Goals
When you have completed this manual, you should be able to:
a. Perform an audit of a validation system (excluding computer systems)
b. Use a range of tools and information, including the contents of this unit to support the audit of a validation system
c. Understand and apply appropriate GMP standards/regulations to an audit of a validation system
d. Recognize compliance or non-compliance of a validation system to applicable regulations
Definitions
Ancillary system: A system that is not directly part of the equipment undergoing qualification. An example is a compressed air system that may be used in packaging to remove dust and other contaminants.
“As-built” drawings: Drawings of the equipment, indicating utilities etc. placement of equipment components, completed as the equipment was being built or manufactured.
“As is “drawings: Drawings of the equipment as it has been placed/modified within the final location.
Design Qualification: Documented verification that the proposed design of the facilities, equipment, or systems is suitable for the in-tended purpose.
Factory Acceptance Testing (FAT): Pre-delivery equipment testing and inspection performed at the factory.
Installation Qualification (IQ): Documented verification that all key aspects of the design, procurement, and installation of the system adhere to the approved design, and that all manufacturers’ recommendations have been complied with.
Operational Qualification (OQ): Documented verification that the equipment or systems and sub-systems, as installed or modified, perform as intended throughout the anticipated operating ranges.
Passivation: The chemical treatment of stainless steel with a mild oxidant, such as a nitric acid solution, for the purpose of enhancing the spontaneous formation of the protective passive film. This process is designed to remove foreign metals, oxides, and corrosion from the surface of stainless steel and corrosion resistant steels, which allows water to move through the pipes and improves corrosion resistance.
Performance Qualification (PQ): Documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications. This phase qualifies process and procedures and demonstrates that the equipment and ancillary systems do what they claim to do.
Piping and installation drawings (P&ID): Mechanical drawing or blueprints of the required piping system for installation of equipment.
Quality risk management: A systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.
Worst Case: Conditions within normal parameters most likely to give failure. For processing purposes, “worst case” means those values of normal operating parameters most likely to cause process failure. For sampling locations, “worst case” means those equipment locations most likely to have higher levels of residues after cleaning. For sampling recovery, “worst case” means those procedures, within normal sampling parameters, most likely to give poorer percentage recovery.
Explanation of Topic
Introduction
Validation is the action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material activity or system consistently leads to the expected results. Documented evidence provides a high degree of assurance that a specific system, equipment or process will consistently produce a product meeting its pre-determined specifications and quality attributes. To put it simply, validation is nothing more than proving that a process actually works.
What should be validated?
We use the terms validation and qualification to cover the documented verification of a spectrum of GMP activities including
a. Facilities
b. Equipment used in manufacturing
c. Equipment used to control the environment(s) where product is manufactured or stored
d. Utilities with product contact (e.g., water systems, compressed gases, air)
e. HVAC systems
f. Alarm systems that monitor utilities and air handling for process and storage areas
g. Analytical methods
h. Analytical instruments
i. Computerized systems (e.g., computerized training system, documentation control system)
j. Cleaning processes
k. Manufacturing processes
Storage facilities, air, water, and systems that come in contact with product, can have a lasting impact on the quality and efficacy of the product. Regulations require that all aspects of facilities and utilities that may directly or indirectly alter or affect products – including laboratories, warehouses, clean rooms, water, ventilation, temperature and humidity systems – be assessed and appropriately validated.
Validation and Qualification
Qualification differs from validation in that it involves components or elements of a system whereas validation involves the entire process for a product or system.
The amount of documentation and level of detail may vary depending upon the type of material to be manufactured/tested, the criticality to GMP and the system’s complexity.
In the excipient industry, full validation programs are not always set up as typical in the pharmaceutical industry. However, most excipient manufacturers have evaluated their processes using process capability studies that usually contain much of the appropriate information.
Validations may be performed prospectively, concurrently or retrospectively.
Ø Prospective validation involves completion of the validation work before manufacture of commercial product.
Ø Concurrent validation is performed in the same way as prospective validation except that each satisfactory batch of product is immediately made available for sale without waiting for confirmation of consistency (completion of all validation batches) and total validation approval.
Ø Retrospective validation is performed by confirming the reliability of an established process by review of historical data gathered from previously produced batches.
Retrospective validation is not an acceptable approach for new systems. If used, for example for existing systems not previously used in regulated areas, the use of retrospective validation must be justified.
