Report on In Plant Training In Beximco Pharmaceuticals (Part-6)

Infusion Unit: Large Volume Parenteral Formulations

Beximco Pharma’s intravenous (IV) fluid manufacturing plant may be regarded as one of the most technologically advanced plants in the world. The plant was designed and installed in collaboration with Pharmaplan of Germany, a sister concern of Fresenius AG of Germany.

In designing the whole process, special care has been taken by providing absolute sterile manufacturing conditions. The prime feature of the process is that there is no human physical contact with the product at any given time. This has been ensured by way of a series of fully automated manufacturing procedures including robotics. The bottle pack aseptic system (Form-Fill-Seal or FFS) is a unique and innovative manufacturing technology. Plastic bottles are blow moulded, filled with the solution and sealed under sterile conditions, in a single working cycle where there is no environmental exposure or human contact during manufacturing. The IV fluids are presented in a scientifically designed bottle where there is an extra protective eurohead cap and a resealable rubber disk. The whole process is performed in a class 100 clean room. The air inside this room is cleaned up to 100 particles per cubic feet passing it through HEPA (High Efficiency Particulate Air) filters.

Thus, an advanced sterile environment is maintained in manufacturing the IV fluids in order to avoid the entry of bacteria, pyrogen and inert particles into products. This ensures the highest standards of quality and purity in order to ensure the highest level of safety.

Water Treatment Process

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Manufacturing and Packaging Steps

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HVAC System

The HVAC system means Heating ventilation and Air conditioning system. The main objective of HVAC system is to maintain a constant temperature and a constant RH in the infusion production area, microbiology laboratory and the office rooms. It is the most modern concept of air conditioning which is the most special features in the infusion unit. HVAC is needed in Pharmaceuticals:

  1. To maintain specified temperature.
  2. To maintain specific relative humidity. (Less than 40% for some hygroscopic material like ranitidine).
  3. To remove dust particle from production area.
  4. To maintain proper airflow to the rooms ensuring that cross contamination does not occur.
  5. To prevent microbial contamination in some area by maintaining particle size within the tolerance range. (Using the HEPA Filters etc).

The process is maintained in the different area by controlling the air pressure (positive and negative).

Microbiology Laboratory

According to the ICH guidelines the microbiological test of raw materials and finished product is an important parameter of the quality drug.  Accordingly the Infusion unit has a special microbiology laboratory in order to carry out the microbiological tests of several sensitive products.

The microbial test program includes the following:

  1. Test of raw material and packaging material.
  2. Test of finished product
  3. Environmental control
  4. Purified water test
  5. Monitoring of surfaces
  6. Personnel hygiene

The microbiology laboratory of contains the following separate rooms:

¨Testing room & Incubation room:

¨ Media preparation room:

There is also a store room to store the reagents, cultures, standard microbes, chemicals and other testing instruments in a required condition

The total testing procedure can be summarized as follows:

Sample collection

Media preparation

Culture preparation

Incubation

Colony count

Identification

Final result

1. Test of Raw and Packaging Materials

Microbial limit test is performed which include:

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1)Total aerobic viable count

2)Total aerobic bacterial count

3)Total fungal count

4)Presence or absence of Pathogens (E.coli, Salmonella sp. , P. aeruginosa, S. aureus)

Microbial Limit Test for Raw Materials and Finished Products (USP)

2. Test of Products

Bioburden check of intermediate products. It is done with the help of membrane filtration method. First 4 and last 4 bottles are tested for microbes.

Sterility test. 20 bottles of products are collected from critical points of the autoclave and are incubated for 14 days and observed.

Bacterial endotoxin test/ LAL test. It is an in-vitro test method for pyrogen. It has been developed utilizing the gelling property of the lysate of amoebocytes of limulus polyphemus. The flow diagram of LAL test is given below:

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3. For the Environmental inspections following tests are performed

i) Settle Plate Method

ii) Air Sampler

4. Purified Water Test

It is done by membrane filtration method. Water is tested from 12 different points daily and 18 different points weekly.

5. Monitoring of surfaces

It is performed by:

i)Contact Plate Method

ii)Swap Test

6. Monitoring of personnel hygiene

Hands, gloves, appearances/clothes are tested by contact plate method.

List of Instrument of Infusion Unit

Sl.

Name of Instrument

Manufacturer/ Supplier

Origin

Uses

1

Deep Tube-well

Aeration Chamber

Sand Bed Filter

Sigma Eng.BangladeshRaw water, supplied water for DM plant

2

Raw water reservoir (Overhead tank – 5000L)Beximco Infusions Ltd.  

3

Dosage station for chlorine with pump and containerLMI MILTON ROYUSAKilling microorganisms

4

Filter housing for raw waterPall  

5

City water tank (2000L)Beximco Infusions Ltd.  

