Journal of Medical Engineering & Technology

ISSN: 0309-1902 (Print) 1464-522X (Online) Journal homepage: https://www.tandfonline.com/loi/ijmt20

OQ & PQ protocols development for medical

device two-level process validation

Yeong-Lin Chen

To cite this article: Yeong-Lin Chen (2019) OQ & PQ protocols development for medical device
two-level process validation, Journal of Medical Engineering & Technology, 43:7, 431-442, DOI:
10.1080/03091902.2019.1692939

To link to this article: https://doi.org/10.1080/03091902.2019.1692939

Published online: 28 Nov 2019.

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JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY
2019, VOL. 43, NO. 7, 431–442
https://doi.org/10.1080/03091902.2019.1692939

RESEARCH ARTICLE

OQ & PQ protocols development for medical device two-level

process validation
Yeong-Lin Chen
Validation Department, SHL Group, Taoyuan, Taiwan

ABSTRACT ARTICLE HISTORY

Medical device industry encompasses a wide range of technologies and applications, which Received 1 August 2019
makes the process validation approach (IQ/OQ/PQ framework) and OQ/PQ implementation Revised 7 November 2019
method difficult to be defined in the industry’s regulation and process validation guidance Accepted 8 November 2019
documents. Based on two-level (component production level and device assembly level) process
KEYWORDS
validation approach, this article proposes 1) a typical section structure & contents for production Medical device process
equipment/system/process validation OQ/PQ protocols, 2) a typical subsection structure & con- validation; two-level process
tents for the protocols’ most critical section - Test Plan, and 3) the validation approach and OQ validation; Equipment
Detailed Test Plan for both common equipment and test equipment. Validation IQ/OQ/PQ;
Process Validation PQ;
detailed test plan

1. Introduction level process validation and final device assembly level

In medical device industry, process validation is critical
to the regulatory compliance and product quality
assurance. A medical device can be an instrument,
apparatus, appliance, software, implant, reagent,
material or other articles, and from syringes and
wheelchairs to cardiac pacemakers and medical imag-
ing technologies (e.g., Magnetic Resonance Imaging
(MRI), Computed Tomography (CT) and X-ray
machines). Due to a wide range of technologies and
applications, medical device manufacturing could
involve multiple technical fields, such as chemical,
mechanical, electronics, software and their combina-
tions. Except the devices with chemical and software
in nature, device mainstream products (e.g., mechan-
ical-based, electromechanical-based) are manufactured
in two levels (i.e., component production level, device
assembly level) based on their manufacturing order
practice. According to the published paper “Two-level
Process Validation Approach for Medical Devices” [1],
it mentioned that the process validation (or stage 2 -
Process Qualification shown in Food and Drug
Administration (FDA) Guidance for Industry, Process
Validation: General Principles and Practices [2], or trad-
itional process validation) approach should align with
the manufacturing order practice and be divided into
two levels including device component production
process validation. For each level’s process validation,
it should have Installation Qualification (IQ),
Operational Qualification (OQ), and Performance
Qualification (PQ) as the validation framework, which
can be further divided into Equipment Validation IQ,
OQ, PQ and Process Validation PQ. Equipment valid-
ation PQ is an option depending on equipment qual-
ity risk, validation financial risk, and machine design
and development activities. Process Validation PQ is
mandatory, which is aimed at the performance test of
the manufacturing process as a whole under the regu-
lar production environment, and is equivalent to stage
2 - Process Performance Qualification (PPQ) shown in
the FDA process validation guidance [2]. This two-level
process validation approach is the base for the subject
article to develop OQ, PQ protocols.
Process validation for medical device manufacturing
is considered a challenge task since 1) regulatorily, the
medical device Global Harmonisation Task Force
(GHTF) process validation guidance (GHTF/SG3/N99-10,
Quality Management Systems - Process Validation
Guidance [3]) only provided general suggestions on
how to execute process validation for an individual
production equipment/process, and it did not illustrate
how to execute process validation for a finished
device product manufacturing which involves an

CONTACT Yeong-Lin Chen ylchenshl283@gmail.com Validation Department, SHL Group, No. 38, Lane 51, Jianguo Road, Lungtan, Taoyuan
325, Taiwan
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
432 Y.-L. CHEN
integrated production system. A device integrated
production system could include several individual
production systems, such as plastic component manu-
facturing system, metal component manufacturing sys-
tem, printing system, and device assembly system, 2)
technically, it involves multiple components produc-
tion and device assembly performance verifications.
To remedy the insufficiency of GHTF process valid-
ation guidance, the paper “Two-level Process
Validation Approach for Medical Devices” provides a
clear validation approach on how to establish the
process validation IQ, OQ, PQ framework for a med-
ical device’s integrated production system. As for the
medical device process validation technical difficulty
involving how to implement the IQ, OQ, PQ exercises
for both device component production level and
device assembly level, the most difficult thing is to
develop suitable and justifiable process validation IQ,
OQ, PQ protocols. For any type of equipment (e.g.,
test equipment, production equipment, facilities, util-
ities), IQ verification items are very similar, and thus
IQ protocol development generally is not considered
a challenge for process validation practitioners.
However, for Equipment Validation OQ, PQ and
Process Validation PQ, the validation verification
items/methods vary widely, also their validation exe-
cutions are much more complex and critical. For the
reasons, the subject article is aimed at how to
develop appropriate OQ, PQ protocols by providing a
typical section structure & contents for the protocols.
Detailed Test Plans, describing the test procedures
for the performance verification of device production
equipment/system/process, are deemed an essential
part of the OQ, PQ protocols. Therefore, a typical
subsection structure & contents for the Detailed Test
Plan are described and analysed. In addition, the val-
idation approach and OQ Detailed Test Plan for com-
mon equipment and test equipment are illustrated
as well.
2. Typical section structure and contents for
OQ and PQ protocols
In order to simplify the process validation protocol
preparation, the main structures (or main section
titles) of OQ and PQ protocols can be kept the same.
A typical section structure and contents for OQ and
PQ protocols, based on the two-level process valid-
ation approach (including Equipment Validation OQ &
PQ for both levels, Component Production Level
Process Validation PQ, and Device Assembly Level
Process Validation PQ), are proposed below.

