Process Validation

Case Study - Inspection of a Process

M. Wilkins April 2004 1

Objectives

 Overview of Regulation
 FDA 483 Trends specific to Process Validation
 Inspection Process

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2004 2
Process Validation

 §820.3(z) – Validation
 Means confirmation by examination and provision
of objective evidence that the particular
requirements for a specific intended use can be
consistently fulfilled

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2004 3
Process Validation

 §820.3(z)(1) – Process Validation

 Means establishing by objective evidence that a
process consistently produces a result or product
meeting its predetermined specifications

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2004 4
Process Validation

 §820.75(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

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2004 5
When is 820.75(a) Applicable?

 The initial validation of a process

 Destructive testing is required to
demonstrate the manufacturing process
produced product meeting specifications
 All quality attributes of a device cannot be
analyzed by routine testing

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2004 6
Question

 If you have a process validation in place,

does this mean you cannot be cited for an
observation under §820.75(a)?

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2004 7
Process Validation

 §820.75(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

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2004 8
Process Validation

 §820.75(b)(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

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2004 9
When is 820.75(b) Applicable?

 Applies to the performance of a process

after the process has been validated
 Routine monitoring
 Manufacturer uses multiple manufacturing
lines or equipment to produce the product

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2004 10
Question

 Must a manufacturer continuously monitor a

validated process?

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2004 11
Preamble Comment 145

 Monitoring can be accomplished at a

determined interval and frequency
 The interval and frequency should be
periodically evaluated for adequacy,
especially during any evaluation or
revalidation that occurs in accordance with
the requirements under §820.75(c)

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2004 12
Process Validation

 §820.75(c)
 When changes or process deviations occur, the
manufacturer shall review and evaluate the
process and perform revalidation where
appropriate

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2004 13
When is 820.75(c) Applicable?

 Process changes
 Equipment changes
 Product (design) changes
 Process deviations

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2004 14
Question

 Do the requirements under §820.70

(Production and process controls) apply to a
validated process?

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2004 15
Preamble Comment 125

 §820.70(b), Production and process changes,

addresses the requirement for production
and process changes to be verified or where
appropriate validated according to §820.75
 The agency notes that whenever changes
may influence a validated process, the
process must be revalidated as described in
§820.75

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2004 16
Preamble Comment 4

 The regulation is less prescriptive and gives

the manufacturer the flexibility to
determine the controls that are necessary
commensurate with risk
 The burden is on the manufacturer,
however, to describe the types and degree
of controls and how those controls were
decided upon

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2004 17
Question

 What type of processes require validation?

 Do these processes require validation?
 Bonding
 Cutting
 Dipping
 Test Methods
 Cleaning
 Assembly

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2004 18
Process Changes

 When do changes to a process require re-

validation?
 Changes to the process could impact or influence
the device
 Specifications
 Performance
 Functionality
 Chemical Properties
 Physical Properties

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2004 19
FDA-483 Trends

Process Validation Observations = 352

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 Percent QSR Observations by Subsystem
October 2000 to March 2004

Document Management
Controls Controls
4% 20%
P&PC
36%
Design
Controls
11%
CAPA
29%

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2004 21
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22
 Observations for 21 CFR 820.75
October 2000 to March 2004

820.75(c),
24
820.75(b),
59 820.75(a)
820.75(b)
820.75(c)

820.75(a),
269

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2004 23
Process Validation Observations

 21 CFR 820.75(a) = 175

 General
 A process whose results cannot be fully verified
by subsequent inspection and test has not been
[adequately] [fully] validated and approved
according to established procedures

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2004 24
Process Validation Observations

 21 CFR 820.75(a) = 88
 Documentation - general
 Process validation activities and results have not
been [fully] documented

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2004 25
Process Validation Observations

 21 CFR 820.75(b) = 40
 Monitoring and control
 Procedures were not [established] [defined]
[documented] [complete] [implemented] for
monitoring and control of process parameters for
validated processes

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2004 26
Process Validation Observations

 21 CFR 820.75(b)(2) = 16
 Documentation of validated process
performance
 There is no documentation of [monitoring and
control methods and data] [the major equipment
used] for a validated process

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2004 27
Process Validation Observations

 21 CFR 820.75(c) = 13
 Documentation – review in response to
changes
 There is no documentation of the [review and
evaluation of a process] [revalidation of a
process] conducted in response to changes or
process deviations

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2004 28
Process Validation Observations

 21 CFR 820.75(c) = 11
 Process changes – review, evaluation and
revalidation
 A validated process was not [reviewed and
evaluated] [revalidated] when changes or process
deviations occurred

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2004 29
Process Validation Observations

 21 CFR 820.75(a) = 6
 Documentation – specific items
 Documentation of process validation activities
and results does not include [the date and
signature of the individuals approving the
validation] [the major equipment validated]

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2004 30
Process Validation Observations

