VALIDATION MASTER PLAN

VALIDATION MASTER PLAN

CONTENTS

SR. NO.	CONTENTS	PAGE NO.
1	APPROVAL
2	INTRODUCTION
3	VALIDATION POLICY
4	OBJECTIVE
5	SCOPE
6	VALIDATION RESPONSIBILITIES
6.1	Validation Team Constitution
7	FACILITY DESCRIPTIONS AND DESIGN
7.1	General Description and Design Concept
7.2	Description of Products
7.3	Description of Process
7.4	Description of Equipments
8	VALIDATION PROGRAM AND SUPPORTING SYSTEMS
8.1	Fundamentals of  Validation Program
8.2	Supporting systems for validation program
9	VALIDATION CONCEPT AND TYPES
10	ACCEPTANCE CRITERIA
11	RISK MANAGEMENT STRATEGY
12	STANDARD OPERATING PROCEDURES
13	CHANGES AND MODIFICATIONS
13.1	Changes and modification to the validation systems
13.2	Changes and modification to the validated systems
14	VALIDATION SCHEDULE
15	ANNEXURE
16	GLOSSARY

• APPROVAL

The Validation Master Plan has been initiated, checked, approved and authorized   for implementation by the undersigned.

INITIATED BY

DESIGNATION	NAME	SIGNATURE	DATE
Quality Assurance Executive [Validation]

CHECKED BY

DESIGNATION	NAME	SIGNATURE	DATE
Quality Control Head
Production Head
Engineering Head
IT Department Head

APPROVED BY

DESIGNATION	NAME	SIGNATURE	DATE
Quality Assurance Head
General Manager

AUTHORIZED BY

DESIGNATION	NAME	SIGNATURE	DATE
Vice President

2.0 INTRODUCTION

• Pharmaceutical Formulation plant having tablet , capsule,liquid  manufacturing facility, which is situated ________________________ India.

• The facility was designed in the year ____________________ to meet the national, International,

regulatory and cGMP requirements.

• The manufacturing facility is supported by Engineering, Ware house, Quality control and Quality Assurance department. All these departments are covered under the relevant validation activities.

• The Validation Master plan is a dynamic document which provides complete over-view of validation program.

• It describes the overall objective, intention approach for establishing performance adequacy of equipment, utilities, processes and systems.

2.6  It identifies the scope of validation, applicable validation protocols-reports, procedures and frequency of validations.

3.0 VALIDATION POLICY 

3.1 The organisation is committed to the concept of validation and all Processes  facilities, equipment’s, Machines, Instruments, Control Systems, Utilities, and analytical methods are put through appropriate qualification and validation cycles before being accepted for use. Performance Qualification shall be carried out for all critical equipment’s used for manufacturing, Engineering and Quality control.

3.2 All systems are subject to ongoing validation to evaluate the impact of changes in process, systems, environment, equipment directly or indirectly on the product.

• Three Validation studies are carried out as per protocol prepared by nominated team members from various departments.

3.4 For certain equipments/ Instruments, on case –by –case basis the manufacturers qualification documents shall also be taken as inputs for  qualification activities. This includes pre delivery inspection and FAT.

4.0 OBJECTIVE

• Validation Master Plan is a document, which describes our company’s intentions and the methods which are related with validation of the equipments, instruments, systems, utilities, facilities, materials, analytical methods and processes.

• Validation program is designed to demonstrate that the facility for the production up to final stage of production of different dosage forms is capable of meeting the process parameters in a repeatable and controllable manner.

• Validation Master Plan ensure that validation activities are carried out as per respective protocols and after completion will determine whether the equipment, system, process and methods,
  • Meets the specifications of its design.
  • Suitable for its intended applications.
  • Confirm to the basic cGMP design criteria.
  • Will satisfy the regulatory requirements.
  • Meets safety requirements as applicable.
  • Is capable of consistently producing a product that is fit for use.

4.4 The critical utilities, equipment & process validation program are established in accordance with the methods and procedures maintained by the product requirements which are based on the currently available product information and the Current Good Manufacturing practices, guidelines and other regulations.

4.6 Validation Master Plan helps :

4.6.1 The management to know and access what the validation programme involves and understand its necessity.

4.6.2 The validation team members to understand their tasks and responsibilities.

4.6.3 To understand the company’s approach towards validation and the set up of organising validation related activities.

5.0 SCOPE     

5.1 The scope of this document is to describe the systems and methodology used to execute the various phases of the validation program .

5.2  It applies to all critical equipments, instruments, procedures, utilities, facilities and other quality supporting systems used for manufacturing, processing, testing, labelling and packaging which may affect the quality of product directly or indirectly.

5.3 Validation Master Plan applies methodology of validation program of following,

1. Facilities
2. Equipments / Instruments / System [ Qualification]
3. Utilities (e.g. HVAC, Water system, Pure steam and Compressed Air.)
4. Control systems (e.g. computer hardware and soft ware)
5. Manufacturing processes
6. Cleaning processes
7. Analytical methods
8. Environmental (Physical & Microbiological)
9. Personnel ( e.g. Analysts, checkers on inspection or packing line).
10. Revalidation or Re-qualification. 

