Validation Theory And Application 3

VALIDATION THEORY AND APPLICATION Presented by: Mrs. Remedios A. Rivera Telstar Mfg. Plant Sta. Rosa, Laguna March 12 & 16, 2009

Outline of Presentation Validation Orientation History of Validation Definition * Key Features 3. Purpose of Validation Benefits of Validation What to Validate Types of Validation a) Retrospective Validation b) Prospective Validation

7) When to Revalidate 8) Organizing for Validation Planning for Validation Validation Master Plan Validation Matrix/Family Tree Validation Protocol Validation Change Control

VALIDATION ACTIVITIES Design Qualification Installation Qualification Operational Qualification Performance Qualification Validation Review Building Validation 6.1. Construction and Layout 6.2. Structure & Finish * Floors & Walls * Ceilings * Doors & Windows

7. System Validation - HVAC System 8. Equipment Validation - Minoga Emulsifying Mixer 9. Process Validation - Baby Lotion

Good Manufacturing Practice (GMP) GMP is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended Use. The basic requirements of GMP are that: HISTORY OF VALIDATION

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 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 operators are trained to carry out procedures correctly;

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;

records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

The proper storage and distribution of the products minimizes any risk to their quality;

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.

TEN COMMANDMENTS OF GMP Thou shalt document (record) thy work! Thou shalt validate thy work! Thou shalt design and build proper facilities and equipment! Thou shalt maintain thy facilities and requirement! Thou shalt be competent (as a result of education training and experience)! Thou shalt be clean! Thou shalt control for quality! Thou shalt audit for compliance!

VALIDATION The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results. WHO expert Committee on Specifications for Pharmaceutical Preparations. 32 nd 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

Proving Sufficient replication of the testing and challenging of each defined critical Stage of a system, process, etc. that has to be performed to give valid levels of assurance KEY FEATURES:

Documenting An adequate System of referenced documentation 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 approved by all designated responsible 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 as never having been performed. written reviewed approved retained DOCUMENTED FOCUS

SYNONYMS Verify Justify 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 cost REDUCTION 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 system is possibly optimized .

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 involve various combinations of the following : WHAT TO VALIDATE? Equipment Environment Methods Materials Software

Controls Processes Personnel 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, location materials 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 BE VALIDATED NEVER ATTEMPT TO VALIDATE ANYTHING THAT YOU o Do not understand o 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 the review of test results. It also requires that the manufacturing process be specific and the same each time a batch is manufactured. Thus, specific raw material specifications (including particle size when necessary, in process specifications (tablet hardness, etc.) and specific manufacturing directions are required. Obviously, any failing batches attributed to the process would necessitate the conclusion that the process is not validated and is inadequate. - “The Gold Sheet “ Vol. 28, No. 5, May 1994.

PROSPECTIVE VALIDATION Validation conducted prior to the distribution of either a new product, or product made under a Revised manufacturing process, where the revisions may effect the product’s characteristic. - Guidelines on General Principles of Process Validation, FDA, May 1997 Validation required to be completed before initial Release of product. It is associated with the studies carried out during the design and development phase of a new or modified product.

WHEN TO REVALIDATE If the composition of the pharmaceutical product, the manufacturing procedure or the batch size is changed In the event of significant alterations to the processing equipment If new equipment is used In the event of major changes of processing conditions After exhaustive preventive maintenance work on machines or equipment

If the findings of the in-process and Quality control results indicate the 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? xx xx xx xx xx xx Accepting xx xx Reporting x Testing xx xx xx xx xx Xx Validation X x x x x xx Project Xx xx Authorization x x x x x xx xx xx Strategy 8 7 6 5 4 3 2 1

Strategy Team Authorization Team Project Team Validation Team Investigation Team (S) Evaluation Team (S) Acceptance Team (S) TEAM FUNCTION/ROLES TEAM FUNCTION APPROACH (Multidisciplinary Team Members)

RESPONSIBILITIES OF VALIDATION PROJECT TEAM MEMBERS To motivate appropriate personnel within their departments of the need for validation in order to obtain adequate resources and to achieve an effective consciousness concerning changes which could have impact on the certification. To contribute towards the estimation of Resources required for each project.

