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Assignment

Topic: - Validation and Calibration of Master Plan

Name: - Patel Harshil K.


M.Pharm Sem-1
Roll no.: 01
Validation of Master Plan

Introduction to Validation of Master Plan: -


Pharmaceutical Formulation plant having tablet, capsule, liquid manufacturing facility. The facility was
designed 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 overview of validation
program. It describes the overall objective, intention approach for establishing performance adequacy of
equipment, utilities, processes and systems. And also It identifies the scope of validation, applicable
validation protocols-reports, procedures and frequency of validations.

Validation policy for Validation of Master Plan: -


The organization 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.
All systems are subject to ongoing validation to evaluate the impact of changes in process, systems,
environment, equipment directly or indirectly on the product. For certain equipment’s/ 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.

Objective of Validation of Master Plan: -


Validation Master Plan is a document, which describes our company’s intentions and the methods which
are related with validation of the equipment’s, 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.
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.

Validation Master Plan helps: -


 The management to know and access what the validation program involves and understand its
necessity.
 The validation team members to understand their tasks and responsibilities.
 To understand the company’s approach towards validation and the setup of organizing validation
related activities.

Scope of Validation Master Plan: -


A. The scope of this document is to describe the systems and methodology used to execute the
various phases of the validation program.
B. It applies to all critical equipment’s, 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.
C. Validation Master Plan applies methodology of validation program of following,
1. Facilities
2. Equipment’s / Instruments / System [ Qualification]
3. Utilities (e.g. HVAC, Water system, Pure steam and Compressed Air.)
4. Control systems (e.g. computer hardware and software)
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.

Validation Responsibilities: -
The overall validation process is coordinated by a team, which is a working group comprising of qualified
personnel as required for the specific validation activities. The validation team is made up of
representatives from the following areas:
 Quality assurance (Validation)
 Production
 Engineering
 Quality control
Validation team is responsible for: -
i. Preparation of Validation Master Plan.
ii. Determining the equipment’s, instruments, systems, facilities and utilities to be validated.
iii. Preparation of validation and Qualification protocols.
iv. Execution of the validation and Qualification protocols.
v. Determining the suitability of the established protocol to qualify a system.
vi. Approving all validation protocols and report for each validation from respective functional
department heads.
vii. Reviewing each protocols and reports content to assure compliance with current regulations and
guidelines.
viii. Verifying the adequacy of the tests used for the verification of the system as established by the
validation protocols.
ix. Determine the extent of revalidation necessity in case of changes in a validated system.
x. Document control.
Other personnel will be utilized, 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.

General Description and Design Concept of facility: -


Pharmaceutical plant has provided 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
minimized 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 Galvanized 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. The
building is surrounded on all sides by a fire hydrant loop, maintained at high pressure.
Fundamentals of Validation Program: -
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.
The Validation Master Plan (VMP) shall be prepared by the Validation Executive.
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 Authorized by Vice
President.
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.
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.
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.
Summary & conclusion Report and Approval After the execution of the protocols, a validation task report
shall be reviewed, summaries, concluded and recommendations made by the team carrying out the
validation activity and approved by the involved team members.

Supporting systems for validation program: -


Protocol and documentation system: The system shall design to assure that all validation documentation
shall prepare accordingly validation policies establish by a validation team, which shall responsible for the
coordinating the validation program and approving all validation activities.
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 store 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 consider 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 provide assurance that the information collected is
timely, correct and is properly reviewed and shall approved by the validation team members.
Change control system: The SOP for Change Control.
Calibration of Master Plan

Introduction to Calibration of Master Plan: -


This Calibration Master Plan is a written document that describes the company’s policy for Calibration of
the instruments, at the formulation Plant. The Calibration Master Plan describes the approach of
Calibration, responsibilities, general guidelines for Calibration, stepwise Calibration activities and
frequency of re-calibration.
The document states the elements of the Calibration Program. This document establishes calibration plan
for the entire formulation Plant, to be used as guidance for resource and technical planning. It defines the
responsibilities of the various functional groups in performance of Calibration and presents a Calibration
schedule. The design and layout of Calibration Master Plan has been prepared in line with the current
standards and industrial practices.