Risk Assessment
A risk assessment approach should be used to determine the scope and extent of validation, e.g., an initial impact assessment should be performed to determine the extent of qualification required. Risk assessment is a systematic approach to identifying the potential failures in processes and quantifying the risk they present to the company and its customers.
The HACCP (Hazard Analysis Critical Control Points) concept may be used. The HACCP concept is an eight-step process designed to identify, characterize, control and confirm the control of hazards to a process. The hazard analysis involves the preparation of a flow chart detailing the individual steps in a process. At each step the hazards to the process are identified and the associated risk and severity are assessed respectively. This may be done using the FMEA (Failure Modes & Affects Analysis) technique where risk priority numbers are calculated taking into account the severity, probability and likelihood of detection of the failure. Appropriate systems are implemented to ensure that the theoretical hazards do not present a hazard to the process. The appropriate limits are set for these systems.
If the risk assessment has been properly carried out and documented, parts of a process that are low risk may be eliminated or paid minimal attention during validation.
Benefits of validation
Validation assures that the entire manufacturing process and support systems work properly before actual production begins.
Validation ensures that safe, quality products are consistently manufactured. The validation process gives the manufacturer a further understanding of the process, possibly improved operational efficiency, more robust processes, reduced risk of failure and improved compliance.
General Validation guidelines
The first step to the overall validation process is to define the key requirements of the product/process, e.g. by documenting the appropriate parameters in a User Requirement
Specification (URS) and a Functional Specification describing what is needed and how the final result is to be achieved. A design qualification (DQ) is performed to collect documented verification that the proposed design of facilities is suitable for the intended purpose.
“The total validation process involves DQ, IQ, OQ, PQ, process validation, maintenance, change control and revalidation.”
Rationales used as basis for validation strategies should be documented.
Since validation consists of different stages, critical sections of each stage must be completed before moving to the next stage. Some of these critical sections include complete testing, investigation of critical deviations and/or exceptions, and repair (e.g. wiring connected incorrectly). Deviations must be closed and interim approval of the stage should be obtained prior to beginning the next stage. The protocol for the next stage may be developed but cannot be executed until the interim approval of the previous stage is obtained. For example, installation qualification should be approved or interim approval received prior to beginning with operational qualification. IQ/OQ may be combined under certain circumstances.
There should be some type of written document or procedure that instructs personnel in:
Ø what to include in validation and qualification
Ø how to perform validation and qualification
Ø what documentation is necessary
Ø how to establish acceptance criteria
Ø how to determine specifications
All documentation and raw data generated during validation activities is considered GMP documentation for retention/archiving purposes. It must be retained in a manner that permits traceability and ensures that it is readily retrievable.
The Validation Protocol, describing how the validation activities are to be executed, must be clearly written with defined acceptance criteria. It must be approved by QA, issued in advance of the work and be version controlled.
At the end of each qualification, a report should be issued. The report must summarize the raw data and deviations that occurred (including corrective and preventive actions for the deviations), and evaluate the work against the acceptance criteria. A clear conclusion needs to be written as to whether the validation has been completed successfully. The report should be reviewed and approved by the appropriate functions.
Validation protocols should be retained for various reasons. A previous protocol can be useful if a similar process or piece of equipment needs to be qualified in the future.
Protocols may also be requested for review by regulatory agencies as proof that qualification activities were performed and that they were performed correctly.
Validation Master Plan
For more complex validation activities, a Validation Master Plan (VMP) should be produced to describe the approach to be followed for each element of validation.
The VMP should present an overview of the entire validation operation, its organizational structure, its content, and planning. The core of the VMP being the list/inventory of the items to be validated and the planning schedule.
All validation activities relating to critical technical operations relevant to product and process controls within a firm should be included in the VMP. This includes qualification of critical manufacturing and control equipment.
Validation Plan
Before each validation or qualification can begin, the site needs to have a “directing” document in terms of activities to be completed, specifications to be met, acceptance criteria to be tested against, etc. This directing document is the Validation Plan (VP).
The VP is a strategic document which identifies the elements to be validated, the approach to be taken for validation of each element, the organizational responsibilities and the documentation to be produced to ensure full consideration is given to product quality aspects. It shows how the separate validation activities are organized and interlinked. Overall it provides the details and relative time scales for the validation work to be performed.
Specific elements of the VP are qualification/validation methodology, qualification activities, personnel responsibilities, schedule, preventive maintenance, change control, relevant SOPs and documentation requirements.