To contribute towards the generation and approval of validation protocols. To contribute towards the generation and assessment of data and establishment of acceptance criteria. To contribute towards the generation of Procedures and acceptance criteria for continuous monitoring by the user.

To accept responsibility for the quality and Time scale of work within his/her area. To identify any need for plant overhaul or replacement.

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 development Validation of analytical test procedures Calibration of instruments and equipment Training 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 Validation Team Organization Schedules Appendix VALIDATION MASTER PLAN

VALIDATION MASTER PLAN A VMP is a summary document which describes a program of work to be done Before the facility or operation can be considered 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 the equipment, 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 PLAN reviewed 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.

INTRODUCTION A 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 VALIDATION MASTER PLAN?

OBJECTIVE A concise statement or statements of the task and will allow a complete understanding of the validation exercise. JUSTIFICATION A discussion of the reasons that support the units will be validated. Also states why other pieces of equipment or systems will not be validated.

APPROACH Defines 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. SCOPE Lists actual units, systems, processes to be validated and the level to which each will be tested (e.g. IQ, QQ, or PQ)

ACCEPTANCE CRITERIA Defines in general terms the agreed standards or ranges, which must be achieved by each unit. SUPPORT PROGRAMS Includes all requirements to achieve and maintain the validated state, including training, calibration, maintenance, change control and validation review. VALIDATION TEAM ORGANIZATION List the members of the Validation team and describes their specific roles or functions for all stages of the validation

SCHEDULES Can 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. APPENDIX Includes 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) Meralco Generator 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 - - x Building x x x Air Conditioning x x x Chlorination x x x Water x x x Sewage Plant x x x Electrical Power Site Services PQ OQ IQ

x - - Processes x x x Equipment x x x Dust Collection x x x Compressed Air x x x Steam x x x Water x x x Vacuum x x x Lighting/Electrical x x x HVAC Utilities/System

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 documented proof that facilities and Equipment are suitable for the intended process. It is a basic requirement for validation and an entire part of this validation. Qualification of equipment includes calibration or Measuring equipment. - Federation International Pharmaceutique, 1990

Documented evidence that quality is built into the design of facilities and operations. 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: Specification Responsible Supplier This is how we will build it Design Specification Supplier This is what we could give you Functional Requirements Specification User This is what we want User Requirements Specifications

Validation V-Model Is based on Is based on Is based on PQ OQ IQ User Specification Functional Specification Design Specification Implementation D E S I G N Q U A L I F I C A T I O N

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 of the data required concerning the installation of 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 is clearly described and suitably labelled as to vendor, model, capacity, materials and other critical 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 control parameters must be recorded and records securely kept Ensure change control system are in Operation Ensure that all system have been verified to operate under no load conditions.

Installation Qualification answers the following 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 facilities and operations function as specified. The OQ protocol should include a complete description of the Purpose, Methodology and Acceptance 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 and maintenance Procedures have been developed and approved for each system, to ensure continued operation under defined conditions.

Ensure that Training Modules and training sessions for Production, Engineering, and support 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 complete description of the Purpose, Methodology and Acceptance Criteria for the Performance tests to 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 are operating Ensure all SOP’s have been finalized and approved at this stage. PQ testing should be carried out by trained personnel who will routinely operate the system 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 to demonstrate 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 Design Qualification (DQ) - will the design work and will it meet all our requirements? Installation Qualification (IQ) - Has the item been supplied and installed as specified? Operational Qualification (OQ) - Does the item performs as specified under operational conditions?

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? 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 to detect or identify test failures during validation activities.

Detection of failures or malfunction gives additional understanding and knowledge of the operation.

More failures detected during validation means more problems are avoided during routine work.

