1.0	Objective	3
2.0	Scope	3-4
3.0	Validation Policy	4
4.0	Introduction	4
5.0	Responsibilities for validation activities	5-7
6.0	Facility description and design	8-9
7.0	Validation approach	10-25
8.0	Calibration program	25
9.0	Quality Risk Management Strategy	25
10.0	Documentation	25-24
11.0	Personnel Training	26
12.0	Change Control System	26
13.0	Preventive Maintenance Program	27
14.0	Glossary	27-29
15.0	Annexures	29
16.0	Abbreviations	29-30
17.0	Revision Details	30

1. OBJECTIVE:

The Validation Master Plan is a document which describes our company`s intentions and the methods related with validation of the facility, equipments, instruments, systems, utilities and processes.

The document serves as a guide with company’s overall approach towards performing validation and qualification activities, in accordance with World health Organization (WHO), current good manufacturing practices (cGMP) and current good laboratory practices (cGLP).      

Validation Master Plan is a dynamic document, which presents an overview of the entire validation activities, its organizational structure and planning.

Validation Master Plan ensures that:

• A suitable validation program is designed, in order to demonstrate that the facility is capable of meeting process/product parameters in a repeatable and controllable manner.
  • The facility is designed to provide the desired degree of environment controls as well as manufacturing controls, for all the production steps and throughout the manufacturing process of the finished dosage forms.
  • The critical programs for utilities qualification, process validation and equipment qualification have been established, in accordance with the product requirements (based on the product information and the cGMP guidelines and other regulations).

VMP adds value to our quality system and provides assurance on product safety, by ensuring that our facility, equipment and processes remain in a state of validation.

• SCOPE:

This VMP applies to all the validation activities, including qualification of facility, manufacturing equipment, engineering equipment, quality control equipment/instruments, analytical methods and cleaning procedures followed.

It also includes verification of Programmable Logic Controllers (PLC) and software used to operate the equipment and analytical instruments.

This validation program applies to all critical equipment, instrumentation, procedures and other quality support systems, used for manufacturing, processing, testing, labeling and packaging of finished dosage forms.

The validation program covers the items, which are listed below, and their related procedures:

• Facility
• Manufacturing/Engineering Equipment
• Manufacturing Processes
• Control Systems (e.g. Software, PLCs of critical equipments)
• Utilities (e.g., Water System, Ventilation etc.)
• Quality Control Instruments/Equipment
• Analytical Methods
• Revalidation or Re-qualification

The purpose is to establish documented evidence, which demonstrates compliance of these systems, as per the design specifications, installation/operational requirements and performance specifications required by the product and any other applicable specifications.

Cleaning procedures validation is covered through a separate validation master plan.

• VALIDATION POLICY:

The company. is committed to the concept of validation. Therefore all the facilities, equipment, manufacturing processes, control systems, utilities and analytical methods shall be put through appropriate Qualification and Validation cycles, before being accepted for use (new or after major renovations).

All systems shall also be subjected to ongoing change control & validation program, in order to evaluate the impact of intentional or un-intentional changes in process, product, systems, computers (software) and processing environment.

A nominated team, comprising personnel from various disciplines, shall carry out validation studies, as per specific protocol requirements.

For some Equipment/ Instruments, the manufacturer’s qualification documents (DQ, IQ, OQ, PQ) may also be taken as basis for qualification activities.

• INTRODUCTION:

The intent of this Validation Master Plan (VMP) is to provide a written plan for establishing documented evidence of the suitability of the facilities, reliability and consistency of the equipment, and validity of the manufacturing process.

This necessitates to put in place, approved “VALIDATION MASTER PLAN” in-order to provide the road map for validation activities and thus ensure planned verification, calibration, qualification and validation of manufacturing facility, equipment’s, utilities, product processes, measuring / weighing / recording devices, software systems, personnel and analytical methods. Approved Validation Master Plan (VMP) shall help in the prevention of omissions, tracking of tasks, identification and corrections of errors / deviations. VMP shall also provide an overview of validation activities for the facility.Validation Master Plan describes company’s overall philosophy, intentions and approach to be adopted for establishing performance adequacy.

the company. is a closely held, Professionally Managed, WHO, cGMP & GLP Certified Pharmaceutical Company; Manufacturing only wide range of  Solid Dosage Form (Soft Gel  Capsules ).

This facility complies to cater domestic & also ROW (Rest of the World) Market and cGMP requirements and is well supported by Engineering, Warehouse, Quality Control and Quality Assurance Departments.

The plant is manufacturing a wide range of Soft Gelatin Capsules products. The plant is well equipped to manufacture only Soft Gelatin Capsules.

• RESPONSIBILITIES FOR VALIDATION ACTIVITIES:

The validation activities shall be carried out by team of Personnel from Validation/Quality Assurance, Quality Control, Manufacturing, Warehouse and Engineering Department, as applicable. The respective department head shall ensure that the person nominated for the validation activity is having adequate knowledge and experience in carrying out the activity/task.

