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VALIDATION THEORY AND APPLICATION
Presented by: Mrs. Remedios A. Rivera
Telstar Mfg. PlantSta. Rosa, Laguna
March 12 & 16, 2009
Outline of PresentationValidation Orientation1. History of Validation2. Definition * Key Features3. Purpose of Validation4. Benefits of Validation5. What to Validate6. Types of Validation a) Retrospective Validation b) Prospective Validation
7) When to Revalidate8) Organizing for Validation9) Planning for Validation10)Validation Master Plan11)Validation Matrix/Family Tree12)Validation Protocol13)Validation Change Control
VALIDATION ACTIVITIES
1. Design Qualification2. Installation Qualification3. Operational Qualification4. Performance Qualification5. Validation Review6. Building Validation 6.1. Construction and Layout 6.2. Structure & Finish * Floors & Walls * Ceilings * Doors & Windows
7. System Validation - HVAC System8. Equipment Validation - Minoga Emulsifying Mixer 9. Process Validation
- Baby Lotion
Good Manufacturing Practice (GMP)
GMP is that part of Quality Assurance which ensuresthat products are consistently produced and
controlledto the quality standards appropriate to their intendedUse. The basic requirements of GMP are that:
HISTORY OF VALIDATION
a) All manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently producing products of the required quality that comply with their specifications;
b) Critical steps of manufacturing processes and any significant changes made to the processes are validated.
C. All necessary facilities are provided including
a) Qualified and trained personnel;
b) Adequate premises and space;
c) Suitable equipment and services;
d) Correct materials, containers, and labels
APPROVED!e) approved procedures and instructions;
d) Suitable storage and transport; and
f) Adequate personnel laboratories, and equipment for in-process controls
d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided
e)operators are trained to carry out procedures correctly;
e) records are made (manually and or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the products are as expected; any significant deviations are fully recorded and investigated;
g) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;
h) The proper storage and distribution of the products minimizes any risk to their quality;
i) A system is available to recall any batch of product from sale or supply;
j) Complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures are taken in respect of the defective products and to prevent recurrence.
VALIDATIONThe documented actof proving that anyprocedure, process,equipment, material,activity, or system actually leads to theexpected results.
-WHO expert Committee on Specifications for PharmaceuticalPreparations. 32nd Report 1992
Action of proving, in accordance with the principles of Good Manufacturing Practice, that any procedure, process, equipment, material, activity, or system actually leads to the expected results.
- Rules and Guidelines for Pharmaceutical Manufacturer 1993
ProvingSufficient replication ofthe testing and challengingof each defined criticalStage of a system, process,etc. that has to beperformed to give validlevels of assurance
KEY FEATURES:
DocumentingAn adequate System of
referenceddocumentation is essential.
• Flow diagrams and schematics should define the system, process, etc. The critical areas must be highlighted, and the written experimental design defined by a protocol. All results and conclusions derived must be recorded in a written report.
All associated paperwork must be collected, analyzed, reviewed and
approvedby all designatedresponsible personnel
• All documents must be signed and dated by the authorized personnel
“Document everything” To Play It Safe
“If there is any question, play it safe. Document everything and document it thoroughly.”
- James Harris, PHD(Director of Sterile
Operations, Merck and Chairman, Computer Systems Validation Committee, Pharmaceutical Manufacturers Ass.) in “The Gold Sheet”, V19, No. 1, Jan.1985.
Work done, but not recorded in writing, for the purpose of validation is considered asnever having been performed.
o written o reviewed
o approved o retained
DOCUMENTED
FOCUS
SYNONYMS o Verify
o Justify
o Designed to assure
PURPOSE OF VALIDATION
Increased product safety
Increased patients safety
Safety
Fewer rejects
Fewer rework
Fewer retest
Fewer wastage/scrap
Maximize yields
Reduce unit costREDUCTION
OF QUALITY COSTS
• Component of GMP•Minimized Regulatory
Exposure
Regulatory Compliance
Assurance of Quality
• Consistent and Producible Quality
• Minimize corporate product liability risk
• Minimize complaints
Process Optimization
Optimum batch size
Reduced processing time
Decreased downtimes
Reduce new facility/ process start-up time
BENEFITS OF VALIDATION
In contrast to in-process and finished product controls, it is possible, by validation data, to predict in which range system parameters have to be maintained.
Through validation of a system, the system is controlled, deficiencies are detected which otherwise may not have been noticed and, most importantly, an intensive scrutiny of the complete system is conducted.
Drug safety and thus safety for the patient is improved.
• The probability of a product
recall is reduced.
• Lately occurring system deficiencies are reduced.
- for presentation in case of an inspection
- as legal proof of safety in a product liability case
-as a document for a marketing authorization application and a certification
The validation documentation can be used:
- provide jobs and more jobs
- capture the market with better quality product at a lower price
System to be validated often involvevarious combinations of the following:
WHAT TO VALIDATE?
o Equipmento Environment
o Methods
o Materials
o Software
o Controls
o Processes
o Personnel
o Facilities
Operating Procedure
SCOPE OF VALIDATION WORK
VALIDATION WORK TESTED FOR
Buildings Design, construction
Services Water (city, deionized,
distilled, water for injection, lighting, heating/cooling, cleaning, ventilation,
waste disposal, sanitation
VALIDATION WORK TESTED FOR
Equipment Design, size, locationmaterials of construction,manufacturer’s drawings,change parts, maintenance, operating parameters, cleaning
Procedures SOP’s, manufacturing directions, sampling, yield calculations, processing time limitations, microbial contamination,
reprocessing
VALIDATION WORK TESTED FOR
Personnel Qualifications,responsibilities
VALIDATION WORK TESTED FOR
Raw material Control, testing,and components storage, vendor
audit
Packaging/Labelling Materials, issue of labels, expiry dating
Warehousing/ General procedures
Distribution Testing, release, Laboratory controls stability testing
special tests, reserve samples, etc.
