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Table of contents:
1. Validation policy
3.1 Production department
3.2 Quality control department
3.3 Engineering department
3.4 Quality assurance department
4. Site summary
4.2 Equipment utility
5. Validation approach
6. Equipment qualification
6.1 User requirement specification (URS)
6.2 Design qualification (DQ)
6.3 Factory acceptance test (FAT)
6.4 Installation qualification (IQ)
6.5 Operational qualification (OQ)
6.6 Performance qualification (PQ)
7. Process Validation
8. Cleaning validation
9. Analytical method validation
10. Computer system validation
11. HVAC validation
12. Temperature mapping
13. Transport validation
14. Validation of aseptic process simulation (Media Fill)
15. Water system validation
18. Acceptance criteria
19. Validation schedule
20. Standard operating procedure
21. Document template
22. Document control and identification
23. Change control
27. Revision history
- Validation Policy
XXXX (company name) is committed to provide high quality product complying with the regulatory requirements. Validation is performed at site in accordance with the principle of regulatory guidance i.e. EudraLex Vol. 4, PIC/S, FDA and WHO etc. Below principles should apply for validation:
- The execution of validation should be in compliance with regulatory requirements.
- Validation should reinforce GMP.
- Quality risk management principles should be applied in determining the need, scope and extent of validation.
- Ongoing review should take place to ensure that the validated state is maintained and opportunities for continuous improvement is identified.
- Time, personnel and financial requirements should be ensured for validation.
The scope of this document is to cover the validation activity of XXXX (company name) and it covers the validation of process, equipment, utility and system.
3.1 Production department:
- Execution of validation protocol, equipment trials and process trials.
- Training of all manufacturing personnel in technical validation and GMP aspects.
- Sampling and execution of process control in coordination with QA
- Preparing reports or any deviation from process parameters.
- Participating in preparing validation protocols.
- Executing (PQ) and assisting in the execution (DQ, IQ and OQ) of validation protocols.
- Operating and maintaining plant, facilities, support systems and specific manufacturing process within its design limits, specifications in coordination with Engineering and Maintenance.
3.2 Quality control department:
- Testing of validation samples.
- Ensuring that the laboratory systems and equipment/devices to be used in the course of validation have been qualified or validated.
- Carrying out analytical methods validation.
- Preparing reports on any deviations from analytical parameters.
- Participating in preparing validation protocols.
- Training of all Quality Control personnel in technical, validation and GMP aspects.
- Participating in preparing validation protocols.
- Preparing laboratory reports and summaries of finding with conclusions
3.3 Engineering department:
- Participating in preparation of validation protocols.
- Preparing all drawings and related system engineering documents such as P and I drawings, Instrument list, Building and room drawings, Operational manuals, Operational recommendations, Maintenance requirements, spare parts lists, Operational manuals
- Equipment component identification, material control procedures, Calibration requirements and procedures and equipment installation and system construction procedures.
- Co-ordination of the calibration activities for all critical instrumentation
3.4 Quality Assurance department:
- Coordinating the efforts to determine the system and equipment/devices to be validated.
- Coordinating and organizing the validation team.
- Coordinating the preparation of validation protocols and execution for each system.
- Conducting process validation by monitoring, sampling, testing and challenging the specific manufacturing process.
- Training of personnel in support of validation / operations.
- Participating in preparing validation protocols.
- Collecting and organizing the validation data.
- Preparing the final validation summaries and certification statements.
- Tracking for routine / non-routine validation requirement.
- Tracking for validation requirement based on review of guidelines / literatures.
- Site summary
Site is involved in manufacturing of tablets, capsules, small volume and large volume parenteral. There are dedicated blocks for sterile and non-sterile products. There is common QC laboratory for both blocks. Warehouse for the storage of raw materials are packaging materials are common, there is separate finished product storage area for sterile and non-sterile products. There is separate entrance and exit for both the blocks. Gowning procedure is followed based on area requirement.
4.2 Equipment and utility:
Facility is having below mentioned key equipment and utility:
- Rapid mixing granulator
- Fluid bed dryer
- Compression machine
- Blister packing machine
- Manufacturing vessel
- Liquid filling machine
- Double door autoclave
- Tunnel sterilizer
- Dry heat sterilizer
- Laminar air flow
- Water system
- Pure steam generator
Manufacturing process is divided in below steps:
- Validation approach
Validation is an integral part of GMP compliance system, it will be implemented through all the areas that could affect the product quality. These areas are applicable to all utilities, processes, equipment, laboratory instruments, analytical methods and cleaning procedures identified in this validation master plan. In order to ensure success of the validation; the support programs must be implemented and a proper sequence of qualifications or validations activities shall be followed.