The Quality Assurance personnel involved in validation activities shall be responsible for coordination of the validation activities, facilitating the protocol preparation, execution of validation activities and compilation of reports of validation activities related to facility, manufacturing equipment and processes.

Quality Control Department shall be responsible for qualification of quality control instruments/equipments and analytical method validation. Quality control department shall also provide support for the analysis of the samples collected during the validation/qualification activities.

The respective warehouse/manufacturing department shall prepare and review the validation protocols related to their respective areas, execute the validation activities and compile the validation reports.

Engineering Department shall prepare/check protocols related to facility, manufacturing equipment’s and shall provide all necessary support for the qualification of equipment/utilities and for ensuring its performance throughout the life of equipment.

Quality Assurance Department shall prepare/review & approve the Validation protocols before implementation, monitor the progress of the validation activities and approve the compiled Validation reports. The final approval of validation reports shall be done by Quality Assurance.

Signatories of protocols/reports

Prepared by: Concerned department personnel/Validation team member (QA)

Checked by: Functional heads

Approved by: Manager – QA & QC

• Validation Team Members:

Each validation activity shall be coordinated by a validation team, which shall comprise of a working group of qualified personnel, as required for the specific validation activities.

Validation Team may be made up of representatives from Quality Assurance, Engineering, Project (as applicable), Production, Warehouse, Vendors (as applicable) and Quality Control.

Other personnel may be co-opted, as and when necessary, as members of the validation team, to assist during the validation of special equipment, utilities, or systems.

The Validation Team shall be responsible for:

• Facilitating the preparation of validation and qualification protocols.
  • Reviewing each protocol contents, to assure compliance with current regulations and guidelines.
  • Determining the suitability of established protocols, to qualify a system.
  • Verifying the adequacy of tests used for the system verification, as established by the validation protocol.
  • Training for the personnel, related to validation activities.
  • Executing the original protocols and collection of validation data for each validation.
  • Determine the extent of re-validation necessary in case of changes to a validated system.
  • Individual Responsibilities of Different Departments:

Individual responsibilities of different departments are described below:

• Project Engineering is responsible for –
• Construction of the building and providing the facilities as per user’s requirement.
• Assisting and providing all information required for civil work and facility qualification activity and handing over the facility along with all relevant documentation to site Engineering and user.

• Engineering is responsible for –
  • Responsible for taking over the facility from Project Engineering and assisting to carry out the qualification of area/equipments/Instruments/Systems and utilities.
  • Preparation/Review of validation protocols and reports of process equipments, utilities, systems etc.
  • Responsible for consistent supply of utilities for the product to be manufactured.
  • Providing all current and approved standard operating procedures related to engineering activities.
  • Carrying out calibration of equipments and instruments, either themselves or from external agency, based on predefined frequency with proper documentation.
  • Carrying out maintenance and preventive maintenance based on predefined frequency or as and when required with proper documentation.
  • Providing information regarding the recent trends in the monitoring devices/equipment to be used for the validation activities/URS support/suppliers documents (certificates, manuals, drawings, designs, diagrams and layouts etc.)/to add/modify the validation activity/process considering the safety aspect on the equipment/personnel & environment.
  • Production is responsible for –
• Carrying out manufacturing activities during qualification & validation as per written procedures.
• Coordinating in preparation of validation and qualification documents.
• Providing all current and approved standard operating procedures to be used as part of manufacturing process.
• Providing information regarding the procedures currently adopted for manufacturing/operation and cleaning aspects, and any modification if required in the current procedure adopted for manufacturing /operating equipment with justifications.

• Quality Control is responsible for –
• Carrying out qualification and calibration of equipments and instruments with proper documentation at pre-determined frequencies.
• Preparation of validation protocols and reports of equipments and instruments of quality control.
• Analyzing all the samples during qualification and validation.
• Providing all current and approved standard operating procedures to be used as part of quality control processes.
• Carrying out analytical and/or cleaning method validation for the product.
• Providing information regarding the test procedures currently adopted for procedures and cleaning aspects, and any modification if required in the current procedures adopted for the testing of validation samples.
  • Quality Assurance is responsible for –
• Coordinating and organizing the validation activities.
• Preparation of validation protocols and reports of process and cleaning validation.
• Ensuring all validation activities as per latest cGMP norms. Responsible for monitoring entire activity, results, reports and subsequent changes in qualification and validation activities.
• Collection of samples as per approved validation protocols.
• Evaluation of the validation data, Preparation of final validation summaries, certification statements and final approval of validation documents.

• FACILITY DESCRIPTION AND DESIGN:
  • General Description:

The facility is located in India. The plant area is spread over 900 square meters covered area and total area of the plot is 1000 sq. meters.

The land, air and water resources are ideal for Pharmaceutical manufacturing activities. 