Objective of Calibration of Master Plan: -


The Calibration Master Plan is written to provide an approach to the calibration management. Calibration
of the Instrument is prerequisite for the initial qualification and ongoing performance of any equipment
or system. Therefore, it is necessary to check the instruments for its calibration during installation of
equipment or system and further recalibration at a prescribed frequency.

Scope of Calibration of Master Plan: -


The scope of the Calibration Master Plan includes calibration of all the instruments of the Facility. The
Calibration Master Plan does not cover the detail of test methodology but concentrates on calibration
management. The Calibration Master Plan is intended for use by engineers, Quality Assurance (QA), and
personnel involved in the management of calibration.

Key Calibration Requirements: -


The Calibration Master Plan shall address the Calibration requirements of the critical instruments based
on impact assessment for the product quality. The impact assessment is the process of evaluating the
impact of operating, controlling, alarming and failure conditions of a system on the quality of a product.
Depending on the facility & Resource available the Instruments are categorized as Internal (In-House) &
External Calibration. From these both categories, The Instruments shall be further classified as critical,
noncritical Instruments.

Critical instrument is an instrument within an equipment/system where the operation, contact, data,
control, alarm or failure may have a direct impact on the quality of a product.
Applicability of any of the following criteria to a given instrument/component will provide an indication
that the component is critical.
1. The instrument/component controls critical process that may affect product quality.
2. The instrument/component is used to monitor the parameters of the manufacturing process.
3. Failure or alarm of the instrument/component will have a direct impact on product quality.
Non-critical instrument is an instrument within an equipment/system where the operation, contact, data,
control, alarm or failure will have an indirect impact or no impact on the quality of the product.

The following statements are related to critical / non critical instruments, they outline the regulatory
requirements for a successfully managed instrument calibration program,
 All instrumentation shall be assigned a unique number and all critical/non critical product,
process, and other instruments should be physically tagged.
 The calibration method shall be defined by Standard Operating Procedures. if having the in house
resources for calibration otherwise all instruments shall be calibrated from external agency.
 There shall be a means of readily determining the calibration status of each instrument.
 Each measuring standard shall be traceable to a nationally, or internationally, recognized
standard, as well as external or in-house calibration.

Periodic Review: -
The Calibration Master Plan shall be reviewed once in one year to ensure compliance and to determine
whether a change is required due to following reasons.
1. Changes in the Calibration Approach
2. Changes in Key Calibration Requirements.

Modification or renovation of existing facility.

Calibration Policy: -
Calibration Program is typically applied to Instruments/components of all equipment’s/systems within the
Facility, regardless of the impact on the product quality. Components, which have been determined to be
critical to product quality, will have more frequent calibration schedules.
The calibration of the critical instruments will be verified in IQ (or as a pre-requisite of OQ) before
undergoing qualification testing, to ensure that the test results are valid. This verification, along with the
calibration certificates and procedures, provides the documented evidence required to demonstrate that
a system operates in a controlled state.
The calibration of instruments attached to process, testing and utility equipment shall be undertaken by
the Engineering Department as a part of the Calibration exercise. The instruments to be calibrated shall
be identified and calibrated during the IQ stage. The specific parameters to test, as well as the relevant
specifications, shall be defined in the Standard Operating Procedure for the instruments.
After completion of operational qualification, the recalibration of the Instrument shall continue at the
predefined frequency as per the respective Standard Operating Procedures for Instrument Calibration or
as per the calibration calendar.
However, there are instruments at the location which don’t have link with IQ / OQ documents, will be
covered under the calibration calendar.
Criticality Assessment Team (CAT): -
The representatives of following disciplines shall represent the CAT:
 Engineering / Instrumentation
 Quality Assurance
Manufacturing The manufacturing person shall sign the Calibration calendar to accept that the
specification of the listed instrument and its limits are appropriate to the related product and process.
Engineering The Engineering representative shall confirm that all instruments are recorded and scheduled
for calibration appropriately, as defined within the Calibration calendar. The engineering representative
shall sign the Calibration calendar to qualify that the specification of the listed instrument and its limits
have been defined and checked as appropriate to the related product and process.
Quality Assurance The QA representative shall also sign the Calibration calendar to qualify that the
specification of the listed instrument and its limits are appropriate to the related product and process. QA
have the final signature to approve the Calibration calendar fit for use. The QA representative shall verify
that all calibration records and procedures are maintained and updated.