- Equipment qualification
Qualification is the planning, execution and recording of tests on equipment and systems that forms part of the validated process, to demonstrate that it will perform as intended. For any new processing / testing equipment system following aspects of qualifications has to be covered sequentially. The documentation will include preparation of URS (User Requirement Specification), DQ (Design Qualification), FAT (Factory Acceptance Test), IQ (Installation Qualification), Operational Qualification (OQ) and Performance Qualification (PQ).
6.1 User Requirement Specification (URS)
The URS provides the list of components and their specification, functionality in the desired equipment, prior to purchase of the equipment. URS is required for all new GMP equipment, items requiring validation. The specification should be developed, even if it is retrospective to equipment order, as it aids in defining qualification requirements.
6.2 Design Qualification (DQ)
It demonstrates the verification of the user requirements for equipment and its ancillary systems. Design qualification is performed prior to installation of the equipment.
6.3 Factory Acceptance Test (FAT)
Factory Acceptance Test ensures the verification of installation parameters, operating parameters and the functional checks at the vendors site itself prior to dispatch of the system / equipment to the customers site. This qualification also ensures any malfunctioning of any component or any changes are required as per the new requirement that can be made to the system / equipment and the correct equipment can be installed.
6.4 Installation Qualification (IQ)
Installation Qualification demonstrates that facility, equipment, control system, utility and selected components are made as per the required standard, installed as per the approved design and at the specified locations with proper identification.
The following sections shall be covered in installation qualification:
- System description
- Component identification
- Utilities verification
- Spare parts verification
- Equipment installation and location documentation
- Standard operating procedures documentation
- Purchase orders, specifications and manuals documentation
- Engineering drawings verification
- Preventive maintenance program
- Calibration documentation
6.5 Operational qualification (OQ)
Demonstrate that facility, equipment, control system utilities and the components of each of the system performed as intended throughout the anticipated operating ranges.
Below is the non-exhaustive list of contents of operational qualification document:
- Critical variables to be met. All critical variables with respect to equipment, area or system under qualification to be mentioned
- Relevant documents like training schedule, layout, SOP etc. completed
- Any changes made against the formally agreed designed parameters
- Review (inclusive of follow up action, if any)
6.6 Performance Qualification (PQ)
Documented veriﬁcation that the equipment or system performs consistently and reproducibly within deﬁned speciﬁcations and parameters in its normal operating environment (i.e. in the production environment).
The performance qualification will also include testing, that demonstrates that all intermediate and final product specifications are met. This phase shall be executed once the process parameters have been defined.
The following sections shall be covered in performance qualifications:
- Critical variables to be met: All critical variables with respect to equipment, area or system under qualification to be mentioned.
- Documents to be attached: Relevant documents like installation certificate, Training schedules, layouts etc., to be attached.
- Any changes made against the formally agreed design parameters.
- Review (Inclusive of follow up action, if any)
- Process Validation
Process validation is defined as a documented evidence to prove that a specific process when carried out within defined parameters will consistently produce an end product meeting its predetermined specifications.
Prospective process validation shall be carried out on the exhibit batches / Pilot scale batches prior to commercial production. The number of batches shall be decided as per the requirements of the specific market and risk assessment.
Concurrent process validation shall be performed on initial three commercial batches of new product.
Revalidation shall be performed when there is change in process, material, change in major equipment used, change in batch size, change in facility and change in vendor.
Process validation protocol will cover below points:
- Time schedule
- Validation team members,
- Environmental monitoring
- Reference documents to be followed
- Product details
- Manufacturing formula
- Equipment and instrument details
- Process flow diagram
- Quality Risk analysis
- Sampling plan and acceptance criteria
- Review and certification etc.
- Cleaning Validation
Cleaning validation should be performed to provide documented evidence that the procedure being followed for cleaning of equipment and accessories is effective and removes residue of previous batch/product up to a predetermined acceptance level, using a well-defined protocol and acceptance criteria. Two methods are employed for sampling during cleaning validation. They are rinse method and swab method.
The cleaning validation approach is established on process equipment related cleaning procedures and/or cleaning mechanisms. Procedures are established for cleaning. Each process, equipment will have a cleaning SOP or the operational SOP describing the cleaning procedure that will address all cleaning aspects for the equipment as applicable to each products. The cleaning validation protocol is developed to show that the established cleaning procedure will effectively and consistently clean the unit for which it is designed. One of the objectives of the cleaning validation protocol is to establish an acceptable level of active ingredient from one product that can be carried on to the next product to be processed on the same equipment. A second objective is to prove that the accepted cleaning procedure removes any detergent residuals (if used), wherever applicable.
The acceptance criteria are established based on pharmacological activity, toxicity, and/or any other applicable product characteristics. Introduction of new products or other potential contaminants shall be assessed to consider their impact on the validated state of cleaning procedures.
