Facility Monitoring Systems Validation: A Practical Approach 7

Subpart B, Paragraph 11.10 states, in part, that the following must be addressed:

• The system must be validated.
• The system must be able to generate accurate, complete copies of data.
• Data records must be protected.
• System access must be restricted.
• Audit trails must be applied to all data.
• Operating system protection methods should be used where possible.
• Authorization checks must be applied.
• Data input/collection verification must be applied.
• Users must be trained.
• Standard Operating Procedures (SOPs) for the use of the system must be in place.
• Documents must be controlled.
• Change control must be applied.

Tests should be included within IQ and OQ to establish that the system does indeed fulfill the above requirements. Many should already be part of any test, but some are outside the scope of the supplier.
Here are some simple methods to make the above process easier and to ensure that a system will pass a validation:.

• Ensure that all transducers, particle counters, and other devices are suitable for the purpose and have valid calibration certificates.
• Do not use complex data collection devices such as programmable logic controllers (PLCs) if they are not required. If a PLC is used, it will have a program, and additional validation will be required.
• When designing a system, consider how things can be tested and how documented evidence can be generated.
• Consider 21 CFR, Part 11 requirements and how these will be fulfilled.
• Use qualified people and reputable suppliers.
• Follow the steps listed within this V-model diagram.

Facility Monitoring Systems Validation: A Practical Approach 6

Tests to check that colors and font sizes on a system are correct can be performed, but they add little to building assurance.
The final part of testing is Performance Qualification (PQ). Normally PQ tests are designed to ensure that the machine operates at the correct rates with the users’ product. With facility monitoring systems, however, this does not apply and in many cases PQ is not performed. With sites where manual methods were previously used to monitor the facility (with portable particle counters, for example, and other instruments), a comparison of the portable particle counters and the FMS particle counters is performed. This can quite often cause test failures due to differences between particle counter optics, electronics, and testing methods. When this happens, I recommend that the manufactures of the particle counters be contacted for guidance.
Other documents should also be generated for a full validation. The main one is a Project Completion Report (PCR) or Validation Review Report (VRR). A summary of the validation of the project, the VRR should list all the documents that have been generated along with the outcome of the tests and should include a clear statement of the system’s suitability for use.
Supplier audits are also common for user to perform. These should be conducted prior to order placement to ensure the supplier has good quality systems and is capable of supplying the required system.

21 CFR, Part 11 Regulation
21 CFR, Part 11 regulation by the FDA relates to electronic signatures and electronic records. Most facility monitoring software systems do not use electronic signatures to approve batch release information. But all facility monitoring software systems hold electronic data, so the regulation applies. In general, facility monitoring systems are closed systems, with access to the system and system data restricted by a control method. In this case, although providing electronic signatures is not applicable, Subpart B, Paragraph 11.10 is applicable.

Facility Monitoring Systems Validation: A Practical Approach 5

The supplier’s module tests and SQ tests can be quite informal. By this I mean that the tests don’t have to be proscriptive. This allows the engineers to really test the system without spending an excessive amount of time generating test documents. The purpose of the test, however, must be clear and there must be documented evidence that the test has been conducted. During IQ/OQ/PQ, the tests must be very proscriptive to enable the user to perform the tests. The test evidence should be more than just a mark in a check box: physical evidence of the test (printouts, screenshots, photos, etc.) should be supplied. It is primarily this test evidence that will be presented to an MCA or FDA inspector to show that the function performed as required. Suppliers are all responsible for ensuring that they provide the user with sufficient documented evidence to pass an inspection.
Tests within Installation Qualification (IQ) may vary. IQ tests should verify that all the items listed in the functional specification have been delivered and that they are of the correct type. The FS may have stated that a differential pressure transducer 0-100 Pa is to be used with 1% accuracy. Has it?

The IQ test should check and verify that:

• All hardware installed on site is as stated—or better.
• All support systems are in place (user manuals, technical manuals, system diagrams, etc.).
• All instruments have been calibrated and the calibration is still valid.
• All software system discs (CDs) are available and have been properly filed.
• A “footprint” (system files, dates and sizes) of the software has been taken at this point.