VALIDATION WORK TESTED FOR
Records and Reports Equipment cleaning and
use, components, containers, closures, labels, master and
batch production control, production record review, laboratory, distribution and complaint records, product returns
ONLY CRITICAL PARAMETERS SHOULD BEVALIDATED
NEVER ATTEMPT TO VALIDATE ANYTHING THATYOU
o Do not understando Can not define
IF YOU DO NOT KNOW, DO NOT VALIDATE,JUST INVESTIGATE
TYPE OF VALIDATION
RETROSPECTIVE VALIDATION - Validation of a process for a product already in distribution based upon accumulated production, testing and control data.
- Guideline on General Principles of Process Validation, FDA,
MAY 1987
Retrospective Validation is not merely thereview of test results. It also requires that
themanufacturing process be specific and thesame each time a batch is manufactured.Thus, specific raw material specifications(including particle size when necessary, inprocess specifications (tablet hardness, etc.)and specific manufacturing directions arerequired. Obviously, any failing batchesattributed to the process would necessitatethe conclusion that the process is notvalidated and is inadequate.
- “The Gold Sheet “ Vol. 28, No. 5, May 1994.
PROSPECTIVE VALIDATION
Validation conducted prior to the distribution ofeither a new product, or product made under aRevised manufacturing process, where therevisions may effect the product’s characteristic.
- Guidelines on General Principles of Process Validation, FDA, May 1997
Validation required to be completed before initialRelease of product. It is associated with thestudies carried out during the design anddevelopment phase of a new or modified
product.
WHEN TO REVALIDATE
If the composition of the pharmaceuticalproduct, the manufacturing procedure or thebatch size is changed
In the event of significant alterations to theprocessing equipment
If new equipment is used
In the event of major changes of processingconditions
After exhaustive preventive maintenance work
on machines or equipment
If the findings ofthe in-process andQuality controlresults indicatethe need.
WHEN TO REVALIDATE
1. Gen. Manager 2. Plant Manager 3. Project Manager 4. QA Manager 5. GMP Manager 6. Production Manager 7. Validation Manager 8. Engineering Manager
ORGANIZING FOR VALIDATION
• Who is in each team?
1 2 3 4 5 6 7 8
Strategy xx xx xx x x x x x
Authorization xx Xx
Project xx x x x x X
Validation Xx xx xx xx xx xx
Testing x
Reporting xx xx
Accepting xx xx xx xx xx xx
StrategyTeam
AuthorizationTeam
ProjectTeam
ValidationTeam
InvestigationTeam (S)
EvaluationTeam (S)
AcceptanceTeam (S)
TEAM FUNCTION/ROLES
TEAM FUNCTION APPROACH(Multidisciplinary Team Members)
RESPONSIBILITIES OF VALIDATION PROJECT TEAM MEMBERS
To motivate appropriate personnel withintheir departments of the need for validation inorder to obtain adequate resources and toachieve an effective consciousness
concerningchanges which could have impact on thecertification.
To contribute towards the estimation ofResources required for each project.
To contribute towards the generation andapproval of validation protocols.
To contribute towards the generation andassessment of data and establishment ofacceptance criteria.
To contribute towards the generation ofProcedures and acceptance criteria forcontinuous monitoring by the user.
To accept responsibility for the quality andTime scale of work within his/her area.
To identify any need for plant overhaul orreplacement.
PLANNING FOR VALIDATION
Development of VALIDATION MASTER PLAN for the facility
Design review of the facility, utilities, and process equipment
Protocol development for the facilities, systems and processes
SOP developmentValidation of analytical test proceduresCalibration of instruments and equipmentTraining in GMP’s, SOP’s and validation
Establishment of equipment history file Administration, direction, scheduling, guidance, and execution of the physical validation
Review, evaluation, certification of the validation data
Contents
Introduction
Objective (s)
Justification
Approach
Scope Acceptance
Support Programs
ValidationTeam
Organization
Schedules
Appendix
VALIDATION MASTER PLAN
VALIDATION MASTER PLAN
A VMP is a summary document whichdescribes a program of work to be doneBefore the facility or operation can beconsidered as validated.
A VMP may apply to the whole, or part, of a facility or operation.
A VMP is a document stating the intention and methods to be used to establish the adequacy of the performance of theequipment, systems, controls or process to be validated.
NONE!The physical format of the VMP is flexible, however, it is desired that the basic contents must be addressed properly to cover all pertinent items.
Is there a specified format for a VALIDATION
MASTER PLAN?
When is the VALIDATION MASTER PLANreviewed and updated?
The VALIDATION MASTER PLAN is a dynamic document which must be reviewed and updated as required during the life cycle of the project.
INTRODUCTIONA brief summary of the
total project including the overall objective of the
validation exercise or program, the statement of
the corporate support for the validation program and a general description of the facility or operation as well as reference to applicable compliance documents to
which the facility or operation has been
designed.
What are the contents of a VALIDATIONMASTER PLAN?
OBJECTIVE
A concise statement or statements of thetask and will allow a complete
understandingof the validation exercise.
JUSTIFICATION
A discussion of the reasons that support the units will be validated. Also states why
otherpieces of equipment or systems will not bevalidated.
APPROACHDefines how the validation will be conducted. Includes information to establish type of documents to be used in the validation including the preparation, approval, implementation, review and reporting. Also includes the review and approval levels required.
SCOPELists actual units, systems, processes to be validated and the level to which each will be tested (e.g. IQ, QQ, or PQ)
ACCEPTANCE CRITERIADefines in general terms the agreed standards or ranges, which must be achieved by each unit.
SUPPORT PROGRAMSIncludes all requirements to achieve and maintain the validated state, including training, calibration, maintenance, change control and validation review.
VALIDATION TEAM ORGANIZATIONList the members of the Validation team and describes their specific roles or functions for all stages of the validation
SCHEDULESCan be either in a summary form or detailed, indicating the prerequisites of the validation as well as all constraints to the successful completion of the program.
Can also include a list of manpower, supplies, services required, document preparation, document handling, validation test equipment, laboratory services and other support services.