Title & Signature Page
Show the document title and approval record with
role (e.g., author, reviewer, approver), title, name,
signature, and date.

Table of Contents
Show the protocol section title and page number.

Purpose
– Equipment (including component production level
and device assembly level) Validation OQ & PQ
Describe what validation, what equipment, and
what medical device are aimed at, and also the
prerequisite validation (e.g., Equipment Validation
IQ) should be completed before starting the
protocol execution. In addition, Equipment
Validation OQ purpose (e.g., documented verifica-
tion that each individual component/feature of
the equipment and the equipment under the
specified operating parameter range (or process
window) can operate according to their predeter-
mined requirements and quality characteristics),
and Equipment Validation PQ purpose (e.g.,
documented verification that the equipment
under the normal (or nominal) operating condi-
tion can consistently produce a product meeting
the predetermined requirements and quality
characteristics) should be stated.
Note: Another important OQ purpose is to iden-
tify critical process parameters and optimise their
operating parameter ranges for worst case test-
ing. Generally, the parameter screening and opti-
misation are conducted via Design of Experiment
(DOE) study, which does not have predetermined
acceptance criteria. Since predetermined accept-
ance criteria are indispensable for process valid-
ation, DOE study should not be categorised as an
event of process validation. Therefore, it is pro-
posed that DOE study had better be separated
from Equipment Validation OQ documents.
– Process Validation PQ for Component
Production Level
Describe what validation, what component pro-
duction process, and what medical device are
aimed at, and also the prerequisite equipment
validation (e.g., Equipment Validation IQ/OQ)
should be completed before starting the protocol
execution. In addition, Process Validation PQ pur-
pose (e.g., documented verification that the com-
ponent production process under the normal
operating condition and regular production envir-
onment can consistently produce a component
product meeting the predetermined requirements
and quality characteristics) should be stated.

– Process Validation PQ for Device Assembly Level
Describe what validation, what device assembly
process (e.g., device assembly lines, plastic
moulding toolsets), and what medical device are
aimed at. In addition, the prerequisite component
production level validation (e.g., plastic compo-
nents, metal components), device assembly level
equipment validation, and device test equipment
validation should be completed before starting
the protocol execution. Further, Process
Validation PQ purpose (e.g., documented verifica-
tion that the device assembly process under the
normal operating condition and regular produc-
tion environment can consistently produce a
device meeting the predetermined requirements
and quality characteristics) should be stated.

Scope
– Equipment Validation OQ & PQ
Describe the validation activity applies to what
equipment, and follows what standard operating
procedure (SOP), validation master plan, valid-
ation plan, etc. In addition, Equipment Validation
OQ test items, and Equipment Validation PQ test
items & how many test batches (e.g., three con-
secutive batches) should be stated.
– Process Validation PQ for Component
Production Level
Describe the validation activity applies to what
component production process, and follows what
SOP, validation master plan, validation plan, etc.
In addition, Process Validation PQ test items &
how many test batches should be stated.
– Process Validation PQ for Device Assembly
Level
Describe the validation activity applies to what
device assembly process, and follows what SOP,
validation master plan, etc. In addition, Process
Validation PQ test items & how many test
batches should be stated.

Responsibilities
Describe what documents (e.g., validation protocol/
report, User Requirement Specification (URS),
Functional Specification (FS), Design Specification (DS),
Failure Mode and Effect Analysis (FMEA), product
drawing, Quality Control (QC) inspection instruction,
equipment operating instruction, instrument calibra-
tion, maintenance instruction) should be prepared,
and what activities for the protocol (e.g., protocol
review and approval, protocol implementation) should
be performed, and by what roles (e.g., validation
leader, Quality Assurance (QA) leader, engineering
leader, calibration leader) in an organisation.
JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY 433

System Description
– Equipment Validation OQ & PQ
Describe the equipment (e.g., equipment name,
equipment number, equipment model number,
equipment serial number, equipment type (e.g.,
production, testing), supplier, equipment dia-
grams/pictures) and equipment operating pro-
cess (e.g., operating process flow chart, flow
chart description, product illustrate).
– Process Validation PQ for Component
Production Level
Describe the component production process
used equipment (e.g., equipment name, equip-
ment number) and component production pro-
cess (e.g., production process flow chart, flow
chart description, product illustrate).
– Process Validation PQ for Device Assembly Level
Describe the device assembly used components
(e.g., part name, part number, moulding tool
number, part drawing number/revision), device
assembly line number and equipment (e.g.,
equipment name, equipment number), and
device assembly process (e.g., assembly process
flow chart, flow chart description, prod-
uct illustrate).

References
– Equipment Validation OQ & PQ
List the validation related documents (e.g., pre-
requisite validation protocol and report num-
bers, URS, FS, DS, FMEA, assembly drawing,
equipment operating instruction, QC inspec-
tion/measurement/test instructions).
– Process Validation PQ for Component
Production Level
List the validation related documents (e.g., pre-
requisite component production equipment &
test equipment validation protocol and report
numbers, production equipment operating
instructions, QC inspection/measurement/test
instructions).
– Process Validation PQ for Device Assembly
Level
List the validation related documents (e.g., pre-
requisite component production process valid-
ation protocol and report numbers, assembly
equipment and test equipment validation
protocol and report numbers, assembly equip-
ment operating instructions, QC inspection/
measurement/test instructions).

