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;
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!
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 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.
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.
- 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:
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
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)
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?
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.
Lists actual units, systems, processes to be validated and the level to which each will be tested (e.g. IQ, QQ, or PQ)
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
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
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
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
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
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 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.
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:
To document that as built structure & finish of the different
rooms & areas in the plant.
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
- 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
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
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
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.
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
5.3.5 Final Cooling NLT 10,000 cps Viscosity 35-40 rpm Mixer Speed 30-35ºC Temperature No Yes Parameters Met? Measured Required
5.3.6 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
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
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
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
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.