APPENDIXIncludes several supporting documents e.g. Definition of terms, Facility Site Plans, Validation Methods references, Process Flow Sheets, Equipment lay-out, People Flow, Product Flow, etc.
Site Services (SSVP)
Electrical Power (SSVP001)MeralcoGenerator
Sewage Plant (SSVP-002)
Water (SSVP-003)
Potable
Hot
Softened
Chlorination (SSVP-005)
Air Conditioning (SSVP-005)
Equipment
Filters
Cooling coils
Heating coils
Fan
Dehumidifies
Condensing units
Cooling Towers
Building
Manufacturing Site
(BUP)
Construction & Layout (BVP-001
Structure & finish (BVP-002)
General
Floor & walls
Ceiling
Doors & windows
Drainage(BVP-003)
Utilities/System (SUP)
HVAC (SVP-001)
Lighting (SVP-002)Electrical/safety
Vacuum (SVP-003
Dust Collection (SVP-004)
Water (SVP-005)
Potable
Purified
Steam (SVP-006)
Compressed Air (SVP-007
Equipment (EVP)
Mixer (EVP-001)
Blender
(EVP-002)
Filler
(EVP-003)Compressor
(EVP-004)
Processes
Product Listing
VALIDATION FAMILY TREE
VALIDATION MATRIX
IQ OQ PQSite
Services
Electrical Power
x x x
Sewage Plant
x x x
Water x x x
Chlorination x x x
Air Conditioning
x x x
Building x - -
Utilities/System
HVAC x x x
Lighting/Electrical x x x
Vacuum x x x
Water x x x
Steam x x x
Compressed Air x x x
Dust Collection x x x
Equipment x x x
Processes - - x
VALIDATION MATRIX/FAMILY TREE
- Use the Matrix to define what qualification test should be applied
- Use the Matrix as the framework for the Validation Master Plan
- Use the Family Tree in the numbering system to develop the protocol list
• A document which details the requirements for validation testing, written and approved.
• Protocols must have a unique reference number and define, as a minimum:
- the task to be achieved- the person preparing the protocol
the item under test- the tests to be carried out and the
information to be recorded- the purpose of each test (approved
before execution)- the persons authorizing the protocol,
before testing and the date of the authorization.
- the persons who will approved the protocol upon completion of testing
VALIDATION PROTOCOL
A formal monitoring system by which qualified representatives from appropriate disciplines, review proposed or actual changes that, might affect validated status and define and authorize appropriate action to be taken that will assure the facilities and operations retain their validated state of control
VALIDATION CHANGE CONTROL
QUALIFICATION
Qualification is the formal,systematic, and documentedproof that facilities andEquipment are suitable for the intended process. It is abasic requirement for validation and an entire part of this validation. Qualification ofequipment includes calibration
or Measuring equipment.
- Federation International Pharmaceutique, 1990
Documented evidence that quality is built into the designof facilities andoperations.
DESIGN QUALIFICATION (DQ)
A typical DQ document includes these basic information:
o Confirmation of the structured and rigorous approach to design, including discussions or comments on modular design, drawings, and specifications produces, hazard operations, zone classification studies, etc.
o Confirmation of design standards adopted referring to national and international codes, and to the key reference texts on GMP issues.
o Confirmation of the use of appropriately qualified staff.
o Confirmation of the attention paid to GMP issues as shown by GMP audits
DESIGN QUALIFICATION
Needs the following:
User Requirements Specifications
This is what we want
User
Functional Requirements Specification
This is what we could give you
Supplier
Design Specification
This is how we will build it
Supplier
Specification Responsible
Validation V-Model
Is based on
Is based on
Is based on
PQ
OQ
IQ
User Specification
Functional Specification
Design Specification
Implementation
DESIGN
QUALIFIC ATION
INSTALLATION QUALIFICATION (IQ)
Documented demonstration that facilities and operations are installed as designed and specified and are correctly interfaced with factory systems.
The IQ protocol should include a statement ofthe data required concerning the installationof the system or equipment to verify that the specification has been satisfied.
The IQ protocol should include, as applicable,but not limited to:
Engineering drawings and documents Building finishes Process and Utilities (Services) flow diagrams Piping and Instrumentation diagrams
The IQ protocol should include, as applicable, but not limited to:
* Manufacturer’s drawings, equipment maintenance and operating manuals
* Spares list
* Maintenance schedules
Ensure that equipment and installation isclearly described and suitably labelled as tovendor, model, capacity, materials and othercritical criteria.
Ensure that instrumentation has been calibrated according to approved procedures and that measurements are traceable to defined national or international standards.
Ensure that calibrations and detailed controlparameters must be recorded and recordssecurely kept
Ensure change control system are in Operation
Ensure that all system have been verified to operate under no load conditions.
Installation Qualification answers thefollowing questions:
Did I get what I ordered as per the design specification?
Was it installed correctly & safely?
Has it been installed into the company quality systems?
OPERATIONAL QUALIFICATION (OQ)
A documented demonstration that facilitiesand operations function as specified.
The OQ protocol should include a completedescription of the Purpose, Methodology andAcceptance Criteria for the operational tests to be performed.
Ensure that instrumentation is in current calibration.
Ensure that detailed control parameters have been established and recorded for each Instrument.
Ensure change control system in operation.
Ensure that standard Operating andmaintenance Procedures have been
developed and approved for each system, to ensurecontinued operation under defined
conditions.
Ensure that Training Modules and trainingsessions for Production, Engineering, andsupport personnel have been developed,conducted and documented during this
stage.
Where appropriate and documented in the VALIDATION MASTER PLAN the IQ, and OQ protocols may form a single document which clearly defines the acceptance for each test.
Operational Qualification (OQ)
Verifies that the facilities, systems and equipment as installed or modified, perform as intended throughout the anticipated operating ranges.
It answers the following questions:- Does it function as per the functional & specification
- What are the operational restriction/requirement?
- Do we have the necessary instruction/training?
Can we calibrate and maintain the equipment?