Test Plan
For OQ and PQ validation protocols, test plan (or test
procedures) section is much more important than any
434 Y.-L. CHEN
other section in the protocols, and it describes how
to validate (or qualify) the equipment/system/process.
Depending on the test plan’s complexity and quality
risk, generally two formats (simple & detailed) of test
plan are used, which are detailed below.
– Simple Test Plan
Simple Test Plan is in a checklist table form used
for simple verification tests. The table form test
plan includes multiple columns, such as verifica-
tion item Identification (ID), verification item
description, test method description, equipment
expected response, whether test results are as
expected, reference to URS item number/FS item
number/Process-FMEA (P-FMEA) item number,
verified by/date. This Simple Test Plan is gener-
ally used for equipment’s individual component/
feature functional verification tests (e.g., safety,
alarm, error proof, interlock feature, parameter
control, computer system, HMI navigation, power
failure test), and therefore it is more suitable to
be used in Equipment Validation OQ protocol.
Some of the activities in the Simple Test Plan
can be moved to Equipment Validation IQ proto-
col while appropriate.
– Detailed Test Plan
Detailed Test Plan is used for complex and inte-
gration verification tests (e.g., Equipment
Validation OQ worst case test, Equipment
Validation PQ normal operating condition test,
Process Validation PQ test for Component
Production Leve, Process Validation PQ test for
Device Assembly Level) in validation OQ & PQ
protocols, and is in a form comprising multiple
subsections shown below.
 Raw Material & Instrument
 Operating Parameter Setting
 Test Batch Setting
 Test Item
 Inspection & Test Method
 Sampling Plan and Sample Number
Designation
 Acceptance Criteria
 Test results and Statistics
Detailed Test Plan is complex and critical, and its con-
tents can vary widely depending on different valid-
ation cases, Therefore, it will be described and
analysed separately in the following Section 3.

Deviation & Abnormal Results Handling
Any deviations (e.g., non-conformance of test
results, validation execution non-compliant with
Standard Operating Procedure (SOP)/validation
protocol) and their handling during the validation
should be summarised in the validation report, and
it should include deviation description, investiga-
tion & root cause analysis, corrective action, re-test
results, and conclusion. While necessary, a formal
and separate deviation report should be prepared
to facilitate the deviation handling. For abnormal
results (e.g., outlier data, unexpected data trend)
but still within the specification, the investigation
extent should be proportional to the incident risk
level, and the investigation results need to be
reported in the validation report.

Revision History
Describe the protocol revision number, effective
date, prepared by, change control number, and
change description.
3. Typical subsection structure & contents for
detailed test plan
A Detailed Test Plan is needed while a test item’s test
procedures are complex and critical, and generally the
test procedures information (e.g., how to conduct the
test, what are the rationales for setting the test batch
size and sampling plan, how to express the test
results, how to judge pass/fail for the test results)
needs to be described in details. For some test items,
each of them needs to utilise a separate Detailed Test
Plan, so multiple Detailed Test Plans could be needed
in one validation protocol. For other test items, all of
them could be covered in a single Detailed Test Plan
if the test information, including raw material, operat-
ing parameter setting, and test batch setting, is the
same. To simplify a validation protocol, minimising the
Detailed Test Plan number could be better. Detailed
Test Plan is an essential part of a validation protocol,
and therefore it should be carefully prepared,
reviewed, and approved by the validation team mem-
bers (including QA). A typical subsection structure &
contents for Detailed Test Plan is proposed and ana-
lysed below for production equipment/system/process
validation. As for common equipment & test equip-
ment validation, their validation approach and OQ
Detailed Test Plans will be separately described and
analysed in the following Section 4.
3.1. Raw material & instrument

Subsection Purpose
To describe what raw materials are used for the
validation test and what instruments are needed

for the validation sample inspection/measure-
ment/test.

Raw Material
For instruction purpose, all raw materials (e.g., plas-
tic resin, metal wire coil/tube, component, subas-
sembly) to be used in OQ/PQ validation exercises
should be described with raw material name, part
number (or drawing number/revision), etc. in the
validation protocols. For traceability and investiga-
tion purposes, all raw materials used for the valid-
ation exercises should be recorded with raw
material name, batch number, etc. in the valid-
ation reports.

Instrument
For instruction purpose, all instruments (e.g., 3D
vision measuring system, functional test machine,
Instron test machine, stand-alone balance) to be
used for OQ/PQ validation sample inspection/meas-
urement/test should be described with instrument
name, model number, etc. in the validation proto-
cols. For traceability and investigation purposes, all
instruments used for the validation exercises
should be recorded with instrument name, equip-
ment number, etc. in the validation reports.
3.2. Operating parameter setting

Subsection Purpose
To describe what equipment operating parameters
and their set values should be used for the valid-
ation test.

Operating Parameter (or Controllable Process
Parameter) Classification (as an example)
– Critical Process Parameter (CPP): A process par-
ameter whose variability has a significant
impact on a critical quality attribute.
– Non-Critical Process Parameter (NCPP): A pro-
cess parameter whose variability has a minor
impact on a critical quality attribute.
– Non-Quality Process Parameter (NQPP): A pro-
cess parameter whose variability has no effect
on critical quality attributes, but has a signifi-
cant impact on process performance (e.g., yield,
cycle time).

