This section will cover discussions on the following Validation topics:
-The Basic Principles of Validation
-The Validation Plan
-Installation Qualification (IQ)
-Process Performance Qualification (OQ/PQ)
-Product Performance Qualification (PPQ)
-Test Method Validation (TMV)
-Software Validation
-Electronic Signatures (CFR Part 11)
-Room Qualification Documentation
Introduction
Validation defined: Confirmation by examination and provision of objective evidence that the particular requirement for a specific intended use can be consistently fulfilled. (1)
Most products and services rely on a manufacturing method and equipment to produce an end result. The more a manufacturer knows about their product, process and the machinery used, the better chance of meeting predetermined specifications and customer needs.
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.
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.
Basic Principles of Validation
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, re-qualify and re-certify the equipment.The Validation Plan (or “Master Plan”)
Before beginning a validation, a plan should be developed with the following agenda (sections are optional where appropriate). A validation plan should always be used when validating a process, product or piece of equipment.
identification of device(s) to be manufactured and what process will be used;
what criteria determines that the study was a success or failure (e.g. all parts in specification for length, or a certain standard deviation);
length and duration of the study (if this is important);
assumptions (what are the known components and equipment, what shift, personnel);
identification of equipment to be used in the process;
identification of utilities for the process equipment and quality of the utilities;
identification of operators and required operator qualifications;
complete description of the process;
relevant specifications including those for the product, components, manufacturing materials, the environment, etc. (what is the process making? what function(s) will this equipment perform to?);
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 (what parameters will be constant/variable? Temperatures, times, pressures, viscosities, etc);
product characteristics to be monitored and method for monitoring;identification of calibration needs for monitoring and measurement devices (pre and post validation calibration to ensure control);
any subjective criteria used to evaluate the product;
definition of what constitutes nonconformance for both measurable and subjective criteria (e.g., identification of defects that may occur);
statistical methods for data collection and analysis (how many samples will be tested or evaluated? Is the method justified and appropriate?);acceptance criteria for determining product failure or allowance;
criteria for what has to happen during validation to indicate that the process should be revalidated;
stages of the study where design review is required; andapproval(s) of the protocol.
Installation Qualification (IQ)
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 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.
The installation and operation qualification phases of process validation include:
examining equipment design and supplied documentation;
determining installation requirements (voltage, ancillary duct work, venting, etc);
establishing any needed environmental controls and procedures (HEPA filters, exhaust, etc);
assuring that the work area has sufficient space to perform the processing and associated activities;
installing the equipment;
verifying correct installation (voltage, proper pressure, etc);
establishing manufacturing procedures for the monitoring, operation, and control of the equipment including the minimum number of operators;
determining calibration, cleaning (what solutions to use, frequency, post-repair procedures, re-start qualifications), maintenance (preventative, spare parts list);
identifying important elements of the equipment that could affect the output or finished device (especially if there is product contact with equipment);
verifying that the system or subsystem performs as intended throughout all anticipated operating ranges; and
documenting the above information.Process Performance Qualification (OQ/PQ)
The purpose of process performance qualification is to rigorously test the process to determine whether it is capable of consistently producing outputs (product) that meet specifications. In entering the process 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. Typically shown as Research and Development or feasibility studies.
process and ancillary equipment and the environment (see Room Qualification section) have been judged acceptable on the basis of installation and operation qualification studies (IQ).
Challenges to the process should simulate conditions that will be encountered during actual production. Challenges should include the range of conditions (OQ) allowed in written standard operating procedures and should be repeated (PQ) 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.Product Performance Qualification (PPQ)
Product performance qualifications are closely related to design validation of initial finished devices. Using the actual processing method mentioned in the Process Performance Qualification above, product testing should demonstrate that the process has not adversely affected the finished product and that the product meets its predetermined specifications and quality attributes. The Qualification should ensure that devices conform to defined user needs and intended uses (design validation).
Criteria that may be applicable and tested for during Product Performance Qualifications are the following:
microbial levels (aerobes, anaerobes, fungi, etc);
sterility assurance;
product bioburden; and
packaging and shipping integrity and stability (packaging validation).Test methods used to verify that products and the process are running under controlled conditions must be validated. Test Method Validations, or TMV’s, shows through objective evidence whether or not a test method will consistently produce a test result for a known set of test samples, under predetermined test conditions, when the test samples are subjected to a specified test method. In other words, the TMV measures confidence in how well a method is measuring what it should.
Typically, Test Method Validations include the following criteria:
product and process description;materials used in the method;
test method development history (purpose, parameters, relevant history, how parameters were established);
validation methodology (what method will be used to validate the test method-how will assurance be known);
sample size justification;
acceptance criteria; and
approval(s) of the protocol.
Test Method Validations generally adopt repeatability and reproducibility studies (R&R) as part of the validation effort. By doing so, the process or inspection operation is verified to be repeatable and reproducible when standardized tools or measurement devices are used by various operators.