PERFORMANCE QUALIFICATION (PQ)
A documented program to demonstrate that an operation when carried out within defined parameters, will consistently perform its intended function to meet predetermined acceptance criteria.
The PQ protocol should include a completedescription of the Purpose, Methodology andAcceptance Criteria for the Performance
teststo be performed.
Before approval is given to allow PQ testing to
proceed, all IQ and OQ should be reviewed.
Ensure change control system are in operation.Ensure that maintenance and calibration areoperating
Ensure all SOP’s have been finalized and approved at this stage.
PQ testing should be carried out by trainedpersonnel who will routinely operate thesystem or equipment.
Ensure all deviations from the validation protocol are investigated and documented
Ensure sufficient lots (at least 3 or as appropriate) have been evaluated todemonstrate adequate process control.
Ensure that any outstanding actions (exceptions) from IQ or OQ are recorded and recommendations for remedial actions are justified and approved.
VALIDATION REVIEW
- A validation review procedure must be firmly defined to ensure that changes
have not been inadvertently occurred
- Any validation review must be documented in detail & results of any test should be compared with the original validation results.
- In the results are comparable, continue operation
- If results are unsatisfactory, suspend operation & revalidate
VALIDATION STAGES
1. Design Qualification (DQ)- will the design work and will it meet all our requirements?
2. Installation Qualification (IQ)- Has the item been supplied and installed as specified?
3. Operational Qualification (OQ)- Does the item performs as specified
under operational conditions?
4. Performance Qualification (PQ)- Do the facilities, system and equipment as connected together, perform effectively & reproducibly based on the approved process method?
5. Process Validation- Does the process delivers a product that consistently meets its predetermined
specifications & quality attributes?
6. Certification - Has the work been executed in a
thorough and responsible manner and are the conclusion and recommendation valid?
• 7. Periodic Review and Evaluation
- Are the system, facilities, equipment and processes maintained in a
validated state?
• 8. Decommissioning- Are obsolete equipment
& facilities removed under change control and in accordance with a pre-
approved decommissioning
plan?
TEST FAILURES
It is important todetect or identifytest failures during validation
activities.
Detection of failuresor malfunction givesadditional understandingand knowledge of theoperation.
More failuresdetected duringvalidation meansmore problemsare avoided duringroutine work.
Failure could bedue to incompleteor SubstandardInstallation (IQ; OQ)
• PROCESS VALIDATION
BEFORE
QC + IPC = PRODUCT QUALITY
NOW
PV + QC + IPC = ASSURED PRODUCT QUALITY
RESTROSPECTIVEVALIDATION
12%
13%
17%
8% 16%
9%
25%
FEATURES
Marketed products
Use HISTORICAL DATA
Use of SPECIFIC PROCESS
WHEN TO DO RETROSPECTIVE VALIDATION
SUN MON TUE WED THU FRI SAT
1 2 3 4
5 6 7 8 9 10 11
12 13 14 15 16 17 18
19 20 21 22 23 24 25
26 27 28 29 30 31
ONLY IF WITHIN a reasonable period of time; Sufficient number of batches
O are produced in adequate facilityO are produced without change in procedureO are produced without technical difficulties
• IF IN PROCESS CONTROL DATA
Have demonstrated that the critical manufacturing steps are under control
If validated analytical methods have demonstrated that the final product is in Conformity with the specification for all Quality Characteristics
GOOD FOLLOW UP STABILITY RESULTS
Products notpreviously validated
Stable manufacturinghistory (20 batches, if available)
Product to be soldor discontinued
Are changesSignificant?
Is timing a consideration Accumulate 20 batches
Candidate forRetrospective validation
(yes)
(no)
(yes) (no) (yes)
(no)
Low priority validation
Selection of candidate for retrospective validation
PROSPECTIVE VALIDATION
FEATURES:• Done before a product is marketed
New product
Modifiedproduct
Use ofNew equipment
Use of NewProcess
COVERAGE
PROSPECTIVE VALIDATION ACTIVITIES
1. Check Manufacturing procedures for Completeness
•Description of starting materials, primary packagingmaterials and technical equipment
•Description of manufacturing procedures and exact definition of the process condition to be observed
•Indication of critical manufacturing steps to be followed to ensure that the intended product Quality is achieved
•Description of climatic and hygienic conditions
•Specification of all intermediates, half finished products, partly packaged product
• Details of IPC methods, including equipment and methodology
2. Qualification of apparatus and equipment tested, calibrated
3. Validation of environmental systems
4. PROCESS VALIDATION EXECUTION
EQUIPMENT VALIDATION
EQUIPMENT QUALIFICATION
Why do we need equipment qualification?
- it is a necessary and critical step in
ensuring that a product or service is provided
accurately and consistently
How do we qualify equipment?- To assure that equipment is
installed according to the manufacture’s instruction (IQ)
- To assure that equipment is operated properly and consistently (OQ)
- To assure that the equipment performs within the requirements determined by the facility (PQ)
Universal requirement of all the qualification steps is the trainingrequired to successfully perform the tasks. This includes the personnel executing the protocol and those operating the equipment.
Utilities verification are also essential for equipment qualification, such as electrical supply, compressed air, water, etc.
Testing instruments also be verified, very often, these requires calibration. These includes gauges, meters, counters, scales, etc.
CALIBRATION
• Calibration is the formal, systematic, and documented proof that the used measuring equipment indicates the values within established/defined ranges.
Federation International Pharmaceutique, 1990.
• The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results should be established.
-Who Expert Committee on Specifications for Pharmaceutical Preparations, 32nd Repot,
1997
What do we need to calibrate?
All equipment used for
In production, analysis or supply whichimpact on product quality.
Testing
Monitoring or
Measuring
Control
What are the requirements of a fully documented calibrated system?
If the equipment is found to be faulty, theprocedure must provide for:
• labelling the equipment as “out of service”.• the removal of the equipment from service
and the appropriate corrective action to be taken.
• the review by Quality Assurance personnel and the initiation of appropriate action to be taken with respect to product processed on the faulty equipment.