Operating Parameter and Range Setting Study
Before setting equipment operating parameters for
CPP and NCPP, their values need to be obtained
through a DOE study. This study encompasses
screening experiments for CPP parameters identifi-
cation, and response surface studies for both CPP
JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY 435
parameter targets optimisation and CPP parameter
process windows finding.

Major Test Cases for Operating Parameter Setting
For Equipment Validation OQ worst case test, both
CPP parameter upper limits and lower limits, NCPP
parameter settings, and NQPP parameter settings
(if existing) should be listed. Normal parameter
(generally the mid-points between the upper and
lower limits of the CPPs) case test is better to be
included in the OQ worst case test, but not manda-
tory. For Equipment Validation PQ and Process
Validation PQ tests, generally only normal parame-
ters are listed. Further, during the batch running
(or sample build), CPP and NCPP parameters must
follow the protocol settings (cannot be changed),
however, NQPP parameters are allowed to be
adjusted while necessary.

Other Test Cases for Operating Parameter Setting
Except for Equipment Validation OQ worst case
test, Equipment Validation PQ test, and Process
Validation PQ test cases, there may be some other
test cases that also need to describe operating par-
ameter settings. For example, assembly equip-
ment’s inspection sensors for checking correct
assembly positions should be verified for their
functionality/capability (e.g., challenge test, Gage
Repeatability and Reproducibility (R&R) test) with a
Detailed Test Plan in the Equipment Validation OQ
protocol, and then the inspection sensor parameter
settings should be listed in the subsection.
3.3. Test batch setting

Subsection Purpose
To describe how many test batches (or test runs)
(e.g., 3 consecutive batches for PQ test, parameter
upper limit condition & lower limit condition
batches for OQ worst case test) should be con-
ducted, what is the test batch size (e.g., producing
1200 pcs/batch for sample build, 4 h running/batch
for sample build), and other important information.

How many PQ Consecutive Test Batches
Consideration
According to GHTF process validation guidance,
the PQ test should be repeated enough times to
assure that the results are meaningful and consist-
ent. Based on FDA 2011 Process Validation
Guidance: Process Validation Revisited [4], it men-
tioned that “despite the pervasive practice of
three-batch validation, FDA’s position remains that
there never was a three-run requirement, and the
protocol should specify a sufficient number of
436 Y.-L. CHEN
replicate process runs to demonstrate reproducibil-
ity and provide an accurate measure of variability
among successive runs. Accordingly, the FDA 2011
guidance recommends an approach to process val-
idation that is tailored to and based upon up-front
learning and knowledge about the product and
process rather than simply getting to the goal of
three acceptable batches.” In addition, from
Pharmaceutical Inspection Co-operation Scheme
(PIC/S) process validation guidance
(Recommendation on validation master plan, instal-
lation and operational qualification, non-sterile pro-
cess validation, cleaning validation [5]), it described
that “it is generally considered acceptable that
three consecutive batches/runs within the finally
agreed parameters, giving product of the desired
quality would constitute a proper validation of the
process.” Therefore, there is no rule of how many
PQ batches should be run, however, if there are no
special reasons that can be justified, at least 3 con-
secutive batches should be conducted for PQ tests.

Process Validation PQ Test Batch Size Consideration
For medical devices manufacturing, generally their
productions are not batch-wise operation, and
therefore there is no requirement that “the Process
Validation PQ should be maintained as the same
batch size as the commercial production” described
in pharmaceutical process validation guidance
documents. For medical device Process Validation
PQ, challenges to the process should include the
conditions that will be encountered during regular
commercial production, which includes human fac-
tor challenge (e.g., stress, shift change) and envir-
onment factor challenge (e.g., temperature,
humidity). In addition, the batch size setting should
consider the following factors: risk assessment of
the equipment/process/product, how long each
machine should operate to test tear and wear of
equipment, the PQ batch size had better be two-
time larger than the inspection sample size so that
the spare samples can be used for investigation
purpose while deviation occurs, customer’s require-
ments, etc.

Test Batch Setting Rationale
The rationale for OQ test batch setting may not be
mandatory in the protocol, however, for PQ tests
(either Equipment Validation PQ or Process
Validation PQ), it should be mandatory to rational-
ise the test batch setting (including how many test
batches and test batch size), because one of the
PQ purposes is to test the operation/process
repeatability and long-term stability. The test batch
setting should demonstrate the PQ purpose can
be achieved.

Actions to differentiate Batches
For the OQ worst case test, since the parameter
settings will be changed between batches, there is
no need to describe any actions between OQ worst
case test batches (e.g., upper limit, lower limit con-
ditions). For the PQ tests, since the process param-
eter settings are the same (at normal values)
between test batches, what actions (e.g., shut
down the machines, change the machine opera-
tors, use raw material of different batches or differ-
ent suppliers, implement line clearance) should be
taken between batches to differentiate them
should be described.

Device Assembly Level Process Validation PQ
Compared with other validation tests, device
assembly level process validation PQ is the most
important validation activity since it combines the
actual facility, utilities, equipment, and the trained
personnel with the commercial manufacturing pro-
cess, control procedures, and all components to
produce simulated commercial batches for final
devices, and that will demonstrate the commercial
device manufacturing process performs as
expected. The PQ test is generally considered
costly because it allocates most resources (includ-
ing operators, engineers, all components, assembly
lines, test instruments/machines) and is deemed
the last validation activity for a medical device pro-
ject. Because the test is for production system as a
whole, except how many PQ batches should be
conducted, what is the PQ batch size, and how to
differentiate PQ batches, there are other important
items should be described in the subsection as
well, such as how many assembly pieces should go
through each assembly line/machine, how to make
the components/sub-assemblies from different
moulding toolsets evenly go through the assembly
lines/machines, how many production batches of
each component should be used, whether different
suppliers’ components should be used, etc.