6.0 VALIDATION RESPONSIBILITIES

6.1  Validation Team Constitution   

6.1.1 The over all validation process is co-ordinated by a team, which is a working group comprising of qualified personnel as required for the specific validation activities.

6.1.2 The validation team is made up of representatives from the following areas:

• Quality assurance (Validation)
• Production
• Engineering
• Quality control

6.1.3 Validation team is responsible for :

• Preparation of Validation Master Plan.
• Determining the equipments, instruments, systems, facilities and utilities to be validated.
• Preparation of validation and Qualification protocols.
• Execution of the validation and Qualification protocols.
• Determining the suitability of the established protocol to qualify a system.
• Approving all validation protocols and report for each validation from respective functional department heads.
• Reviewing each protocols and reports content to assure compliance with current regulations and guidelines.
• Verifying the adequacy of the tests used for the verification of the system as established by the validation protocols.
• Determine the extent of revalidation necessity in case of changes in a validated system.
• Document control.

6.1.4 Other personnel will be utilised, as necessary, by the members of the validation team to assist the assessment of the special equipment, system, utilities  where their area of expertise will facilitate the development & execution and assure the quality of the validation efforts.

6.1.5 Individual responsibilities of different departments as follows:

1. Production: It is responsible for,

• Describing the production process in collaboration with Quality assurance.
• Preparation of the batch records in collaboration with Quality assurance.
• Transferring the processes to the production facility, in collaboration with Quality assurance.
• Providing all current and approved standard operating procedures to be used as part of manufacturing process.
• Providing personnel and materials as required for the execution of validation protocols, equipment trials and process trials.
• Training of all manufacturing personnel in technical, validation and GMP aspects.
• Sampling and execution of process controls.
• Preparing reports on any deviation from occurs during process.
• Participating in preparation of draft validation protocols.
• Executing DQ, IQ, OQ & PQ with validation team members as per validation protocols.
• Tracking for validation requirements.
• Operating & maintaining plant, facilities, equipment, support systems and the specific manufacturing processes within its design limits.

2. Engineering: It is responsible for,
   • Building and room drawings
   • Calculations
   • Instrument list
   • Maintenance requirements
   • Spare part list
   • Calibration requirements and procedures
   • Equipment design, installation and system construction procedures.
   • Operational recommendations

• Co-ordination of calibration activities for all critical instruments as defined by the validation team
• Participating in preparation of draft validation protocols.
• Executing DQ, IQ and OQ tasks and assisting in the execution of
• Preparing and maintaining calibration records for all critical instruments.
• Executing the installation and maintenance of production facilities and laboratories.
• Training of all engineering personnel in technical, validation and GMP/ GEP aspects.

NOTE: Critical instruments are those which have direct impact on the product   quality, i.e. Instruments which measure, monitor, or control manufacturing,processing and testing parameters. 

3. Quality Control: It is responsible for,

• Participating in preparation of draft validation protocols.
• Training of all Quality control personnel in technical, validation and GMP/ GLP aspects.
• Testing of validation sample as per validation protocols and specifications.
• Preparing laboratory reports by collecting data and verified summaries of findings and conclusions.
• Ensuring that the laboratory systems, instruments, devices and equipment to be used in the course of validation studies have been qualified, validated and calibrated.

4. Quality Assurance: It is responsible for,

• Co-ordinating and organising the validation team.
• Co-ordinating the preparation of the validation protocols for each Area, system, Facility, Utility, equipment, Instrument.
• Co-ordinating the process validation by monitoring, sampling, testing and challenging the specific manufacturing processes.
• Co-ordinating all change control approvals. Organising the changes required to approved protocols resulting from specification changes or changes in operating parameters.
• Training of personnel involved in validation activities.
• Collecting and organising the validation data.
• Tracking of all validation requirements based on the review of guidelines or literatures.
• Preparing the final validation summaries and certification statements. 

7.0 FACILITY DESCRIPTIONS AND DESIGN 

7.1 General Description and Design Concept of facility as follows:-

7.1.1  Pharmaceutical plant have provide manufacturing facility for different dosage forms as tablets,Liquid & capsule.

• The plant is functionally divided into different blocks viz. Change Rooms, Administration, Quality Assurance, Quality Control, Production, Service Floor, Warehouse, Utility, Engineering Workshop, Canteen and the Gate House. Quality Control Laboratory is contagious to production operations, whereas there exists an In-Process Quality Control Laboratory inside the production area.

• The production area has infrastructure to manufacture tablets,liquid & capsule.

• The Production and supporting areas have been made in a cluster module with covered interconnecting corridors and feasibility for modular expansion. The building is made of Reinforced Cement Concrete (RCC), and designed such, that no beams or columns are visible in the manufacturing and testing areas. The walls of the plant are constructed of brick and plastered to provide a hard smooth finish, with minimised recesses. The Production, Quality Assurance, and the interconnecting corridors have quota stone and only warehouse have hygienic Epoxy flooring.

• The return air risers of the HVAC system are concealed within the wall to avoid recesses. The terminal filters and lighting fixture are recess type, ceiling mounted. All the services to the manufacturing area are provided from the first floor, (designated as the Service Floor) through Galvanised iron.