Maintenance and calibration recordmust be retained at a minimum of 7years after the equipment or process
towhich they refer ceased to be in use.
What are the requirements of a fully documented calibration system?
• The calibration must be carried out using standards which are traceable to the local national standard, a recognized international standard, or if appropriate, a specified physical constant or standard. The traceability must be documented.
Equipment must be clearly labelled to indicate the date when is was last calibrated, an indication of the person or contractor who carried out the calibration and the date when it is due for next calibration.
What are the requirements of a fully documented calibration system?
A master list of all equipment requires calibration and impact on product quality.
• All such equipment must be permanently identified and labelled.
Procedures must specify:
• The calibration method• The acceptable limits of accuracy, and/or
precision• The records to be kept• The frequency of recalibration
The maintenance, calibration and/or checking must be carried out at the defined intervals by trained personnel or approved contractors.
BUILDING VALIDATION
BUILDING VALIDATION
Consists mainly of the verification of the conformance to the specification of the construction and layout, structure and finish
Changes and deviations from design are documented stating what, how and why modifications were made
Establish suitability of the modification to the process flow, material flow and personnel movement
Verify that the layout should result to more efficient manufacturing process or operation
Building Validation Protocol
SubjectConstruction & Layout
BVP-001
Prepared by/Date: Reviewed by/Date: Approved by/Date:
Date of issue: Review Date: Page ___of _
Copies to:
Objective:
To document that the building was constructed according to the approved lay-out & plan (Reference: Roombook)
Procedure:1. Inspect the newly constructed area against
the approved layout & plan & room book specification
2. Follow the flow of people and materials and establish compliance to GMP requirements
3. Document deviations from design and evaluate its impact to the efficiency of the plant in terms of flow of people,material & process.
4. Have the as built drawing prepared if deviation are noted
5. Prepare validation report and submit for approval of the validation team
6. Issue certificate of Compliance
Building ValidationConstruction & layout (BVP-001)
Checklist• Check each room against Room book
specification: Place (√) for conforming (X) for non-conforming
Room Size DoorSwitche
s Window Air Supply Air Return Fire SensorRemark
s
1 √ √ √ √ √ √ √
2
3
4
5
6
7
8
9
10 Inspected by:Date:
Verified by:Date
Building Validation Protocol
SubjectSTRUCTURE & FINISH
BVP-002
Prepared by/Date: Reviewed by/Date: Approved by/Date:
Date of issue: Review Date: Page ___of _
Copies to:
Objective:
To document that as built structure & finish of the differentrooms & areas in the plant.Procedure:1. Inspect each room and check compliance to GMP
requirements2. Document findings based on the attached checklist.
Defects must be rectified3. Prepare validation report and submit for approval of the
validation team4. Issue certificate of compliance.
Building Validation (BVP-002) ChecklistPut (√) for conforming and (X) for non-
conforming
A. FLOOR 1 2 3 4 5 6
- Smooth, Non porous free from cracks, crevices
- Not affected by cleaning materials
- Sloped towards floor drains (1/8 inc/foot
- Coved joints with wall
Room No./ID
B. WALLS 1 2 3 4 5 6
- smooth, Non porous free from
cracks, crevices
- coved joint with ceiling
- utilities with sloped tops (45º)
- not affected by cleaning agents
- ducting sealed at the point of entry
Room No./ID
C. CEILINGS 1 2 3 4 5 6
- Free from flaking and other visible
deterioration
- smooth, easy to clean
- free from cracks
- ducting, pipes passing through
the ceiling must be sealed
Room No./ID
D. DOORS 1 2 3 4 5 6
- smooth, hard, close tightly
- frames flush with the surrounding walls
- opening clearance of maximum 3.0mm
- must have automatic closer
- door kick plates beveled or flat
Room No./ID
E. WINDOWS 1 2 3 4 5 6
- smooth, hard
- tightly sealed not permitted to open
- flush with the surrounding walls
Room No./ID
F. DRAINAGE 1 2 3 4 5 6
- adequate size
- trapped gulleys and properly ventilated
- with cover & easy to clean
- with air break or other mechanical device to
prevent back flow.
Room No./ID
Inspected by:Date:
Verified by:Date:
Equipment ValidationProtocol
Subject :Minoga EmulsifyingMixing Machine AS-500As
EVP-001
Prepared by/Date: Checked by/Date: Approved by/Date
Reference: Operations
Date of issue: Page of___of____
Copies to:
A.Objective: To verify that the Minoga Emulsifying mixer equipment is installed according to supplier’s
Instruction and will operate properly & consistently within requirements
B. Installation Qualification:1. Design/specification
Verify that the machine delivered is compliant to the design and user specification
2. Get installation report fromEngineering and verify that machine was installed
properly3. Verify presence of SOP for
maintenance
4. Verify that training has been made on the use & maintenance of the machine
5. Issue Certificate of Compliance
C. Operational Qualification1. Verify that the following major parts are operating as per user specification
1.1 Raw Material Pouring1.2 Discharging1.3 Emulsifier1.4 Scrapping Mixing1.5 Vacuum System1.6 Hydraulic System
1.7 Heating System1.8 Cooling System1.9 Temperature Control1.10 Lighting System1.11 Speed adjustment1.12 Safety Devices
2. Document Results3. Issue certificate of Compliance
D. Conclusion:From the data obtained from the above qualifications draw
conclusion and prepare the final qualification report.