Training
Production, QC personnel should be trained for the
related production/test equipment operation, SOPs,
and the test plans of validation protocols.

Product Disposition in Device Assembly Level
Process Validation PQ
Only the product (or finished device) from Device
Assembly Level Process Validation PQ batches can

be for commercial use, and therefore in the subsec-
tion, it should mention that the disposition of the
product should be documented in the PQ report.
3.4. Test item

Subsection Purpose
To describe what items (e.g., appearance, dimen-
sion, force, ink permanency, function, assembly
condition) should be inspected, measured and
tested. While there is no separate validation trace-
ability matrix, the test items sourced requirements
should be referenced for traceability.

Test Item Source
Test items are generally sourced from URS, p-FMEA,
QC inspection instruction, equipment work instruc-
tion, process validation SOPs, etc.

P-FMEA Source
In the p-FMEA score sheet, the critical risk items
with Severity (SEV)  xx and/or RPN (Risk Priority
Number)  yy should be addressed by the valid-
ation tests.

Plastic Injection moulding Process Test
Generally, it could include the test items of part
dimension, appearance, function, etc.

Device Assembly Level Equipment Validation OQ
worst Case Test and PQ Test
Generally, it could include the test items of sub-
assembly dimension, appearance, function, assem-
bly condition, etc.

Device Assembly Level Process Validation PQ Test
Generally, it could include the test items of final
assembly (or final device) dimension, appearance,
function, etc.
3.5. Inspection & test method

Subsection Purpose
To describe what methods (or instructions) should
be used for each test item’s sample inspection/
measurement/test.

Method Validation Requirement
Except for simple inspection (e.g., visual), test
methods/instruments should be qualified/validated
to secure the valid results before being used for
OQ/PQ validation sample inspection/measure-
ment/test.

Method Validation Approach
According to 21 CFR Part 820, Medical Devices -
Quality System Regulation QSR [6], Section 820.72,
it mentioned that “Inspection, measuring, and test
equipment: Each manufacturer shall ensure that all
JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY 437
inspection, measuring, and test equipment is suit-
able for its intended purposes and is capable of
producing valid results.” For medical devices, gen-
erally, the inspection/measurement/test are for
physical property (e.g., dimension, force, time,
weight) instead of chemical property (e.g., impurity,
assay). The qualification of physical property meas-
urement is focussed on accuracy and precision.
Accuracy mainly relies on instrument calibration,
and precision is secured by Gauge R&R study. Both
of which should be executed to prove the method/
instrument is suitable for its intended use. The
term of “test method validation” is more used for
chemical property measurement (or analytical
method) qualification, which includes more test
items, such as accuracy, precision, specificity, linear-
ity, range, detection limit, etc.
3.6. Sampling plan and sample number
designation

Subsection Purpose
To describe what acceptance sampling plans and
their sample number designations should be used
for the validation test.

Acceptance Sampling Plan
According to GHTF process validation guidance,
Section A1, it mentioned that “Acceptance sam-
pling plans can be useful in optimising the number
of samples to be tested and to demonstrate con-
formance to specification.” Section A3 described
that “an acceptance sampling plan takes a sample
of product and uses this sample to make an accept
or reject decision.”

High Degree of Assurance
According to 21 CFR Part 820 - Section 820.75, (a),
“where the results of a process cannot be fully veri-
fied by subsequent inspection and test, the process
shall be validated with a high degree of assurance.”
Based on FDA Process Validation Guidance: General
Principles and Practices [2], Section IV, C, 3, PPQ
Protocol, it described that “The sampling plan
should include sampling points, number of sam-
ples, and the frequency of sampling for each unit
operation and attribute. The number of samples
should be adequate to provide sufficient statistical
confidence of quality both within a batch and
between batches. The confidence level selected
can be based on risk analysis as it relates to the
particular attribute under examination. Sampling
during this stage should be more extensive than is
typical during routine production.” Therefore, a
438 Y.-L. CHEN
high degree of assurance means a relative compari-
son. For example, for the same test item, validation
test’s acceptance sampling plan should be stricter
and/or with more extensive sampling than that of
routine production QC lot release test to demon-
strate a high degree of assurance that the process
capability of conformance to the test item specifi-
cation can be reached in validation.

Sampling Plan Procedure
Each device company should establish sampling
plan SOPs that describe how to the select statistic-
ally valid acceptance sampling plans for inspection
by attribute (pass/fail, go/no go results) and vari-
able (numerical results) data types for both routine
production and process validation. In addition,
acceptance sampling plan selection should be
based on defect risk severity level (e.g., low, moder-
ate, critical, catastrophic) which could bring out dif-
ferent confidence levels, probability content levels,
AQLs, RQLs, etc., and then lead to different sam-
pling plans.

Sampling Plan Standard
Where appropriate, sampling plan standard ISO
2859-1 [7] (or ANSI/ASQ Z1.4 [8]) for attribute test
and ISO 3951-2 [9] (or ANSI/ASQ Z1.9 [10]) for vari-
able test can be used. At the same Acceptance
Quality Limit (or Acceptable Quality Level) (AQL),
process validation is recommended to adopt
General Inspection Level II and single sampling
plan for tightened inspection while the routine pro-
duction uses the single sampling plan for nor-
mal inspection.