- Analytical method validation
An acceptable method of analysis is based on sound scientific principles and validated for the purpose intended, and revalidated in case of significant change. All test methods used to analysis of products, raw material etc. should be validated. Such methods may include, but are not necessarily limited to:
- Test methods (pharmacopoeial and non-pharmacopoeial) for finished product testing
- Test methods for raw material and consumables testing
- Test methods used for stability programs
- Test methods for In-process checks
Both chemical and microbiological test methods should be validated.
- Computer System Validation
All computer systems performing critical GMP functions are required to be validated. Such systems may include, but are not limited to:
Manufacturing automation computer system/software: PLCs (Programmable logical controllers), MMI (Man Machine Interphase), BMS (Building Management System) etc.
Production monitoring computer system/software: Material management software, Material requisition and issuance software, work order management software, stock management software.
Laboratory computer system/software: Laboratory management software, computer system associated with HPLC, GC, LCMS/MS, UV-VIS spectrophotometry etc., laboratory calculations related software.
Batch release and other QMS system related computer system/software: Batch release software, QMS recording software, labelling software.
Computer system validation protocol shall contain following non-exhaustive content:
– Roles and responsibilities
– Tools required
– Acceptance criteria
– Test data sheet
- HVAC Validation
The objective of HVAC system qualification is to verify the new/existing HVAC system is able to give the required environmental condition in the rooms to which the HVAC caters. These parameters are as follows:
- Temperature of the area
- Relative Humidity in the areas
- Differential pressure in the area with respect to adjacent areas
- Number of air changes, fresh air changes
- PAO testing of filters
- Non-viable particle monitoring
- Microbial (viable) monitoring
HVAC validation is carried out as per ISO14644.
- Temperature mapping
All new temperature-controlled storage areas must be temperature-mapped as part of a fully documented verification process, before the installation is commissioned and handed over by the installer.
The temperature mapping procedures should:
- demonstrate the air temperature profile throughout the storage area, when empty and in a normal loaded condition;
- define zones which should not be used for storage of products (for example areas in close proximity to cooling coils, cold air streams or heat sources); and
- if required, demonstrate the time taken for temperatures to exceed the designated limits in the event of a power failure.
- Transport validation
Finished products and samples should be transported from manufacturing sites in accordance with the conditions defined in the marketing authorisation, the approved label, product specification file or as justified by the manufacturer.
A risk assessment should be performed to consider the impact of variables in the transportation process other than those conditions which are continuously controlled or monitored, e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility and any other relevant factors.
- Validation of aseptic process simulation (Media Fill)
The aseptic process simulation is indented to prove high degree of confidence to fulfil the quality attributes of sterile product.
- All aseptic processing lines are subjected to media fill trials on six monthly basis.
- Aseptic processing lines are subjected to liquid media fill in the product containers, instead of the product. The entire production process from manufacturing to filling is same only using nutrient liquid broth instead of product.
- The type/size of container used in media fill trials is varied every six months to cover all pack size.
- Water System validation
Validation of new water system and periodic validation is necessary to ensure that the water system unit will perform effectively as it is supposed to perform. Operational considerations should be given including:
- Start up, commissioning and qualification
- System reviews
Water systems are “direct impact systems”. Therefore, stages to be considered in qualification should include DQ, IQ, OQ, PQ.
- DQ: Design review influenced by source water and required water quality.
- IQ: Installation verification of the system
- OQ: Operational qualification
- PQ: PQ demonstrates consistent and reliable performance of the system. Performance qualification involves three phase approach recommended over extended period – proves reliability and robustness.
Phase-I: It involves exhaustive sampling for 2-4 weeks. It involves chemical and microbiological monitoring.
Phase-II: It involves sampling for 2-4 weeks. It involves chemical and microbiological monitoring. It demonstrates consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs.
Phase-III: It is carried out over one year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase. It demonstrates that extended reliable performance of water system and also seasonal variations are evaluated.
After Phase 3 – system review needed. Based on review including results, routine monitoring plan will be established. Trending is done for all parameters.
Water system shall be validated by challenging of various parameters like level alarm, conductivity set points, temperature set points, TOC set points. Sampling frequency for chemical testing and microbial testing shall be increased during validation period.
If any major change / modification in the design of water system affecting water system unit, water system to be re-qualified by authorization of the documented change proposal through the change control procedure.
All measuring equipment (temperature, weight etc.) shall be periodically calibrated, frequency of calibration for critical temperature and pressure gauges are once in six months.
Revalidation is the scheduled re-testing and certifying of equipment, products, procedures or methods as required by assessment. Revalidation shall be done periodically to assess the fitness of existing process or in case of any significant change in equipment, material, process or system. Revalidation frequency is defined in below table:
|Validation Type||Revalidation Frequency|
|Media Fill||6 months|
|Stability chamber||12 months|
|Grade A area HVAC||6 months|
|Above Grade A area HVAC||12 months|
|Performance qualification||5 years|
|Process validation||5 years|
|Stability chambers||12 months|
Other items may be considered for routine revalidation if recommended as a result of initial validation outcomes.
