The document outlines the importance and methodology of validation in pharmaceutical processes as defined by FDA, WHO, and European Commission guidelines. It details the objectives, scope, and merits of validation, along with components of a Validation Master Plan (VMP) and Calibration Master Plan (CMP). Additionally, it highlights the necessary qualifications for personnel, equipment calibration, and compliance standards required to ensure consistent product quality.

1. VALIDATION
MEHAK AGGARWAL
M.PHARM (PHARMACEUTICS)

2. CONTENT
Introduction
Objectives of Validation
Scope & Merits of Validation
Validation Master Plan
Calibration Master Plan
ICH and WHO guidelines for Calibration & Validation of equipment
References
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3. INTRODUCTION
•As per FDA Validation, It is defined as “ establishing a Documented evidence, which provides a
high degree of assurance that a specific process will consistently produce a product meeting its
pre-determined specifications and quality attributes”.
•As per WHO, Validation means providing documented evidence that any procedure, process,
activity or system actually leads to the expected results.
•According to European commission, validation is “Action providing in accordance with the
principles of GMP, that any procedure, process, equipment, material, activity or system actually
lead to the expected results”.
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4. OBJECTIVES
•To reach risk of regulatory non-compliance.
•Reduction of time to the market for the new products.
•Eliminates the scrap and reduces the defect cost.
•To reduce chances of product re-call from market.
•The final release of product batch would be expedited.
•It requires less in-process control and end process testing.
•Parametric release of batch can be achieved in validation.
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5. SCOPE OF VALIDATION
•Pharmaceutical validation is a vast area of work and it practically courses every aspect of pharmaceutical
processing activities, hence defining scope of validation becomes a really difficult task. However, a
systematic look at the pharmaceutical operations will point out at least the following areas for
pharmaceutical validation:
Analytical
Facilities
Manufacturing operations
Product design
Cleaning
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6. MERITS OF VALIDATION
•Knowledge of the process increases during the validation process.
•Consistency of the process is ensured.
•It decrease the risk of the manufacturing problems.
•Ensures the fluency of the production.
•Decrease the expenses.
•Decrease the risk of failing in GMP.
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7. VALIDATION MASTER PLAN
(VMP)
•A validation master plan(VMP) is a comprehensive document describing the
applicable validation requirement for the facility, and providing a plan for the
meeting those requirements.
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8. Scope of VMP
•VMP includes all relevant expects relating to the production of pharmaceuticals in the
production facility. The principle of validation, the organization of qualification and equipment
are also described.
•All facilities used in various production areas, storage, services and the rooms for staff.
In short, it is a documented evidence that provides a high degree of Assurance that a specific
process will consistently produce a product that makes its predetermined specifications and
quality attributes.
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9. Why to perform VMP?
•VMP is not a requirement of FDA, but it has become almost an industry standard.
•It is important to include such a document, as it sets the overall goals and limits that will be followed
during validation and can be referred to throughout the project.
•As a reference document, the plan permits the reviewer immediately to understand the scope of the
validation and avoid misconceptions.
•The validation plan is thus used to set the limits of validation, to define the scope of the project, the
systems included and not included in the qualification and what the project will attempt to prove.
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10. Members of VMP
•Validation manager, QA department
• Member from production
•Member engineering
•Member from calibration lab
•Member from QC lab
•Member from maintenance
•Member from HVAC department
•Member from product development lab
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11. Qualification
•Qualification must be in accordance with the job requirement in combination with experience.
•The resumes of validation team members are presented in a separate folder, including contract help.
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Content of VMP
1. Introduction
•Introduction to validation process and facility.
•Includes- description of facility, premises, equipment, purpose, intension and scope of validation.

12. 2. Methodology
•It addresses pre-determined requirements by identifying standard that are to be applied to facility.
•These are then used in development of the acceptance criteria that are used to judge the validation.
•It involves planning, execution of documents, reports,
Standards involve three elements-
a) Regulatory and guidance document
b) National standard
c) Company standards
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13. 3. Qualification
•This section encompasses all aspects of design, installation and procurement, installation and commissioning process.
4. Personnel
•VMP should lay down the qualification requirements.
•It must address the aspects like experience of personnel, in-house training reports etc.
•Documenting the training is essential and is a requisite of the GMPs.
5. Schedule
•Work program is essential and should be prepared at an early stage. A good plan will contain all necessary features which
are to be considered during execution of a plan and determine control of project.
