Design Qualification (DQ) Protocol Form Fill Seal
Blow-Fill-Seal (BFS) technology is a manufacturing technique used to produce small, (0.1mL) and large volume, (500mL +) liquid-filled containers.
The basic concept of BFS is that a container is formed, filled, and sealed in a continuous process without human intervention, in a sterile enclosed area inside a machine. Thus, this technology can be used to aseptically manufacture sterile pharmaceutical liquid dosage forms.
Table of content
1. Introduction
2. Guidance
3. Objective
4. Scope
5. Scope of Supply
6. Machine Description
7. Technical Specification of components
8. Utilities
9. Material of Construction
10. Brief Description of Process
11. Safety features and alarms
12. Procedure of FAT
13. List of Abbreviations
14. Design Qualification Document Approval
The process is multi-stepped: first, pharmaceutical-grade plastic resin is vertically heat extruded through a circular throat to form a hanging tube called the parison. This extruded tube is then enclosed within a two-part mould, and the tube is cut above the mould. The mould is transferred to the filling zone, or sterile filling space, where filling needles (mandrels) are lowered and used to inflate the plastic to form the container within the mould. Following the formation of the container, the mandrel is used to fill the container
with liquid. Following filling the mandrels are retracted and a secondary top mould seals the container.
All actions take place inside a sterile shrouded chamber inside the machine. The product is then discharged to a non-sterile area for labelling, packaging and distribution.
Blow-fill-seal technology reduces personnel intervention making it a more robust method for the aseptic preparation of sterile pharmaceuticals. BFS is used for the filling of vials for parenteral preparations and infusions, eye drops, and inhalation products. Generally, the plastic containers are made up of polyethylene and polypropylene. Polypropylene is more commonly used to form containers which are further sterilized by autoclaving as polypropylene has greater thermo stability.
As per the guidance, it is intended to help manufacturers meet the requirements in the Agency’s current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when manufacturing sterile drug products using aseptic processing. This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance.
This guidance document should be read in conjunction with the guidance on the content of sterile drug applications entitled Guideline for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products.
The Submission Guidance describes the types of information and data that should be included in drug applications to demonstrate the efficacy of a manufacturer’s sterilization process.
This guidance compliments the Submission Guidance by describing procedures and practices that will help enable a sterile drug manufacturing facility to meet CGMP requirements relating, for example, to facility design, equipment suitability, process validation, and quality control.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance describes the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended but not required.
Objective
To design the FFS Machine with Form Fill Seal Technology as per URS of Customer for the intended use.
To prove, each operation proceeds as per the URS and design specifications and the tolerance prescribed there in the document are the same at utmost transparency and to meet the validation process to meet the quality of the product to get complete satisfaction of customer.
Scope
The scope of this qualification document is to get complete customer satisfaction to get intended quality of product as desired.
Qualification of utilities is not within this document, and the required utilities are given.
The equipment is designed as per URS and shall use for the FFS Technology as per the drawing and specifications. The equipment’s should place in sterile conditions room, and the Equipment shall operate with a qualified, rained Engineer or Operator under validated conditions as per CGMP norms.
Scope of Supply:
Description:
Model: VLM-875D
Number of Cavities: 40+40
Number of stations: 2
Product filling range: 2.5 ml to 04 ml
Output: 16500 units / Hour for 04 ML
Material to be use: Approved LDPE only
Accessories: FFS Machine with Extruder Assembly, Parrison Control, Filling Head under LAF CIP System, SIP System, Hydraulic System, Pneum. System, Nicron wire cutting System Auto Manual System total under PLC
Auto loading of LDPE Granules to Hopper, Heat Exchanger of Product Solution.
Material of Construction: Machine Frame with SS 304with matt finish, All product contacts parts are SS 316L
Safety Futures: Adequate safety features for Man and Material are provided.
Control System: The FFS machine can control Manual or PLC system
Electrical System: Electrical System is designed as per Adequate Safety futures as per CGMP.