MINOGA Emulsifying Mixing (EVP-001) Checklist
A. Installation Qualification:1. Design Specification
As Designed As Found Acceptable
Not Acceptable
1.1 Model
500 As
1.2 Tank 3 Layer a) Inner SUS 316 b) Middle SUS 304 c) Outer SUS 304
As Designed As Found
Acceptable
Not Acceptable
1.3 Tank Capacity
650 L
1.4 Tank Lid * Silicone Packing*Viewing Window with wiper*Light Injection device•Meter Sucking Inlet•Air Filter•Liquid Adding port•Vacuum Safety Device•Vacuum meter•Level sensor for vacuum
As Designed AsFound
Acceptable Not Acceptable
1.5 Emulsifying mixer
7.5 HP Variable speed (540-3600 rpm) with inverter
1.6 Scrapping Mixer
5HP variable speed 12.6-63 rpm with inverter
1.7 Lid Rising 2HP Hydraulic Motor
1.8 Vacuum Part
5 HP vacuum pump with safety device (water type)
1.9 Temperature Control
Sensor
As Designed AsFound
Acceptable Not Acceptable
1.10 Heating System
1.11 Cooling System
Jacket
1.12 Product discharge
a) Bottom valveb) hydraulic
1.13 Control Box
1 set
1.14 Light
1.15 Power
60 w
220v, 60 HZ 3 phase
2. Installation Verification
ok not ok
2.1 Location * stable & even * good drainage system * base & frame properly fixed
2.2 Power Connection *voltage/power stability (±10% ) * grounded connection * no electrical leakage * correct voltage (220V)
ok not ok
2.3 Power Indicator * will switch on
2.4 Circulation water * piping acceptable
2.5 Motor Direction * Scrapping Motor * Emulsifying Motor * Hydraulic Motor * Vacuum Motor
2.6 Cleaning SOP
2.7 Maintenance SOP
2.8 Training Done
3. Operational Qualificationok not ok
3.1 Material charging port * lid can be opened * material sucked by vacuum
3.2 Discharging * can be tilted * bottom valve discharge
3.3 Emulsifier * Speed adjustment
3.4 Scrapping Mixer * speed adjustment
3.5 Vacuum pump * vacuum is achieved & maintained
3.6 Hydraulic Part * lid can go up & down
ok Not ok
3.7 Steam Heating
3.8 Cooling System * functioning
3.9 Temperature Control * Controller records * Temperature Sensor by Thermocouple
3.10 Light Injection * Functioning
3.11 Safety Devices * limit switches functioning * over loading protection * vacuum safety device * emergency stop functioning * alarm device functioning * level sensor functioning
PROCESS VALIDATION
Process Validation Protocol
SubjectBaby LotionW1 RD-048
PVP-001
Prepared by/Date: Checked by/Date:
Approved by/Date:
Issue Date: Effectivity Date: Page of__of___
Reference
Copies to:
Objective: To demonstrate that the processing of baby Lotion using Minoga Emulsifying Mixer will produce consistently product meeting specification
Precaution:1. Observe high degree of cleaning &
sanitation throughout the process
2. Wear clean room attire
Validation Pre-requisites:1. Verify that the current formula, manufacturing procedures are in use.2. Verify that the raw materials issued are in accordance to the issued formula & manufacturing procedure, dispensed in the correct
amount and released by QC
3. Verify that the Minoga Emulsifyingmixer has been validated and certified by the validation team
4. Verify that the machine and processing room are cleaned and sanitized.
5. Procedure: Manufacture the product following the manufacturing instruction and check the following critical parameters
5.1 Preparation of Carbopol Water Phase
RequiredMeasured Parameters Met?
Yes No
Water Temperature 75ºC
Mixer Speed 1200 rpm
Carbopol Dissolution
No fish eyes
5.1.3 Transfer by vacuum of the water phase into the emulsifying
tank. Record vacuum setting and agitation used
RequiredMeasured Parameters Met?
Yes No
VacuumTo be established
Mixer Speed 30 rpm
5.2.1 Preparation of Oil PhaseRecord temperature & mixer
speed
RequiredMeasured Parameters Met?
Yes No
Temperature 75-80ºC
Mixer Speed 300 rpm
5.3 Emulsification Water and oil phase must have
the same temperature to have a good emulsion. Record mixer speed.
RequiredMeasured
Parameters Met?
Yes No
Water Phase 75-80ºC
Oil Phase 75-80ºC
Vacuum Reading record
Mixing Speed 35-40 rpm
5.3.1 Viscosity Adjustment5.3.2 Get initial viscosity after
20 minutes mixing. Document the following
RequiredMeasured
Parameters Met?
Yes No
Temperature 75-80ºC
Mixer Speed 30-40 rpm
pH record
Initial Viscosity record
5.3.2 Addition of Sodium Hydroxide
Required Measured Parameters Met?
Yes No
Volume Added record
Temperature record
pH record
Viscosity record
Mixer Speed 35-40 ºC
5.3.2.3 Force Cooling
RequiredMeasured
Parameters Met?
Yes No
Temperature 45ºC
Mixer Speed 35-40 rpm
ViscosityTo be established
5.3.5 Final Cooling
RequiredMeasured Parameters Met?
Yes No
Temperature 30-35ºC
Mixer Speed 35-40 rpm
ViscosityNLT 10,000 cps
5.3.6 Take sample for Top, Middle.& Bottom
Unload into 6 containers. The first 2 representing the bottom, the next two the bottom and the last two containers the top parts. Take samples representing TOP, MIDDLE & BOTTOM for QC evaluation. Tabulate results.
6.0 If results are satisfactory, write the manufacturing procedure indicating the actual parameters used in this batch.
7.0 Produce three consecutive batches following the procedure.
8.0 Tabulate results
9.0 Draw conclusion from the data generated from the 3 batches
BABY LOTION (PVP-001) Checklist
A. Validation Pre-requisitesA.1 Manufacturing formula, procedure
Raw Materials QC released
Quantity Correct
Minoga Machine Validated
Processing Area cleaned & sanitized
Minoga Machine cleaned & sanitized
current not current
yes no
yes
yes
yes
yes
no
no
no
no
5.1.2 Carbopol Water Phase
Conclusion
RequiredMeasured Parameters Met?
Yes No
Water Temperature 75ºC
Mixer Speed 1,200 rpm
Carbopol Dissolution No fish eyes
5.1.3 Vacuum Transfer
Conclusion
RequiredMeasured Parameters Met?
Yes No
VacuumTo be established
Mixer Speed 300 rpm
5.2.1 Oil Phase
RequiredMeasured Parameters Met?