A system must be able to be re-validated at a later date. IQ tests to ensure that all inputs/outputs of a data collection unit are operational and that must be conducted to ensure that all switches, lights, transducers, and such are functional. These tests can be regarded as operational tests; some companies include such tests in the Operational Qualification (OQ) test document. Once it has been documented that the system has been supplied as detailed within the FS, OQ can begin. The purpose of OQ is to verify that the system functions (operates) as stated within the FS. There must be a test to show that each of the items listed within the FS have been tested, but the tests should go further than this, especially with FMSs—or for that matter, with any other data collection system. There must be clear tests that show data is being collected correctly and that manipulations are being correctly applied, and that data is being stored correctly and can be retrieved correctly.

Facility Monitoring Systems Validation: A Practical Approach 4

Module tests must be drawn up against the module specifications to ensure each module functions as stated. In the case of a panel, it is important to ask whether all the equipment has been installed, whether it has been wired correctly, and whether it meets all relevant standards.
With software, it is common for module specifications to be wider than the user requires. This allows modules to be reused on other projects. But it is important to be sure that the module, as specified, functions as stated. Again, the module specification is used to draw up a set of tests that verify that all functions have been completed and work as specified. This set of tests must include stress testing of the software to ensure that normal error conditions have been correctly handled.
After completion of module tests, the system must then be brought together, with another set of tests (Software Quality, SQ) applied to the completed system to ensure that it functions as detailed within the overall DS. Some companies do this on site, but if there is a problem, they then incur the added costs of staff working on site—and, typically, the design engineers are not on site. When it is difficult or impossible to build the system on the supplier’s site, simulators should be used.
Users may state that they wish to perform a Factory Acceptance Test (FAT). This is very common with delivery of machinery, but less so with FMS. The purpose of a FAT is for the user to be able to see how the system functions before allowing it to be delivered to site (this is also normally a payment stage). The simplest way to perform a FAT is to use the system’s Installation Qualification (IQ), Operational Qualification (OQ), and Production Qualification (PQ) documents and to state on the tests that simulators have been used as applicable or that the test is not possible. Again, if there are any test failures, it is far simpler—and less expensive—to solve problems on the supplier’s site than on the user’s.
After either SQ or FAT, the system is then shipped to site, installed, and commissioned. Once the system has been commissioned, I strongly recommend that user training be conducted before and after the final validation tests (IQ/OQ/PQ). There are two reaýons for this: There will inevitably be minor differences between what has been asked for in the URS and how the operators actually use the system. Performing training before IQ/OQ/PQ allows these small differences to be addressed under change control, with other documents being revised. Also, within IQ, there must be a test to confirm that users have been trained.
From this moment on, any change to the system must be very carefully considered. Change control must be applied. (In fact, change control should be applied before this stage, because any change may have an effect on specification documents and previous tests; in the extreme, a single, seemingly innocuous change can actually cause failure, in that a “bug” may be introduced.)

Facility Monitoring Systems Validation: A Practical Approach 3

At this stage, the user should require the supplier to produce a Quality Plan (QP) or Master Validation Plan (MVP) in which the supplier specifies how the project will be controlled, who will be responsible for each project stage, and the time scale for each project stage.
Once the system has been fully specified and agreed upon in the FS, the design of the system must be specified within an Overall Design Specification (DS). This specification should be a top-level document that clearly states what items are required and how mechanical and software items are to be connected together to meet the function specification requirements.
Design Qualification (DQ) is linked to the URS, FS and DS. It is essential to check that all items listed within the preceding document have been addressed (not fulfilled, but addressed). DQ prevents missing a requirement.
Next are Module Specifications (MS). A “module” may be a control panel or a program. It make no difference. If something has to be built, or programmed, the requirements of the module must be clearly defined.

The Testing Phase
The final action of the first part of the V-model is to actually build the panels, order the particle counters and associated equipment or instrumentation, then write and/or configure the software. But as this V-model shows, this is only half the project. Once all hardware has been built or delivered to the supplier’s site, and its software written and configured, the system must be connected together and tested to ensure it all works.

Facility Monitoring Systems Validation: A Practical Approach 2

An FMS will typically include several monitoring devices: temperature, humidity, and pressure sensors or transducers, and perhaps velocity sensors and particle counters as well. It may also include digital devices for monitoring vacuum pumps or machine running states and feature digital outputs for alert/alarm indicators such as lights or sirens, and for other control functions.