• Sanitary type drains have been provided in the production and testing areas. Further, concealed drainage line has supplied to effluent treatment plant. All drainage is treated to bring down the COD and BOD to predetermined levels. This treated water is then used for gardening.

• The Ware house is dust resistant and controlled environment.

• The Power Supply system features the facility to control voltage fluctuations and an automatic changeover system from the state power supply to stand by power generation system in case of power failure.

7.1.9 The building is surrounded on all sides by a fire hydrant loop, maintained at high pressure.                        

 7.2  Description of Products:  As per attached Annexure (Make and attached Product list here)

 7.3   Description of Process flow:As per attached Annexure (Make and attached  list here) 

7.4 List of equipments: As per attached Annexure (Make and attached  list here)

8.0 VALIDATION PROGRAM AND SUPPORTING SYSTEMS 

8.1 Fundamentals of  Validation Program:-

8.1.1  The validation program shall be divided into five phases as follows,

• Phase I – Preparation and Approval of the Validation Master Plan.

• Phase II – Preparation and Approval of the Validation Protocols.

• Phase III – Execution of Validation protocols,  tests laid down in Validation Protocols and data collection.

• Phase IV – Preparation of Validation Report, Compilation of data collected during Validation, review, recommendations and Approval of  Validation Report. Document shall be kept under custody of the Quality Assurance.

• Phase V – Ongoing evaluation, review, Change Control, Deviations and Revalidation.

8.1.2  The Validation Master Plan (VMP) shall be prepared by the Validation Executive.

8.1.3   The document shall be checked by the heads of all Functional area.

The document shall be approved by the Quality Assurance Manager and General Manager. The document shall be Authorised by Vice President .

8.1.4   There shall be separate Protocols for DQ, IQ, OQ, PQ (where ever applicable), Environment Control, Analytical method validation, Facility, Utility,  Process Validation, and Cleaning Validation etc. All the protocols shall be numbered as per SOP for the numbering of protocols and reports.

8.1.5  The Protocols shall consist of the Objective, scope, responsibilities,procedures for conducting the tests for Validation. The results observed during the validation studies, summary, conclusion and final approval shall include in the reports.

• Validation Executive and Concerned department Executive shall initiate

the Validation Protocols. Concerned  HOD and HOD’s of  the Production, Engineering shall approve. Quality Assurance Manager & General Manager shall finally authorize the validation protocols.

8.1.7  The Approved Master copies of protocol shall be kept in the custody of the Quality Assurance Manager. During execution of validation protocol, validation report shall be prepared as per protocol and attached the collected data of the same to the reports.

8.1.8 Summary & conclusion Report and Approval

• After the execution of the protocols, a validation task report shall be reviewed, summarise, concluded  and recommendations made by the team carrying out the validation activity and approved by the involved team members.

8.2 Supporting systems for validation program:

8.2.1 Protocol and documentation system:

The system shall designed to assure  that all validation documentation shall prepare accordingly validation policies establish by a validation team, which shall responsible for the co-ordinating the validation program and approving all validation activities.

8.2.2 Documentation control system:

This system shall design to manage all documents generated during the validation process, including that from the change control program. The system will include a numbering system to identify each protocol and an index to list of all approved protocols. It assures that all documentation shall properly stored and controlled so as to maintain its integrity.

• Protocol execution system:

This system shall assure that all requirements outlined in the approved validation protocol are met and thus system shall considered to valid. To comply with these requirements this system shall establishes the procedures to be followed for co-ordination of the validation tasks through the validation team. This system shall also provides assurance that the information collected is timely, correct and is properly reviewed and shall approved by the validation team members. 

8.2.4  Change control system:The SOP for Change Control

 9.0  VALIDATION CONCEPT AND TYPES

9.1  Definition:

9.1.1 ‘The collection and evaluation of data, beginning at the process development stage and continuing through the production phase, which ensures that the facility, equipment, manufacturing process, control systems, utilities including personnel and materials are capable of achieving the intended results on a consistent and continuing basis and thus is capable of consistently producing a product that meets the established products specification’.

9.1.2 Validation is an documented evidence which can confirm predetermined critical parameters.     

       9.2  Validation Types:

 

1. Facility validation: 

• Room no. and location

• Purpose of area for use 

• Dimension of area:

Height (Meter),  Length (Meter), Width(Meter), Area (M² / Ft²) Volume (M³/Ft³  ). 

• Area Details:

• Walls:

Wall to floor,  wall to false ceiling,  Wall to return air riser,  Wall to door frame.

• Ceiling: Type, Finish,  Painting Shade & Jointing.
• Door:

Type, Dimension (W X H meter),  No of doors, Location,  Painting, No and type of door closer,  No and type of handle,  Size of  glass   view panel,  Door interlocking.

• Windows:

     Type & No of windows,  Dimensions (W x H meter),  Jointing.

• Drainage:

     Type of trap,  No and location,  Material of construction.

• Electrical work:

Wiring type,  no. of light fittings and type arrangement for emergency light.  No. of telephone points,  no. of computer points, no. of  Power  sockets, no. of single phase sockets & type,  no. of three phase sockets & type,  no. of lighting switch box & type  Illumination level in Lux. 

• Building management system:

Indication box, Size, Location Indication, pressure Indication,  temperature Indication, humidity and Door status. 

