Validation and Qualification
INTRODUCTION TO VALIDATION / QUALIFICATION
EXPLANATION OF KEYWORDS
Validation Plan - Specifies the validation steps and order thereof. The validation plan must also specify responsibilities and include a time plan.
User Requirements Specification (URS) - This document specifies the "needs" of the production process, based on technical reports, production and cleaning methods, and regulatory requirements (i.e. cGMP and 21 CFR part 11).
Functional Design Specification (FDS) - The purpose of this document is to define a system that meets the expectations and requirements as specified in the User Requirements Specification (URS).
System Quotation - This is the quotation from the system supplier that outlines the details including prices, delivery time, warranties, spare parts and education as agreed and specified in the Functional Design Specification. The URS, FDS, and System Quotation are also referred to as the Design Qualification.
Supplier Audit - It is recommended that a supplier audit be made to verify that the system supplier meets the demands as specified by the pharmaceutical producer. The audit will verify that the supplier's routines for development and production of the suggested software and hardware adhere to that required for using the system for pharmaceutical production.
System Construction - Based on agreements in the FDS and System Quotation, a system can be constructed by the system manufacturer/supplier. This is done according to the in-house SOPs and all documents required are either completed or created. In the last phase of the system construction, the system and all of its components are tested to verify functionality. In cases when large and/or customized systems are constructed, a Factory Acceptance Test (FAT) can be performed. This verifies that the system meets the design and functionality demands while still at the construction site.
Installation and Commissioning - Unpacking the system and installation in the operating environment take place at the pharmaceutical production facilities. Commissioning follows installation, and can be described as a general system check to verify that all components work correctly after transportation and installation. When the system has been commissioned, a Site Acceptance Test (SAT) can be performed. The purpose of a SAT is to verify that everything defined in the System Quotation has been delivered and that the system is complete, installed, and operational. After completion/approval of the SAT, the formal responsibility for the system rests with the pharmaceutical producer.
Installation Qualification (IQ) - An IQ is a detailed verification that all system components are in place, correctly installed, and the accompanying documentation is correct.
Operational Qualification (OQ) - Performed after the IQ, the OQ will verify that all components and instruments work correctly according to the system specification, both as stand-alone and as part of the computerized system. The IQ and OQ are also referred to as the Equipment Qualification.
Process/Performance Qualification (PQ) - PQ is documented verification that the process consistently performs as intended in routine use in its normal operation environment, and consistently produces product of acceptable quality. PQ will also verify that the specific methods (production, cleaning, storage) work in the system. When the PQ is completed and approved, the system can be put into production and the validation process is complete. A validation process is complex, time-consuming, expensive, and requires that certain steps are performed in a predefined and specific order.
TYPES OF QUALIFICATION (DQ/IQ/OQ/PQ)
Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation and records that equipment and ancillary systems or sub-systems have been commissioned correctly and that all future operations will be reliable and within specified operating limits.
DESIGN QUALIFICATION
The first element of the validation of new facilities, systems, or equipment is design qualification (DQ). Design qualification should establish and provide documentary evidence that the premises, the supporting utilities, the equipment, and the processes have been designed in accordance with the requirements of GMP. The compliance of the design with GMP should be demonstrated and documented.
INSTALLATION QUALIFICATION
Installation qualification should establish and provide documentary evidence that the premises, the supporting utilities, the equipment and the processes have been built and installed in compliance with their design specifications. Installation qualification (IQ) should be performed on new or modified facilities, systems, and equipment. IQ should include, but not be limited to the following:
- Installation of equipment, piping, services and instrumentation checked to current engineering drawings and functional specifications.
- Collection and collation of supplier operating and working instructions and maintenance requirements.
- Calibration requirements.
- Verification of materials of construction.
OPERATIONAL QUALIFICATION
Operational qualification should establish and provide documentary evidence that the premises, the supporting utilities, the equipment and the processes operate in accordance with their design specifications. Operational qualification (OQ) should follow Installation qualification. OQ should include, but not be limited to the following:
- Tests that have been developed from knowledge of processes, systems and equipment.
- Tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions.
The completion of a successful operational qualification should allow the finalization of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems, and equipment.
PERFORMANCE QUALIFICATION
Performance qualification should establish and provide documentary evidence that the premises, the supporting utilities, the equipment and the processes will consistently produce a product meeting its pre-determined specifications and quality attributes.Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. PQ should include, but not be limited to the following:
- Tests, using production materials, qualified substitutes or simulated product that has been developed from knowledge of the process and the facilities, systems or equipment.
