Application of combo filling line for vaccine sterile

production
Paddy . Peng

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 1 The existing problems

2 How to solve the challenges

CONTENTS 3 Detailed introduction of solution

4 How to control risks

5 Case study

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1 The existing problems

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Multiple containers are used for vaccine small volume injections just now,

such as ampoules, vials, prefilled syringes, cartridges, and so on…

Different container needs different machines to filling product, such
as:
Ampoule filling line
Vials filling line
Syringe filling line
Cartridge filling line
……

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If one vaccine factory have many breeds vaccine being manufacture and filling into
different container.
So drug factory had to build several factory and buy several different filling line to filling
product into different container.
It is means more money, longer time, and low efficiency…

Actually, factory needs such a machine—automation，flexible，stable operation，

safety，Small batch，quick turnover, compatible for product R&D and commercial
production

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2 How to solve the challenges

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Combo Filling Line —
One filling line could filling multiple containers

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 Combo Filling Line —
➢ Smaller footprint
➢ Smaller clean room
➢ Lower clean room grade ( > EU grade D / IOS 8 )
➢ Decrease time to market
➢ Reduce cost

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 Combo Filling Line could used for
✓ R&D batch (liquid＜10,000 pcs/batch, lyophilizer ＜1㎡)
✓ Clinical batch (liquid＜30,000 pcs/batch, lyophilizer ＜5㎡)
✓ Mass batch (liquid＞90,000 pcs/batch, lyophilizer ＞5㎡)

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 Combo Filling Line could used for
✓ Vaccine (common )
✓ Vaccine (toxicity)
✓ Vaccine (Active)
✓ Vaccine + adjuvant (suspension)
✓ Vaccine + adjuvant (viscose)
✓ Vaccine + adjuvant (oily)
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➢ Combo filling line is a aseptic filling line integrated
with full sealing isolator
➢Combo filling line is specially designed for small
scale injection filling. It can be used for R&D, clinic
trial and commercial production
➢ Combo filling line is suitable for vaccine, Mabs,
recombinant protein’s filling, and also suitable for the
aseptic filling for toxic drugs, such as cytotoxin, live
virus

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3 Detailed introduction of solution

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1. For R&D and Clinical batch (liquid＜10,000 pcs/batch, lyophilizer ＜1㎡)

◆ For small batch

◆ Choose ready-to-use
containers will better
（Cancel wash machine and Tunnel ）

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1. For R&D batch (liquid＜10,000 pcs/batch, lyophilizer ＜1㎡)
De-lid&liner Filling and closing Filling pump Buffer tank
Combo Filler

For Syringe

For Cartridge

For R&D

HMI Center part system Vibration bowl

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1. For R&D batch (liquid＜10,000 pcs/batch, lyophilizer ＜1㎡)

Mini KUFill
For RTU tray vial
For R&D

Processing Machines
Pass-box with VPHP Filling and Closing Freeze Drying Capper External Washer
Package

RTU Tray Vials —

√ √ √ √
(Aseptic)

RTU Tray Vials

√ √ √ √ √
(Aseptic and Containment)

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2. For Clinical batch (liquid＜30,000 pcs/batch, lyophilizer ＜5㎡)
Combo Fill Line(Two in one)

Process machine De-lid & liner

De-bagging machine Filling and stoppering De-nest ing Capping
Container type machine

RTU Syringe √ √ √ — —
RTU nest
RTU Cartridge √ √ √ — —

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2. For Clinical batch (liquid＜30,000 pcs/batch, lyophilizer ＜5㎡)
Combo Fill Line (Three-in-one)

Process machine De-lid & liner

De-bagging machine Filling and stoppering De-nest ing Capping
Container type machine

RTU Syringe √ √ √ — —

RTU nest RTU Cartridge √ √ √ — —

RTU Vial √ √ √ √ √

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2. For Clinical batch (liquid＜30,000 pcs/batch, lyophilizer ＜5㎡)
Combo Fill Line (Four-in-one)

Process machine De-bagging De-lid & liner Filling and De-nest Loading & Outer wall
Freeze dryer Capping
Container type machine machine stoppering machine unloading cleaning

RTU Syringe √ √ √ — — — — —

RTU RTU Cartridge √ √ √ — — — — —

nest

RTU Vial √ √ √ √ √ √ √ √

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 Combo Filling Line Capacity
Packaging Nest Capacity (per hour)
specification
material specification PFS 1000 PFS 2000 PFS 5000 PFS 10000
0.5ml 160 1000 2400 5200 9200