Machine Description
Basic Machine
1. The Basic Frame of the machine is made with SS 304
2. The entire portion of the machine is enclosed in polished stainless steel including front doors, side doors, Belt guards and electrical control cabinets. Mold and carriage Assembly
3. The Mold carriage system is operated with Servo system in Left and Right.
4. The main mold clamp is actuated with Hydraulic system
5. All hydraulic cylinders are Nickel plated.
Extrusion System
6. The Thermo Plastic extruder has mixing zone on the screw and is made out of EN41 B-MUSCO material
7. The barrel temperature is controlled in five zones by separate specially designed electric heaters with proper insulation to minimize the heat loss.
8. The plastic LDPE is supplied and feuded through a stainless-steel hopper with auto loading system and feeding by water cooled fed throat.
9. The Extruder is driven by 18.5 Kw AC motor with VFD Control and with gear box.
10. Extruder output is up to 100 Kg maximum of LDPE Granules.
Pneumatic System
11. Pneumatic system consists of FRL, regulated and manifold mounted solenoid control valves for ballooning, forming and other machine functions,
12. Air should be Oil free, Dry, Clean, and 0.2μ filtered at a pressure of 7 Kg/cm²
Vacuum System
13. Vacuum System consists of vacuum reservoir and manifold mounted regulators and solenoid valves
14. Vacuum should be passing through clean rust less piping of 500 Hg/mm2 Cooling System
15. Cooling System must supply coolant water flow of 500 Liter. / Hour at 4 Kg/cm² pressure 14ºc -16 ºc.
16. The FFS Machine is internally equipped with separate cooling circuits for the main mold, Seal mold, holding jaws, extruder feed throat zone, hydraulic power unit and extruder barrel cooling system with proper flow control valves.
17. An air cylinder actuated hot knife is electrically actuated by a solid-state controller.
Smoke Arrester
18. Smoke arrester system consists of blower on the parson cut off knife which exhausts air to the outside of the machine clean room.
Safety Measures
19. The machine has been designed to meet utmost safety precautions, guards, and safety devices to protect operator and maintenance personnel. Also, there are provided various – Caution—Danger—and informational sign posted on the machine as per the compliance with the occupational safety and health act.
20. Doors and Access panels are equipped with electrical safety and interlocks
Product Filling System
21. Filling System is electronically controlled pressure fill nozzle assembly.
22. Product filling system consists of CIP, SIP, Filter drying and Filling of Product. The Cleaning and sterilization of all products feeding line are in place. The Product filling station is under LAF and maintained as aseptic.