The manufacturing site comprises of RCC (Reinforced Cement Concrete) buildings viz., Second (Two) Floors. Ground floor is designed for All liquid store, quarantine, under test sampling area, production manufacturing area, Bottle filling area/Washing, Filling/Sealing Area, Packing Area and BSR/FG Store. First floor is designed for Quality Assurance, Quality Control (Stability Chambers, Micro Section), RM Approved area, Dispensing area and Second floor is designed for Purified Water Plant, and Utility/HVAC System/Area etc.

The layout facilitates unidirectional flow for men and materials. 

The facility and critical systems have been designed to provide an established degree of environmental and manufacturing control.  

• Equipment Description:

All the process equipments required for Dispensing, Manufacturing, Washing, Filling/Sealing and packing are provided in the facility along with PLC and MMI on critical process equipments.

Equipments/Instruments/Systems are designed, procured & installed as per the specific requirements of each area of operation. All these equipments/systems to be validated and certified through approved protocols.

On site cleaning provisions are available for the equipments that cannot be moved to a washing room for cleaning.

Quality Control Lab is provided with all the instruments and equipments required to carry out the chemical as well as microbiological analysis of the raw material, in-process material, finished products and packaging materials. All the instruments and equipments are qualified before being put into operation.

• Utility System Description:HVAC System  

Total 14 Air Handling Unit, ventilating and  DX Unit are provided catering to warehouse, dispensing, manufacturing, product storage, packaging and Quality Control and Quality Assurance area, systems are being provided.

Differential Pressure regimes are maintained between the processing areas and the corridors to prevent cross contamination. HEPA filters have been provided in AHU terminal to all critical process and packaging areas maintaining appropriate classification for sampling, dispensing, manufacturing, washing, filling/sealing and packing areas.

Temperature, relative humidity (if required) and differential pressure are controlled and monitored using BMS.

• Water System

The water system is divided into two segments, namely Primary Treatment and Secondary Treatment. The Primary Treatment generates RO Water from Raw Water and the Secondary treatment generates Purified Water from the RO Water. Purified Water System is capable of generating a volume of 250 liters per hour.

• Manufacturing/Analytical Procedures DescriptionManufacturing Process

The following operations are carried out during the manufacturing and packing:

• Dispensing of Raw Materials;
• Gelatin Preparation
• Medicament Preparation (Medicine)
• Encapsulation
• Drying
• Inspection 
• Packaging of Blister & Bottling.

• Cleaning Process

All equipments involved in processing of above said unit operations have their respective cleaning procedures. Manual cleaning procedures are in place for most of the processing equipments. For equipments like Manufacturing/Storage Tank, Pipe Line and for Filling/Sealing Machine, Clean-in-place cleaning procedures are in place.

• Analytical Procedures

For analysis of all raw/packing materials, in-process materials, finished products and stability samples, standard analytical procedures are in place.

• VALIDATION APPROACH:

Validation process is carried out according to validation approach chart with written protocols that describe the detail procedures to be followed and acceptance criteria to meet. Area verification of new or modified area shall be carried out. Different types of Qualification and Validation activities shall be performed following proper documented procedures.

• Qualification of Process Equipments:

The extent of qualification and re-qualification shall be decided based on criticality of equipment or system.

• The equipments that directly impact the product quality, User Requirement Specifications will be prepared before commissioning of these equipments. Design Qualification document will be provided by the vendor/Supplier/Consultant. Factory acceptance test and site acceptance test shall be performed wherever appropriate. Installation, Operational and Performance qualification shall be performed before hand over of equipment to the concerned department for regular use. Re-qualification shall also be performed.
• The equipments that do not directly impact the product quality but may impact the product quality indirectly, User Requirement Specifications will be prepared before commissioning of these equipments. Design Qualification document will be provided by the vendor/Supplier/Consultant. Factory acceptance test and site acceptance test shall be performed wherever appropriate. Installation and Operational qualification shall be performed. It may or may not be required to carry out Performance Qualification of these equipments. And it shall be performed before hand over of equipment to the concerned department for regular use.
• The equipments that do not impact the product quality directly or indirectly, User Requirement Specifications may not be required. Design Qualification, Factory acceptance test and site acceptance test may not be performed. Installation, Operational qualification shall be performed. Performance Qualification shall not be performed for these types of equipments.

The sequence of operations with documentation requirements of qualification are enumerated below:

• User Requirement Specification (URS)

The URS defines the functions to be carried out, the required parameters on which the system will operate and the operating environment. It includes the details of description and technical specifications of new equipment/ utilities facilities, functional requirement specification and safety features.

User shall prepare URS for new equipment/utility/facility on the basis of product, process, critical quality attributes, capacity, regulatory and cGMP compliance.

The user shall send URS for new equipment/utilities/facilities to the vendor.