• Other facilities:

Fly killer,  Air curtain,  PVC strip door, SS corner angle, SS fenders,  Fan Safety, Pass box.  

1. Analytical Method validation: 

This type of validation shall be done at Analytical  Research Development department.

1. Vendor Qualification : 

• Vendor Qualification shall be carried out for all vendors of Raw and Packing Materials, to ensure that the components of the product, consistently meet predetermined specifications.

• Vendor evaluation shall be done on the basis of questionnaire, pre-shipment samples, machine trials and/or a vendor audit .

• The supplied materials shall be checked / analysed with respect to in- house specifications.

1. Control system validation: 

• Computer software and hardware Validation.

• The objective of the computer system validation is to demonstrate that the computer system performs (Create, modify, archive, and retrieve) as it is supposed to.
• This shall be based on following:
• Specification for hardware and software depending on intended use.
• Computer and manual modes of data validation giving similar results.
• Accessibility, durability and accuracy of stored data.
• Levels of authority for data entry and change.
• Accuracy and reliability of data entered.
• Security system to ensure any alteration or pilferage of data.

v  Qualification (DQ/ IQ/ OQ/ PQ) of  Computer Hardware and software:

• To control the equipment/ instrument/ system, computer hardware and software systems used as a part of equipment or instrument or system must be validated. Design qualification, Installation qualification and operational qualification shall be executed prior to performance qualification of associated equipment/ instrument/ system.

• To expedite the process of validation, the computer system validation shall be done as a part of equipment/ instrument/ system validation.

• The following are the contents for computer hardware and software validation: 

1. Detail description of control system

• Control panel
• Power supplies
• Temperature sensor (Wherever applicable)
• Humidity sensors (Wherever applicable)
• Smoke detectors (Wherever applicable)
• CPU

• Location
• Manufacturer
• Model
• Processor
• Capacity
• Disk type
• Floppy disk drive
• Hard disk drive
• Ports
  • Monitor
• Manufacturer
• Model
• Type
• Size
• Software
• Operating system version
• Application program version
• Password control
• Input devices
• RAM
• CDROM

2. Computer Hardware

• Manufacturer
• Model No.
• Serial No.
• CPU board Model No.
• CPU board Serial No.
• Communication processor
• Printers
• Screens
• Floppy disk drives
• Hard disk drives
• Computer operating environment:-

• Temperature
• Humidity
• Electromagnetic field

• Calibration – List of all calibrated instruments for the computer control systems and make this list as a part of validation document.

• Electrical – Verification of the control system and/ or control wiring has been installed as per manufacturer’s drawing and specifications and confirm correct identification of wires or air control lines in the control panel and the control panel / computer system are properly grounded.

3. Computer Software

• Software
• Verification that software prevents unintentional access.
• Verify back up procedures.
• Verification of restart of software procedures after system failure.
• Verification of software change control procedures.
• Verification whether the controller operates as a stand alone device or as part of a distributed system. If the controller operates as part of a distributed system, verify that the program is written to prevent unauthorised access between the system.
• Verification that the following phases of software life cycle have taken place ,
  • Requirements
  • Design phase
  • Installation and check out phase
  • Operation and maintenance phase
  • Performance phase

• Verification that supplier has provide the following
  • Logic flow diagram
  • Operating manual
  • Software description
  • Where does memory reside ( RAM, Tape Disk)

4. Controlled devices:

• Verification that the controlled devices for the system as per approved drawings, specifications and authorised change orders.
• Verification that all the controlled devices have been installed and tagged as per ,
  • Manufacturer
  • Model
  • Location
  • Description
  • Function
  • Calibration date
  • ID number
• Verification that all the wiring done as per specifications. Execution of point to point verification between the control panel. Confirm the correct identification of wires and / or air control lines.

• Evaluate the controlled functions for their potential effect on the quality strength, purity and safety of the final product.

1. Equipment validation (Qualification):
2. Design Qualification
3. Installation Qualification
4. Operational Qualification
5. Performance Qualification

1. Design Qualification (DQ)

The following sections are to be included in design qualification:

• User requirement specification (U.R.S.)
• User requirement specification (U.R.S.):
• The following sections are to be included in User Requirement Specification:

1.0 Introduction

2.0 Overview

3.0 Operational Requirements

3.1 Capacity

3.2 Specifications

3.3 Functional Requirements

3.4 Environment

3.5 Maintenance

4.0 Life Cycle

4.1Prefered vender list

4.2Development

4.3Testing

4.4 Delivery

4.5 Support

5.0 Glossary

6.0 References

7.0 Approval

Note: Numbering system as per SOP of User requirement specification

• Functional Requirement specification ( FRS):
  • Specification provided by the supplier end is to be attached to the report.

• Factory acceptance test procedure (F.A.T.):
  • Remark of team of selector on F.A.T.
  • Approval

2. Installation Qualification (IQ)

• Installation Qualification is documented check that all key aspects of the installation adhere to appropriate codes, approved design intentions and that manufacturer’s recommendations are suitably considered.

• To qualify, the specifications of the new equipment received, must match with the URS . Any exceptions to the original Purchase order or Functional specification shall be documented and justified. Attribute inspection of the equipment/ Instrument/ System shall be carried out, documented and proper installation shall be verified.