Defect Risk Severity Level Analysis
P-FMEA is a source of risk severity level analysis.
However, if the test item is not covered by p-
FMEA, then the risk severity level can be assessed
by several aspects, such as device end user safety
(e.g., life threatening injury, non-life threatening
injury, temporary discomfort), device function
impact (e.g., loss of device function, cosmetic
defect), and production impact (e.g., major disrup-
tion of production, minor disruption of production).

Sampling Plan Rationale
According to FDA 21 CFR Part 820, Section O –
Statistical Techniques, “(a) Where appropriate, each
manufacturer shall establish and maintain proce-
dures for identifying valid statistical techniques
required for establishing, controlling, and verifying
the acceptability of process capability and product
characteristics. (b) Sampling plans, when used, shall
be written and based on a valid statistical rationale.
Each manufacturer shall establish and maintain
procedures to ensure that sampling methods are
adequate for their intended use.” For Equipment
Validation OQ/PQ, it could be better if sampling
plan rationale is provided, however, it is not man-
datory. For Process Validation PQ, since it is a simu-
lation of commercial production, a valid statistical
rationale for sampling plan should be documented
to provide evidence that it will have a higher level
of sampling and/or greater scrutiny of process per-
formance than would be typical of routine com-
mercial production.

Sample Number Designation
Generally, sample number should be designated
and marked on the samples to prevent test data
mix-up, secure the correct test data trend, and
facilitate investigation once non-conformity is
detected. Sample number should indicate which
validation batch the sample is used for, what test
item the sample is used for, the sampling point,
sampling time sequence along the validation batch
running, etc.
3.7. Acceptance criteria

Subsection Purpose
To describe what specifications and their accept-
ance criteria for each test item should be used for
the validation test.

Specification
For each test item, the test specifications, including
both individual sample test specification (e.g.,
appearance, dimension) and statistical specification
(e.g., Cpk, Ppk, k value, data normal distribution),
should be clearly described so the test result
“conformed/non-conformed” judgement can be
correctly made.

Acceptance Criteria
For each test item, both acceptance criteria (e.g.,
accept: 0/reject: 1, accept: 2/reject: 3) for individual
sample test specification and the acceptance crite-
ria (e.g., conformed to the specification) for statistic
specification should be clearly described so the test
item results pass/fail judgement can be correctly
made. Except for cosmetic defect, the acceptance
criteria for individual sample test specification is
better to set at accept: 0, reject: 1. Otherwise, while
some failure samples are detected, the test item
result still could be deemed passed. Under the cir-
cumstance, the defect samples generally still need
to be investigated for their failures, and it will cost
time. In addition, choosing accept: 0, reject: 1 sam-
pling plan (if allowed) means a smaller sample size

is used for the test, and that is considered
more efficient.

Acceptance Criteria for statistical Specification
For the test data in variable, it is preferred to use
the variable test sampling plan (e.g., ISO 3951-2,
ANSI/ASQ Z1.9) with statistical specification (e.g., k
value) to verify the process capability. And the rea-
son is: under the same level of quality assurance
(e.g., same AQL) the test sample size of variable
test sampling plan can be significantly reduced
while compared with the attribute test sampling
plan (e.g., ISO 2859-1, ANSI/ASQ Z1.4). However,
there are some concerns over the acceptance crite-
ria for variable test sampling plan, such as the test
data resolution should be sufficient (e.g., It is better
to use at least two more decimal places of the
measured data while compared with the specifica-
tion ones.). Otherwise, it will affect the Ppk, k value,
and normality test (e.g., Anderson Darling p value)
results, and consequently impair the meaning of
the statistical results (e.g., 99.7% of all data points
will be within ±3standard deviation). In addition,
variable data with non-normal distribution could
be a problem for meaningful statistical results. To
overcome the concerns, sometimes attribute test
sampling plan is preferred to variable test sam-
pling plan.

Commonly Used Process Capability Acceptance
Criteria
If there is no variable statistical specification
requirement, a simple way is to use process cap-
ability index Ppk (or Cpk), which had better be set
at ⭌1.33. Ppk set at ⭌1.0 could be acceptable
while the risk severity level is not high or there is a
proper justification. For example, during plastic
injection moulding process validation, the Ppk of
critical dimension for each cavity could be set at
⭌1.33, however, the Ppk of critical dimension for
cross-cavity (or total population) set at ⭌1.0 is
deemed reasonable/acceptable because cross-cav-
ity Ppk value is generally lower than that of single
cavity. In addition, the test sample size should be
large enough (e.g., better ⭌30 pieces) to make the
Ppk result more meaningful.
3.8. Test results and statistics

Subsection Purpose
To describe how test results should be analysed, as
well as what test results, defect amounts, statistical
data (e.g., mean, maximum, minimum, standard
deviation, k value, Ppk), test result pass/fail
JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY 439
judgement, and results expression forms (e.g.,
table, graph) that should be presented in the valid-
ation report.

Device Assembly Level Process Validation PQ Test
Results
Device Assembly Level Process Validation PQ Test
(equivalent to the Process Performance
Qualification (PPQ) shown in FDA process valid-
ation guidance [2]) is most important and last val-
idation activity in a device project, and it integrates
all the component production performance and
assembly equipment operation to demonstrate that
the final medical device can be consistently pro-
duced that meets its predetermined specifications
and quality attributes (e.g., appearance, dimension,
function). For variable test results, except for the
statistical result table for descriptive statistics and
process capability indices, process stability should
be checked by using a scattered data graph or
Statistical Process Control (SPC) chart for sample
data trend. If any abnormal data trend (e.g., con-
tinuous increase/decrease along the validation
batch running, data points jump/fall to another
steady level, outlier data occurrence) is identified
and considered risky to the product quality, the
incident should be investigated for root cause find-
ing (e.g., component batch number change, assem-
bly equipment status change, test equipment
status change), and corrective actions should be
taken to prevent the recurrence.

