3. Contents
Medical devices and categories
Medical device validation in quality systems
Regulatory requirements of validation for
medical devices
Validation for medical devices
Process validation for medical devices
Validation of medical devices and critical
issues
Risk assessment for validation
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4. Medical devices and categories
A medical device is an implant and
equipment to be used either to
achieve disease diagnosis, medical
treatment, or disease prevention for
human and animals, or to influence
the physical structure and function
of human and animals.
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5. Contin….
Medical devices for humans may
also be classified based on
whether and how long the device
is in contact with tissue or cells
and on the degree of disjunction
induced by the device when in a
disabling situation.
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6. Categories
Category 1: Medical devices that are
controlled by in-process tests, with critical
specifications designed for both individual
products and a group, but not implemented
in human and animals.
Category 2: Medical devices that are
composed in batches and are tested with
representatives in a batch.
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7. Category 3: Medical devices that are controlled
with each component (part) for assembly in
the manufacturing process, and constituted
(assembled) and maintained at the user site. Of
course, the function of the medical device after
assembly must be tested before release.
Category 4: Medical devices that are controlled
by in-process tests, with critical specifications
designed for both individual products or a
group, and are implemented in human and
animals for the long term.
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8. Medical device validation in quality systems
1. ISO 13485: The supplier shall establish, document,
and maintain a quality system as a means of
ensuring that product conforms to specified
requirement. The supplier shall prepare a quality
manual covering the requirements of ISO 9001.
2. CFR21 Section 820.5 Quality System: Each
manufacturer shall establish and maintain a quality
system that is appropriate for the specific medical
device(s) designed or manufactured, and that meets
requirements of this section.
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9. 3. Global Harmonization Task Force
(GHTF), which was formed to harmonize
regulatory requirements for the medical
device may recommend referring to ISO
10013 for general guidance on the content of
a quality manual.
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10. Regulatory requirements of validation for
medical devices
Validation includes the design concept (design
of product developed), design verification,
each qualification for manufacturing, and
assay/test equipment, including the
establishment of a maintenance program, the
development stage of manufacturing operation
conditions and test methods, and individual
validation (process validation and analytical
method validation).
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11. Contin….
Validation is thus required to ensure the
establishment of product specifications,
how the manufacturer maintains the
quality of a product in the
manufacturing process, and what factors
are critical in assuring the proper
functioning of the medical device.
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14. Process validation for medical devices
Validation in quality systems includes
establishment of procedures on how to qualify
the equipment and machinery, how to verify
the design of products, how to verify the
process designed, how to verify the
achievement of production procedures, how to
validate the process developed, and how to
validate the methods for measurement and
assay.
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15. Contin…..
Validation also requires verification of
specifications or acceptance criteria of in-
process parameters relating to both raw
materials and intermediate (in-process
product) and finished products, and
verification of acceptance criteria for in-
process parameters relating to operating
conditions of machinery and equipment.
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18. Risk assessment for validation
Because validation is required to establish
the quality of the medical device,
including reproducibility, each process
shall undergo risk assessment. Risk
assessment includes two criteria:
1. How the process can avoid the
appearance of rejected goods or other
unsatisfactory goods in each process, and
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19. 2. How the in-process parameters, including
in-process product specification, can detect
goods to be rejected or otherwise
unsatisfactory goods. Risk assessment for
medical devices is thus required to provide
satisfactory goods to customers by
controlling the manufacturing process and
by testing in-process product as well as final
product.
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21. Validation of in vitro diagnostic tests
Validated Diagnostic Test should:
“Provides test results that identify
positive or negative for an analyze or
process (e.g. antibody, antigen or in
duration at skin test site) with a degree
of statistical certainty”
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22. Development and validation of in vitro diagnostic
tests
Outline:
1) Analytical Validation
2) Clinical Validation
3) Regulatory Perspectives
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24. Analytical validation
Development Stage:
1. Feasibility Studies
- determine or identify a method for a particular use
- determine if the selected reagents and protocol
have the capacity to distinguish between a range
of antibody concentrations to an infectious agent
while providing minimal background activity
- Give initial estimates of repeatability, and of
analytical sensitivity and specificity
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25. Development/Validation Stage:
2. Assay Development and Standardization
Selection of optimal reagent concentrations
Determine the optimal temporal, chemical, and physical
variables in the protocol, e.g. incubation temperatures
and durations; pH, molarity of diluent, washing, and
blocking buffers
Repeatability – preliminary estimates (agreement
between replicates within and between runs)
Determination of analytical sensitivity (the smallest
detectable amount of the analyte) and specificity (the
degree to which the assay does not cross-react with
other analytes)
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26. Validation Stage:
3. Determining Assay Performance Characteristics
Determine diagnostic sensitivity and specificity
Precision- a measure of dispersion of results for a
repeatedly tested samples
Repeatability- the amount of agreement between
replicates
Reproducibility- the amount of agreement between
results of samples tested in different laboratories
Accuracy- the amount of agreement between a test
value and the expected value for an analyte in a
standard sample of known activity (clinical samples;
compare to cleared or gold standard method )
Selection of the cut-off/reporting threshold/LOD for
qualitative/LOQ for quantitative
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28. Considerations:
Purpose – assess clinical sensitivity,
specificity and reproducibility
Studies should be performed in a
representative sample of the intended use
population
Common components – Precision,
Reproducibility, and non-specificity of the
investigational assay
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30. Regulatory perspectives
FDA guidelines – 21 CFR 809.3(a)
In vitro diagnostic products are those reagents,
instruments, and systems intended for use in the
diagnosis of disease or other conditions, including a
determination of the state of health, in order to cure,
mitigate, treat, or prevent disease or its sequel. Such
products are intended for use in the collection,
preparation, and examination of specimens taken
from the human body. These products are devices as
defined in section 201(h) of the Federal Food, Drug,
and Cosmetic Act (the act), and may also be
biological products subject to section 351 of the
Public Health Service Act.
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31. Regulation by Risk
Risk defined by possible harm to patient of
unrecognized incorrect result
Three classes from low to high risk (Class I, II
&III) - Regulatory control increases from Class I
to Class III
Class I – most exempt from Premarket
Notification 510(k)
Class II – most require Premarket Notification
510(k)
Class III – most require Premarket Approval
(PMA)
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32. – A 510(k) is a premarketing submission made to FDA
to demonstrate that the device to be marketed is as
safe and effective, that is, substantially equivalent
(SE), to a legally marketed device that is not subject
to premarket approval (PMA).
– A PMA is an application submitted to FDA to
request approval to market, or continue marketing, a
class III medical device. PMA approval is based on
scientific evidence providing a reasonable assurance
that the device is safe and effective for its intended
use or uses. PMA process is more involved and
includes the submission of clinical data to support
claims made for the device.
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