Documentation
The most important document for any proposed system is the User Requirement Specification (URS). Without this document, it is impossible to validate a system. This may come as a surprise to some, but validation is defined as no more—or less—than the process of generating documented evidence to provide a high degree of assurance that a system will consistently fulfill its stated function.
The URS states the required functions of the system. It need not be lengthy, but it must state the functions the system is to fulfill. Despite its name, it is not necessary for the user to generate the URS; the supplier can generate the document, but the URS must be authorized by the user. Its purpose is to ensure that both the user and the supplier understand what is required. The document should have a list of must-haves, want-to-haves, and would-be-nice-to-haves. The supplier must provide all the must-haves, but not necessarily the want-to-haves and the nice-to-haves.
From the URS, all other validation documents and stages then follow. This progression is normally shown in the form of the practical Validation Model (V-model) described in this article. These documents and processes are referred to as the Life Cycle Documents.
After the URS, the next step is for the supplier to generate a Functional Specification (FS). This document, which must address all the user’s must haves, want to haves, and would be nice to haves, should be generated before order placement. If some requirements cannot be met, as will inevitably be the case, the non-compliances must be listed within the FS. Quite often the requirement can be fulfilled in a different way; sometimes, the requirement is not even essential. The FS should include a cross-reference matrix so that the user can easily see how the supplier proposes to meet each requirement.

Facility Monitoring Systems Validation: A Practical Approach 1

By Mike Gough

While most professionals working in the pharmaceutical industry have thorough understanding of process validation, the validation of computer systems in process applications is less widely understood.
The problem is, of course, that microprocessors are now built into equipment throughout the pharmaceutical facility. They’re in formulation, stock control, integrated manufacturing, environmental monitoring, laboratory analysis, vision inspection systems, and even in chart recorders and temperature controllers. To ensure process integrity, each one of these devices must be properly calibrated as part of the larger validation process.
Simply having an understanding of computers and software systems isn’t enough: it’s not only essential to fully understand the process, but the equipment being validated as well. This can be difficult because those who best understand the equipment are the manufacturers, but often they may know little or nothing about validation.
This article addresses only one critical aspect of computer-based systems validation: the validation of Facility Monitoring Systems (FMS).
FMSs are normally used only for cleanrooms and associated areas. Such systems cannot be used to classify an area or facility; they perform a monitoring function only, providing evidence that the environmental conditions in the monitored area have been maintained within specified limits. FDA and other regulatory bodies do accept, however, that for users of an FMS, the period of reclassification can be extended (see ISO 14644-2).