•It ensures that all personnel involved in VMP are not only aware of engineering targets but also validation targets.
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14. 6. Preventive maintenance
•It is responsibility of site maintenance and operation department.
•This activity should be performed during the design phase and that documentation required should
be, included in the requisition.
7. Procedures
•These cover engineering standards used in project design, through to commissioning phases and the
facilities standard procedures(SOPs).
8. Change control
•Requirements for a set of procedures for change control that cover:
oproject through design, construction and commissioning
o ongoing change that will inevitably occur in both process, equipment and engineering aspects.
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15. 9. Documentation
•Identify the documentation that should be produced for the processing like
oengineering drawing
oEquipment supplier drawing and documents
ofactory acceptance documents
oIQ document
oOQ document
oPQ document
10. Appendices
•Appendix is mostly used VMP to hold information of type of documents and formats that will be used
in execution stage.
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16. CALIBRATION MASTER PLAN
CALIBRATION
•To maintain accuracy and precision of test equipment at all times.
•To ensure the highest level of confidence in all measurement that affect materials deposition decision
with unbroken chain of traceability to national standard.
•To determine whether equipment is still fit for its intended purpose.
•It is based on comparison of a primary standard or instrument of known accuracy with another
equipment (to be calibrated).
• It is used to detect, report or eliminate by adjustment of any variation in the accuracy of equipment
being calibrated.
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17. CMP
•Assigning responsibilities for equipment users, equipment managers, quality assurance personnel and
calibration vendors to help and Shaw company-wide consistency and regulation of your processes.
•Approving calibration vendors such that they are in compliance with the guidelines of your quality
system.
•Identifying and labelling equipment.
•Processing investigations of out of tolerance conditions and other calibration related issues that may
necessitate corrective action.
•Controlling and storing records, including calibration certificates, status change forms and calibration
SOPs.
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18. WHY CALIBRATE?
•Components age and equipment undergoes changes in temperature and humidity or sustains
mechanical stress and therefore their performance degrades. This is called drift. Then test results
become unreliable. While drift cannot be eliminated, it can be detected and either corrected or
compensated for through the process of calibration.
•Calibration:
ooptimizes resources
oensures consistence
oensure measurements
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19. EQUIPMENT CLASSIFICATION
a) Critical equipment
•Direct measurement that affect the final product quality specification.
b) Non-critical equipment
•Indirect measurement that will not directly affect the final product quality.
•Shall be maintained based on company maintenance schedule.
PROCESS OF CALIBRATION
•Calibration process must be managed and executed in a professional manner. A particular place for all calibration
operations to take place and keeping all instruments for calibration.
•Separate room is preferred because
obetter environmental control
obetter protection against unauthorized handling or use of calibration instruments.
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20. •Performance of all calibration operations is assigned as the clear responsibility of just one person.
•Calibration procedures, used for QC function are controlled by International standard ISO 9000. It
required that all persons using calibration equipment be adequately trained.
VERIFICATION
•Applicable to equipment that cannot be calibrated (adjustment, correlation, etc.).
•Verification against measurement standard with correlation factor documented.
•Actual reporting of result shall include the correlation factor-
correlation factor = -2ºC
measured value =24ºC
reported value = 24ºC-2ºC=22ºC
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21. CALIBRATION RECORDS
CMP include the control of all critical measurement equipment that contain the following detail.
•Name
•Identification by model number and serial number
•Location
•Owner/responsible
•Calibration frequency
•Calibration due date
•Calibration certificate
•Calibration procedure
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22. CALIBRATION CERTIFICATE
•Name and address of contracted calibration laboratory.
•Name and address of client.
•Description and identification of item calibrated.
•Environment conditions when calibration was made.
•Date of receipt of instrument, date of calibration and date of next calibration.
•Calibration method.
•Result of calibration.
•Signature and title of person responsible for the calibration.
•External calibration contract shall be awarded to accredited by Nation Institution.
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23. ICH AND WHO GUIDELINES FOR CALIBRATION &
VALIDATION OF EQUIPMENT
ICH GUIDELINES FOR CALIBRATION OF EQUIPMENT
•Local identification by a unique identification number and involvement in master GMP instrument list
•Procedure for instrument history file.
•Approval by quality unit.
•Generation of procedure for verification and standardization of accuracy and reliability.
•For approval of procedure, it must contain steps and forms required for calibration.