• All modifications in existing equipments shall be properly documented through a change control procedure.

• It may not be possible to inspect and verify every feature associated with a piece of equipment. In such cases, a

certificate of conformance shall be consider, obtained from the equipment manufacturer.

• The following sections are to be included in Protocol of Installation Qualification protocol:

• Approval
• Objective
• Scope
• Responsibility
• Procedure
• Re-qualification criteria
• Abbreviations
• Reference

3. Operational Qualification (OQ)
   • OQ demonstrates that the equipment/ Instrument/ System can operate throughout it’s dynamic range of operation, within limits and tolerances as per specified in the operating manual or instructions.

• This demonstration of equipment’s basic operation shall involve all control parameters of the equipment.

• OQ shall be carried out for equipment/ Instrument/ System that will be used routinely in manufacturing, testing or in critical utilities.

• The following sections are to be included in Operational Qualification protocol:
  • Approval
  • Objective
  • Scope
  • Responsibility
  • Procedure
  • Re-qualification criteria
  • Abbreviations
  • Reference

4. Performance Qualification (PQ)     

• Performance qualification is documented verification of performance of equipment/ Instrument/ System as intended for the process under specified operating ranges.

• All critical equipment / Instrument/ System are qualified for performance verification.

• The study shall involve the challenging of the system to simulated worst case situations, and establishment of operating variables.

• The following sections are to be included in performance qualification protocol:
  • Approval
  • Objective
  • Scope
  • Responsibility
  • Procedure
  • Acceptance criteria
  • Re-qualification criteria
  • Abbreviations
  • Reference

NOTE: All equipment, Instrument and system shall have required separate qualification protocol and report.

1. Process validation:

• Process validation is established 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.

• If a new product is duplicasy of the existing product then its validation shall be bracketed with the existing product. 

• 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 production batches. 

• The validation protocol shall be a written document that defines and gives the detail of critical steps of manufacturing process. It shall state, how the validation program will be conducted and lists acceptance criteria for  successful validation.

The process validation batches shall be taken for packing after completion of 30 days hold time study for the initial batches manufactured, Provided the product meets the Finished product / release specification/ upon re analysis.

• There are four types of the process validation.
  • Prospective validation
  • Concurrent validation
  • Retrospective validation
  • Revalidation 

1. Prospective validation:

• Prospective Validation shall be carried out on the small scale or R & D batches during development stage.

• These validations were carried out to identify the processing steps, equipment settings and process timings, which can prove to be critical in overall impact of product quality. All these steps, equipment setting and process timing are evaluated to finalise the setting parameter. Limits of all critical parameters shall put tentatively.

• This draft form of study can lead towards the finalisation of Batch Manufacturing Record / Batch Packing Record for large scale batches.

• The prospective validation shall take care of following:

1. Process description
2. Investigation summary of critical processing steps
3. Finished product release specification
4. Calibration of equipment
5. Appropriate analytical methods
6. Proposed in process control with acceptance criteria
7. Sampling plan
8. Method for recording and evaluating results and responsibilities. 

2. Concurrent validation:
   • This validation comprises of determination and evaluation of process parameters applicable from scale up to large scale batches.

• Process validation for establishing the predetermined limits of all critical parameters by conducting three consecutive commercial or large scale batches.

• Validation carried out during routine production or products manufacturing for sale.

• The tests are finalised based on evaluation of the results of these batches. These batches were monitored for stability and quality trends.

• Matrix approach can be applied to process validation. The matrix approach means that a plan to conduct process validation on different strength of same product, manufactured by the same process and similar type of equipment. e.g. validation on one strength (preferably smallest) as a representative amongst the multiple strength of the same product. This approach should be in accordance with cGMP and should demonstrate that the process is consistent for all the strength. 

Note: The batches will not be dispatched unless and until the analysis of the validation sample is completed. 

3. Retrospective validation:

• Historical trending of all critical parameters obtained from analytical results and / or IPQC results observed after testing of physical, chemical and microbiological parameters of product manufactured by same process. To ensure that all the parameters shall be in the limit and in uniform range.

• Retrospective validation shall done yearly of products or batches manufactured in previous year.

• Minimum first 20 batches shall consider for retrospective validation. If less than 20 batches were manufactured in one year then batches of previous years were consider for trending.

4.   Revalidation:

• Periodic revalidation: This type of revalidation shall be done on periodic basis as per specified frequency. The revalidation shall be governed by the Change Control procedure.

• Revalidation after any change : All validated equipment, systems, processes, products etc. shall be continuously monitored for any change, to be considered for revalidation of the same. 

• Revalidation / Requalification [Verification of validation] shall be considered in the case of :

• Equipment / Instruments / System:

1)  Substitution of existing equipment with a new equipment /instrument/System.

2) Change of site /location of the equipment / instrument / System from qualified existing place to other place.

3) Any major modification in the existing equipment / instrument /System since purchase which can have an adverse effect on the quality and efficacy of the finished product. 

• Manufacturing Process:

A change in the validated manufacturing process that has an effect on the quality and efficacy of the finished product,  which includes a change in the following :

1) Master formula or manufacturing process.