Validating Processes For Surface Preparation

Validation of processes for surface preparation is crucial to many industries, including pharmaceuticals, biomedical device and even food preparation. The effectiveness of the methods for surface preparation in these industries should be established, documented and monitored on an on-going basis.
Validation helps ensure that the surface has been cleaned to an acceptable contamination level. This maximum tolerable contamination level may be termed the target level. Sampling and analysis techniques must have the specificity, sensitivity, reliability and robustness to assure that contamination does not exceed the target limit. The areas of surface where contamination is most adherent or where the negative consequences of contamination are greatest must receive special attention. The nature of potential contaminants must also be considered. While much attention is paid to biological debris, microbes, and pyrogens, other organic and inorganic contaminants can potentially impact product quality.
As applied to processes for surface preparation, validation is a quantifiable, structured approach to demonstrate and document process effectiveness and process consistency. The following are suggestions for a comprehensive validation process.
Process efficacy must be evaluated prior to implementing the procedure. The procedure should require re-validation after changes to the processes that may significantly affect the types and amount of contamination left on the surface, or when significant changes are made to the cleaning process and result of re-validation must be documented.
The essence of process validation is documented, scientific proof of consistent successful process performance. Full, detailed documentation is an integral part of the validation process to show that the process consistently performs as expected and yields a result that consistently meets predetermined specifications. Predetermined specifications in this situation refer to the maximum acceptable level of contamination that can be tolerated on the surface. Written procedures must be established detailing the surface preparation processes. Those responsible for performing, approving and documenting the validation study and the acceptance criteria must be included, as should documentation of the frequency of process monitoring. Written procedures on how process changes will be validated and requirements for documentation of validation should also be developed.
Sampling and analysis methods must provide for sample collection and detection of levels of contamination relevant to the target limit. The technique must be suited to the types and the target level of contamination. The detection technique should be reviewed periodically for its effectiveness and relevance to the type and level of contaminants currently encountered. Prior to accepting and implementing a validation procedure, the analytical or surface testing technique itself should be evaluated and successfully replicated at least three times. Where possible, direct surface monitoring is desirable and may be preferred over indirect, extractive methods. Part configuration and test method sensitivity must be considered.
Establishing appropriate target levels of maximum acceptable contamination is a challenge. Generally, the main consideration should be as to how much surface contamination can be tolerated. There are many ways of establishing contamination limits. Cost must be considered in determining the target contamination level. For each level of surface contamination there is an associated cost of achieving that level. In addition, with each level of contamination there is a level of non-conformance or failures. The cost associated with each level of non-conformance must also be considered. The maximum acceptable level (Target Level) is the one where the incremental cost of removing more contamination is not offset by the corresponding reduction in the non-conformance or failure cost. If, however, the cost of non-conformance is a health threatening, or life threatening product failure, then the target contamination level must be adjusted to an appropriately low level.The situation is akin to extrapolating from animal studies to humans using the lowest dose of a drug or chemical at which no adverse effects are seen.The appropriate “safety factor” or risk factor will depend on the nature of the observed problem animals or the anticipated consequence in humans.
Some general considerations in establishing target levels include the effect of different levels of contamination on the success of subsequent operations; the detection capability of the various analytical techniques available; the anticipated end-use and performance requirement of the product; and the economic and social cost of non-conformance or failure.

Process Validation

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INTRODUCTION

The Quality System (QS) regulation defines process validation as establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications [820.3(z)(1)]. The requirement for process validation appears in section 820.75 of the Quality System (QS) regulation. The goal of a quality system is to consistently produce products that are fit for their intended use. Process validation is a key element in assuring that these principles and goals are met.

The process validation requirements stated in the QS regulation and the guidance offered here have general applicability to manufacturing processes for medical devices. Many technologies are used in the production of medical devices. The details of process validation will vary according to the nature of the medical device (e.g., sterile or non-sterile) and the nature and complexity of the process being validated.

Processes are developed according to the design controls in 820.30 and validated according to 820.75. The process specifications, hereafter called parameters, are derived from the specifications for the device, component or other entity to be produced by the process. The parameters are documented in the device master record per 820.30, 820.40 and 820.181. The process is developed such that the required parameters are achieved. To ensure that the output of the process will consistently meet the required parameters during routine production, the process is validated.

The basic principles for validation may be stated as follows:

• Establish that the process equipment has the capability of operating within required parameters;

• Demonstrate that controlling, monitoring, and/or measuring equipment and instrumentation are capable of operating within the parameters prescribed for the process equipment;

• Perform replicate cycles (runs) representing the required operational range of the equipment to demonstrate that the processes have been operated within the prescribed parameters for the process and that the output or product consistently meets predetermined specifications for quality and function; and

• Monitor the validated process during routine operation. As needed, requalify and recertify the equipment.

TERMS AND DEFINITIONS

Terms other than those used herein may be found in the literature.

Validation: confirmation by examination and provision of objective evidence that the particular requirement for a specific intended use can be consistently fulfilled.

Process validation: establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.

Installation qualification: establishing documented evidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Process performance qualification: establishing documented evidence that the process is effective and reproducible.

Product performance qualification: establishing documented evidence through appropriate testing that the finished product produced by a specified process(es) meets all release requirements for functionality and safety.

Prospective validation: validation conducted prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product's characteristics.

Retrospective validation: validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Validation protocol: a written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.

WHY VALIDATE PROCESSES

There are many reasons, in addition to the regulatory requirements, for validating processes. A manufacturer can assure through careful design of the device and packaging, careful design and validation of processes, and process controls, that there is a high probability that all manufactured units will meet specifications and have uniform quality. The dependence on intensive in-process and finished device testing can be reduced. However, in-process and finished product testing still play an important role in assuring that products meet specifications. A properly validated and controlled process will yield little scrap or rework, resulting in increased output. Consistent conformance to specifications is likely to result in fewer complaints and recalls. Also, when needed, the validation files contain data to support improvements in the process or the development of the next generation of the process.

