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  2. DEFINITION:  Validation is the action of proving that any procedure, process, equipment, method, material or activities actually leads to the expected results which produce a quality product.  Validation is “Establishing document evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes”.
  4. PROCESS VALIDATION  As per FDA Nov 2008 “the collection of data from the process design stage throughout production, which establish scientific evidence that the product is capable of consistently delivering quality products”.  Process validation life cycle Stage 2 : process qualification Stage 3: continued process verfication Stage 1: process design
  5. TYPES OF PROCESS VALIDATION There are three basic types of process validations.  Prospective (pre-market) validation- validation is a completed prior to the manufacture of finished product that is intended for sale.  Concurrent validation- when prospective validation is not possible, it may be necessary to validate process during the routine production.  Retrospective validation – processes that have been in use for some time without any significant changes may also be validated according to an approved protocol.  There is one more type of validation apart from the three mentioned above, known as ‘revalidation’. Revalidation is repetition of validation process or some specific portion of it. Changes occur in components (raw materials, packaging materials); equipment is modified.
  6. PROSPECTIVE VALIDATION  It is usually undertaken whenever a new formula, process and facility need to be validated before routine pharmaceutical production starts. Eg: switching to new filter medium, leak testing of lyophiliser.  It is also usually employed when sufficient historical data is either unavailaible or insufficient and, inprocess and final product testing is inadequate to ensure high degree of confidence for product quality characteristics and reproducibility. Eg: a sterile solution filled on new equipment should only be released after a media fill validation.  FDA guidelines on pre-approval inspection, associated with NDA/ ANDA submission, added a new dimension to this type of validation.
  7.  FDA is seeking evidence that the manufacturing process is validated before it allows a product to enter the market for sale.  FDA favours prospective validation for high degree of confidence and minimal risk, as it ensures process to be under control and effective prior to manufacture or release of the product.  Higher degree of confidence is associated with higher cost of production, therefore a due consideration must b given to FDA preference and cost to benefit analysis.
  8. CONCURRENT VALIDATION  Concurrent validation is appropriate when:  It is not possible to complete a validation programme before routine manufacturing starts and it is known in advance that finished product will be for sale. eg: during the transference of process to contract manufacturer.  It is more appropriate to validation a process during routine production due to well understanding of process. eg: change in tablet shape or strength.  Extensive testing and monitoring ensures the desired quality characteristics of product with high degree of confidence but does not provide a degree of assurance that subsequent batches processed under the same condition and parameter will attain same quality attributes.  Due to the limited acceptability of prospective and retrospective validation, the concept of concurrent validation under the paragraph “Acceptability of product testing” in validation process guidelines have been included by FDA.
  9. RETROSPECTIVE VALIDATION  There are many processes in use in many companies that have not undergone a formally documented validation process.  Validation of these processes is possible provided sufficient historical data is available to provide documentary evidence that various processes are considerably stable.  Retrospective validation is preferred because of cost effectiveness  It is acceptable only for well established processes and where critical quality attributes and critical process parameters have been identified and documented.
  10. CONT.,  In general, data from 10 to 30 consecutive batches should be examined to assess process consistency. The review should include any batches that failed to meet specifications.  Any discrepancies or failure in the historical data may be excluded provide there is sufficient evidence that the failure was caused by isolated occurrences. Eg: employee error.  The Sources of data for this validation may include batch documents, control charts, maintenance logbooks, records of personnel changes, process capability studies, finished product data, trend cards and storage stability results.
  11. REVALIDATION/CHANGE CONTROL  It is a repetition of the validation process or a specific part of it.  It is either performed periodically to ascertain the process or to incorporate some changes in the procedure.  1.Changes to validated system: A system once validated, continues to remain validated as long as all conditions and control parameters are not changed.  Therefore, a change control quality assurance system must be established, which requires revalidation whenever there are changes in product characteristics or conditions, which can impact on in product characteristics .  eg: changes in the test procedure, raw materials, packaging system, plant site, facilities, equipment, processing steps, batch size, etc.  2.Periodic Revalidation: some manufacturers revalidate certain systems at pre-established periodic intervals, even when no change is believed to occur.  The need for periodic revalidation of non sterile processes is considered of limited usefulness than for sterile processes.