2) Raw Materials

3) Equipment

4) Batch Size

5) Change in manufacturing site or location.

1. Cleaning validation: 

Definition:

·      Validation of the process by which the equipments are cleaned is called as cleaning validation.

Objective:

• Cleaning validation is an important mechanism to protect the pharmaceutical products from cross contamination. A pharmaceutical product can be contaminated by previous product residues, traces of cleaning agent, micro-organisms or any foreign particle as borne particles, dust, raw materials etc.

• This should be performed to provide a documented evidence that the procedure being followed for cleaning of equipment and accessories is effective and removes residues of previous batch / product up to a predetermined acceptance level, using a well defined protocol and acceptance criteria.

• For equipments which are not product specific, cleaning procedure for such equipment should be able to ensure that it can consistently remove residues to the predetermined level.

Procedure:

• There are two methods employed for sampling during cleaning validation. These are Rinse and Swab method. Rinse method will be applicable when swabs are not practically possible.

• Cleaning procedures for products and processes, which are very similar are do not need to be individually validated. Representative of similar range can be selected to justify the validation programme, which addresses the critical issues relating to selected products and processes.

• A single validation study under consideration of the “worst case” can be carried out on the basis of the maximum strength, potency, solubility and LD₅₀. The cleaning validation can be evaluated,
  1. For highest strength product in multi strength products or all products.
  2. For highest potency product in all products.
  3. For least solubility in common cleaning solvent i.e. Water.

This “worst case” term can also be referred as “bracketing”. And such approach is called as matrix approach.

• Three cleaning validations exercise shall be performed and shown to be successful in order to prove that the method is validated.

• The documentation of  cleaning  validation  shall  include  validation protocol, cleaning procedures, sampling plans, surface area calculations, testing procedures and executed record of the cleaning event, a record of the sampling and  testing events and a validation report which contains clear conclusions against acceptance criteria.

• This validation shall covers sanitation, microbiology as well as removal of external agents like detergents, using sampling techniques capable of detecting and measuring to very low levels wherever applicable.

• There are two criteria’s for the cleaning validation, one is dose criteria and second is 10 PPM criteria.

• Validated analytical methods used for cleaning validation shall have sensitivity to detect residues or contaminant of previous product . The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptance level of residues or the contaminant.

• Equipment surface area calculation:

1. The product contact surface area for each equipment shall be calculated by theoretically breaking down the equipment in to basic geometric shapes [cylindrical, cubical, cone, rectangle etc.] and then apply to relevant area calculation formulae.
2. Amount of contaminant, mix from previous product to next product, depend on the common surface area of equipment used for both previous and next product.

Responsibility:

• Quality Assurance:

Generation of validation protocol

Sampling during validation

Review and compilation of validation data & certification

• Production:

            Ensuring cleaning of equipment

 

1. Utilities Validation: 

• Equipments / Machineries used for plant utility as,

1. HVAC system
2. Water system
3. Pure steam generator
4. Compressed air system

1. HVAC system:- 

• Air Handling Unit system, ventilation system, and evaporating system are the part of HVAC system which is one of the utility have directly or indirectly impact on products.

• Total ____ number of independent air handling units, _____ number of ventilation systems with supply and exhaust duct have been provided in the facility. Each critical operational area has a dedicated air-handling unit (AHU) and has temperature and humidity controls. Each room is provided with terminally filtered air, as per the requirement of operation, to be carried out in the room. Total ___ number of evaporating units in service floor  are provided.

• The core corridors are provided with controlled environment. Pressure balancing of each room has been done to avoid any cross contamination, by any ingress of air / drug product from adjacent areas.

• There is provision to automatically control and record temperature and percentage relative humidity & monitor and record the pressure differential across Rooms, by means of a computer interface.

• This system is qualified initially, monitored at regular intervals and revalidated once in a year in oral dosage form area.

• Initially Temperature control test, Humidity control test, Air velocity & number of air changes test, Differential Pressure Control test, Air borne Particle Count test, Microbial count test, Air flow direction test shall be conduct to perform the system.

• Limits for each test shall mentioned in the validation protocol as acceptance criteria.

2. Water system:- 

• Water system is one of the utility which have directly or indirectly impact on products. There are mainly three types of water system as follows,

Raw water system [Potable water]

DM water system [Deionised water]

Purified water system

• New water system shall be established and use for regular purpose after one year validation study includes the results of chemical and microbiological quality of the water.
  • For qualifying the DM water system & purified water system, Chemical and Microbiological Test shall be conduct mentioned as follows.
  • Temperature, PH, Conductivity, Colour, Total hardness, Total dissolved solids, Turbidity, Alkalinity and presence of ions or minerals, Microbial counts, pyrogens and endotoxins. Test method for each tests shall be mentioned in the protocol.
  • Location of sampling points shall be done as per specified in Validation protocol or as per SOP.
  • Frequency for all above mentioned tests shall be mentioned in the individual validation protocol.
  • Validation of water system shall divide in to three different phases as follows. Frequency of sampling, number of samples taken and no. of sampling locations are reduces from phase I level to next phase level.

Phase – I       –

Phase – II      –

Phase – III     –

• Following acceptance criteria:

1. Raw water circulation and its storage shall be requalified if microbial load is if,more than 500 CFU / ml and chemical water quality shall confirms to In-house standards.