Yes No
Temperature 75-80ºC
Mixer Speed 300 rpm
5.3 Emulsification
RequiredMeasured Parameters Met?
Yes No
Water Temperature 75-80ºC
Oil Phase Temperature 75-80ºC
Mixing speed 35-40 rpm Vacuum
settingTo be established
5.3.1 Viscosity Adjustment After 20 minutes mixing
RequiredMeasured Parameters Met?
Yes No
Temperature 75-80ºC
Mixer speed35-40 rpm
pH record
Initial Viscosity record
5.3.2 After adding sodium hydroxide
Required Measured Parameters Met?
Yes No
Volume Added record
Temperature record
pH record
Viscosity record
Mixer Speed 35-40 rpm
5.3.3 Force Cooling
RequiredMeasured Parameters Met?
Yes No
Temperature 45ºC
Mixer Speed 35-40 rpm
Viscosity record
5.3.5 Final Cooling
RequiredMeasured Parameters Met?
Yes No
Temperature 30-35ºC
Mixer Speed 35-40 rpm
ViscosityNLT 10,000 cps
5.3.6 Final Analysis
Required Top Middle Bottom
Appearance Emulsion
Color white
pH 5.5 - 7.5
Specific gravity 0.95-1.00
Total Aerobic Microbe
LT 100,000 cfu/gm
Viscosity NLT 10,000 cps
Yeasts and Molds Negative
6.0 Final Validation Tabulate results of 3 consecutive
batches.7.0 Conclusion Draw conclusion from the data generated
HVAC VALIDATION
Types of HVAC & Applications
Class 100,000 /D
Class 10,000 /C
Class 100/B
Class 100/A+ + + +
+ + +
+ +
+
Comparison of the Different Classification System
PIC/S US US ISO WHO
Annex 1/GMP Customary 209E 14644 GMP
A M 3.5 100 ISO5 A
B M 3.5 100 ISO5 B
C M 5.5 10,000 ISO7 C
D M 6.5 100,000
ISO8 D
USER REQUIREMENT SPECIFICATION(HVAC)
A. Description 1. The HVAC system shall be designed to
provide controlled environment and maintaining pressure differential between rooms to avoid cross contamination.
2. The system will utilize incoming fresh air and combining return clean air at percentage of 20% and 80% respectively
3. The HVAC system may be manually balanced and must remain stable during operation of the dust extraction system.
HVAC system
4. Air is supplied at high level and extracted at low levels in area where dust is generated
5. Rooms are pressurized with airflow designed to avoid cross contamination
6. Exhaust air is to be filtered before exiting the building
B. LocationThe HVAC system is required for the manufacturing and packaging areas.
C. Performance The HVAC system is
required to deliver conditioned air to rooms in the manufacturing & packaging areas
D. ReliabilityThe HVAC should be able to
operate continuously and reliable for 24 hours per day, 7 days per week, 52 weeks per year
HVAC system
E. Maintenance Preventive maintenance shall be
capable of being carried out as planned
System Validation Protocol
Subject: HVAC System
SVP-001
Prepared by/Date: Checked by/Date: Approved by/Date:
Review Date Date of Issue Page___of ____
Copies to
Objective:To verify that heating, Ventilating
and Air Conditioning system will produce air of acceptable standards and quality
B. Design Qualification
The system as design should be able to serve the areas identified to conform to standards stated mainly under PIC/S
1. Floor layout & Air flow Diagram.
Drawing as supplied should state room grade & pressure
layout. (Design specification & operational specification)
2. Room Grade or Classification3. Filtration System4. Air Handling unit Filtration System5. Fan Coil Unit Filtration System6. Functional Specification
6.1 Filtration System 6.2 Pressure Differential & Air
flow Pattern 6.3 Room Operating Condition 6.4 Air Changes 6.5 Duct work 6.6 Dust Extraction System 6.7 External Environment
Protection 6.8 Monitoring System
7.0 Calibration of critical instrument8.0 Maintenance & Calibration of
HVAC System9.0 Documentation
C. Installation Qualification1. Verify that the rooms as
stated in the design are served by the HVAC system
2. Verify Specification versus order
3. Verify certification documents- Electrical safety check- Material certificate- Filter Certificate
- AHU Pressure Test- Coil Pressure Hold Test
4. Verify Engineering Documentation- Commissioning procedure- Manufacturer’s Maintenance Manual- Full parts List- Spare parts List- Lubricant List- Maintenance Schedule
5. Verify presence of as built drawings
6. Verify installed components 6.1 air handling unit 6.2 30 % pre-filter 6.3 65% pre-filter 6.4 Pre-cooling Coil 6.5 Cooling Coil 6.6 Supply air fan 6.7 Supply air fan motor 6.8 95% filters 6.9 Desiccant Dehumidifier
D. Operational Qualification1. Confirm that HVAC balancing was done2. Check air change and supply
air volumes of each room3. Determine Room Pressures
4. Test Filters for Integrity 5. Check temperature levels of
each room 6. Verify equipment logbook
7. Review Training Records
E. Validation Report/Conclusion Prepare validation report & draw conclusion from the data generated
HVAC System (SVP-001) Checklist
A. Design Qualification1. Floor Layout & Airflow
Diagram
2. Room Grade/Classification System
2.1 Unclassified Rooms
(List) 2.2 Classified room
(Filtered air is supplied)
(List)
Attached Not Attached
Identified Not Identified
Identified Not Identified
3. Filtration System
Room As Per Design
Room ID
Classification
AHU No
Washing 1 UC AHU 1
External Corridor 2 UC AHU 1
Filling 3 C AHU 2
Compounding 4 C AHU 2
Airlock 5 C AHU 2
Conclusion conforms not conforming
Air Handling Filtration SystemFiltration system Should be as
specified below
Primary Secondary Final Filter
Type of Filter Efficiency
Type of Filter Efficiency
Type of Filter Efficiency
Washable 25-30% Disposable 80-85% Disposable 90-95%
Conclusion conforms not conforming
Water Cooled AHU 1&2
5. Fan Coil Unit Filtration System The FCU filtration system should
be as follows
Primary Secondary Final Filter
Type of Filter Efficiency
Type of Filter Efficiency
Type of Filter Efficiency
Washable 25-30% Disposable 80-85% Disposable 90-95%
Conclusion conforms not conforming
Filtration System
6. Functional Specification
6.1 Filtration System Yes No
6.1.1 Final Filter downstream of the blowing fan (to blow air through the system)6.1.2 With pressure differential device
6.2 Pressure Differential & Air Flow Pattern
6.2.1 Airflow must be mfg to filling room, Filling room to corridor Filling room to next room6.2.2 Pressure should be 5-9 pascals from room to corridor
6.3 Operating room condition controlled
6.4 Air changes specified per room
6.5 Duct work - free from asbestos - low pressure type - clean & sealed - pressure tested - Flexible duct NMT 2 meters - flushed for 12 hours before installation of filters