The VP is required to be prepared and approved at an early stage of the project. This plan may or may not include design installation and operational performance qualification protocols as individual documents. Not all projects need to be included in a VP. This document is required when the coordination of many validation activities is necessary.
Examples are:
Ø Construction of a new manufacturing facility
Ø Purchase and installation of a new utility, (e.g. a new purified water system)
Ø Installation of a new packaging line
Ø Significant refurbishment to existing facilities, utilities and equipment
Equipment Qualification
To ensure that a manufacturing or testing process will work properly, the equipment used in the process must perform reliably and within specifications. To achieve this, the equipment must be qualified.
Design, installation, operation and performance qualification (DQ/IQ/OQ/PQ) are phases of validation that support the startup of new, modified, or retrofitted equipment.
DQ/IQ/OQ/PQ studies establish confidence that the equipment and ancillary systems are capable of consistently operating within the established design and operating limits and tolerances.
Design Qualification (DQ)
Design qualification (DQ) may be established as a separate process with its own protocol or may be combined in the Validation Plan. The purpose of this qualification is to assure that a proposed new or modified facility, system or equipment meets GMP requirements, is suitable for its intended purpose and defines how the Users Requirement Specification (URS) are to be met.
The URS establishes agreed and properly defined facilities/utilities/ equipment functionality requirements. Variables should be specified in terms of expected reliability, consistency and capability.
For relatively simple and off the shelf equipment, the URS and design qualification may be documented by reference to a supplier’s specification and included in the purchasing order/specification.
The design qualification documents (actual specification documents) should be reviewed, at a minimum, by both technical personnel for feasibility and suitability and QA for compliance with GMPs. The design qualification takes place before actual construction or installation.
During this qualification, the design for routine cleaning of the equipment should be considered. All design reviews should be documented In addition, for some systems/equipment, extensive Factory Acceptance Testing (FAT) may be performed.
The need to repeat some or all of this testing on site should be considered. Justification for reduced site acceptance testing should be documented.
FAT is an important step in the project and the subsequent validation phases. FAT includes more than just a physical examination of the item to check that all components are present and have been fulfilled. It should ensure that the item meets the agreed specification and requisition and confirm that all vendor documentation is in place. A well-executed FAT can provide a significant, positive contribution to the IQ at the site.
Installation Qualification (IQ) Documentation
Before any work can be started, all installation qualification activities must be recorded and approved in an Installation Qualification protocol. A suggested protocol format includes:
Ø Signature and Pre-Approval Page
Ø Publication Record (history of revisions to the document)
Ø Signature and initial log
Ø Objectives of Qualification
Ø System Description
Ø Installation Qualification Procedure
Ø Equipment Specifications
Ø Site Specifications – varies according to qualification
Ø Safety Specifications
Ø Set-up, Calibration, Maintenance and Cleaning Procedures and frequency – varies according to site
Ø Spare/replacement parts listing and location
Ø Training for Operators and Maintenance Personnel
Ø A description of tests and a section for recording test results
Ø Deviation/Exception Summary or List
Ø Amendments – varies according to site
Ø Signature and Final Qualification Acceptance/Approval
Ø Utilities
The protocol should include the roles and responsibilities for IQ development, execution, assurance of completion and maintenance. It should identify functional groups required to review and approve the protocol. Functional groups should include those who can provide a technical evaluation (e.g., Engineering, Maintenance) and QA. QA should always be an approver to ensure that all GMP and regulatory requirements have been considered, met, and documented as appropriate. If all critical items in the protocol have been addressed and approved, but there are some remaining items, the next phase of qualification may be executed provided that there is written documentation to justify it.
The IQ protocol should include piping and instrumentation diagrams (P & ID), HVAC drawings and equipment drawings.
Installation Qualification Execution
Installation qualification (IQ) occurs during the equipment installation phase. Equipment is compared to the original design and installation plans, found either in the Purchase Order or design specification. This phase ensures that the manufacturer’s and the company’s engineering specifications agree. Equipment type and “as – built” conditions are verified against the design specifications. During this phase, materials of construction, manufacturer’s identification (serial number) are verified against the purchase specifications and the manufacturer’s specifications.
During the installation qualification, utilities completion and calibration take place. The utilities, (electrical, water, steam, vacuum, compressed gases and HVAC) are checked to determine if they are connected properly. Wiring installation of electrical lines (loop checks) is conducted. Software that is used in a computer is checked for the correct version and that it is installed correctly.