  12.  3.Change control classification: The change-control program should provide a classification scheme to evaluate changes in raw/packaging materials, manufacturing site/location, batch size, manufacturing equipment and production processes, product attributes (changes in formulation, strength).  The classification procedure should be used in determining the level of testing, validation and documentation is needed to justify changes to a validated process.  Changes should be categorised as minor and major changes (depending upon the nature an extent of the changes)  A minor change is defined as the one that is unlikely to have a detectable impact on the critical attributes of the product.  A major change is the one that would likely, significantly affect the critical quality attributes of the product.
  13.  FDA in its scale up and post approval changes (SUPAC) guidelines classifies the classifies the various levels of changes depending upon the impact of changes on quality and performance of product  Level 1 changes: changes that are unlikely to have any detectable impact on formulation quality and performance.  Level 2 changes: changes that could have a significant impact on formulation quality and performance.  Level 3 changes: changes that are likely to have significant impact on formulation quality and performance.
  14. EQUIPMENT VALIDATION  Equipment validation starts from the decision to bring a piece of new equipment to the organisation and continues till the decommissioning of equipment at the end of useful life.  It goes through the three following phases:  Pre-purchase or Pre-qualification phase – vendor specification, design qualification  Post-purchase or Qualification phase- installation, operational & performance qualification  Routine operation or Ongoing evaluation phase.
  15. PHASES OF VALIDATION PIdentify needs User requirement Design qualification justificatio n PRE PURCHASE Site preparation Commission protocol IQ, OQ, PQ Review & approval POST PURCHASE Operation SOP Calibration & performance verification maintenance decommission Routine operation
  16. PRE PURCHASE PHASE  Usually an operating department will require the purchase of a piece of equipment.  The rationale to bring a new piece of equipment should be well founded.  The benefits of acquiring the equipment, such as increasing productivity, meeting a specific need, or enhancing the capability should outweigh the expenditure of valuable and limited resources required to acquire the equipment and support its operation.  The operating department should establish the requirements in order to start a project.  The user should first decide on the basic functional requirement to define a type of equipment required to fulfil their needs.  A more detailed operational requirement can then be defined based on the functional requirements.  All these should be recorded in the user requirement document.
  17. Vendor specification  Initially various units available in the market should be taken at a glance.  The extent of resources and funds to accomplish the task should also be given due consideration .  The least expensive equipment may not be the best investment.  The most expensive may not be the appropriate instrument for operation.  Many of the functionality of the equipment system may not be required at all for the organization.  A consideration must also be given to the general background of the final user.  Simplicity is beauty and not all users are ready to tackle the complicated operations due to time constraints and training.  Although technical and economic factors have a major bearing on the selection of the vendor, no final decision should be made before analysing each prospective vendor’s capabilities in each of these areas.
  18.  Important considerations of vendor specification: o The vendor’s previous experience in implementing similar projects. o The vendor’s financial stability o The vendor’s guarantee of installation, training, start up support and after sales support, o The level of training offered by the vendor o Delivery times o The vendor’s familiarity with regulatory requirements of the equipment. o The vendor’s documentation and support of testing o Experience of current users.  On final selection, the vendor can be considered a team player. The vendor should offer time to assist in establishing the equipment validation plan or protocol with project team. Acceptance criteria and operational limitations shall be clearly understood by the vendor and project team.
  19. Design Qualification (DQ)  Design qualification outlines the key feature of the system designed to address the user requirements, regulatory compliance and selection rationale of the particular supplier.  Caution should be taken when putting together a design qualification since it will have major impact on installation, operation and performance qualifications.  The more functions that are specified in the DQ, the more work have to included in the installation, operation and performance qualification process.  The compliance of the basic design with the user requirement and regulatory requirement should be demonstrated and documented.
  20. POST PURCHASE PHASE site preparation  Careful planning is required to ensure that the necessary preparations to house the new equipment in the organization are completed.  Insufficient site preparations can cause major inconvenience and long delays in the installation process.  It is the wastage of money and time to have engineer show up in premises but not able to do anything due to lack of site preparation.  It is a common mistake to under estimate the effort and time required for site preparation
  21.  The following are the key considerations for the site preparation:  Physical dimension of the equipment and accessories- it must be made sure that there is enough space to accommodate equipment along with accessories and the bench is strong enough to support the instrument.  Suitable operating environment for the instrument- proper temperature, humidity and vibration control must be maintained.  Utilities- some instrument will require one or more of the following utilities to operate: custom power supply, electrical plug, gases, special ventilation and enclosure and water supply  Health and safety requirement- eg: special licenses are required to operate instruments that use radioactive substances.
  22. Qualification  Instrument qualification is required to establish the functional capabilities and reliability of the system for its intended use.  The instrument post purchase qualification can be divided into three stages:  Installation qualification  Operation qualification  Performance qualification.