WHAT PROCESSES SHOULD BE VALIDATED

Where process results cannot be fully verified during routine production by inspection and test, the process must be validated according to established procedures [820.75(a)]. When any of the conditions listed below exist, process validation is the only practical means for assuring that processes will consistently produce devices that meet their predetermined specifications:

• Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy of the finished devices;

• Clinical or destructive testing would be required to show that the manufacturing process has produced the desired result or product.¹

• Routine end-product tests do not reveal all variations in safety and efficacy that may occur in the finished devices.² [RETURN from footnotes]

• The process capability is unknown, or it is suspected that the process is barely capable of meeting the device specifications.

TYPES OF PROCESS VALIDATION

Process validation may be conducted at different points during the life cycle of a product. The types of process validation are defined in terms of when they occur in relation to product design, transfer to production and release of the product for distribution.

Prospective Validation

Prospective validation is conducted before a new product is released for distribution or, where the revisions may affect the product's characteristics, before a product made under a revised manufacturing process is released for distribution.

Concurrent validation is a subset of prospective validation and is conducted with the intention of ultimately distributing product manufactured during the validation study. Concurrent validation is feasible when nondestructive testing is adequate to verify that products meet predetermined specifications and quality attributes. If concurrent validation is being conducted as the initial validation of a new process or a process which has been modified, product should be withheld from distribution until all data and results of the validation study have been reviewed, and it has been determined that the process has been adequately validated.

Concurrent validation may be conducted on a previously validated process to confirm that the process is validated. If there have been no changes to the process and no indications that the process is not operating in a state of control, product could be released for distribution before revalidation of the process is completed. There is some risk to early release of product in that subsequent analysis of data may show that the process is not validated.

Retrospective Validation

Retrospective validation is the validation of a process based on accumulated historical production, testing, control, and other information for a product already in production and distribution. This type of validation makes use of historical data and information which may be found in batch records, production log books, lot records, control charts, test and inspection results, customer complaints or lack of complaints, field failure reports, service reports, and audit reports. Historical data must contain enough information to provide an in-depth picture of how the process has been operating and whether the product has consistently met its specifications. Retrospective validation may not be feasible if all the appropriate data was not collected, or appropriate data was not collected in a manner which allows adequate analysis.

Incomplete information mitigates against conducting a successful retrospective validation. Some examples of incomplete information are:

• Customer complaints which have not been fully investigated to determine the cause of the problem, including the identification of complaints that are due to process failures;

• Complaints were investigated but corrective action was not taken;

• Scrap and rework decisions that are not recorded, investigated and/or explained;

• Excessive rework;

• Records that do not show the degree of process variability and/or whether process variability is within the range of variation that is normal for that process, for example, recording test results as "pass" or "fail" instead of recording actual readings or measurements results in the loss of important data on process variability; and

• Gaps in batch records for which there are no explanations. (Retrospective validation cannot be initiated until the gaps in records can be filled or explained.)

If historical data is determined to be adequate and representative, an analysis can be conducted to determine whether the process has been operating in a state of control and has consistently produced product which meets its predetermined specifications and quality attributes. The analysis must be documented.

After a validated process has been operating for some time, retrospective validation can be successfully used to confirm continued validation of that process if no significant changes have been made to the process, components, or raw materials.

Statistical process control is a valuable tool for generating the type of data needed for retrospective analysis to revalidate a process and show that it continues to operate in a state of control.