Statistical Results Pass/Fail Judgment
The statistical techniques of process capability
index, process stability, and data distribution nor-
mality are rough rules of thumb, and they should
be carefully used while making important decision
on the validation results pass/fail judgment. In
other words, if any negative statistical result (e.g.,
capability indices do not meet the specifications,
process is unstable, test data are not normally dis-
tributed) occurs, unless the failure is obvious and
certain, a more detailed and formal statistical ana-
lysis should be performed, or statisticians should
be consulted to further clarify the issue and make
the right decision.
4. Validation approach and OQ detailed test
plan for common equipment and
test equipment
Since the production equipment/process are the focus
for GHTF process validation guidance, their validation
approach is more described in the guidance. For
440 Y.-L. CHEN
common equipment and test equipment, they are
important as well, however, not much validation
approach is illustrated in the guidance. For the reason,
the following provides the validation approach and
OQ Detailed Test Plan for these two types
of equipment.
4.1. Validation approach and OQ detailed test
plan for common equipment validation
Common equipment means non-project specific
equipment which needs to install additional project
specific tools or fixtures to perform their functions. For
example, injection moulding machine needs to install
a project specific moulding tool to perform plastic
injection moulding production, ink printing machine
needs to install a project specific printing plate to per-
form printing production, and Instron test machine
needs to install project specific test fixtures to perform
testing function.
For common equipment, it is better to utilise two-
step validation approach, which includes 1st step of
common equipment’s Equipment Validation IQ, OQ to
verify the common equipment (without installing pro-
ject specific tools or fixtures) performance, and 2nd
step of project specific tools or fixtures’ Equipment
Validation IQ, OQ and Process Validation PQ (where
applicable) to verify the combined equipment (com-
mon equipment þ project specific tools or fixtures)
performance. For clarification, three examples are
given below.

Example 1
For the combined equipment of “injection mould-
ing machine þ project specific moulding tool”, 1st
step validation is the common equipment
“injection moulding machine” needs to conduct
Equipment Validation IQ/OQ, and 2nd step valid-
ation is the project specific moulding tool needs to
conduct Equipment Validation IQ, OQ, and Process
Validation PQ.

Example 2
For the combined equipment of “ink printing
machine þ project specific printing plate”, 1st step
validation is the common equipment “ink printing
machine” needs to conduct Equipment Validation
IQ/OQ, and 2nd step is the project specific printing
plate needs to conduct Equipment Validation IQ,
OQ, and Process Validation PQ.

Example 3
For the combined equipment of “Instron test
machine þ project specific test fixtures”, 1st step
validation is the common equipment “Instron test
machine” needs to conduct Equipment Validation
IQ/OQ, and 2nd step is the project specific test fix-
tures needs to conduct Equipment Validation IQ,
OQ, and Process Validation PQ (where applicable).
The advantages of the two-step validation
approach include: 1) Simplified re-validation: Once
common equipment is relocated, the moved common
equipment only needs to be re-validated for its IQ, OQ
with using a reduced-scale validation approach (e.g.,
re-validate those items, shown in the initial common
equipment validation protocols, impacted by the
relocation), and there is no connection to the project
specific tools or fixtures; 2) Efficient documentation:
The separation of the common equipment’s validation
documents from the project specific tools or fixtures’
validation documents is beneficial to the documents
archiving and retrieval.
The OQ test items of a common equipment should
be aimed at the performance by itself, and there
should be no linkage to the project specific tools or
fixtures of the common equipment. For example,
Instron test machine OQ test could design a test pro-
gramme which does not need to use project specific
test fixtures, and the test programme could include
four testing parameter items (displacement, speed,
force and time) with different settings for each item to
verify the Instron’s key functional performance by
itself. The common equipment’s Equipment Validation
OQ test plan can use the same subsection structure of
Detailed Test Plan shown in the Section 3 above.
4.2. Validation approach and OQ detailed test
plan for test equipment validation
According to EU Guidelines for Good Manufacturing
Practice for Medicinal Products for Human and
Veterinary Use, Annexe 15: Qualification and
Validation [11], Section 5.9 described that “equipment,
facilities, utilities and systems used for process valid-
ation should be qualified, and test methods should be
validated for their intended use.” Section 9.1 men-
tioned that “all analytical test methods used in qualifi-
cation, validation or cleaning exercises should be
validated with an appropriate detection and quantifi-
cation limit where necessary.” In addition, based on
GHTF process validation guidance, Section A.3, it
described “Gauge R&R Study – study for evaluating
the precision (repeatability & reproducibility) and
accuracy of a measurement device should be con-
ducted.” As mentioned earlier, the term of test

method validation is more used for chemical property
measurement qualification especially in pharmaceut-
ical industry. For physical property measurement quali-
fication in medical device industry, only accuracy test
and precision test (Gauge R&R test) from the test
method validation are required. Based on the above,
for medical device test equipment, except for simple
measurement instruments (e.g., balance, calliper, force
gauge), all the other test equipment (e.g., Instron test
machine/test fixture, bespoke test machine), involving
custom-made test fixtures and test instructions, need
test equipment validation. For which, it includes 1st
step of common test equipment’s Equipment
Validation IQ, OQ, and 2nd step of project specific test
fixtures’ Equipment Validation IQ, OQ. To simplify val-
idation practice and documentation, the accuracy test
and precision test from the test method validation can
be performed in conjunction with the test fixtures’
Equipment Validation OQ.
For any type of equipment (e.g., test equipment,
production equipment, facilities, utilities), the IQ check
items are very similar, which generally include equip-
ment design features, installation conditions, environ-
mental conditions, safety features, supplier documents,
calibration, preventive maintenance, spare parts, and
computer system (including software) verification, etc.
However, there is almost no description of how to con-
duct OQ/PQ for test equipment in medical device GHTF
process validation guidance. Hence, the test items
below are proposed for the Detailed Test Plans of test
fixtures’ Equipment Validation OQ protocol.

