Audit
Audit Type Auditor Selection Preparation Checklist
s
82
Systems Audit
Process Audit
Product Audit
83
Systems Audit Are systems requirements
(manuals, policies, standards,
regulations) being met?
84
Process Audit Are Process requirements (inputs,
outputs, procedures, plans, methods) being met?
85
Product (or Service) Audit Are attribute
requirements (specifications) being met?
86
Other Common Terms
Desk Audit First, Second, and Third-party
audit Internal, customer, and external
audit Dock Audit Gap Analysis
87
Auditor Selection
You may have a conflict of interest if The
procedure or process was developed by you A
close friend works in the area You currently
work for the department There is an
interpersonal problem with someone in area You
are a previous employee of the area You have
previous relationships with people in
area Remember The only thing that the ISO
standard prohibits is the auditing of your own
work and the law prohibits?
88
Audit Preparation
Establish the Scope Why?
What are we trying to learn? Verify compliance
against a spec? Or to verify that contract
requirements are met? Against a standard? Train
new auditors? Program assessment/ gap analysis.
Close previous findings or concerns?
Who? What? Where? When?
Are we auditing a department? A whole facility?
Multiple shifts? Travel arrangements? Team?
Other resources needed?
89
Audit Preparation
Set Up the audit
  • Complete paperwork required by the organization.
  • Contact the auditee to arrange times, dates,
    and communicate the scope. Audits are never
    surprise inspections. (except for the FDA)
  • Arrange for advance document transfer to you
    (if necessary.)
  • Prepare checklists for the audit.

90
Read the Requirement with Care
Shall, must, will Should, might, can,
may An auditor should never make up rules
that they think you should comply with.
91
4.2.3 Document Control
  • A procedure shall be established to ensure
  • Approval of documents prior to use
  • Review, update, and re-approve documents
  • Identification of changes and revision status
  • Relevant documents are available at the points of
    use
  • Documents remain legible and identifiable
  • External documents are identified and controlled
  • The prevention of the use of obsolete documents

Who does annual reviews? Who stamps old
procedures OBSOLETE and puts in a file? Who has
a document master list?
92
Checklists
  • Canned checklists
  • provide a useful starting place,
  • give structure to a new program,
  • BUT
  • do not provide flexibility,
  • And will not necessarily reflect your needs

93
Performing the Audit
Audit Meetings Physical Evidence Open-ended
Language Interview Questions
94
Opening Meeting
Degree of formality will vary by the company and
culture Introductions Thank/greet your
host Review plans, scope, standards Workout
any access/security/safety and escort issues
Review audit methods/reports/schedule Request
resources such as telephone/maps/documents etc.
Confirm meeting schedules morning/closing/exit
meetings
95
Ongoing Meetings
Keep the auditee informed Progress what is
finished Findings/observations/problems
Changes or additional concerns New document
requests Review audit methods, reports, or
schedule
96
Physical Evidence
Documents and records note references on
audit checklists copy if problem
detected Physical Examination if you looked
or counted it, record it Observations Pay
attention to the area be inquisitive Interview
s talk to the people who do the process
97
Other Concerns
If you observe unethical or unsafe activities,
record and report them Corroborate whenever
possible Put the interviewees at ease Always
explain what you are doing to the auditee
98
Open-ended Language
Timely, readily, promptly, periodic, without
undue delay The organization shall ensure
control over such processes Top management must
ensure the QMS is suitable Exercise care with
customer property The organization shall
preserve conformity of the product
99
Open-ended Language
We are used to thinking of these as Quality
issues but what do they mean to us as
auditors? A poor auditor will use these as
gotchas. The auditor should challenge the
interviewee/auditee to explain their
interpretation Have you worked out what
exercise care means to you? Have you defined
periodic in the current context?
100
Interviews
Dont ask Did you receive training in this
task? Show me the work instruction. Where
are the criteria for this job? Who is
responsible for adjustments to this
process? These will be interpreted as
accusatory by some people. The formulated
response in their heads to all of these is, Why,
am I doing it wrong?
101
Ask Instead
How do you know what to do? (Tells you if
there is a plan, procedure, training) Show me
how you do it? (Verifies training, competency,
knowledge) How is it checked? How do you know
its right? (Reveals acceptance criteria, QC
plans If its not right, what do you do? What
is next action? (evidence of corrective actions,
follow up
102
Checking
Analysis Classification Report
103
Analysis
Is there enough data to confirm your
observation(s)? Is there contradictory evidence?
One time? Repetitive problem? Is it a critical
process step? What is the consequence?
104
Classification
Nonconformity Minor or major violation Finding
Systemic problems Observation Might become a
problem Improvement point/opportunity could be
better Defect minor violation Concern Might
become a problem Issue Might become a
problem Positive practice Something done well
105
Report
SWOT analysis Strengths You can show
directness, objectivity Weaknesses You can
demonstrate indecisiveness, etc Opportunities
Communication/improvement opportunity Threats
Audits reviewed by upper management Be direct.
Cite evidence. Be willing to discuss issues. Stay
within scope. A well written finding answers
Who, What, Where, When and Why
106
Other Issues
Do not discuss auditee information outside of the
proper channels Be willing to follow up as
necessary your judgment went into the
decisions Speak your truth quietly and
clearly Dont take ownership of the problems
107
Acting on What Weve Learned
Follow the corrective action process for your own
audits conduct a formal review, but Could I
have done something better? Did I overlook
something? Did I cause problems by stepping out
of scope? Discuss audit procedures/forms/techniqu
es with Management Representative or QA Manager
anything that could have gone better? Something
out of scope that concerned you? Additional
resource or training needs?
108

Review
  • Pay attention to the words in the standards and
    procedures.
  • Document everything that you look at. Make copies
    of problematic records to back up your findings
  • Auditors who are out to get em are not doing
    it right.
  • Ask questions. Be honest.

109
Part III Audit Simulation
110
Auditing is simple but not easy
The best way to learn quality system auditing is
to perform it! Since were not in a company
with ready-made procedures to audit against,
were going to try a little game. Everyone
will get a turn at the various roles
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