Failure could be due to incomplete or Substandard Installation (IQ; OQ)

BEFORE QC + IPC = PRODUCT QUALITY

NOW PV + QC + IPC = ASSURED PRODUCT QUALITY

RESTROSPECTIVE VALIDATION 12% 13% 17% 8% 16% 9% 25% FEATURES Marketed products Use HISTORICAL DATA Use of SPECIFIC PROCESS

WHEN TO DO RETROSPECTIVE VALIDATION ONLY IF WITHIN a reasonable period of time; Sufficient number of batches O are produced in adequate facility O are produced without change in procedure O are produced without technical difficulties 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 SAT FRI THU WED TUE MON SUN

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 not previously validated Stable manufacturing history (20 batches, if available) Product to be sold or discontinued Are changes Significant? Is timing a consideration Accumulate 20 batches Candidate for Retrospective 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 Modified product Use of New equipment Use of New Process COVERAGE

PROSPECTIVE VALIDATION ACTIVITIES 1. Check Manufacturing procedures for Completeness Description of starting materials, primary packaging materials 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 Qualification of apparatus and equipment tested, calibrated 3. Validation of environmental systems 4. PROCESS VALIDATION EXECUTION

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 training required 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, 32 nd Repot, 1997

What do we need to calibrate? All equipment used for In production, analysis or supply which impact 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, the procedure 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 record must be retained at a minimum of 7 years after the equipment or process to which 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 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

Objective: To document that the building was constructed according to the approved lay-out & plan (Reference: Roombook) BVP-001 Subject Construction & Layout Building Validation Protocol Approved by/Date: Reviewed by/Date: Prepared by/Date: Page ___of _ Review Date: Date of issue: Copies to:

Procedure: Inspect the newly constructed area against the approved layout & plan & room book specification Follow the flow of people and materials and establish compliance to GMP requirements Document deviations from design and evaluate its impact to the efficiency of the plant in terms of flow of people,material & process. Have the as built drawing prepared if deviation are noted Prepare validation report and submit for approval of the validation team Issue certificate of Compliance

Building Validation Construction & layout (BVP-001) Checklist Check each room against Room book specification: Place (√) for conforming (X) for non-conforming Inspected by: Date: Verified by: Date 10 9 8 7 6 5 4 3 2 √ √ √ √ √ √ √ 1 Remarks Fire Sensor Air Return Air Supply Window Switches Door Size Room

Objective: To document that as built structure & finish of the different rooms & areas in the plant. Procedure: Inspect each room and check compliance to GMP requirements Document findings based on the attached checklist. Defects must be rectified Prepare validation report and submit for approval of the validation team Issue certificate of compliance. BVP-002 Subject STRUCTURE & FINISH Building Validation Protocol Approved by/Date: Reviewed by/Date: Prepared by/Date: Page ___of _ Review Date: Date of issue: Copies to:

Building Validation (BVP-002) Checklist Put (√) for conforming and (X) for non-conforming Room No./ID - Coved joints with wall - Sloped towards floor drains (1/8 inc/foot - Not affected by cleaning materials - Smooth, Non porous free from cracks, crevices 6 5 4 3 2 1 A. FLOOR

Room No./ID - ducting sealed at the point of entry - not affected by cleaning agents - utilities with sloped tops (45º) - coved joint with ceiling cracks, crevices - smooth, Non porous free from 6 5 4 3 2 1 B. WALLS

Room No./ID the ceiling must be sealed ducting, pipes passing through - free from cracks - smooth, easy to clean deterioration - Free from flaking and other visible 6 5 4 3 2 1 C. CEILINGS

Room No./ID - door kick plates beveled or flat - must have automatic closer - opening clearance of maximum 3.0mm - frames flush with the surrounding walls - smooth, hard, close tightly 6 5 4 3 2 1 D. DOORS

Room No./ID - flush with the surrounding walls - tightly sealed not permitted to open - smooth, hard 6 5 4 3 2 1 E. WINDOWS

Room No./ID Inspected by: Date: Verified by: Date: prevent back flow. - with air break or other mechanical device to - with cover & easy to clean - trapped gulleys and properly ventilated - adequate size 6 5 4 3 2 1 F. DRAINAGE

Objective: To verify that the Minoga Emulsifying mixer equipment is installed according to supplier’s Instruction and will operate properly & consistently within requirements Page of___of____ Date of issue: Reference: Operations Approved by/Date Checked by/Date: Prepared by/Date: EVP-001 Subject : Minoga Emulsifying Mixing Machine AS-500As Equipment Validation Protocol Copies to:

