Process Validation and Revalidation in Medical Device Production
Process Validation and Revalidation in Medical Device Production
Process Validation and Revalidation in Medical Device Production
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ScienceDirect
Procedia Engineering 174 (2017) 686 – 692
Abstract
In this paper, the author according to ISO13485:2003, YY / T 0287-2003 quality management system for medical device
regulatory requirements, and process validation guidance document GHTF-SG3-N99-10-2004, combined with the actual
implementation process in the enterprise, detailed the process and applications of process validation. Then share some the
statistical methods of data collection and analysis, describe how to do Design of Experiment experiments by Minitab software.
© 2016The
© 2017 TheAuthors.
Authors. Published
Published by by Elsevier
Elsevier Ltd. Ltd.
This is an open access article under the CC BY-NC-ND license
Peer-review under responsibility of the organizing committee of the 13th Global Congress on Manufacturing and Management.
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-review under responsibility of the organizing committee of the 13th Global Congress on Manufacturing and Management
Keywords: Process Validation, Minitab, Design of Experiment
The process validation is establishing by objective evidence that a process consistently produces a result or
product meeting its predetermined requirements. Since in some cases, such as some defect of product can’t be direct
verified by process inspection, but it will become manifest only after the product has been used. These processes
should be identified in advance or validation in order to ensure process capability and control all key parameters of
process.
Thus the process validation is to establish a documentary evidence that specific procedure can produce product of
meeting predefined specification and quality characteristic continuous with high confidence.
1877-7058 © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Peer-review under responsibility of the organizing committee of the 13th Global Congress on Manufacturing and Management
doi:10.1016/j.proeng.2017.01.207
Yincheng Zhao et al. / Procedia Engineering 174 (2017) 686 – 692 687
Concrete steps of validation is as follows. First, the establishment of the validation team, clearly functions as a
member. Determine process validation purposes. Clear the need of process. Master the principles of the process for
determining the specific process parameters and desired output. Determine the evaluation and acceptance criteria,
test methods, test tools, statistical analysis tools.
Then write process validation protocols, implement IQ, OQ, PQ. Finally, determine ongoing process controls,
and process monitoring. When appropriate, get on revalidation. A flow chart shown in Fig. 1.
Process validation protocols include a detailed scheme about how to implement Installation Qualification (IQ),
Operational Qualification (OQ), Performance Qualification (PQ), and revalidation.
Identification and
description of the process to
be confirmed
Making process
validation protocols
Installation
Qualification
Operational
Qualification
Performance
Qualification
Validation Summary
Report
Monitoring process
Revalidation decision
End
A detailed plan is the basic requirement to ensure the process is sufficient. Process validation program typically
includes the following components:
1) Objective of process validation
2) The scope of process validation including the operator, equipment, etc.
3) Responsibility and authority of personnel
4) Background and principles, including the description of the device, system, and process
5) Sample preparation programs
6) Process validation test items, test methods and acceptance criteria. Full accounting criteria of measurable and
subjective, defining which cases are substandard
7) OQ, PQ test program
8) The requirements about document output
9) Statistical methods of data collection and analysis
10) Consider maintenance equipment
11) Standard of revalidation
Installation Qualification is to check whether the device is properly installed, the various system checking after
the equipment installed and documented work about technical data.
The contents of Installation Qualification include:
1) Installation conditions, such as: wiring, water supply, power supply, air supply, auxiliary equipment etc.
2) The installation environment, such as: clean room requirements, temperature, humidity and so on.
3) Checking supplier documents, prints, drawings, manuals and so on. Software-controlled device needs to
consider software backup and inspect installation environment;
4) Checking equipment / component operation and safety devices
5) Make sure the main technical parameters of the equipment, including software functional;
6) Analyzing the device parameters affect the degree of process. Parameter stability should be evaluated and
analyzed by status of real process. Find out the fluctuation range of key parameters, in order to confirm the
extreme conditions of process parameters in OQ.
OQ is running various tests and documentation works to prove the device or system reaches the set requirements.
OQ stage need to determine the process parameters and its control range, such as: time, temperature, pressure, speed,
etc. Before the start of the test should be clear requirements of raw materials, personnel training requirements,
process procedures. OQ the actual implementation process can be divided into the following steps.
In the parameter range of options use Full Factorial DOE. The center point was repeated twice, come to trial
schedule, and then follow the table pilot scheme to test, fill the results, test result data can be obtained (Table 2);
For 5 or more factors, due to the larger sample size of Full Factorial DOE, fractional factorial experiments can be
used to identify significant factors, and then to do Full Factorial DOE about significant factors.
2) Fit model
We can use Minitab software for data fitting model to obtain the following results (Table 3 and Figure 2):
From the above analysis, model main effect is remarkable, P value is 0.015> 0.05, which means model is
effective as a whole. Curvature value is 0.611, no curvature. Lack of Fit value is 0.085, no lack of fit. R-Sq is close
to R-Sq (adjustment). That the model is appropriate, a significant factor is heating temperature.
If the model has a curved, it should be further response surface design (RSM) to fit.
3) Analysis of selected models
Analysis of the main effects of the model, interaction (Figure 3 and Figure 4):
As can be seen from the main effect of the figure to make the maximum breaking strength, three factors should
be taken of all high-level, and then we can get the optimal combination of parameters combined with Response
Optimizer. (FIG. 5)
Fig.6 The relationship between the limit of failure, process limit and tolerance limit
In the PQ stage, the key objective is to demonstrate the process under normal operating conditions can continue
to produce compliant products. Need to inspect the actual situation in production about the process parameters of
establishing by OQ stage, in order to verify the acceptability of the process. Continuous producing at least three
batches of samples by operators under normal production conditions. Sample making should consider the time span,
as well as the impact of equipment and personnel fluctuations as far as possible.
Validation Summary Report is the final conclusion includes IQ, OQ, PQ and validation activity. VSR should
outline the program and the results of process validation, and confirm the conclusion of the process. At the same
time, we need to determine the control method after the validation, such as SPC control about key parameter.
692 Yincheng Zhao et al. / Procedia Engineering 174 (2017) 686 – 692
3. Revalidation
Revalidation is to confirmed that verified status is no drift occurs. Due to the process is complicated and change
or the relevant regulations, some processes require periodic revalidation according to the characteristics of the
process. Such as the sterilization process.
Any process or product changes, including procedures, equipment, personnel, etc., should assess the impact of
the process and the need for re-confirmation, and determine the scope of the re-confirmation. For example, the
following occurs:
1) Change in the actual process that may affect quality or its validation status.3
2) Negative trend in quality indicators.
3) Change in the product design which affects the process.
4) Transfer of processes from one facility to another.
5) Change of the application of the process.
Even when the obvious change did not happen, it should be revalidation at intervals, in order to prevent small
changes can’t be aware to cumulative affect the results of the process.
4. Summary
With the improvement of living standards, the development of an aging population, the demand for medical
products will increase. How to ensure the safety and stability of medical products, is an issue for all medical device
manufacturers. Medical device product quality directly affects the safety of life of patients. Therefore, process
validation is more important to the medical device manufacture. It is not only for regulations, but also is a way to
ensure that the manufacturing process is continuing effective.
Acknowledgements
The authors gratefully acknowledge the financial support of the innovation practice program of Shanghai
(IPP12048), and the national natural science foundation, China (No. 71432006)
References