Software validation is mandatory for manufacturers of medical devices(2) and pharmaceuticals(3). Any software used to automate any part of the device production process or any part of the quality system must be validated for its intended use, as required by 21 CFR §820.70(i). This requirement applies to any software used to automate device design, testing, component acceptance, manufacturing, labeling, packaging, distribution, complaint handling, or to automate any other aspect of the quality system.
While the device community must comply with software validation, today’s market finds software central to most processes. Therefore, software validation can be a useful tool in any industry. Often times, it is software that determines tolerances, controls dimensions and weights, or inspects product for visual defects. When the process and quality decisions rely on software programs, the manufacturer should know the software is functioning properly.
Protocol criteria involves the following steps for validating software:
Step 1: Validation Methodology:
The methodology used to develop computer systems is important in determining the level of effort required to perform verification and validation activities. Software is typically developed in the following manner:
Custom Developed
Modified-off-the-shelf (M.O.T.S)Commercial-off-the-shelf (C.O.T.S)
Step 2: User Requirement Specifications (URS):
User Requirements are established to determine what the customer/system user and application requires from the software. User requirements provide an overview of what software capabilities are necessary.
Step 3: Software Requirements Specifications (SRS):
The software requirements specification outlines what the manufacturer plans for the software to do; how it should function, the revision level, any patches that are or will be used, etc. In essence, the SRS shall outline the intended use of the software. Coupled with the software risk analysis, the SRS will show that a manufacturer has addresses all potential risk factors associated with software performance.
Step 4: Software Risk Analysis (Hazard Analysis):
A risk analysis must be completed addressing each potential concern that may take place with the software installed. Much like a hardware or device risk analysis, the software risk analysis will outline methods in place to reduce any anticipated risk. These methods often include software design, testing, or appropriate labeling and/or instruction for the user or technician.
Step 5: Performance Qualification TestingTests are conducted to ensure both SRS and URS requirements are achieved. Tests cases are executed in order to provide objective evidence for predetermined software requirement specifications. Functional execution, such as Input Boundary (IBT) and Regression testing, are often conducted as a subcomponent to Performance Qualification testing.
Electronic Signatures (21 CFR Part 11)
Electronic signature compliance is mandatory for manufacturers of medical devices.(4) Clear Vision Consulting provides training and consultation services for meeting the demands of Part 11 compliance.
Program consultation includes the following:System Inventory to determine which applications are part of the quality system;
System evaluations to determine detailed compliance with the entire Part 11 guideline.
Remediation planning to establish reasonable and feasible implementation plans.
Remediation efforts to ensure system gaps are adequately addressed for compliance.Room qualifications may be conducted at various levels depending on application and use. Qualifications may be executed to test parameters of temperature and humidity controls of a room (stability) or be more complex and include parameters found in a clean room facility such as microbial and non-viable particulate organisms.
For all room qualifications, Installation, Operational and Performance phases are executed to test various aspects of room behavior. Possible test protocols executed as part of room qualification are as follows:
HEPA Filter Leak Test
Filter face of all HEPA filters are scanned for leaks using probes to locate leaks in the bond between the filter pack and the housing frame, as well as leaks in the seal between the frame and grid structures of the HEPA unit itself.
Filter Airflow VelocityUsing a multimeter or equivalent, airflow velocity of all HEPA filters identified are measured in feet per minute (fpm), taking measurements in a predetermined location.
Particle Count Test
Particle count testing is performed at locations that will meet both Federal Standard 209E and ISO 14644-1 requirements. Test locations will help determine if non-viable particulate (e.g. dirt and foreign material) is a concern in the manufacturing process.Room Pressure Differential
Using a multimeter device or equivalent, air pressure in the controlled environment is verified for predetermined required positive pressure. All room entrance/exit points are to be measured. Using these measurements, magnehelic gauges are confirmed for reading pressures accurately as recorded.Room Temperature and Relative Humidity
Using a temperature and humidity monitor or equivalent, verify the ambient air temperature and relative humidity at each sample site indicated is verfied and recorded against predetermined specifications.
Maintenance of Validation
Conditions requiring re-qualification using the applicable portions of this IQ/OQ protocol are identified. Additional work shall be added to the validation file. The same approval process is required as the original IQ/OQ activity.
Additional Room Qualification Documentation
In addition to functional testing identified above, equipment design and identification will be executed and documented. Instruments, utilities and devices for used for calibration are verified prior to execution of performance qualifications.
1. Guideline on General Principles of Process Validation, May 1987, FDA,
CDRH/CDER2. See Final Rule Guidance for Industry-General Principles of Software Validation,
version 2.0 dates 1/11/2002.
3. See Supplier Guide for Validation of Automated Systems in Pharmaceutical Manufacture, GAMP Forum Version 3.0, March 1998.
4. See Code of Federal Regulations (CFR) Title 21 Part 11.
-The Basic Principles of Validation
-The Validation Plan
-Installation Qualification (IQ)
-Process Performance Qualification (OQ/PQ)
-Product Performance Qualification (PPQ)
-Test Method Validation (TMV)
-Software Validation
-Electronic Signatures (CFR Part 11)
-Room Qualification Documentation