This document shall describe all essential requirements as described below

• Equipment Name
• Capacity
• Brief Process Requirement
• Key Process Parameters
• Operational Parameters
• GMP features
• Utility requirement
• Technical requirement
• Material of construction
• Surface Finish (if applicable)
• Level of automation
• Software validation
• Safety features
• Documents required

For standard procedure of carrying out Preparation of User Requirement Specification refer “Standard Operating Procedure for Site Acceptance Test.

• Design Qualification (DQ)

DQ is the documented verification that the proposed design of facilities;          systems and equipments are suitable for the intended purpose.

On the basis of User Requirement Specification (URS), the design and functional specification may be received from the vendor(s) for each new equipment/ instrument (to be procured or modified). These documents shall be reviewed by User department along with Engineering/Project (wherever applicable) & QA. The approved design shall be forwarded to concerned department for further proceedings. This describes the equipment or system in sufficient detail to enable it to be built.

The key design specifications are identified as below

• Major components design specification includes MOC for critical component.
• Process control instruments/ device specifications Description of features including alarms/ interlocks.
• Required utilities with specifications.
• Systems/ equipments engineering drawings (Mechanical electrical)
• Piping/process and instrumentation diagram (P & ID)
• Software /PLC specifications including drawings, wiring diagrams etc.

The vendor/supplier/consultant in conjunction with Projects department prepares Design Qualification. The design qualification links to IQ phase, wherein all the specifications stated are being verified.

7.1.3        Installation Qualification (IQ)

Installation qualification is associated with the installation of the system/equipment. It verifies static attributes through defined procedures and supporting documentation that all critical aspects of the system have been installed in accordance with the approved Design Qualification and manufacturer’s recommendations.

The following test shall be covered in installation Qualification. In each of the following tests the documents/parameters/systems described in the appropriate test data sheet shall be verified as per the procedure outlined therein.

§  URS/PO verification

• Vendor records verification
• Drawing/Diagrams verification
• Equipment positioning verification
• General installation safety checks verification
• Major components verification
• Essential utility services installation verification
• Lubricants verification
• Calibration verification
• Standard operating procedures verification

For standard procedure of installation qualification and respective formats of Installation Qualification Protocol/Report, refer SOP “Standard Operating Procedure for Installation Qualification.

• Operational Qualification (OQ)

Operational qualification function is to verify the equipment operation with functional testing throughout the operating ranges. The operational tests will be designed to demonstrate the equipments ability to operate in accordance with approved functional specifications.

The following tests shall be covered in Operational Qualification. In each of the following tests the parameters /functional keys described in the appropriate test data sheet shall be verified as per the procedure outlined.

§  Testing of main panel/control panel

• Power communication failure recovery verification
• Safety features verification
• Other operation verification
• Critical operating parameters
• Verification of standard equipment/master instrument used for qualification

For standard procedure of operation qualification and respective formats of Operation Qualification Protocol/Report, refer SOP “Standard Operating Procedure for Operation Qualification.

7.1.5        Performance Qualification (PQ)

The function of performance qualification is to verify through testing whether the system/equipment can operate the process as specified in the User Requirement Specification under normal and boundary conditions.

The PQ protocol generally include the following

• Describe the specific test to be conducted and rationale for testing.
• Test procedure includes sampling plan and acceptance criteria.
• A list of all test instruments used in the execution of the PQ with calibration status.
• Test data sheet to document all testing and test results.

For standard procedure of performance qualification and respective formats of Performance Qualification Protocol/Report, refer SOP “Standard Operating Procedure for Performance Qualification.

Re-qualification:

Re-qualification shall be carried out periodically after two years (± 60 days) or if there is any change

 in following:

• Design of Equipment/System/facility
• Location or site
• Operational procedure
• Major Breakdown

Re-qualification shall be done for equipments and systems that may have direct or indirect impact on quality.

Re-qualification shall be done as per planned date and frequency of re-qualification as per standard operating procedures. The planner shall be prepared for next due date by considering effective date of performance qualification report.

• Qualification of Quality Control instruments/ equipments:

The sequences of operations with requirements of documentation are enumerated below:

• User Requirement Specification (URS):

The User Requirement Specification shall include, but not limited to following details –

• Introduction
• Functional requirements
• Operational requirements
• GMP/GLP requirements
• Safety requirements
• Discussion /review & comments
• Glossary

For standard procedure of User requirement specifications of Quality control Instruments/equipment refer SOP “Standard Operating Procedure for User requirement specifications of Quality control Instruments/equipment.