Process Parameter Window Test
Generally, all the equipment test parameters are set
at the appropriate values before the OQ test, and
there is no allowable parameter range that can be
adjusted during sample testing. Under the general
case, there is no need to conduct the parameter win-
dow test. However, for a special case while the
equipment test parameter settings (e.g., position
range parameter settings for peak force searching in
Instron testing) may need to be changed during sam-
ple testing, the window test should be conducted.

Test Programme Verification Test
While a test programme is needed for a project
specific testing (e.g., Instron þ test fixtures), the test
graphs should be checked to verify whether the
test data captured is correct by following the test
description.

Accuracy Test
To check a project specific testing accuracy. While
the measurement is direct (e.g., force test by load
JOURNAL OF MEDICAL ENGINEERING & TECHNOLOGY 441
cell), instrument calibration should be sufficient to
prove the measurement accuracy. However, while
the measurement is indirect or the accuracy could
be impacted by the test programme, the accuracy
test (e.g., compare the test data obtained in the
indirect measurement with those obtained in the
direct measurement) should be performed.

Good and Bad Samples Test
To check whether a project specific testing can dif-
ferentiate good samples from bad ones. Generally,
the bad samples (or failure samples) should be pur-
posely made. The good and bad samples test
should be conducted especially while the test fix-
tures, test programme are custom-made and the
test system (i.e., common test equipment þ test fix-
tures þ test programme) is equipped with auto-
matic pass/fail judgment.

Repeatability Test & Reproducibility Test
This is commonly known as Gauge R&R test. For
non-destructive test (e.g., dimension measurement),
Gauge R&R test is straightforward. However, for
destructive test, Gauge R&R test is more difficult
since the test samples cannot be re-tested, and
controlled sample groups used for the test could
be difficult to be prepared.

Comparison Test
To compare the test results from a new and differ-
ent type test system with the existing one to
ensure the test results between the new and old
test systems are equivalent.
Generally, there is no need to develop a dedicated
PQ protocol for test equipment, because the long-
term stability and repeatability performance require-
ment of the test equipment can be verified in the
Process Validation PQ (either in the Component
Production Level Process Validation PQ or Device
Assembly Level Process Validation PQ depending on
where the test equipment is used). The test fixtures’
Equipment Validation OQ test plan for all the test
items above can use the same subsection structure of
Detailed Test Plan shown in the Section 3 above.
5. Conclusion
Based on the description and analysis above, the fol-
lowing conclusions can be drawn:

The terms of qualification, validation, and process
validation are a little bit tricky, and should be
clearly defined in the medical device company’s
SOPs, validation master plans, etc. In the subject
442 Y.-L. CHEN
article, the term of validation is used instead of
qualification even though these two terms should
be interchangeable in medical device industry. For
example, Equipment Validation IQ/OQ/PQ is used
instead of Equipment Qualification IQ/OQ/PQ. The
term of process validation (or traditional process
validation) includes individual equipment’s
Equipment Validation IQ, OQ, PQ and integrated
process/system’s Process Validation PQ.

For process validation practitioners, one of the most
challenge tasks is to develop process validation pro-
tocols, especially for OQ and PQ. A typical section
structure (including Title & Signature Page, Table of
Contents, Purpose, Scope, Responsibilities, System
Description, References, Test Plan, Deviation &
Abnormal Results Handling, and Revision History)
and contents for OQ and PQ validation protocols
are provided based on the medical device two-level
process validation approach, and that should facili-
tate the OQ/PQ validation protocols development.

Test plan describing how to validate the equip-
ment/process/system is an essential part of OQ/PQ
validation protocols, and two formats (simple &
detailed) of test plan are proposed. Simple Test
Plan with a simple table form is mainly used for
the equipment’s individual and simple component/
feature functional verification test and that is gen-
erally with characteristics of lower risk and less
complex. Detailed Test Plan with multiple subsec-
tions in the OQ/PQ protocols is more suitable to be
used for both individual and complex component/
feature functional verification test and integrated
equipment/process/system functional verification
test that are generally with characteristics of higher
risk and more complex. Detailed Test Plan is more
critical than Simple Test Plan.

Detailed Test Plan’s subsections, including Raw
Material & Instrument, Operating Parameter Setting,
Test Batch Setting, Test Item, Inspection & Test
Method, Sampling Plan and Sample Number
Designation, Acceptance Criteria, and Test results and
Statistics, are proposed, which should be able to make
the test plan description clear and complete with
rationales to justify how the test plan is set based on
science, risk, statistics and regulatory requirement con-
siderations. In addition, the subsection contents are
provided with analysis, which should be able to help
process validation practitioners develop appropriate
and justifiable Detailed Test Plans.

Except for the validation approach (IQ/OQ/PQ
framework) and Detailed Test Plan used for produc-
tion equipment’s Equipment Validation OQ/PQ and
production process’ Process Validation PQ, valid-
ation approach and OQ Detailed Test Plan used for
common equipment & test equipment are pro-
vided and analysed as well, and that should make
the validation approach and Detailed Test Plan
more clear and complete for the whole picture of
medical device process validation.
Disclosure statement
No potential conflict of interest was reported by the author.
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