- Tests to include a condition or set of conditions encompassing upper and lower operating limits.
Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ.
Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.
PLANNING FOR VALIDATION
All validation activities should be well planned. The key elements of a validation program should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. The VMP should be a summary document which is brief, concise and clear. The VMP should contain data on at least the following:
- Validation policy.
- Organizational structure of validation activities.
- Summary of facilities, systems, equipment and processes to be validated.
- Documentation format: the format to be used for protocols and reports.
- Planning and scheduling.
- Change control.
- Reference to existing documents.
VALIDATION PLAN
During product development the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/parameters that may affect the quality of the finished product.
A series of experiments should be devised to determine the criticality of these factors. Representatives from Production, QC/QA, Engineering, and in some cases Research and Development will normally be involved in this process. These experiments may incorporate a challenge element to determine the robustness of the process. Such a challenge is generally referred to as a "worst case" exercise. The use of starting materials on the extremes of the specification may indicate the ability of the process to continue producing finished product to the required specification.
Each experiment should be planned and documented fully in an authorized protocol. This document will have the following elements:
- A description of the process.
- A description of the experiment.
- Details of the equipment/facilities to be used (including measuring / recording equipment) together with its calibration status.
- The variables to be monitored.
- The samples to be taken - where, when, how and how many.
- The product performance characteristics/attributes to be monitored, together with the test methods.
- The acceptable limits.
- Time schedules.
- Personnel responsibilities.
- Details of methods for recording and evaluating results, including statistical analysis.
All equipment, the production environment, and analytical testing methods to be used should have been fully validated, (Installation/ Operational Qualification). In practice, Operational Qualification may be carried out using batches of actual product. This work may also fulfill the requirements of Process Validation.
Master Batch Documentation can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. Using this defined process (including specified components) a series of batches of the final product should be produced. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation.
It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data.
During the processing of the batch/run, extensive testing should be performed on the product at various stages. Detailed testing should also be done on the final product and its package. The batches/runs under validation should be documented comprehensively. The following items should be included in the validation report:
- A description of the process - Batch/Packaging Document, including details of critical steps.
- A detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be found.
- Any work done in addition to that specified in the protocol or any deviations from the protocol should be formally noted along with an explanation.
- A review and comparison of the results with those expected.
- Formal acceptance/rejection of the work by the team/persons designated as being responsible for the validation, after completion of any corrective action or repeated work.
Upon completion of the review, recommendations should be made on the extent of monitoring and the Process Analytical Technology necessary for routine production. These considerations should be incorporated into the Batch Manufacturing Record and appropriate standard operating procedures (SOPs). Limits, frequencies and actions to be taken in the event of the limits being exceeded should be specified and comply fully with the requirements of Good Manufacturing Practices (GMPs).
PROCESS VALIDATION
Process Validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality. This covers the initial validation of new processes, subsequent validation of modified processes and re-validation.
Any manufacturing or packaging process will involve a number of factors that may affect product quality. These factors will be identified during the development of a product and will facilitate process optimization studies.
On completion of development and optimization, Process Validation provides a structured way of assessing methodically the factors that impact on the final product.
In theory, a validation exercise should only need to be carried out once for any given process. In practice however the process rarely remains static. Changes occur in components (raw materials and packaging materials), equipment is modified and the process environment cannot be assumed to remain as during the initial validation. A regular program of re-validation is essential.
CLEANING VALIDATION
Cleaning validation is the methodology used to assure that a cleaning process removes residues of the active pharmaceutical ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes. All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by waste from the previous product.
Cleaning Validation is a critical aspect of pharmaceutical manufacturing systems. Preventing contamination that can potentially harm a patient is of critical importance in pharmaceutical manufacturing plants. Based on the result of your cleaning validation risk assessment you must decide on the level of science needed to justify your cleaning validation strategy.
Utilizing automation and Process Analytical Technology (PAT) such as online conductivity and TOC analyzers ensure your CIP cycles are consistently effective with optimal cycle times. Cycle data can also be trended and collected in batch records or process historian.
Cleaning Validation Master Plan
The CVMP should include the following elements.
- Risk Assessment
- Establishment of acceptance criteria
- Cleaning methods and procedures
- Analytical method and its validation
- Sampling Procedure and necessary validation
- Training Records
- Change Control procedure
- Validation protocols
- Validation Summary Report
Pharma-Tech will help provide a sound, practical approach to your cleaning validation master planning, calculating residual acceptance limits, and cycle development.
If you would like to know more about evaluating and optimizing your validation plans. Please contact us.