• Installation Qualification (IQ)

The installation qualification protocol shall include, but not limited to following details –

• Objective
• Scope
• Responsibility
• Pre-installation check
• Instrument description
• Installation checks (which further may includes – documents and drawing, general arrangement, technical specification, utility connection, material of construction and calibration).
• Spare parts
• Safety
• Change control
• Conclusion
• Abbreviations
• Approval

7.2.3        Operational Qualification (OQ):

The operational qualification protocol shall include, but not limited to, following details –

• Objective
• Scope
• Responsibility
• Instrument description
• Operational checks (which further may includes verification of normal start up, power failure recovery, safety feature verification, other operation verification, critical operating parameters and verification of normal shut down)
• Safety
• Change control
• Training
• Conclusion
• Abbreviations
• Approval
  • Performance Qualification (PQ):

The performance qualification protocol shall include, but not limited to, following details –

• Objective
• Scope
• Responsibility
• Instrument description
• Experimental design
• Safety
• Change control
• Training
• Conclusion
• Abbreviations
• Approval

For standard procedure of Installation Qualification, Operational qualification and performance qualification of Quality control Instruments/equipment refer SOP “Standard Operating Procedure for Qualification of Quality control Instrument/equipment.

Re-qualification:  Re-qualification shall be carried out periodically after two years

(Not more than 60 days) or if there is any change in following:

• Design of Instrument / Equipment
• Location or site
• Operational procedure
• Major Breakdown

Re-qualification shall be performed for testing instruments/equipments as per Re-qualification Schedule of Testing instrument/equipment.

• Qualification of Critical Utilities

The critical utility systems that must operate at certain level to maintain the required quality level of the final product shall be validated.

Installation qualification and operational qualification will be carried out as described in sections 7.1.5 and 7.1.6.

Critical Utility Systems are:

• Heating ventilation and air conditioning (HVAC) with BMS System
• Water System (Purified Water)
• Compressed Air System

• Heating Ventilation Air Condition (HVAC) with BMS system

HVAC system comprises of 14 Air handling and 2 ventilating units.

These Air Handling Units cater to various rooms and areas to achieve the required environmental conditions, degree of cleanliness and number of air changes.

Once the installation and operational qualification have been completed the performance qualification shall be carried out to verify that the system does consistently as per the requisite specifications when operated under the operationally established standard operating conditions.

Performance qualification shall describe all essential test plans and acceptance criteria of different tests of HVAC system.

Re-qualification:

• Air velocity and air changes test: 12 months (Not more than 30 days)
• Filter integrity test (PAO Test): 12 months (Not more than 30 days)
• Temperature, relative humidity (If required) test: 12 Months (Not more than 60 days) (For three consecutive days).
• Pressure differential test: 12 Months (Not more than 30 days) (For three consecutive days)
• Particle Count Test: 6 Months (Not more than 7 days) (For ≤ ISO Class 5) & 12 Months (Not more than 30 days) (For > ISO Class 5).
• Microbiological Monitoring: 12 Months (Not more than 30 days) (With settle plate and Active air sampler for consecutive seven days).
• Recovery Test: 24 Months (Not more than 60 days)
• Air flow pattern test: 12 Months (Not more than 30 days)

Re-qualification shall be performed as per re-qualification planner for HVAC system.

• Water System (Purified Water)

Once the installation and operational qualification have been completed, the performance qualification shall be carried out to verify that the system does consistently produce water of the requisite pharmaceutical specifications when operated under the operationally established standard operating conditions.

Therefore the extensive sampling programme is required to establish and conform that the entire system will operate within specified operating ranges to develop and evaluate the system operation and maintenance procedures and to verify that the water produced and delivered to the points of use consistently meets the required quality specifications and acceptance criteria.

The sampling programme and evaluation of results is usually subject to pre approved protocol with clearly defined acceptance criteria.

The sampling programme consists of three successive phases, each with a specific purpose and sampling scheme as outlined below. The initial phase of sampling programme typically begins after the water system is fully operational as demonstrated through integrated system testing in operation qualification.

Phase	Primary Objectives	Duration
1	Develop appropriate operating rangesDevelop and finalize operating, cleaning and maintenance proceduresDemonstrate production and delivery of water of the required quality	4 weeks
2	Demonstrate consistent operation within established rangesDemonstrate consistent production and delivery of water of the required quality	4 weeks
3	Demonstrate extended performanceEnsure that potential seasonal variations are evaluated and treated	One year

Revalidation: Any modification, addition/deletion, change in equipment          or relocation of water system, which can alter the quality of water, shall be subjected for revalidation of water system.

For standard procedure of validation of water system refer “Protocol for validation of water system, as per Protocol.

• Compressed Air System

The installed systems shall be verified as per the installation and operational qualification protocols. After completion of the installation/operation verification, the performance qualification shall be carried out to verify that the system consistently produces compressed process air of requisite quality when operated under the operationally established standard operating conditions.
The performance of the compressed process air system shall be evaluated at user points for moisture content, oil mist content and bio load.

Revalidation: Revalidation of compressed air shall be carried out annually or any change in routine user point, process air system and process air equipment.

For standard procedure of validation of process air system refer “Protocol for validation of process air system.