Instruments are also calibrated to verify that indicators for temperature, pressure, flow, weight, volume, etc. are accurate. Piping systems are reviewed to verify that they have been correctly installed and that the composition of materials is in agreement with the design specifications. Piping systems are also reviewed to ensure that the lines have been degreased, and passivated, if the water systems use stainless steel piping. Piping should also be identified and tagged.
The installation qualification should include a review of pertinent maintenance procedures; repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product
Information from the installation qualification should be used to:
Ø develop written procedures on calibration
Ø establish a preventative maintenance program
Ø determine which calibration, maintenance and adjustment requirements could affect the process and product.
The IQ/OQ protocol becomes part of the Master Validation Protocol. In the Master Validation protocol, critical parameters and critical attributes are specified for the process. This drives what acceptance testing will take place for the equipment.
For example, if the piece of equipment is a centrifuge and the operating range is between 1500 rpm-2000 rpm, the acceptance criteria and testing should test that range as well as the operating claims made by the manufacturer of the centrifuge (e.g., full range and intended operational use range).
“Prior to executing the OQ, all critical exceptions in the IQ must be closed and interim approval of the IQ should be obtained.”
Deviation Documentation During Qualification
If, during the verification of equipment specification or during a test/challenge, equipment does not meet or perform within its design specifications, a deviation or exception must be documented. The exception should be evaluated to determine if it affects the established operating design. If appropriate, the cause of the failure should be identified. Corrections should be implemented and documented. The operational tests are re-executed to verify that the equipment performs within specifications. If the exception does not impact the intended operation of the equipment, then the exception may be accepted. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process.
Operational Qualification (OQ) Documentation
Documentation should include an approved Operational Qualification protocol. All tests should include specification under which they should be conducted. Acceptance criteria should be clearly stated in terms of ranges and units. Test results should contain actual data and units (when applicable), not the terms “satisfactory” or “unsatisfactory”.
Operational Qualification Execution
The operational qualification (OQ) phase tests each function of the equipment and ancillary systems. The goal is to verify equipment operation by determining if operation is within the ranges expected by the design specification. This includes testing of equipment under “worst case” conditions, which might include continuous operation, extended operations at both the low and high limits, minimum and maximum loads.
Critical process parameters that should be tested include temperature, pressure, speed, rotation, flow, volume handling, weight, timing, distillation rate, etc. Testing should be conducted to find errors!
Performance Qualification Documentation
Depending on the site and the validation procedure, performance qualification testing may be considered either as part of Operational Qualification or part of Process Validation. In these cases there will not be a separate protocol for the performance qualification, but the activities will be captured in the appropriate protocol. This must be clearly documented in the site SOP and the respective protocols.
Performance Qualification Execution
Performance qualification is a bridge between Operational Qualification and Process Validation. In Performance Qualification, production materials, qualified substitutes, or simulated product may be used to test the upper and lower operation limits or “worst case” conditions. Performance Qualification is a test of the overall system, with equipment and ancillary systems tested together.
Process Validation
Process Validation includes establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.
A predetermined number of validation batches should be manufactured to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make an acceptable product. It should normally cover the manufacture of at least three consecutive batches of material.
Validation should be performed under conditions to be used for routine manufacture. The batch size should be the same as or representative of the intended commercial scale batches. Sampling and testing should be carried out to ensure compliance with the most stringent requirements.
If the validation batches are intended for commercial use, the conditions under which they are prepared and manufactured must comply with the GMP requirements.
Prospective process validation should normally be applied to API and to medicinal products. The general principle is to validate a manufacturing process and the “same” process can typically be used for several related products. Rather than to develop a plan for each product manufactured by a process, it can be possible to develop a plan for that process instead. There are two general principles that could be applied. “Matrix approach” generally means a plan to conduct process validation on different strengths of the same product. “Family approach” describes a plan to conduct process validation on different, but similar products. Either approach must demonstrate that the process is consistent for all the strengths or products involved. The plan should be designed to evaluate all likely sources of variation in the products manufactured by the process.
Process validation must be completed, evaluated, documented and approved before commercial distribution.
Worst Case and Challenge Tests
The process should be challenged by making deliberate changes to demonstrate its robustness and to define its limits of tolerance. In challenging a process to assess its adequacy, the conditions should simulate those that could be encountered during actual production. These tests should be repeated enough times to assure that the results are meaningful and consistent.