6.6 Dust Extractor System - installed as per design drawing
6.7 External Environment Protection Solids – negative pressure room Liquids – positive pressure vs corridor
6.8 Monitoring System Functioning and in suitable location
7.0 Critical Instrument Calibrated?
8.0 Maintenance & Calibration of HVAC available
9.0 Documentation Available
B. Installation Qualification Yes No
1. Room built as per design
2. HVAC specification VS order conforms
3. Availability of Certification Documents
- electrical safety check - material certificate - filter certification - AHU pressure test - coil pressure test
4. Availability of Engineering Documents - commissioning report - manufacturer’s manual - full parts list - spare parts list - lubricant list - maintenance schedule - as built drawing
5. Verification of Installed Components 5.1 air handling unit 5.2 30% pre-filter 5.3 65% pre-filter 5.4 pre-cooling coil 5.5 cooling coil 5.6 supply air fan 5.7 supply air fan motor 5.8 95% filter
• 5.9 Desiccant Dehumidifier• 5.10 Calibration of Instruments
D. Operational QualificationD.1 Air balancing
HVAC was confirmed balanced and operating correctly
YES NO CORRECTED
D.2 Room Air change & supply Air Volumes D.2.1 Objective : To demonstrate that total air
supply volumes delivered to each room provide sufficient air
to satisfy minimum air change rates D.2.2 Acceptance Criteria
Packaging rooms – minimum 9 air changes per hour
Offices, storage - minimum 6 air changes per hour Mechanical, equipment room - minimum 4
air changes per hour Clean room - minimum 20 air changes
per hour
D2.3 Test Equipment Velometer
D2.4 Method 1) AHU should be in normal
mode of operation 2) doors must be closed and
room pressures are stable 3) Avoid traffic during test 4) position airflow meter over
each terminal & record readings
5) Measure volume of supply air & calculate air changes
Air change = supply air volume (m3/hr) room volume (m3)
Room No. Room
Supply Air Minimum Calculated Accepted
Volume Volume Air Change Air Change Yes No
1
2
3
4
5
6
7
8
9
10
Conclusion:
D.3 Room PressuresD.3.1 Objective
To demonstrate capability of air handling system to maintain room pressure levels within specified limits
D.3.2 Acceptance Criteria Room pressures should corresponds
to the design values D.3.3 Equipment Calibrated Barometer
D3.4 Method 1. Air handling system should be
in normal mode of operations. 2. Doors should be closed and
room pressures are stable 3. Avoid traffic during the test. 4. Measure room pressure and
read pressure display after stabilization of minimum
2 minutes 5. Record results
Room Pressure (Solids)
Room No. Design Measured Accepted
Pressure Pressure Yes No
1 (Weighing) 12.5 pascals
2 (Office) 25.0 pascals
3 (Dispensing) 12.5 pascals
4 (Gowning) 12.5 pascals
5 (Mfg) 12.5 pascals
6 (Filling) 12.5 pascals
Conclusion:
D.4 Filter Integrity D.4.1 ObjectiveTo confirm that there was no damage onthe filter during installation. Test thefollowing:
* Filter Media * Between media & interior of filter * filter gasket & filter housing * construction of the filter housing
(joints)
D.4.2 Acceptance CriteriaEfficiency as per design
D.4.3. Equipment Smoke generator PhotometerD.4.4 Method 1. Introduce thermally
generated oil aerosol into the air stream ahead of the hepa filters
2. Adjust concentration
3. Hold photometer probe approx 25 mm for the filter face & passing the probe in slightly over lapping strokes at a rate of NMT 0.05 m/s to sample the entire filter face. Make separate measurement on periphery and the filter medium & frame and joints
4. Record results
Room No.
Type of
Test Scan
Uptream Concentration
ug/L
Down Stream
Penetration (Design)
ActualPenetratio
n
AllowablePenetratio
n Accept
Yes No
1 Face
Peripher
y
Mounting
Joints
2 Face
Peripher
y
Mounting
Joints
Conclusion:
D.5 Temperature
D.5.1 ObjectiveTo demonstrate the ability of the AHU to maintain temperature at the required set points within the room
D.5.2 Acceptance CriteriaRecorded temperature must be within +/- 5ºC of the acceptable temperature for each room
D.5.3 EquipmentCalibrated temperature probe capable of indicating
temperature change of 0.1ºC
D.5.4 Method1. Run AHU continuously for
at least 24 hours2. All lights must be on during the 24 hours pre-conditioning
period3. Record temperature at the
center of each room at a height of approximately 1 meter above the floor level
4. Record results
Conclusion:
Room No.
Temperature Accept
Expected TempMeasured Room
Temp Yes No
1 21ºC ± 0.5 ºC
2 21ºC ± 0.5 ºC
3 22ºC ± 0.5 ºC
4 25ºC ± 0.5 ºC
5 25ºC ± 0.5 ºC
6
7
6.0 Equipment Log Book
7.0 Training Records
G. Validation Report/ Conclusion
available Not available
available Not available
Have A Nice Day