• Validation of Supporting Systems or Control Systems Programmable Logic Controller with operator interface terminal controlled

Installation and operational qualification shall be carried out to verify   sequence of directions for operation controlled by Programmable Logic     Controller (PLC). Satisfactory installation and integration of the      control system for the equipment shall be verified by executing the qualification studies. The test data sheets shall be used to document the installation of the control system and to verify that the components of the control system confirm to design specifications. The operation of PLC is to be verified by verification of system healthiness, PLC system inputs/outputs, PLC system access control, HMI display screens, system communication failures and alarms etc.

Revalidation: PLC shall be validated after five years (± 60 days) and if there is any change in major components of PLC.

7.4.2        Computer/Software Validation

This is to ensure that Software system, wherever replaced by manual operation in a system, shall not make any adverse impact on product quality or Good Manufacturing Practice.

The validation shall be considered for complete life cycle of computer system. This shall include planning, specification, programming, testing, commissioning, document operation, monitoring and modifying.

Software used in HPLC, UV Spectrophotometer etc shall be validated.

Also the software programme used for material management in the plant (CBO) and Building management System (BMS) shall be validated as per the GMP standards and as per 21CFR Part 11 US federal regulation.

The Information Technology department detailing the following aspects shall prepare a validation protocol and report.

• Receipt, issue and control of materials.
• Status labeling and controls for the same.

Access control shall be governed by passwords and restriction of authority for the above functions.

Revalidation: Revalidation shall be carried out if there is any change in existing software.

• Manufacturing Process Validation

Process Optimization shall be conducted when there is new product, with the different formulation from existing product, introduced in the facility. Initially one batch shall be considered for the optimization purpose to finalize the process parameter. After successful optimization of the process, process validation shall be carried out.

Process validation is a documented programme, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.

The purpose of process validation is to demonstrate the reliability and reproducibility of manufacturing process, within established parameters and to assure batch uniformity and integrity of drug products. A process validation program shall establish a documented evidence of three full-scale consecutive production batches.

There are three basic types of process validation:

• Prospective Validation

It is establishing documented evidence that a system/process does what it purports to do based on preplanned protocol.

• Validation shall be undertaken when a new product or a product manufactured by revised formula/revision in manufacturing procedure where in the revision is expected to alter the product characteristics.
• This validation activity shall be undertaken before the commercial distribution of the batch and is associated with the technology transfer from the Drug Delivery Research Lab to production.
• During product development the production process should be broken down to individual steps.
• Each step should be evaluated on the basis of theoretical considerations to determine the critical parameters that may affect the quality of the finished product.
• The number of batches to be taken up for the validation studies shall be three consecutive batches or in line with regulatory requirement of that particular country.
• The validation batches shall be subjected to stability studies as per the standard procedure.
• Each experiment shall be Planned and documented in an authorized protocol.
• Product shall be released for sale and distribution after completion of validation activities ensuring that product is complied within predetermined acceptance criteria.
  • Concurrent Validation

Concurrent Validation is establishing documented evidence that a process does what it purports to do based on data generated during actual implementation of the process.

• Validation shall be undertaken during actual process of product manufacture and shall involve monitoring of critical processing steps and final product analysis to generate data to establish that process is under control.
• The number of batches to be taken up for validation studies shall be three consecutive batches or in line with the regulatory requirement of that particular country.
• The validation batches shall be subjected for post-production stability study.
• It is appropriate to validate a process during routine production where the product is different strength of previously validated product, a different tablet shape or where the process is well understood.
• Documentation requirements are same as prospective validation.
• Product shall be released for sale and distribution after completion of validation activities ensuring that product is complied within predetermined acceptance criteria.

• Retrospective validation

It is establishing documented evidence that a process does what it purports to do based on review and analysis of historic information.

Validation shall be undertaken if products already in commercial distribution and have long history of compliance to established standards.

Retrospective validation shall involve in depth analysis of production, testing and control data. A minimum of 20 consecutive batches shall be required for data generation to certify the process. In case if 20 batches are not manufactured per year, then lesser number of batches can be included.

This validation shall be carried out only for well-established processes that are in routine use. The batch records, process control charts, finished product data including trend charts and storage stability results etc. will be source of data for this validation.

Revalidation: Revalidation of process shall be carried out once in three years and if any change is done in any of the following:

• Facility
• Composition
• Manufacturing process
• Raw material
• Change or replacement in a critical equipment
• Batch size
• Pharmacopoeial reference
• Sequential batches that fail to meet product and process specification

Re-validation shall be performed as per Re-validation schedule for process validation.

For standard procedure of carrying out process validation refer “Standard Operating Procedure for process validation of drug products.

• Cleaning validation

Cleaning validation has separately been covered under Cleaning Validation Master Plan No. as per SOP for cleaning validation.

• Analytical Method Validation

Validation of an analytical method is the process by which it is established by laboratory studies that performance characteristics of the method meet the requirements for the intended analytical application through certain standards of accuracy and reliability.

Validation is required for any new or amended method to ensure that it is capable of giving reproducible and reliable results when used by different operators employing analogues equipment in the same or different laboratories.