Ranges and Limits: -


While deciding on calibration ranges and limits, the manufacturer’s accuracy and the process
requirements shall be taken into account. For example, an instrument would normally be calibrated across
its operating or full range.
Calibration Accuracy: The agreed specific working accuracy of the instrument. This is usually set at the
manufacturer’s accuracy, but could be relaxed or increased to reflect the process requirements.
Calibration Failure Limits: The limits set for instrument failure, as determined by the process
requirements or results go beyond the acceptance criteria. If the calibration failure limits are exceeded
then a possible non-conformance has occurred, and the response should be documented.
Calibration Acceptance Limits: The limits set for instrument Acceptance If the readings are go beyond
calibration acceptance limits then a possible nonconformance has occurred, and the response should be
documented.

Periodicity: -
The periodicity of calibration shall be based on the Category of instrument Critical instrument, Non-Critical
Instrument.
In-house calibration The frequency of calibration is once in a year for non-critical Instruments & once in
half year for critical Instruments or as defined in the respective sop of the instruments.
External agency calibration The frequency of calibration is once in a year for non-critical Instruments &
once in half year for critical Instruments or as defined in the respective sop of the instruments.

Change Related to Calibration: -


There are circumstances where instrument criticality and its associated calibration details may change
regularly, such as in multi-purpose plants.
Any change to the instrument Calibration Calendar, SOP, frequency of calibration shall be documented in
support of these amendments as a part of change management procedure.
Standard Operating Procedures: -
Sop for Engineering Departmental Accountability: these SOPs are applicable only if the Instruments
calibrated in-house. E.g. calibration of vacuum gauges, calibration of thermometer, calibration of Pressure
Gauges, calibration of Thermocouple, etc.
Sop for QC Departmental Accountability: these SOPs are applicable only if the Instruments calibrated in-
house. E.g. SOP On Operation, Calibration, Cleaning and Maintenance of Bacteriological Incubator, SOP
On Operation, Calibration, Cleaning and Maintenance of BOD Incubator, SOP On Operation, Calibration,
Cleaning and Maintenance of LAF, SOP On Operation, Calibration, Cleaning and Maintenance of Vertical
Autoclave, etc.

Guidance for the method of Instrument Calibration: -


Instrument shall be calibrated against reference standard as per SOP. Reference standard shall be
calibrated to or traceable to any national standard. Calibration of the reference standard shall be carried
out in NPL or NABL accredited laboratory. Calibration of the instrument and reference instrument shall be
carried out at a predetermined frequency. Instruments are checked for its calibration throughout its
operating range. Instrument is considered calibrated when output of the instrument is within the
acceptable range of deviation from the expected output. If test of calibration shows deviation more than
acceptable range, instrument is replaced or subjected for the maintenance. After maintenance it is again
calibrated prior to use.
The instruments, which cannot be calibrated in-house due to unavailability of the facility & Resources, are
sent for calibration to an outside calibrating agency.

Calibration Process: -
Specification of the Instrument: There is a very large range of instruments available in the market that
makes selection difficult, and simply relying on the high accuracy claims of a manufacturer is not the
answer. There are other important factors and influences to consider, which shall be taken into account
before any decisions are made, including:
 Accumulative errors due to non-linearity
 Hysteresis
 Temperature effects
 Repeatability
Important questions to consider include:
What does the instrumentation have to do?
What are the required calibration failure limits and across what range?
An instrument can then be selected which shall, ideally, be at least two times more accurate than the
process requirements.
Non-Conformance: A non-conformance investigation shall be conducted when a critical instrument has
failed to meet the acceptance criteria for the calibration. If the ‘as found” results indicate that the
instrument is outside the calibration limits, then the following actions are taken:
1. Previous calibration labels shall be removed, where applicable.
2. An ‘out of calibration’ label shall be attached.
3. A non-conformance report shall be raised for all failed critical instruments.
4. The action to repair, adjust, or replace the instrument shall be followed.
5. The impact study shall be done as per the current version of SOP on corrective & Preventive action.
In the event of non-conformance, on the basis of impact study the QA department shall be informed to
recall of approved / dispatched products.