2. Demineralised water circulation and its storage shall be qualified if microbial load is if, more than 100 CFU / ml and chemical water quality shall confirms to In-house standards.

3. Purified water circulation and its storage shall be qualified if microbial load is if,more than 10 CFU / ml and chemical water quality shall confirms to In-house standards.

4. For acceptance criteria of chemical and microbiological tests of purified water,USP – 41 [NF – 36] shall be refer.

• Sanitization of purified water system shall be done after 15 days

• Water system shall be revalidate if there is any major change, replacement or modification in existing system. It shall be periodically revalidate or verified once in a year on the basis of monthly, weekly or daily testing data as per scheduled trend.  

3. Pure steam generator:-

• Pure steam is one of the utility which have directly or indirectly impact on the quality of the product.

• Conductivity, PH, Total organic carbon, Bacterial endotoxin and Microbial count test of pure steam condensate shall be carried out during validation.

• Frequency for sampling and testing shall be mentioned in the protocol.

• Sampling locations of pure steam shall be carried out from pure steam generator as per specified in the validation protocol.

• Data of chemical and microbiological analysis of all months shall be reviewed and trend shall be prepared for year.

• Based on the trend data of the year summary report shall be prepared and shall be approved at unit levels.

• Limits or Acceptance criteria for each tests shall defined in the validation protocol.

• Pure steam generator shall be revalidate if there is any major change, replacement or modification in existing system. It shall be periodically revalidate or verified once in a year on the basis of monthly, weekly or daily testing data as per scheduled trend.

 

4. Compressed air system:-

• Compressed air system is one of the utility which have directly or indirectly impact on the quality of the product.

• Sampling locations shall be mentioned in the validation protocol. Sampling method of Compressed Air shall be carried out as per respective Standard Operating Procedure.

• Following test shall conduct to qualify compressed air system. Limits or Acceptance criteria for each tests shall defined in the validation protocol.

1. Water vapour: Dew point and moisture content in air shall identify.

1.1 Pressure Dew point : 0 to + 3° c.

1.2 Atmospheric Dew point :  – 15  to – 20° c.

2. Compressed Air must be oil free so during the course of generation it

does not comes in contact  with Oil.

3. Hydrocarbons should be less than 5 mg / m³.
4. Micro organisms should be less than 3 CFU/ m³.
5. Particulate matter such as fibres and metal particles should be NMT 100 particles of 0.5 mper cubic feet of air.

6. Compressed air system should meet the class 100 requirement.

• Frequency of different tests of different frequency should be specify in to the validation protocol.

• Data of chemical and microbiological analysis collected monthly or quarterly shall be reviewed and trend shall be prepared for year.

• Based on the trend data of the year summary report shall be prepared and shall be approved at unit levels.

• Compressed Air System shall be revalidate if there is any major change, replacement or modification in existing system. It shall be periodically revalidate or verified once in a year on the basis of monthly and yearly testing data as per scheduled trend.

Note: During validation program of above described utilities some tests were conducted by external party and some tests were in-house, specified in validation protocol.

10.0   ACCEPTANCE CRITERIA 

10.1 The specific acceptance criteria for the experimentation results, during    validation, shall be defined in detail in the respective validation protocol. Recognised national or international standards shall be cited for reference.

11.0 RISK MANAGEMENT STRATEGY

11.1 Risk: It is defined as the combination of like hood and consequences of specified hazardous event occurring.

11.2 Hazards: It is defined as the source or situation with potential for harm in terms human injury or ill health, damage to property, damage to work place, damage to environment, or a combination of these.

11.3 Any aspect of the operation that can affect the quality attributes i.e. Identity, purity,strength, safety of the product directly or indirectly, obviously that can affect the health of customer, that’s why, assessment of impact of risk requires.

11.4 This shall be based on the comprehensive understanding of the product, process,system and components. Where possible this assessment of impact shall be defined in the user requirement specification & process validation.

11.5 Risk and issue management strategy:-

Sources of risks: Risk sources are broadly categorized into,

• New project
• Introduction of new equipments in to the existing facility
• Changes in the existing facility or utility or equipments
• Introduction of new product
• Change in the approved vendor.

11.6 Method of Risk identification and Evaluation:

Impact assessment : The risk is identified and categorized in to impact and no impact.

Identify the system

Develop system boundaries

Does the system have an direct impact on product quality

Is it linked with direct                       Direct impact

impact system

No impact system    Indirect Impact               Develop supporting rational

11.7 Based on the findings, if the impact of the risk is direct or indirect one, then the extent of validation is decided i.e. whether it requires a process, equipment, analytical method, cleaning process or vendor qualification.

11.8 Risk categorization, validation priorities, schedule preparation, depth of validation including timelines shall be determined by the functional team members from the  production, QA, QC and Engineering.

11.9 When a new product is introduced in to the existing system, the risk is assessed by using matrix vs. does form which is evaluated in the product development plan for the process validation and cleaning validation.