1ml 100 900 2100 4500 8000

Prefilled 3ml 100 760 1700 3800 6800

syringe 5ml 64 670 1570 3800 6000

10ml 42 360 840 3300 3200

20ml 30 220 520 1800 2000

2R 120 1000 2200 5000 9000

4R 120 850 1870 4200 7600

6R 48 420 930 2100 3800

Vial
8R 48 300 800 1500 2600

10R 48 300 800 1500 2000

20R 25 150 400 3000 1000

Cartridge 3ml 100 760 1700 5000 6000

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The filling line integration by Stand Alone Machine as following:
De-bagging machine: FB0102
De-lid & liner machine: FL0202
Filling and stoppering machine: FS0102、FS0202、FS0205 、FS0210
Nested vial de-nesting machine: FN0101
Vial capping machine: FCVC 0501
Containers specification:
Prefilled syringe: 0.5ml, 1ml long, 1ml, 2.25ml, 3ml, 5ml, 10ml, 20ml
Vial: 2R, 4R, 6R, 8R, 10R, 20R
Cartridge: 3ml
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3. For Mass batch (liquid＞90,000 pcs/batch, freeze dryer ＞5㎡)

Syringe RTU

Container Cartridge RTU

Vial Bulk

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3. Combo Filling Line (liquid Bulk Vial & RTU Syringe & RTU Cartridge)
RTU syringes & cartridges

Bulk vials

Process De-bagging De-lid & liner Washing Filling and

Tunnel Capping
machine Container type machine machine machine stoppering
RTU syringe √ √ — — √ —
RTU nest RTU Cartridge √ √ — — √ —
Bulk Vial — — √ √ √ √
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3. Combo Filling Line (Freeze dry Bulk Vial & RTU Syringe & RTU Cartridge)
RTU syringes & cartridges Bulk vials (Freeze dry)

Bulk vials (liquid)

Auto-
Process machine De-bagging De-lid & liner Washing Filling and
Tunnel loading & Freeze dryer Capping
Container type machine machine machine stoppering
unloading
RTU syringe √ √ — — √ — — —
RTU nest RTU Cartridge √ √ — — √ — — —
Bulk Vial — — √ √ √ √ √
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4 How to control risks

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Risk 1. Cross-contamination of different drugs
Use same machine to filling different vaccines production, cross-contamination is a big problem.
In addition to carefully cleaning and validating the cleaning results, we recommend that:
✓ Avoid the production of two of mutually affected drugs on the same machine
✓ Available for using single-use drug solvent bag instead of stainless steel buffer tank to
decrease cross-contamination risk and validating work
✓ peristaltic pump can be used, no need online or offline sterilization after the end of production
✓ If rotary piston pump need be used, you can choose to equip two sets piston filling pump

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 Single-use filling system introduction

产品料液袋
Flexboy

夹子Pinch clamp

连接器
Sterile connector

Y-Dispensers
Filling heads
Y型-分配器
灌装针头

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Risk 2- Product is oxidized
If the product is lower anti-oxidation abilities, oxygen content should be control.
The method we can take:
✓ Fill the buffer tank with nitrogen to separate the surface of the liquid and the air
✓ Nitrogen flushing when filling product
✓ Nitrogen flushing before stoppering
✓ Vacuum stoppering

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Risk 2- Product is oxidized
Comparison of the size residual bubbles after stoppering for syringe

Bubble size
Bubble size
＞140 microlitre
＜6 microlitre

Common stoppering Vacuum stoppering

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Risk 2- Product is oxidized

Oxygen content detection

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Risk 3 – How to ensure the sterility of the entire filling process
At any stage, we need to ensure the sterility of the vaccine product.
For the filling and stoppering equipment, you need to pay attention to the following
points:
✓ Equipped with isolation systems that meet regulatory requirements, depending on the level of
background environment and product characteristics(Grade B or grade C/D? Toxicity？)
✓ The inside of isolator chamber is design for easy cleaning
✓ Configuring particle and microbial detection systems in isolator
✓ All of parts contacting with product, containers’ inner surface and stoppers need to be sterilized
✓ Gas pipelines can be sterilized or aseptic

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5 Cases Study

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Case 1 Mini Combo Fill Line-PFS 1000M France project, Syringe and vial, Isolator, CMO
Toxic product, Gread D, Area 14㎡

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Case 2 Mini Combo Fill Line- PFS 2000M Malaysia project, Syringe +Vial +Cartridge

◆ Biopharmaceutical
◆ Toxic
◆ Isolator
◆ Lyo (0.5㎡) for vials
◆ Filling room 51.82 ㎡
◆ Lyo room 16.14㎡
◆ Processing room 10.71㎡

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Case 3：Combo Fill Line- PFS 5000 Netherlands project, Syringe +Vial +Cartridge

◆ Biopharmaceutical
◆ Toxic
◆ Isolator
◆ Four in one
◆ Lyo (2㎡) for vials
◆ Room size 14.1m*5.8m

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Case 4：Super Fill Line- PFS 36000 Chendu OLYMVAX project, Syringe, ORABS

◆ Vaccine
◆ 0.3 Billion per year
◆ ORABS
◆ De-baging room 13.5 ㎡
◆ Filling room 48.96 ㎡
◆ Outfeed room 12.71㎡

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Contents review

1. The problems faced by the R&D, pilot and small-scale production of

macromolecular drugs: the need for flexible production equipment, saving
upfront capital investment
2. How to solve the problem: use Combo Fill line
3. Combo Fill line is compatible with a variety of packaging materials, but based
on RTU Nest/Tray packaging materials

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