  23. INSTALLATION QUALIFICATION (IQ)  IQ simple means, “is it correctly installed?’’  This is ensured through appropriate tests, related documents and records that equipment and ancillary system have been correctly commissioned, and are in conformity with installation specification, equipment manuals schematics and engineering drawing.  It further consists of documented verifications that all key aspects of equipment are in working condition and have been properly installed in accordance with the manufacturer’s specification and placed in an environment suitable for its intended use.  IQ means the documentary evidence to prove that the premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications.
  24.  The installation qualification of equipment may include, but not limited to the following verifications: 1.Preventive maintenance The IQ should document that the equipment is enrolled in a preventive maintenance program to assure that the system continues to operate properly and no component of the system becomes inoperable due to wear and tear. 2.Equipment information and supplier instructions The IQ should document equipment information including manufacturing agency, model number, and the serial number and verify that the information complies with the purchase orders and user requirements.  In addition, verification of equipment compliance with regulatory requirement should be performed.  Supplier’s working and operating instructions, maintenance requirements, calibration requirements and cleaning including sanitation and sterilisation requirement for the equipment should be collected
  25. 3.Calibration  The IQ should document that specific devices contained with the equipment have been calibrated to traceable standards.  documentation should include date on which calibration was performed and when calibration is due.  The test required to calibrate the equipment, the acceptance criteria and frequency of each test should be included in the calibration section of the SOPs.
  26. INSTRUMENT DATA SHEET INSTRUMENT FEATURES: Description 1.Identification number 2.Model number 3.Serial number 4.Capacity 5.Location 6.Dimension 7.Purpose CALIBRATION INFORMATION 1.Calibration frequency 2.Calibration number 3.Calibration sop no. and title 4.Calibration limits 5.Utilization range: max….. Min… Complied by….. Date….
  27. 4.Verification of components and equipment Once the equipment reaches the owner’s plant, a parts list should be reviewed. This is to verify that all the parts against shipping and purchase order have been found acceptable. documentation should include operating system name and version, software name and version, software name and version, backup files and CPU requirement such as processor speed, RAM capacity, etc. 5.SOPs The IQ should document all SOPs pertaining to the approved equipment and its installation place. Applicable SOPs may include preventative maintenance, calibration, operation, document archival, and equipment logbook usage. 6.Utilities and environmental conditions The IQ should document the manufacturer’s specification for required utilities and verify that appropriate utilities are available for the system. The utilities and building service section should cover the following areas: electricity, air, plumbing, steam, vacuum, pest control, heating, ventilation and air conditioning(HVAC) and cleaning.
  28. OPERATIONAL QUALIFICATION  All documents to support the testing equipment calibration should be included in the qualification report .  OQ must be performed via an established and accepted protocol  The proper operation will be verified by performing the test functions specified in the protocol.  The OQ testing should describe all aspects of the testing in detail.  The plans for OQ should identify the studies to be undertaken on the critical variables, the sequence of those studies and measuring equipment to be used and acceptance criteria to met.  SOPs and draft cleaning procedures are issued and approved after the completion of successful OQ.
  29. PERFORMANCE QUALIFICATION (PQ)  PQ is defined as the process to verify that the system is repeatable and consistently producing a quality product or in other words ‘ the process to demonstrate that the instrument can fulfil requirement outlined in the DQ.  The PQ can be demonstrated by running a typical application in DQ, which requires the system components to work function together properly to deliver the expected test results.  PQ should follow an authorised protocol, may include the following:  Tests using production materials that have been developed from the specialist knowledge of the process and how the equipment or system is intended to deliver its performance characteristics.  Studies utilising production materials to include a condition or set of conditions encompassing upper and lower operating limits.
  30. ROUTINE OPERATION PHASE (QUALIFICATION OF ESTABILISHING/IN-USE EQUIPMENTS)  After the instrument is qualified and has been transferred to the operating department , SOPs must be strictly followed for operation, maintenance and calibration of equipment. 1.USAGE AND SERVICE RECORD: Good usage and service record for the equipment must be maintained through a logbook. Such a record is required for the GMP purposes, further it facilities the notification to the user in case of system failure. The service records will also provide useful information about the system, which may simplify the troubleshooting effort in some instances. 2.CALIBRATION RECORD: A calibration record logbook must be maintained for each equipment , stating information about date of calibration test done, name and signature of responsible person who performed calibration and due date of next calibration test.