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

10. APPROVED! e) approved procedures and instructions; d) Suitable storage and transport; and f) Adequate personnel laboratories, and equipment for in-process controls

17. 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!

20. 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:

21. Documenting An adequate System of referenced documentation is essential.

25. “ 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.

32. Process Optimization Optimum batch size Reduced processing time Decreased downtimes Reduce new facility/ process start-up time

39. - 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:

55. 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)

61. Contents Introduction Objective (s) Justification Approach Scope Acceptance Support Programs Validation Team Organization Schedules Appendix VALIDATION MASTER PLAN

70. 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

72. 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

75. 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

81. 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

103. BEFORE QC + IPC = PRODUCT QUALITY

104. NOW PV + QC + IPC = ASSURED PRODUCT QUALITY

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

106. 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

108. If validated analytical methods have demonstrated that the final product is in Conformity with the specification for all Quality Characteristics

109. GOOD FOLLOW UP STABILITY RESULTS

110. 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

115. EQUIPMENT VALIDATION

130. BUILDING VALIDATION

132. 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:

136. 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

137. 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

139. 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

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

141. 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

150. 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

152. 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

153. 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

154. 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

155. 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

156. PROCESS VALIDATION

157. 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

166. 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

174. 5.2.1 Oil Phase 300 rpm Mixer Speed 75-80ºC Temperature No Yes Parameters Met? Measured Required

175. 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

176. 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

177. 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

178. 5.3.3 Force Cooling record Viscosity 35-40 rpm Mixer Speed 45ºC Temperature No Yes Parameters Met? Measured Required

179. 5.3.5 Final Cooling NLT 10,000 cps Viscosity 35-40 rpm Mixer Speed 30-35ºC Temperature No Yes Parameters Met? Measured Required

180. 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

182. HVAC VALIDATION

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

184. 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

193. 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

203. 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

204. 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

205. 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

206. 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

207. 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

208. 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

210. 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

218. 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.

222. 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.

225. 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.

227. Have A Nice Day