B. Installation Qualification: 1. Design/specification Verify that the machine delivered is compliant to the design and user specification 2. Get installation report from Engineering and verify that machine was installed properly 3. Verify presence of SOP for maintenance

Verify that training has been made on the use & maintenance of the machine Issue Certificate of Compliance

Operational Qualification 1. Verify that the following major parts are operating as per user specification 1.1 Raw Material Pouring 1.2 Discharging 1.3 Emulsifier 1.4 Scrapping Mixing 1.5 Vacuum System 1.6 Hydraulic System

1.7 Heating System 1.8 Cooling System 1.9 Temperature Control 1.10 Lighting System 1.11 Speed adjustment 1.12 Safety Devices Document Results 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 Installation Qualification: 1. Design Specification 3 Layer a) Inner SUS 316 b) Middle SUS 304 c) Outer SUS 304 1.2 Tank 500 As 1.1 Model Not Acceptable Acceptable As Found As Designed

* 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 1.4 Tank Lid 650 L 1.3 Tank Capacity Not Acceptable Acceptable As Found As Designed

Sensor 1.9 Temperature Control 5 HP vacuum pump with safety device (water type) 1.8 Vacuum Part 2HP Hydraulic Motor 1.7 Lid Rising 5HP variable speed 12.6-63 rpm with inverter 1.6 Scrapping Mixer 7.5 HP Variable speed (540-3600 rpm) with inverter 1.5 Emulsifying mixer Not Acceptable Acceptable As Found As Designed

60 w 220v, 60 HZ 3 phase 1.14 Light 1.15 Power 1 set 1.13 Control Box Bottom valve b) hydraulic 1.12 Product discharge Jacket 1.11 Cooling System 1.10 Heating System Not Acceptable Acceptable As Found As Designed

2. Installation Verification 2.2 Power Connection *voltage/power stability (±10% ) * grounded connection * no electrical leakage * correct voltage (220V) 2.1 Location * stable & even * good drainage system * base & frame properly fixed not ok ok

2.8 Training Done 2.7 Maintenance SOP 2.6 Cleaning SOP 2.5 Motor Direction * Scrapping Motor * Emulsifying Motor * Hydraulic Motor * Vacuum Motor 2.4 Circulation water * piping acceptable 2.3 Power Indicator * will switch on not ok ok

3. Operational Qualification 3.6 Hydraulic Part * lid can go up & down 3.5 Vacuum pump * vacuum is achieved & maintained 3.4 Scrapping Mixer * speed adjustment 3.3 Emulsifier * Speed adjustment 3.2 Discharging * can be tilted * bottom valve discharge 3.1 Material charging port * lid can be opened * material sucked by vacuum not ok ok

3.11 Safety Devices * limit switches functioning * over loading protection * vacuum safety device * emergency stop functioning * alarm device functioning * level sensor functioning 3.10 Light Injection * Functioning 3.9 Temperature Control * Controller records * Temperature Sensor by Thermocouple 3.8 Cooling System * functioning 3.7 Steam Heating Not ok ok

Objective: To demonstrate that the processing of baby Lotion using Minoga Emulsifying Mixer will produce consistently product meeting specification Page of__of___ Effectivity Date: Issue Date: Approved by/Date: Checked by/Date: Prepared by/Date: PVP-001 Subject Baby Lotion W1 RD-048 Process Validation Protocol Copies to: Reference

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

Verify that the Minoga Emulsifying mixer 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 No fish eyes Carbopol Dissolution 1200 rpm Mixer Speed 75ºC Water Temperature No Yes Parameters Met? Measured Required

5.1.3 Transfer by vacuum of the water phase into the emulsifying tank. Record vacuum setting and agitation used 30 rpm Mixer Speed To be established Vacuum No Yes Parameters Met? Measured Required

5.2.1 Preparation of Oil Phase Record temperature & mixer speed 300 rpm Mixer Speed 75-80ºC Temperature No Yes Parameters Met? Measured Required