•Involvement of calibration stickers and auxiliary stickers program.
•Procedure for tracking of Scheduled calibration activities.
•Procedure for notifying users of calibration due dates, overdue calibrations and out of tolerance findings.
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24. •Review of all systems, calibration records and procedure by quality unit.
•Involvement of procedure for reporting any GMP critical instrument.
•Involvement of calibration forms which are developed to record the calibration results.
WHO GUIDELINES FOR CALIBRATION OF EQUIPMENT
•Regular calibration.
•Establishment of specific procedure of calibration for every equipment.
•Only authorized personnel should operate equipment.
•Availability of up-to-date instructions for calibration verification results must be recorded on a control chart.
•Unique identification of each item of equipment for calibration.
•Keeping of records of each item of equipment to perform calibration.
•Systematic verification of laboratory to prevent contamination.
•Establishment of maintenance procedure.
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25. •Out of service equipment.
•Labelling of equipment.
•Verification of equipment function and calibration status.
EXAMPLE FOR CALIBRATION OF UV SPECTROPHOTOMETER
1. Control of wavelength
• Verify wavelength scale using absorption maxima of holmium per chlorate solution with the line of
hydrogen or deuterium discharge lamp or lines of mercury vapor arc.
•The permitted tolerance is +/-1 nm for the range 200 to 400nm.
2. Control of absorbance
•Check the absorbance using potassium dichromate solution UV at different wavelengths.
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26. 3. Limit of stray light
•Detected at a given wavelength with suitable filters or solutions; for ex. potassium chloride.
4. Resolution power
•Record the spectrum of a 0.02% v/v solution of toluene in hexane UV. Ratio of the absorbance is NLT
1.5 .
5. Spectral slit width
•Spectral slit width must be small compared with the half- width of the absorption band.
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27. ICH GUIDELINES FOR VALIDATION OF EQUIPMENT
•1 meter distance from walls and other obstacles.
•Easy to operate, clean and maintainable.
•Working should be at proper commissioned position.
•Certification of equipment.
•Checking of overhead heights.
•Proper source of light.
•Drop down utility system.
•Design of equipment.
•Layout of equipment.
•Marking of pipelines as per their flow of direction.
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28. •Sop the equipment.
•Tracing of equipment.
•Identification marking for equipment.
•Cleaning of equipment.
•Distinguishing of the equipment.
•Record of each processing.
WHO GUIDELINES FOR VALIDATION OF EQUIPMENT
•Equipment must be located, designed, constructed, adapted and maintained to suit the operation.
•Layout and design of equipment.
•Instalment of equipment.
•Production equipment.
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29. •Labelling of fixed pipe work.
•Cleaning of equipment.
•Labelling of equipment.
•Establishment of written procedures for each operation.
•Record keeping.
EXAMPLE OF VALIDATION OF TABLET COMPRESSION MACHINE
1. Execution of Design
2. Qualification Execution of IQ, OQ and PQ
3. Procedure Followed for Performance Qualification
•The blend/dummy material was unloaded into the hoppers on the both sides and the compression
machine was operated at low speed (20RPM) as per operating instructions. Then the machine was set to
run for 20 minutes continuously after adjusting the following parameters-
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30. oIndividual tablet weight variation
oWeight of 20 tablets
oHardness
oThickness
oDisintegration time
oFriability
•Repeat the procedure at both medium (40RPM) and high speed (60RPM) with same set of parameters.
•Checking of parameters at different speeds.
•Report the results.
•Sampling Plan
1. Collect 100 tablets for every 05 minutes.
2. Compression parameters checked at different speeds.
•Optimum results obtained at 40 rpm speed.
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31. REFERENCES
•Potdar MA, “cGMP, current good manufacturing practises for pharmaceuticals”, 2nd reprint,
Pharmamed press, Hyderabad, p. 85,88-101,413-423.
•Joseph Busfield. cGMP, instrument and calibration. “Facilities, utilities and requirements, GXP, Ivt
network”. Feb 21,2007;5-7. Available from: https://www.ivtnetwork.com/article/cgmp-equipment-
instruments-and-calibration
•Guidelines : ICH. “ICH harmonization for better health”. Available from:
https://www.ich.org/page/ich-guidelines
•Essential medicines and health products information portal. “WHO expert committee on
specifications for pharmaceutical preparations”. World Health Organization.Technical report series
no. 902-36th report.2002.
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