PROCESS VALIDATION STUDIES

Planning the Process Validation Study

Careful planning of a validation study is essential to ensure that the process is adequately validated. The plan should include design reviews. The plan for the validation study is documented in the validation protocol. A copy of the protocol and validation results are placed in the Design History File (DHF) [820.30 (j)] or quality system record file (820.186). The operational, monitoring, and other production-related procedures are part of the device master record (DMR) (820.181). Planning for the validation should include the following elements as well as any other relevant issues that must be addressed to conduct the validation study:

• identification of the process to be validated;

• identification of device(s) to be manufactured using this process;

• criteria for a successful study;

• length and duration of the study;

• assumptions (shifts, operators, equipment, components);

• identification of equipment to be used in the process [820.75(b)(2)];

• identification of utilities for the process equipment and quality of the utilities;

• identification of operators and required operator qualifications [820.75(b)(2)];

• complete description of the process {may reference the DMR [820.181(b)]};

• relevant specifications including those for the product, components, manufacturing materials, the environment, etc. [may reference the DMR and quality system files {820.181(a) and (b); 820.186};

• any special controls or conditions to be placed on preceding processes during the validation;

• process parameters to be controlled and monitored, and methods for controlling and monitoring [820.70(a); 820.75(b)(2)];

• product characteristics to be monitored and method for monitoring [820.70(a)(2); 820.75(b)(2); 820.80(c)];

• any subjective criteria used to evaluate the product;

• definition of what constitutes nonconformance for both measurable and subjective criteria;

• statistical methods for data collection and analysis (820.250);

• consideration of maintenance and repairs [820.72(a)];

• conditions that may indicate that the process should be revalidated [820.75(c)];

• stages of the study where design review is required; and

• approval(s) of the protocol.

The validation plan should also cover the installation and operation qualification of any equipment used in the process, process performance qualification, and product performance qualification.

Installation and Operation Qualification

After process equipment is designed or selected, it should be installed, reviewed, calibrated, challenged, and evaluated to ensure that it is capable of operating within established limits and tolerances as well as throughout all anticipated operating ranges. Installation and operation qualification studies establish confidence that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use [820.70(g)].

The installation and operation qualification phases of process validation include:

• examining equipment design and supplied documentation;

• determining installation requirements;

• establishing any needed environmental controls and procedures;

• assuring that the work area has sufficient space to perform the processing and associated activities;

• installing the equipment;

• verifying correct installation;

• establishing manufacturing procedures for the monitoring, operation, and control of the equipment including the minimum number of operators;

• determining calibration, cleaning, maintenance, adjustment, and expected repair requirements;

• identifying important elements of the equipment that could affect the output or finished device;

• verifying that the system or subsystem performs as intended throughout all anticipated operating ranges; and

• documenting the above information.

Equipment fabricators may perform qualification runs at their facilities and analyze the results to determine that the process equipment is ready for delivery to the medical device manufacturer. Device manufacturers should obtain copies of the suppliers' qualifications studies to use as guides, to obtain basic data, and to supplement their own qualification studies. However, it is usually insufficient to rely solely upon the representations and studies of the equipment supplier. The device manufacturer is ultimately responsible for evaluating, challenging, and testing the equipment and deciding whether the equipment is suitable for use in the manufacture of a specific device(s). The evaluations may result in changes to the equipment or process. Such changes must meet QS requirements in 820.30, Design Control; 820.40, Document Controls; 820.50, Purchasing Controls; 820.70, Process Controls; 820.72, Inspection, Measuring, and Test Equipment; 820.75, Process Validation; 820.181, Device Master Record.

Installation and operation qualifications should include establishing pertinent methods, procedures, and schedules for calibration, cleaning, and maintenance, and establishing a repair parts list for each piece of equipment. Planning for eventual maintenance and repairs can reduce or prevent confusion during emergency repairs which could lead to improper repairs such as the use of the wrong replacement part. Post-repair cleaning, calibration, and re-start requirements should be established if necessary to prevent inadvertent manufacture of nonconforming devices. The objective is to assure that all repairs can be performed in a way that will not affect the characteristics of material processed or devices manufactured after repairs.

Process and monitoring equipment (instruments) should be calibrated at the beginning of the validation study, and the calibration should be checked at the end of the study to establish confidence in the validation of the process. Equipment found out of calibration at the end of a process validation study may indicate that the process has not been operating in a state of control and cannot be considered validated. More frequent calibration or more robust equipment may be necessary, or you may wish to use stand-alone instruments in parallel with the built-in process monitoring equipment.

It is important to document installation and operation qualification studies. Such documentation can substitute for part of the requalification of equipment in future process validation studies. When equipment is moved to a new location, installation and operation should be requalified. By comparing data from the original installation and operation qualification and the requalification, the manufacturer can determine whether there have been any changes in equipment performance as a result of the move. Changes in equipment performance should be evaluated to determine whether it is necessary to revalidate the process.