5.3 Emulsification Water and oil phase must have the same temperature to have a good emulsion. Record mixer speed. 35-40 rpm Mixing Speed record Vacuum Reading 75-80ºC Oil Phase 75-80ºC Water Phase No Yes Parameters Met? Measured Required

5.3.1 Viscosity Adjustment 5.3.2 Get initial viscosity after 20 minutes mixing. Document the following record Initial Viscosity record pH 30-40 rpm Mixer Speed 75-80ºC Temperature No Yes Parameters Met? Measured Required

5.3.2 Addition of Sodium Hydroxide 35-40 ºC Mixer Speed record Viscosity record pH record Temperature record Volume Added No Yes Parameters Met? Measured Required

5.3.2.3 Force Cooling To be established Viscosity 35-40 rpm Mixer Speed 45ºC Temperature No Yes Parameters Met? Measured Required

5.3.5 Final Cooling NLT 10,000 cps Viscosity 35-40 rpm Mixer Speed 30-35ºC Temperature No Yes Parameters Met? Measured Required

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 Validation Pre-requisites A.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 No fish eyes Carbopol Dissolution 1,200 rpm Mixer Speed 75ºC Water Temperature No Yes Parameters Met? Measured Required

5.1.3 Vacuum Transfer Conclusion 300 rpm Mixer Speed To be established Vacuum No Yes Parameters Met? Measured Required

5.2.1 Oil Phase 300 rpm Mixer Speed 75-80ºC Temperature No Yes Parameters Met? Measured Required

5.3 Emulsification 35-40 rpm Mixing speed 75-80ºC Oil Phase Temperature 75-80ºC Water Temperature No Yes Parameters Met? Measured Required To be established Vacuum setting

5.3.1 Viscosity Adjustment After 20 minutes mixing record Initial Viscosity record pH 35-40 rpm Mixer speed 75-80ºC Temperature No Yes Parameters Met? Measured Required

5.3.2 After adding sodium hydroxide 35-40 rpm Mixer Speed record Viscosity record pH record Temperature record Volume Added No Yes Parameters Met? Measured Required

5.3.3 Force Cooling record Viscosity 35-40 rpm Mixer Speed 45ºC Temperature No Yes Parameters Met? Measured Required

5.3.6 Final Analysis Negative Yeasts and Molds NLT 10,000 cps Viscosity LT 100,000 cfu/gm Total Aerobic Microbe 0.95-1.00 Specific gravity 5.5 - 7.5 pH white Color Emulsion Appearance Bottom Middle Top Required

6.0 Final Validation Tabulate results of 3 consecutive batches. 7.0 Conclusion Draw conclusion from the data generated

Types of HVAC & Applications Class 100,000 /D Class 10,000 /C Class 100/B Class 100/A + + + + + + + + + +

Comparison of the Different Classification System D ISO8 100,000 M 6.5 D C ISO7 10,000 M 5.5 C B ISO5 100 M 3.5 B A ISO5 100 M 3.5 A GMP 14644 209E Customary Annex 1/GMP WHO ISO US US PIC/S

USER REQUIREMENT SPECIFICATION (HVAC) 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. Location The 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. Reliability The 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

Objective: To verify that heating, Ventilating and Air Conditioning system will produce air of acceptable standards and quality Page___of ____ Date of Issue Review Date Approved by/Date: Checked by/Date: Prepared by/Date: SVP-001 Subject: HVAC System System Validation Protocol Copies to

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 Classification Filtration System Air Handling unit Filtration System Fan Coil Unit Filtration System 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 instrument 8.0 Maintenance & Calibration of HVAC System 9.0 Documentation C. Installation Qualification 1. Verify that the rooms as stated in the design are served by the HVAC system 2. Verify Specification versus order

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

Operational Qualification 1. Confirm that HVAC balancing was done 2. Check air change and supply air volumes of each room 3. 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 Design Qualification 1. 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 Conclusion conforms not conforming AHU 2 C 5 Airlock AHU 2 C 4 Compounding AHU 2 C 3 Filling AHU 1 UC 2 External Corridor AHU 1 UC 1 Washing AHU No Classification Room ID Room As Per Design