- Acceptance Criteria
Each validation protocol must include acceptance criteria which should be based on scientific rationale, regulatory/GMP guidance, suppliers recommendation/manual and operation/function.
- Validation schedule
Validation schedule shall be prepared annually for equipment, process, system and utility. Validation shall be carried out as per schedule.
- Standard operating procedure
Following SOPs are available at site for execution of validation activity:
|SOP number||SOP Title|
|SOP03||Water system validation|
|SOP04||Aseptic process simulation study (Media fill)|
|SOP05||Computer system validation|
- Document Template
Validation document template is available at site, however additional contents can be included wherever deemed necessary. Template helps to maintain the consistency and uniformity among the validation documents.
Internal templates of following documents are in place:
- User requirement specification
- Installation qualification
- Operational qualification
- Performance qualification
- Process validation protocol
- Temperature mapping protocol
- Transport validation protocol
- Computer system validation protocol
- Aseptic process simulation study protocol
- Validation report
- Document control and identification
Validation document shall be managed, handled and retained as per document control and handling SOP. Each validation document shall be numbered as per document numbering SOP.
- Change control
All changes to validated equipment, processes, systems and methods should be formally requested, documented and accepted by representative of concerned department. The likely impact (risk assessment) of the change on the product should be evaluated and the need for and extent of re-validation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized.
|System||An organization of engineering components that have a defined operational function (e.g. piping, instrumentation, equipment, facilities, computer hardware/ software etc).|
|Impact Assessment||The process of evaluating the impact of the operating, controlling, alarming, and failure conditions of a system, on the quality of the product.|
|Critical Component||A component within a system where the operation, contact, data, control, alarm, or failure may have a direct impact on the quality of the product.|
|Non-Critical Component||A component within a system where the operation, contact, data, control, alarm, or failure may have an indirect impact or no impact on the quality of the product.|
|Calibration||The performance of tests and retests to ensure that measuring equipment (e.g. for temperature, weight, pH) used in a manufacturing process or analytical procedures (in production or quality control) give measurements that are correct within established limits.|
|Concurrent Validation||Validation carried out during routine production of products intended for sale.|
|Cleaning Validation||A documented evidence that a cleaning procedure is consistent in reducing product and cleaning agent residue from equipment within the acceptance limit and to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation.|
|Design Qualification (DQ)||Design Qualification is documented evidence that the proposed design of the facilities, systems and equipment are suitable for intended purpose.|
|Factory Acceptance Test (FAT)||Testing conducted at the supplier’s factory usually involving the user to determine whether or not a system satisfies its acceptance criteria and to enable the customer to determine whether or not to accept the system.|
|Installation Qualification (IQ)||Installation Qualification is a documented verification that the facilities, systems and equipment’s as installed or modified; comply with the approved design and manufacturer’s recommendations.|
|Operational Qualification (OQ)||The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications for the anticipated range of operation.|
Performance Qualification (PQ)
|Performance Qualification is the documented evidence which verified that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged period.|
|Process Validation||Documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.
|Prospective Validation||Validation carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations.
|Qualification||Qualification is the act of planning, carrying out and recording of tests on equipment and systems, which form part of the validated process, to demonstrate that it will perform as intended.
|Validation exercise to validate the system /equipment /process / method which is in state of validation & changes done which may impact its earlier state of validation.
|User Requirement Specification (URS)||A requirement specification that describes, what the equipment or system is supposed to do, thus containing at least asset of criteria or conditions that have to be met.
|Validation||Validation is the establishment of documented evidence that a system does what it is supposed to do. It is the collection and evaluation of data, which ensures that the manufacturing process including equipment, building, materials are capable of achieving the intended results on the consistent and continuous basis.
|Validation Protocol||The validation protocol is a written plan stating how validation will be conducted, including test parameters, product characteristics, and production equipment and decision points on what constitutes acceptable test results.
|Validation Report||The validation report is a written report on the validation activities, the validation data and the conclusions drawn.
|Validation Master Plan||A document providing information on the Company’s validation work programme, it should define details of and time scales for the validation work to be performed. Responsibilities relating to the plan should be stated.
|Worst Case||A condition or set of conditions encompassing upper and lower processing limits which pose the greatest chance of product or process failure when compared to ideal conditions and which are actually evaluated in the validation exercise.
Attachment I: Annual validation schedule template
EudraLex – Volume 4 – Good Manufacturing Practice- Annexure 15
PIC/S guide to Validation master plan installation and operational qualification Non-sterile process validation cleaning validation
- Revision History
|Date||Revision Number||Details of change|
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