Third Party Calibration: Calibration may be carried out by third parties (e.g., contractors or instrument
suppliers), but the responsibility for ensuring that calibration procedures have been correctly followed
shall remain with the instrument owner (i.e., the equipment user and the maintenance Personnel).
The competence of the contractors (the Contract Acceptors) shall maintain suitable premises, equipment,
knowledge, experienced, and competent personnel, and may not pass to a sub-contractor any of the work
entrusted to him, nor change any of the agreed tests, standards, or limits, without the Contract Giver’s
prior evaluation and approval.
There shall be a written contract with the Contract Acceptor and any technical arrangements made
concerning it. This contract shall include:
1. Specify the respective responsibilities of the Contract Giver and Contract Acceptor.
2. Describe (or reference) the tests to be done and the standards and limits to be applied.
3. Specify the documentation to be used, produced, and retained by the Contract Acceptor, and to be
supplied by the Contract Giver.
4. Describe any hazards associated with the use or testing of the item(s).
5. Be drawn up with the involvement of suitably qualified and experienced Personnel
6. Sharing of information of any change (s) done at the contract acceptor’s end.

Documentation, supplied by the Contract Acceptor to the Contract Giver on completion of calibration,
shall clearly identify the item(s) concerned, show the initial test results, indicate any adjustments made,
and (where relevant) the test results after adjustment.
When the Contract Giver receives the item(s) returned from the Contract Acceptor, the item(s) should be
carefully examined for possible damage in transit. An appropriately qualified and trained person should
review and approved the given by Contract Acceptor.
Technical Agreement: Make a technical Agreement with the contract Acceptor and furnish following
details of the Instruments to calibration agency.
1. Name of the instrument
2. Make of the instrument
3. Instrument Identification Number
4. Acceptance Limit.
5. Range.

After receiving the calibrated Instruments from Contract Acceptor or after calibration of instrument at
our location ensure/check the following details.
1. Date of calibration.
2. Reference standard used for calibration & its traceability with national/international
standards
3. Calibration results & error with remarks, if any
4. Next due for calibration.
Labeling: -
It is a minimum requirement that all product, process, and Utility instruments are uniquely labelled. This
Guide recommends that for critical /non critical instruments Calibration tag shall detail the next
calibration due date.
Function: Labelling of Instrument will be performed to serve the following functions:
– Alert the user to its calibration and operating status.
– Show that the instrument is part of the inventory and scheduling system.
– Demonstrate that each piece of Instrument has been studied regarding its need for calibration or
maintenance.
– Location: Where practical, all Calibration status tag will be placed in a prominent place on the
instrument. This alerts the user of its calibration status.
– Types of labels: The different types of labels that will be used are:
– Calibration Tag: These labels are placed on instruments calibrated, as required, on a periodic basis.
– Under Maintenance: These labels indicate that the instrument is under maintenance and cannot be
used.
– Daily Calibration: These labels indicate that the calibration is done on a daily basis and respective entries
are made on logbook.
– Calibration label for external agency: Place the tag given by external agency in case external agency
could not provide, the calibration Status tag should be as per detail mentioned by certificate.

Documentation: -
Calibration Records: Calibration records shall demonstrate the capability of a measuring instrument or
system to measure a variable to a required accuracy over a specific range of values. The calibration record,
including the prime data, shall be unambiguous and retrievable. Handwritten data should be in pen, with
mistakes crossed out with a single line. The amended data should be signed and dated. Calibration
information shall be recorded on the calibration certificate to enable the calibration to be reproduced
under similar conditions.
Calibration calendar: The calibration calendar is prepared the calendar content of Instruments with
calibration Due Dates & location / Machine at which the Instrument has installed. The periodicity of
recalibration shall be based on the category of the Critical instrument, Non Critical Instrument.

Certificate of Calibration: -
Certificates of calibration shall contain:
 Unique identification of the instrument under test
 The ‘as found’ readings and, if adjusted, the ‘as left’ readings
 The date of the calibration
 Name of the person carrying out the calibration.
 Due Date of calibration
 Reference SOP Number.
 Due Date/Validity of calibration for Master Instruments
 Calibration certificate no of Master Instruments.
References: -
1. Syed Imtiaz Haider, Validation Standard Operating Procedures, St. Lucie Press.
2. url:- http://pharmaguidances.com/calibration-master-plan/ Accessed on :- 18 September 2018.
3. url:- http://pharmaguidances.com/validation-master-plan/ Accessed on :- 18 September 2018.