List of validation parameters

• Specificity
• Linearity
• Precision
• Accuracy
• Robustness
• System suitability
• Solution Stability
• Filter Interference

Revalidation: Revalidation of the analytical procedure will be carried out if there is any change in the Analytical procedure and product specification.

• Vendor Qualification

Vendor Qualification is the procedure that describes a step-by-step approach for          all necessary actions to qualify a vendor. This procedure is applicable for all suppliers, except COMPANY’s own manufacturing sites, providing raw materials and packaging materials.

Warehouse department shall not accept any raw material or packaging material received from vendor other than from approved vendor list.

Depending upon the market conditions or to provide an alternative to the existing approved vendors, new vendors shall be developed.

Purchase department shall ask for three pre-purchase samples from the vendor for APIs from three different batches and one batch sample for excipients along with the COA, ROS, stability data and MSDS.

DDRL or Site QA shall arrange the analysis of sample as per COMPANY specification. DDRL shall carry out performance trial of the sample, if passing as per specification.

QA shall thoroughly evaluate the filled vendor questionnaire and shall audit the facility of the vendor.

Subject to approval of pre-purchase samples, purchase department or DDRL sourcing shall raise the necessary change control form to add the vendor as an approved vendor in the approved vendor list.

Re-qualification: All the approved vendors shall be re-qualified every three years.

For standard procedure of Vendor qualification refer “Standard Operating Procedure for Vendor qualification of raw materials (API and excipients),  and “Standard Operating Procedure for Vendor qualification of packaging materials.

• Analyst Qualification

Analyst qualification activity shall be carried out for every analyst in the laboratory. New analyst in triplicate shall analyze latest approved sample and mean of three shall be used for comparison. The variation shall be compared and based on the method and specific limit analyst shall be qualified.

For standard procedure and formats of analyst qualification, refer SOP “Standard Operating Procedure for Analyst Qualification.

• CALIBRATION PROGRAM:

All Process and facility instruments are covered in the calibration program.

All instruments providing critical process information necessary to make a quality determination are calibrated with the available standards.

Calibrations of Instruments utilized in validation studies are performed to ensure data accuracy. Certificate from outside agency shall be applicable.

All QC instruments/equipments shall be calibrated as outlined in Calibration Schedule as per “Standard operating procedure for calibration of instruments/equipments (If any individual SOP is in place)”.

• QUALITY RISK MANAGEMENT STRATEGY:

Quality Risk Management shall be separately covered under Quality Risk Management Master Plan No. TTIPL-QRM-001 as per “Standard Operating Procedure for preparation of Quality Risk Management Master Plan.

10.0    DOCUMENTATION:

General Requirements

For effective use of documents, they should be designed and prepared with utmost care. The documents shall be prepared as per respective standard operating procedures and shall

• Have a clear title
• Have a particular identification number
• Be approved by Authorized persons
• Have the effective date

Origination, Execution and Approval

• Validation team/concerned department shall generate validation protocols in a standard format, functional heads shall review and Quality Assurance head shall do pre-approval before the effective date.
• Approved protocols shall be forwarded to validation execution team for execution as per the schedule.
• Execution team shall execute IQ, OQ and PQ protocols and generate report.
• Discrepancies (if any) that are found during the execution of validation study shall be recorded and the impact will be fully evaluated. These discrepancies shall be rectified and recorded.
• QA representative of Execution team shall review the data of final report. Functional heads shall review the reports and finally Quality Assurance Head shall approve the report.
• Documentation system shall provide provision for revision of any document, or its part, through a change control. Manager QA & QC shall approve such revised versions. Revised versions shall supersede the previous version.
• In case of any additional tests /information to be added to the existing document, a new protocol as a supplement or addendum shall be prepared. Supplement or addendum shall be retained along with existing protocol.
• Format style and content of protocols and reports shall be as per SOPs.

 

11.0    PERSONNEL TRAINING:

Personnel training shall be covered in a structured training program. All employees shall be trained on Current Good Manufacturing Practice (cGMP) and job related activities.

Only approved trainers shall conduct internal training programs. Trainings are also been imparted by External trainers either at site or external sites.

Induction trainings, on job trainings and cGMP trainings are also in place for the employees.

Personnel performing validation activities should have technical knowledge and training in the area of job assignment. This includes validation/calibration aspects as per international regulations, documentation, operating procedures and use of measurement equipment and standards.

Training evaluation shall be carried out with proper training records as per standard operating procedures.

For standard procedure for carrying out personnel training refer “Standard Operating Procedure for Training of Personnel.

12.0    CHANGE CONTROL SYSTEM:

A strict change control procedure shall be followed as per the standard procedure. All changes shall be formally requested, documented and accepted by the representatives of Quality Assurance, initiating department and Regulatory affairs as appropriate. The likely impact of the change shall be evaluated along the need for and extent of revalidation. The change control system shall ensure that all notified or requested changes are satisfactorily investigated, documented and authorized.