Such worst case or challenge tests should preferably be performed prior to manufacture of validation batches. Typically they are done during the OQ or PQ stage of validation.
Cleaning validation
The consistent preparation of safe high quality products depends in no small part on the ability to satisfactorily clean and decontaminate premises and equipment to minimize the potential for cross-contamination. Contamination may be chemical as well as microbiological.
The potential consequences for cross-contamination includes regulatory, quality as well as safety aspects. An effective strategy for the development and confirmation of effective cleaning procedures may consist of three phases; assessment of risk, validation of cleaning procedures and development of monitoring procedures to confirm the ongoing effectiveness.
Cleaning validation is performed in order to establish documented evidence that a specified cleaning procedure will provide a high degree of assurance that it can be used to consistently clean a piece of equipment or a facility to a predetermined acceptable level of cleanliness.
A general approach to the validation of cleaning is to use the equipment for the intended process, hold for a predetermined maximum time, clean as per procedure, sample (product residues, cleaning agent) and repeat to show reproducibility. Sampling is generally performed by visual examination (where feasible), swab samples and rinse samples. Sampling sites selected should be representative and include locations difficult to clean.
A range of analytical methods may be required for cleaning validation. Methods may be specific (e.g. bioassay, HPLC or activity assay) or non-specific (e.g. total organic carbon, conductivity or pH). Whichever method used, it should be validated for the application.
Limit of detection and recovery are key criteria in such method validations. Recovery studies should be performed prior to sampling and on the material included in the cleaning validation.
Acceptance criteria established for each piece of equipment should be practical, achievable and verifiable. The manufacturer should be able to demonstrate by means of data that the residual level permitted is scientifically sound. Traditionally the pharmaceutical industry has set analytical and clinical/toxicological criteria. In a multi- product facility cleaning validation may be performed based on bracketing of compounds. Worst case or representative compound/-s are then chosen and the data obtained is used to support effective cleaning of all compounds in that bracket.
The established and verified cleaning method should be implemented and conformed to.
The cleaning procedures should include the method to be used, maximum allowed intervals between cleanings and between use and cleaning, and for how long time equipment is considered clean prior to use. For modern, highly automated, equipment the logical sequencing of cleaning activities should be critically reviewed for adherence to validated procedures. Maximum permitted time for campaign manufacturing should be included in cleaning validation studies.
Normally an ongoing monitoring program is set up to confirm satisfactory operation of the established cleaning process. Key process parameters may be reviewed for automated systems, in other cases monitoring based on swabs/rinse samples or visual examination may be conducted.
Validation of Analytical (Chemical, Physical and Microbiological) Test Methods
Validation of methods is performed to confirm that the performance characteristics of a method meet the requirements for the intended application. An assessment of validation studies demonstrating that the method is suitable for its intended purpose shall be documented appropriately.
Test methods described in any submission for manufacturing authorization, including development pharmaceuticals, in-process control during manufacture, control tests on intermediate products, control tests on finished products and stability testing should be appropriately validated for the phase of development before use. Methods used in testing of commercial finished products, raw material or packaging component must be validated before use.
Appropriate level of revalidation of methods may be required by regulatory authorities when methods are transferred from one site to another, methods are transferred from one laboratory to another, if significant changes are made in the manufacturing of major starting materials or if the composition of the finished product is changed.
Methods and equipment described in pharmacopoeias may be considered validated.
Suitability for use of pharmacopeial methods should be established by testing/technical review and documented. When claiming compliance with pharmacopoeias, unless the exact method is being used, a cross validation should be performed.
A number of parameters should be considered in validation of quantitative methods.
These parameters include tolerance limits, specificity, accuracy, precision, detection limit, quantification limit, linearity and range.
Maintenance of Validated Status/Change Control
The suitability of a facility, utility, process or equipment must be maintained through its operating life. Systems and documentation need to be in place to support this. Such monitoring systems should include SOPs, performance monitoring, calibration, maintenance and cleaning, change control, and periodic review by internal audits. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
A written change control procedure should be in place to modify qualification/validation requirements if change is proven to be necessary. Change control procedures should define the need to repeat and document some or all, of the qualification work. The change control system should also include an assessment after maintenance or calibration work to determine if requalification/-validation is necessary.