11.10 Impact assessment: The applicability of any thing of the following criteria was taken as an indication that the system has direct impact or indirect impact on the product. Systems such provides Utility which has direct contact with the product are compressed air, purified water, Pure stem and HVAC system

Description	Name of System / Equipment / Instrument	Direct impact	Indirect impact	Remark
Area	—	Y	—	—
Utilities	HVAC System	Y	—	—
	Compressed air	Y	—	—
	Purified water	Y	—	—
	Potable water	N	Y	—
	Pure steam	Y	Y	—
Equipments	All equipments used in the manufacturing processes	Y	—	—
	All equipments or machineries used for storage	N	Y	—

 

12.0   STANDARD OPERATING PROCEDURES 

12.1   The Standard Operating Procedures relevant to the equipment, process,and analytical methods shall available at individual site.

13.0 CHANGES AND MODIFICATIONS: 

13.1 Changes and modification to the validation systems:

Any changes or modifications to the validation protocol, test reporting formats and other related documents must be approved by the validation team prior to becoming effective through a ‘Change Control’ system.

13.2 Changes and modification to the validated systems:

All changes or modifications to a validated systems must be evaluated and

approved by following ‘Change control system’.  A supplement to be attached to the revised protocol to reflect the approved changes as it may be deleted part or additional part in the validation protocol. 

14.0  VALIDATION SCHEDULE

14.1 The Validation for equipment, instruments, systems and processes which requires to be periodically revalidated at defined frequency as per individual validation protocol within ± 1 month of the due date.

15.0 ANNEXURE (To be prepared and attached)

1. Annexure – I Product list
2. Annexure – II Equipment list
3. Annexure – III Process flow
4. Annexure – IV Equipment validation schedule
5. Annexure – V Process validation schedule 

 

16.0  GLOSSARY

1. Acceptance criteria:

The product, equipment, and /or process specifications and limits, such as acceptable quality level and unacceptable quality level, that is necessary for making a decision to accept or reject.

2. Calibration:

Demonstrating that a measuring device produces results within specified limits of those produced by a reference standard device over an appropriate range of measurements. This process results in corrections that may be applied if maximum accuracy is required.

3. Change control:

A formal system by which qualified representatives of appropriate discipline reviewed proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure and document that the system is maintained in the validated status.

4. Certification:

Documented testimony by qualified authorities that a system qualification, calibration, validation or revalidation has been performed appropriately and that the results are acceptable.

5. Critical variable study:

A study that serves to measure variables or parameters , critical to the satisfactory operation of a piece of equipment or plant and to assure their operation within monitored and controlled limits. Examples of variables are pressure, Temperature, Flow rates , Time etc.

6. Limit of detection:

The lowest amount of analyse in a sample which can be detected but not quantitiated as an exact value. The limit of detection is mostly a parameter of the limit test.

7. Limit of Quantitation:

The lowest amount of analyse in a sample which can be quantitatively determined with defined precision and accuracy under the stated experimental condition. The limit of detection is mostly a parameter of the limit test.                       

8. Inspection:

The process of measuring, testing or otherwise comparing the item to requirement.

9. Installation Qualification:

Documented verification that all key aspects of the installation adhere to appropriate codes and approved design intentions and that manufacturer’s recommendations are suitably considered.

10. Operational Qualification:

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

11. Performance qualification:

Documented verification that the equipment performs as intended for the process,as specified by operating ranges .

12. Process optimisation:

To optimise the process for maximum efficiency while maintaining quality standards.

13. Process validation :

Establishing documented evidence that a process does what it purports to do. It is an documented verification that the integrated system functions as intended in its normal operating environment. The term performance qualification may also be used.

14. Pre determined acceptance criteria:

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

15. Protocol:

A document that gives a direction or guideline for any process as what , where, when, who, why and how to do.

16. Proven acceptable range:

All values of a given control parameter that fall between proven high and low worst case conditions.

17. Qualification:

The performance of tests to determine if a component of a manufacturing process possesses the attributes required to obtain a specified quality of a product.

18. Quality assurance:

The activity of providing , to all concerned , the evidence needed to establish confidence that the quality function is being performed adequately .

19. Quality control:

The regulatory process through which industry measures actual quality performance , compares it with standards and acts on the difference .

20. Quality function:

The entire collection of activities from which industry achieves fitness for use, no matter where these activities are performed .

21. Revalidation:

Repetition for verification of the validation and qualification process or a specific portion of it.

22. SOP: Standard Operating Procedure.

23. State of control:

A condition in which all operating variables that can affect performance remain within such ranges that the system or process performs consistently and as intended .

24. Validation change control:

A formal monitoring  system by  which qualified representatives of appropriate disciplines review proposed or actual changes that might affect validated status and cause corrective action to be taken that will ensure that the system retains its validated state of control .

25. Validation task report:

A scientific report of the results derived from executing a validation protocol  A brief summary  of   conclusions   from  a  specific task conclusions report, usually indicating validation success and designating proven acceptable ranges that have resulted. The conclusions are formally approved .

26. Validation Master Plan:

A document providing information on the company’s validation activities. It should be define details of  and time scales for the validation works to be performed. Responsibilities relating to the plan should be stated.

27. Worst case:

A condition or set of conditions encompassing upper and lower processing limits and circumstances within standard operating procedure, which pose the greatest chance of  product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

28. Critical Part:

Part of an equipment which can affect the quality of product directly is known as critical part.

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