Change control format comprises of the following:

• Detail of change requested
• Reason for proposed change
• Impact and risk assessment of change
• Change control approval
• Change control implementation and closure

For standard procedure and formats of change control refer “Standard Operating Procedure for Change control.

13.0    PREVENTIVE MAINTENANCE PROGRAM:

The preventive maintenance phase commences at project completion. It embodies all maintenance and support activities necessary to ensure that the validated status of the system is maintained throughout its operation life and is the responsibility of the site engineering personnel.

The system/equipments and its associated field instrumentation shall be incorporated in to the planned preventive maintenance activities and schedule the periodic re-calibration of the field instruments. They can be same as that of the process equipment in general with additional requirement that the sensors and other measuring devices shall be calibrated.

All test equipments must be traceable back to a reproducible standard reference source.

A periodic review shall be conducted to examine the quality and technical acceptability of all maintenance activities carried out on the equipment /instrument system to ensure that it has maintained its validated status. Part of the review process must conclude and examination of any change recorded to ensure that the effect of the changes have been thoroughly investigated and implemented.

For standard procedure of carrying out preventive maintenance of equipments refer “SOP for preventive maintenance of equipments.

14.0    GLOSSARY:

1. Acceptance criteria

The criteria assigned before undertaking testing, to allow evaluation of test results demonstrate compliance with a test phase of delivery requirement.

1. Calibration:

Means the set of operations, which establish, under specified conditions, the relationship between values indicated by a measuring instrument or system or values represented by a material measure and the corresponding known values of reference standard.

1. Commissioning:

An engineering term that covers all aspects of bringing a system or sub-system to apposition here it is regarded as being ready for use in pharmaceutical manufacture. Commissioning involves all the basis requirements of installation qualification (IQ) and operation qualification (OQ).

1. Installation Qualification (IQ):

The performance and documentation of tests to ensure that equipment (such as machines, measuring equipment) used in a manufacturing process are appropriately selected, correctly installed and work in accordance with specification.

1. Operational Qualification (OQ):

Documented verification that the system or sub system performs as intended throughout all anticipated operating ranges.

1. Performance Qualification (PQ):

Documented evidence that the equipment is performing as per parameter defined and that it gives result that meets predetermined acceptance criteria.

1. Process/piping and Instrument Diagrams (P&ID)

Engineering schematic diagrams that provide details of the inter-relationship of equipment, services, material flows, plant controls and alarms. The P& ID also provide the reference for each tag or label used for identification.

1. Process Validation:

Documented verification that the integrated system functions as intended, in its normal operating environment (The term performance qualification may also be used).

1. Qualification:

Identification of equipment attributes to the performance of a particular function or functions and allocation of certain limits or restrictions to those attributes.

1. Validation Master Plan:

A document providing information of the company’s validation work programme. It should define details of and timescales for the validation work to be performed. Responsibilities relating to the plan should be stated.

1. Validation:

Establishing documented evidence which provides a high degree of assurance that specific process, procedure, equipment, material, activity or system will consistently meets its pre-determined specifications and quality attributes.

1. Validation Protocol

A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results.

1. ABBREVIATIONS:

Sr. No.	Abbreviations	Details
01.	ARL	Analytical Research laboratory
02.	BMS	Building Management System
03.	CFR	Code of Federal Regulations
04.	cGLP	Current Good Laboratory Practice
05.	cGMP	Current Good Manufacturing Practice
06.	CVMP	Cleaning Validation Master Plan
07.	COA	Certificate of Analysis
08.	DDC	Direct Digital Controller
09.	DDRL	Drug Development Research Laboratory
10.	PAO	Poly Alpha Olefin
11.	DQ	Design Qualification
12.	EHS	Environment, Health and Safety
13.	Engg.	Engineering
14.	GM	General Manager
15.	HEPA	High Efficiency Particulate Air
16.	HPLC	High Performance Liquid Chromatography
17.	HVAC	Heating, Ventilation and Air Conditioning
18.	IQ	Installation Qualification
19.	ISO	International Organization for Standardization
20.	MOC	Material of Construction
21.	MSDS	Material Safety Data Sheet
22.	OQ	Operational Qualification
23.	P & ID	Piping and Instrument Diagram
24.	PLC	Programmable Logic Controller
25.	PO	Purchase Order
26.	PQ	Performance Qualification
27.	PVC	Polyvinyl Chloride
28.	PVDC	Polyvinyl Dichloride
29.	QA	Quality Assurance
30.	QC	Quality Control
31.	QRMMP	Quality Risk Management Master Plan
32.	RA	Regulatory Affairs
33.	ROS	Route of Synthesis
34.	SOP	Standard Operating Procedure
35.	Sr.	Senior
36.	URS	User Requirement Specification
37.	UV	Ultra Violet
38.	US	United States
39.	VMP	Validation Master Plan
40.	μ	Micron

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