Air Handling Filtration System Filtration system Should be as specified below Conclusion conforms not conforming Water Cooled AHU 1&2 90-95% Disposable 80-85% Disposable 25-30% Washable Efficiency Type of Filter Efficiency Type of Filter Efficiency Type of Filter Final Filter Secondary Primary

5. Fan Coil Unit Filtration System The FCU filtration system should be as follows Conclusion conforms not conforming Filtration System 90-95% Disposable 80-85% Disposable 25-30% Washable Efficiency Type of Filter Efficiency Type of Filter Efficiency Type of Filter Final Filter Secondary Primary

6. Functional Specification 6.2 Pressure Differential & Air Flow Pattern 6.1.1 Final Filter downstream of the blowing fan (to blow air through the system) 6.1.2 With pressure differential device No Yes 6.1 Filtration System 6.2.1 Airflow must be mfg to filling room, Filling room to corridor Filling room to next room 6.2.2 Pressure should be 5-9 pascals from room to corridor

6.6 Dust Extractor System - installed as per design drawing 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 6.4 Air changes specified per room 6.3 Operating room condition controlled

9.0 Documentation Available 8.0 Maintenance & Calibration of HVAC available 7.0 Critical Instrument Calibrated? 6.8 Monitoring System Functioning and in suitable location 6.7 External Environment Protection Solids – negative pressure room Liquids – positive pressure vs corridor

Availability of Certification Documents - electrical safety check - material certificate - filter certification - AHU pressure test - coil pressure test 2. HVAC specification VS order conforms 1. Room built as per design No Yes B. Installation Qualification

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 4. Availability of Engineering Documents - commissioning report - manufacturer’s manual - full parts list - spare parts list - lubricant list - maintenance schedule - as built drawing

5.9 Desiccant Dehumidifier 5.10 Calibration of Instruments

D. Operational Qualification D.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) Conclusion: 10 9 8 7 6 5 4 3 2 1 No Yes Air Change Air Change Volume Volume Accepted Calculated Minimum Supply Air Room Room No.

D.3 Room Pressures D.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) Conclusion: 12.5 pascals 6 (Filling) 12.5 pascals 5 (Mfg) 12.5 pascals 4 (Gowning) 12.5 pascals 3 (Dispensing) 25.0 pascals 2 (Office) 12.5 pascals 1 (Weighing) No Yes Pressure Pressure Accepted Measured Design Room No.

D.4 Filter Integrity D.4.1 Objective To confirm that there was no damage on the filter during installation. Test the following: * Filter Media * Between media & interior of filter * filter gasket & filter housing * construction of the filter housing (joints)

D.4.2 Acceptance Criteria Efficiency as per design D.4.3. Equipment Smoke generator Photometer D.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

Conclusion: Joints Mounting Periphery Face 2 Joints Mounting Periphery Face 1 No Yes Accept Allowable Penetration Actual Penetration Down Stream Penetration (Design) Uptream Concentration ug/L Type of Test Scan Room No.

D.5 Temperature D.5.1 Objective To demonstrate the ability of the AHU to maintain temperature at the required set points within the room D.5.2 Acceptance Criteria Recorded temperature must be within +/- 5ºC of the acceptable temperature for each room

D.5.3 Equipment Calibrated temperature probe capable of indicating temperature change of 0.1ºC D.5.4 Method 1. Run AHU continuously for at least 24 hours 2. All lights must be on during the 24 hours pre-conditioning period 3. Record temperature at the center of each room at a height of approximately 1 meter above the floor level 4. Record results

Conclusion: 7 6 25 º C ± 0.5 º C 5 25 º C ± 0.5 º C 4 22 º C ± 0.5 º C 3 21 º C ± 0.5 º C 2 21 º C ± 0.5 º C 1 No Yes Measured Room Temp Expected Temp Accept Temperature Room No.

6.0 Equipment Log Book 7.0 Training Records G. Validation Report/ Conclusion available Not available available Not available

Validation Theory And Application 3

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