 21 CFR 820.75(b)(1) = 3
 Performed by qualified individual
 A validated process was not performed by a
qualified individual

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2004 31
Process Validation Observations

 21 CFR 820.70(b) = 120

 Changes to a [specification] [method] [process]
[procedure] were not verified or validated
 Procedures for changes to [specification]
[methods] [processes] were not [established]
[defined] [documented] [complete]
[implemented]
 Established procedures were not followed in
making changes to [specifications] [methods]
[processes] [procedures]
 Changes were not [documented] [followed]
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2004 32
Process Validation

Case Study – Inspection of a Packaging

Process

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Packaging Process Validation

 The package of a sterile medical device

serves to protect the product and maintain
sterility of the product until the package is
opened by the user
 Why validate the packaging process?
 Maintain package integrity
 Assure the integrity of the seal
 Maintain microbial barrier

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2004 34
Inspection Process

 The packaging materials’ ability to be

sterilized and maintain its sterility is
determined by
 Material selection
 Package design
 Process development
 Procedures
 Packaging process validation
 Package testing
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2004 35
Inspection Process

 Indicators from other subsystems may guide

the investigator to cover the packaging
process under the P&PC subsystem.

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2004 36
Management Controls Subsystem

 Management controls over the sterile device

packaging development and operations
 Quality audits
 Employee training
 Adequate resources
 Knowledge of the nature of the product/package
and its limitations during sterilization, handling,
and storage
 Quality System Procedures

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2004 37
Design Control Subsystem

 Materials selected must:

 Compatible with the product, manufacturing
method, and sterilization method
 Maintain product sterility until time of use
 Provide product protection
 Consider biocompatibility for the intended use

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2004 38
Package Materials and Design

 Requirements to consider
 Permeability
 Microbial barrier properties
 Formation of toxins during processing
 Interaction between products and package
materials
 Chemical properties – pH value, chloride and
sulfate content
 Labeling of package

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2004 39
Package Materials & Design

 Requirements to consider
 Physical properties – tensile strength, thickness
variation, tear variation, burst strength
 Adhesive, coated materials – coating patterns,
minimum specified seal strength

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2004 40
Design Control Subsystem

 Design control requirements for the

development of physical specifications of
the packaging materials
 Physical requirements
 Dimensions
 Tolerances
 Description of raw materials, components
 Thickness
 Coatings required
 Graphic treatment
 Colors, type of ink, type of printing process

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2004 41
Design Control Subsystem

 Design control requirements for the

development of performance specifications
of the packaging materials
 Performance requirements
 Porosity
 Bursting strength
 Seal strength
 Peel strength
 Tensile and elongation properties
 Permeability to gases and moisture

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2004 42
Corrective & Preventive Actions
(CAPA) Indicators
 Complaints
 Open packages
 Poor seal
 Tears
 Loss of sterility
 Infections
 Foreign objects

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2004 43
CAPA Indicators

 Medical Device Reports

 Toxins formed during processing
 Infections
 Recalls-Packaging Problems/Loss of Sterility
 Holes in packaging
 Unknown/unspecified packaging complaints
 Seams or seals
 Design or process
 Packaging/labeling mix-ups
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2004 44
CAPA Indicators

 Returned Goods Authorization

 Open package
 Poor seals
 Tears
 Non-conformances
 In-process failures
 Receiving inspection non-conformances
 Finished testing non-conformances

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2004 45
Inspection Process - P&PC

 Review the procedures

 Methods for controlling and monitoring the
packaging process
 Review device history records
 Non-conformances
 Review of process or material changes
 Training records

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2004 46
Inspection Process

 Purchasing controls
 Supplier evaluation and approval
 Material specifications/changes
 Packaging process validation
 Installation Qualification
 Operational Qualification
 Performance Qualification

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2004 47
Validation Deficiencies

 Lack of operational qualification data to

support the parameters/ranges used in the
process
 Failure to define the process parameters
prior to the performance of the qualification
runs
 Sampling sizes not based on statistical
rationale

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2004 48
Validation Deficiencies

 Failure to demonstrate consistent results

over time through successful runs
 Failure to validate test methods
 Failure to perform shipping or
environmental stress testing
 Failure to include product in package seal
testing
 Lack of data to demonstrate reproducibility

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2004 49
Packaging Process Deficiencies

 Lack of written procedures for the

inspection of incoming packaging materials
 Failure to establish sealing parameters
 Failure to perform finished product seal
integrity testing
 Samples collected for testing are not
representative of the packaging run

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2004 50
Packaging Process Deficiencies

 Failure to document results and maintain

records of the packaging inspections
 Failure to maintain and/or calibrate
equipment
 Failure to monitor the temperature,
pressure, and dwell time for the heat
sealers

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2004 51
Packaging Process Deficiencies

 Lack of a supplier evaluation/qualification

 Failure to monitor or control the product
received from suppliers
 Failure to establish or reference the
specified requirements

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2004 52
Questions

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2004 53