Process Performance Qualification

The purpose of process performance qualification is to rigorously test the process to determine whether it is capable of consistently producing an output or in-process or finished devices which meet specifications. In entering theprocess performance qualification phase of validation, it is understood that the:

• device, packaging, and process specifications have been established, documented, and essentially proven acceptable through engineering, laboratory or other verification methods [820.30; 820.70(a)]; and

• process and ancillary equipment and the environment have been judged acceptable on the basis of installation and operation qualification studies [820.70(g)].

Challenges to the process should simulate conditions that will be encountered during actual production. Challenges should include the range of conditions allowed in written standard operating procedures and should be repeated enough times to assure that the results are meaningful and consistent. Challenges may need to include forcing the preceding process to operate at its allowed upper and lower limits.

Process and product data should be analyzed to determine what the normal range of variation is for the process output. Knowing what is the normal variation of the output is crucial in determining whether a process is operating in a state of control and is capable of consistently producing the specified output.

Process and product data should also be analyzed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include:

• temperature,
• humidity,
• variations in electrical supply,
• vibration,
• environmental contaminants,
• purity of process water,
• light, and
• inadequate employee training.

Appropriate measures should be taken to eliminate controllable causes of variation. For example, extreme variations in temperature can be eliminated by installing heating and air conditioning. Employee training can be improved and conducted more frequently, and employees can be monitored more closely to assure that they are properly performing the process. Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree of assurance that the output will consistently meet specifications.
After routine production begins, data derived from monitoring the process and output product can be analyzed for variation and compared to the normal range of variation. Such analyses can detect when the process output is shifting so that corrections can be made before, or soon after, nonconforming product is produced.

Product Performance Qualification

The purpose of product performance qualification is to demonstrate that the process has not adversely affected the finished product and that the product meets its predetermined specifications and quality attributes. Product performance qualification and design validation of initial finished devices are closely related. According to the design control requirements, design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents [820.30(g)]. Products used for design validation should be manufactured using the same production equipment, methods and procedures that will be used in routine production. Otherwise, the product used for design validation may not be representative of production units and cannot be used as evidence that the manufacturing process will produce a product that meets pre-determined specifications and quality attributes.

Design validation can be conducted using finished products made during process validation studies and will satisfy the need for product performance qualification. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing production units under actual or simulated use conditions [820.30(g)]. Original designs and design changes are subject to design control requirements [820.30(i)]. The results of design validation are subject to review under the design control review requirements [820.30(e)].

DOCUMENTATION

The requirements for process validation are described in section 820.75 and include documentation requirements for the process validation study phase as well as for routine production using a validated process. Records of validation activities and results must be maintained [820.75(a)]. Validation protocols and results may be filed in the DHF [820.30(j)] or in the QS files (820.186). Records must include the date and signature of the individual(s) approving the validation and, where appropriate, the major equipment validated [820.75(a)]. Procedures for monitoring and control of process parameters must be established and maintained for validated processes [820.75(b)]. Procedures for the operation, monitoring and control of processes are part of the DMR (820.181).

When a validated process is used for manufacturing finished devices, the process must be performed by a qualified individual [820.75(b)(1)]. Records must be maintained of the monitoring and control methods and data; where appropriate, the individual(s) performing the process; the date performed; and major equipment used. The records should be maintained in the DHR (820.184).

REVALIDATION

As long as the process operates in a state of control and no changes have been made to the process or output product, the process does not have to be revalidated. Whether the process is operating in a state of control is determined by analyzing day-to-day process control data and any finished device testing data for conformance with specifications and for variability.

When changes or process deviations occur, the process must be reviewed and evaluated, and revalidation must be performed where appropriate [820.75(c)]. Review, evaluation, and revalidation activities must be documented.

Processes may be routinely validated on a periodic basis; however, periodic validation may not be adequate. More important is appropriate monitoring so that if problems develop or changes are made, the need for immediate revalidation is considered.

REFERENCES

1. Guideline on General Principles of Process Validation, May 1987, FDA, CDRH/CDER
2. Journal of Validation Technology, Vol. 1, No. 4, August 1995