6

Booster pumps (3000L/H)GrundfosGermany 

7

Activated carbon filter (1100L)Hager + Elsasser, GmbHGermanyReplace organic substance from water and declorinate water for DM plant area

8

Filter house (2.5μ)Pall  

9

Filter house (0.22μ)Pall  

10

Demineralization plants (1 and 2) (Anion and cation exchanger)Hager + Elsasser, GmbHGermanyProduction of DM water for distillation plants, boiler etc.

11

Mixed bed filter (3.5m3/h)Hager + Elsasser, GmbHGermanyPolishing DM waters

12

Filter housing (0.22μ)Pall  

13

Filter housing (0.22μ)Pall  

14

Regeneration and neutralization system (9000L)Pharma PlanGermany 

15

DM water tank (4870L)Pharma PlanGermany 

16

Distillation Plant 01EKSTROM & SONSSweden 

17

Distillation Plant 02KEMITERM ENGNEERING A/SSwedenProduction of WFI and pure steam

18

Distillate Storage Tank 01 (7000 L)Pharma PlanGermany 

19

Distillate Storage Tank 02 (7500 L)GetingeSweden 

20

Steam Boiler (2.6 T/H)StandardKesselGermanyProvide Technical steam

21

Oil Free Air Compressor 01 & 02Mehrer Operating electronumeric valves & preparing sterile compressed air

22

Water Chiller 01Finetee CenturyKoreaSupply chilled water for HVAC & Production

23

Water Chiller 02Linde AktiengesellschaftGermanyDo

24

Water Chiller 03Kyungwon-Century Co. Ltd.South KoreaDo

25

Air Handling Unit 01 & 02MEISSNER & WURSTGermanySupply & maintain clean class, positive air pressure

26

Cooling Tower 01Linde AG, MainzGermanyProvide cooling air

27

Cooling Tower 02BSCSingaporeProvide cooling air

28

Injection Moulding MachinePO Yuen (To’s) Machine FactoryHong KongProduce Cap

29

Preparation Tank 01 & 02Pharma PlanGermany 

30

Preparation Tank 01 & 02GetingeSweden 

31

Fully Automatic Bottlepack  Machine for 1000ml & 100ml BottlesRommelagGermanyBottlepacking

32

Cap Welding Machine for 1000ml & 100ml BottlesPharma PlanGermanyCap welding

33

Fully Automatic Bottlepack Machine for 500ml & 250ml BottlesRommelagGermanyBottlepacking

34

Cap Welding Machine for 500ml & 250ml BottlesPharma PlanGermanyCap Welding

35

Spray Type AutoclaveSauter-SulgenGermanyAutoclaving

36

Spray Type AutoclaveGetingeSwedenAutoclaving

37

Pressing Conveyor BeltPharma PlanGermanyLeak testing

38

Conveyor BeltPharma PlanGermanyConveying

39

Visual checking Devices   

40

Conveyor BeltPharma PlanGermanyConveying

41

Labeling Machine with Batch No. PrinterPharma PlanGermanyLabeling

42

Ink Jet PrinterImageFrancePrinting on Overpack

Engineering Department

Major functions

The main aim of this dept is to support the production department for smooth running. Machineries of this department are of 2 types-

  1. Production machinery
  2. Utilities

A. Operation & maintenance of utility machineries are as follows:

a)      Power supply

b)      water system

c)      Steam

d)      Central compressor

e)      Central air conditioning system

f)       Dehumidification

g)      Fork lift

h)      Hand pallet truck

i)        Vacuum cleaner

j)        Gas

B. Maintenance of production machinery.

a)      Scheduled maintenance

b)      Troubleshooting or breakdown maintenance

C. Maintenance of Q.C machinery.

Utility Machineries

Power station

Machines

Name

Origin

Capacity

Generator-1WAUKESHAU.S.A920   KW
Generator-2CATERPILLARU.S.A1020 KW
Generator-3WAUKESHAU.S.A900   KW
Generator-4WAUKESHAU.S.A900   KW
Diesel generatorDETROIT DIESEL ALLISON  

 

Primary Requirements to run through Gas engine in the power station:

  •   Gas
  •   DM Water
  •   Soft Water
  •   Lube Oil
  •   Battery
  •   Compressed Air
  •   Air

Boiler  

There are 2 boiler machines.

MachinesNameOriginCapacity
Boiler-1Cleeve BrooksU.S.A.3 Ton steam/hr
Boiler-2Cleeve BrooksU.S.A.2 Ton steam/hr

Hapa Foil Printer

Model: Hapa 226

Origin: Switzerlan

Water Purifying System

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