Certain types of equipment (e.g., for sterile product manufacturing) require routine requalification at defined frequencies. Lists of such equipment and their requalification frequencies should be held by the user and approved by QA.
Audit Strategy
As an auditor, you will need to complete a walk-through (tour) and a documentation review. The walk-through should focus on comparing existing drawings and diagrams to actual placement of equipment and utilities on the site.
There are several types of validation documents that, as an auditor, you will be reviewing. To begin auditing validation documents, request copy(s) of site procedure(s) and VMP to determine how new equipment/processes/ methods, relocated equipment, replaced equipment “like for like” (similar), or significantly modified equipment are validated. Next review completed protocols of different validation stages. Examine for completeness and accuracy. Determine if the equipment in operation is operating within the parameters specified during validation. Review change controls and investigation reports to determine if the manufacturing process continues to perform within processing controls and meets specifications as defined during validation.
Key Parameters in Auditing a Validation System
Prior to the Audit
a. Review the critical manufacturing equipment and utilities in use at the site.
b. Review the types of processing performed at the site.
During the Audit
A. Walk through the area with copies of the P&ID and HVAC blueprint and determine if:
Ø The field conditions are the same as indicated in the drawings
Ø The location of the piping and HVAC is correctly indicated
B. Ensure that the site has an approved established procedure for performing validation and qualification including a Validation Master Plan (VMP).
C. Ensure the extent of qualification/validation is justified.
D. Ensure that supplier’s documentation has been reviewed for:
Ø Completion of activities
Ø Certification that their work has met the design specification
E. Verify that a Validation Protocol exists for each validation project, which identifies qualification activities for DQ/IQ/OQ/PQ and their locations.
F. If DQ is performed as a separate qualification,
Ø Verify that there is a system to manage the setup of a preventive maintenance and change control program for new equipment. This management system may be part of the IQ/OQ process or part of the site’s change control system.
G. Ensure that the site has performed the following checks during the IQ phase.
Ø For electrical and instrumentation completion,
H. Verify that there is documentation of loop checks.
I. Verify that the software version installed is documented.
Ø For installation and instrumentation,
J. Verify that the delivered equipment and instrumentation meet the defined specifications of equipment order.
Ø For utilities completion,
K. Verify that there is documentation (e.g., a utilities checklist) of the connection of utilities to equipment.
Ø For piping systems completion,
a. Verify that the system “walk down” was completed.
b. Verify that any red line changes to the P&ID’s have been submitted.
Ø Verify that the following documentation is correct:
a. As built engineering and installation drawings
b. calibration documentation
c. weld documentation
d. material of construction certifications
e. Ensure that the Operational Qualification is complete.
Ø Verify that the valve sequencing (e.g. API tanks) is correct by comparing it against the piping and installation drawing.
Ø Verify that ranges for process and safety alarms have been set according to process parameters.
Ø Verify that critical alarms are present by comparing the alarms against a list of critical parameters.
Ø Verify that the range tested in the protocol encompasses the current alarm condition.
Ø Verify that “worst case” conditions have been tested for the equipment and ancillary systems.
L. Ensure that the documentation system is operating in full compliance.
Ø Verify that when any protocol has been approved, any changes to the protocol followed the site’s change control process.
M. Ensure that the Performance Qualification is complete.
Ø Verify that the testing performed is within established acceptance criteria.
N. Ensure that appropriate SOPs and batch documentation are developed for the equipment and systems being qualified. Ensure that any restrictions to use are implemented.
O. Ensure process validation has been performed and that manufacturing is performed within validated criteria
P. Ensure that an appropriate level of cleaning validation has been performed and that the validated cleaning process is implemented and conformed to.
Q. Ensure that analytical methods used are appropriately validated for the intended purpose.
R. Ensure that individuals involved in the qualification activities are adequately trained and that their training is documented.
S. Ensure validation reports are written in a timely manner, that acceptance criteria are met and that results are concluded
T. Ensure validated systems are subject to change control
U. Ensure there is a process for periodic review of validated system and that requalification/revalidation is performed where required
V. A number of issues that are identified by inspectors as concerns with validations are listed below.
a. Trying to “validate” a process that clearly is poorly developed.
b. Poorly organized documentation
c. Validation requirements remain unfulfilled
d. Illogical validation priorities – important work left out
e. Validation approach inconsistent
f. Not adhering to validated processes
g. Poor or even non-existing change control