23. PLC, Controlled panel is provided with machine to control the machine to get desired output with quality.
Technical Specifications of Components
1. Extruder Motor
2. Extruder Gear
3. Extruder Barrel
4. Extruder Hopper
5. Hopper Loader N/A
6. Mould
7. Hydraulic Motor
8. Hydraulic Pump
9. Hydraulic valves
10. Hydraulic valves
11. Hydraulic valves
12. Hydraulic valves
13. Hydraulic valves
14. Hydraulic cylinder
15. Hydraulic cylinder
16. Hydraulic cylinders
17. Hydraulic cylinders
18. Hydraulic cylinders
19. Hydraulic cylinders
20. Hydraulic cylinders
21. Servo Motor LEFT STATION
22. Servo Motor RIGHT STATION
23. Pneumatic System
24. Pneumatic FR
25. Pneumatic FR
26. Pneumatic Cylinder- CUTTER
27. Pneumatic Cylinder- VACCUM
28. Pressure gauge-
29. Pressure gauge-
30. Pressure gauge-
31. Vacuum Gauge-
32. Solenoid Valves-
33. Heater
34. Heater
35. PLC
36. Sensor-
37. Sensor-
38. VFD
Utilities
Following Utilities are required
1. Electric Supply: 415 V, 50 Hz, 72 KW.
2. Compressed Air Oil free : 6-7 Kg / cm²
3. Chilled Water : Temp. 14 – 16º c, 25 – 30 Ltr. / Min., 3.5 Kg/cm²
4. Cooled Water: Temp. 28 – 30º c, 25 – 30 Ltr. / Min., 3.5 Kg/cm²
5. Vacuum: 550 Hg/ Inch
6. WFI: 40º c, 10 Lt. / Min.
7. Pure Steam: 2.5-3 Kg/cm²
Material of Construction
1. Machine frame: SS 304
2. Panels and doors: SS 304 and Transparent Acrylic Sheet/GLASS
3. Locking Unit: SS 304
4. Bushes with wiper Seal: GM-2
5. Tie Rods: SS304
6. Product Contact Pipes: SS 316 L
7. Filling Unit: SS 316 L
8. Filling Nozzles: SS 316 L
9. Extruder Base: MS Epoxy Coated
10. Barrel Screw: EN41B
11. Extruder: CASTING
12. Hopper: SS 304
13. Mould : Aluminum Bronze
14. Machine Head: C45&EN24 With Hard Crome Plated
15. Heater: Nicron wire with asbestos cover with hot pad Insulators
16. Hydraulic Oil Tank: MS Powder Coated
17. CIP / SIP System: SS 316 L
18. Cooling & Vacuum Line: SS 304
Process Description
The virgin approved LDPE Granules extruded through barrel by a barrel screw.
During extrusion Granules are heated by different heating zone
The heated granules are melted and flow like liquid and reaches to head and then to torpid, where it is passes to five different chambers and flow to die punch and form as tubes.
The tubes are collected by mold and blow by sterile filtered air and form the Bottles inside the mold
The QA released product is collecting to the buffer tank and is filtered through 0.2μ cartridge filter and fill in the bottles formed in the mold.
After filling of the product at desired volume the bottles are sealed inside the mold.
The filled and sealed bottles have come out from the mold and passes through the conveyer to the collection area.
The entire formation of bottle, filling of the product and sealing are in aseptic condition under LAF.
The Machine operated at an environment of Class C as per WHO GMP.
Safety Measures
The entire machine operation is under closed conditions and is covered with panels and doors.
All the functions are interlocked, and if any mal function happened the machine will stop automatically.
Emergency stop button and alarm is provided with HMI and in Panel frame.
All the electrical components are highly insulated and covered.
All the heaters are insulated and covered.
Proper earthling is provided from the control electric panel Operator assesses are functioning with 24V DC Supply
Factory Acceptance Test
Factory Acceptance test is as per the URS and Design drawing and as per the Design qualification.
After the completion of machine as per Design qualification, the client shall be informed for factory acceptance test.
During the factory acceptance test client can test the machine as per URS and design qualification.
Factory acceptance test consists of
1. Design of machine as per the drawing submitted.
2. Interlock and safety measures provided
3. Specifications of Components fitted with machine
4. Functioning of FFS machine
5. Test run of the machine
6. Trial product run and bottling
Reference Documents
1 Material of construction, test certificates
2. Calibration certificates of required components
3. Test Certificates of Motors
4. Lay out drawing of BFS Machine
5. Drawing of Product flow
6. Drawing of CIP and SIP System
7. Instruction Manual of PLC
8. Aseptic area Validation certificates.
a. HEPA Integrity Test Certificate
b. Particle count test certificate
c. Air Velocity test certificate
Abbreviations used
LDPE : Low Density Poly Ethylene
FFS : Form Fill Seal
CGMP : Current Good Manufacturing Procedures
WHO : World health organization
SOS : Scope of Supply
V : Voltage
AC : Alternate Current
DC : Direct Current
SS : Stainless Steel
PLC: Programmable Logic Control
Kw : Kilo Watt
Hz : Hartz
Kg : Kilogram
FAT : Factory Acceptance Test
URS: User Requirement Specification