Sterile Department:

Sterilization:

Sterilization can refer to the elimination of microbiological organisms to achieve asepsis,

a sterile microbial environment.

ARISTOPHARMA's Sterile Production Facilities:

Class 100 Clean Room:

The specification of class 100 clean room is that airborne particle ≥0.5 µm in size do not
exceed 100 in number per cubic feet area. This is essential for sterile production. The
clean room is maintained by HEPA filter & laminar air flow.

HEPA (High Efficiency Particulate Air) filters:

HEPA (high efficiency particulate air) filter is installed at terminal points so that only
HEPA filtered air can enter the clean area. HEPA filters can remove at least 99.97% of
airborne particles of 0.3 µm in diameter.

64
Laminar Air Flow:
It is generally defined as airflow in which the entire body of air within a confined area
moves in essentially unidirectional velocity along parallel flow lines. The filtered air may
be directed vertically or horizontally across the work area. This laminar flow of clean air
protects materials in the work area from particulate and cross contamination.

Room Construction:
All walls & ceiling of the plant are made of Sandwich panels giving a smooth & easily
cleanable surface free of cracks or crevices. The floors are coated with Self-leveling
Epoxy (SLE) to provide a hard impact & chemical resistant surface. All corners between
the floor, walls & ceiling are finished with PVC coving to prevent the accumulation of
debris & moistures.

Uninterrupted Power Supply:

An automatic gas generator is installed in this plant, which provides uninterrupted
power supply to maintain smooth operations of HVAC and machineries of this
ultramodern plant.

Product in Sterile Department:

There are two types of product are produced in sterile department.

1. Injectable products
I. Powder for injection
II. Lyophilized injection

2. Prefilled syringe

3. Eye drops
I. Eye solution.
II. Eye suspension
III. Eye emulsion

4. Eye gel

5. Eye ointment

65
Injectable

ARISTOPHARMA is a leading pharmaceutical company in Bangladesh and leading to

produce ophthalmic product in Bangladesh. ARISTOPHARMA is now manufacturing
different types of sterile dosages form including Ophthalmic Eye drop, Eye Ointment,
Eye Cream, Nasal Drop, Ear Drop as well as IV and IM injection and recently included
lyophilized product. At recently they are going to launch their MDI and Insulin product.
They have a future plan for manufacturing of amino acid product.

Commonly the small volume Parenteral or Injectable products are filled in-

 Ampoules
 Vials

Generally the products are manufactured by two ways:

 Aseptically Sterilized
 Terminally Sterilized

Injectable Products Filling in Ampoule:

Injectable products are dispensed in ampoules according to the following procedure-

Ampoule De-boxing

Ampoule washing

Sterilization

Ampoule filling (under laminar air flow, LAF)

66
 

Ampoule Sealing

Terminal Sterilization were applicable

Ampoule Inspection

Sealed Ampoules & blister packaging

Process Flowchart of Aq. Injection manufacturing:

Washing of empty ampoules

Slogging under LAF

Sterilization & Depypozenation

Slogging under LAF (cool room)

Aseptic Transportation to filling room

Slogging under LAF

67
 Filling (4 headed) filling Aseptic filtration

Sealing Compounding

TS

Slogging RM Dispensing

Quarantine

Visual Inspection

Blistering

Cordoning

Ampoule Washing:

Sequence of “ampoule wash” by Ampoule Washing Machine is following

Purified water (inner-outer) → Distilled water → Compressed air spray → WFI

Figure: Flowchart of ampoule washing

Ampoule Filling & Sealing Process Flow Chart (under laminar air flow):

Ampoule on the filling belt

68
 N2 pugging  Filling  N2 pugging  sealing by flame  Ejection

Figure: Flowchart of ampoule filling

Different Sterilization Techniques & their uses:

Sterilization Technique Temperature Exposure Time Pressure Uses

( 0C ) (Bar)

180 2 1.1 Vials

Dry Heat Sterilization 220 2.5 1.1
(DHS) 250 1 1.1
Ampoules, Filters,

Steam Sterilization
121 15-35 minutes 1.1
/Autoclave
Figure: Different sterilization techniques

Production process flow:

The processes are done in fully aseptic area. Manufacturing of injectable preparations
require a clean room which should have the following standard

Class Cfu/m3 Particle of 0.5 micron/ft3 Particle of 5 micron /ft3

100 <1 NMT 100 0

1000 NMT 10 NMT 1000 NMT 7

69
10,000 NMT 100 NMT 10,000 NMT 70

1,00,000 NMT 1,00,000 NMT 700

Table: Clean Room Classification (ISO)

Another classification is as follows

Area Clean room standard

Filling point (A) 100

Filling room (B) 1,000

Vial washing & sterilization loading room 10,0000

Filling room corridor 10,000

Fabrics change room 10,000

Dress Changing Room 1000

Table: Clean room Classification (FDA)

Flow Chart of Sterile Process:

RM Dispensing

Compounding

Aseptic Filtration

70
 Staging for Filling

Filling Line 4 nozzles filling, stoppering

Vials Capping

Quarantine

Visual Inspection

Labeling

Blistering

Cordoning

71
Figure: 100 Room

1000 Room

72
Figure: Automatic steam sterilizier

Figure: Dry Heat Oven

73
Prefilled Syringe

The last two decades saw an increase in the administration of parenteral drugs by pre-
filled syringes. Usage of pre-filled syringes are increasing with the technological
development in devices used for administering sophisticated drugs. Self–filling syringe is
not only a slow process but also has the chance of incorrect dosing and spillage. The key
benefits of Pre-filled syringes (specialized delivery technology) are:

 Easy & convenient in use

 Time savings in emergency situations

 Dosing accuracy or reduced medication error

 Increased assurance of sterility

 Easy storage & disposal

 Eliminates the chance of vial overfill

 Reduced chance of cross infection or neddlestick injury

ARISTOPHARMA's pre-filled syringe:

 Intravas-40 IM/IV injection: Enoxaparin Sodium 40 mg

 Intravas-60 IM/IV injection: Enoxaparin Sodium 60 mg

 Intravas-80 IM/IV injection: Enoxaparin Sodium 80 mg

 Nipotin 2000, 3000, 4000. 5000 & 10000 (New Proposal)

74
Ophthalmic

Aristovision, the Ophthalmic division of ARISTOPHARMA LTD. started operation in 2002

with the commitment to infuse vision into the people and turn the idle hands of the
society to working hands. It is now the leader of ophthalmic products in the drug market
of Bangladesh. The present market share of Aristovision is around 30%. It is the first
Bangladeshi company to export its ophthalmic products to developed country like Hong
Kong. Moreover, ARISTOVISION's products are exported to Singapore, Hong Kong, Sri
Lanka, Myanmar, Vietnam, Macau, Jamaica, Nigeria, Somalia, Philippine, Maldives & Fiji
regularly and many more countries are in pipeline. In Myanmar it is no. 1 in ophthalmic
market among all local & foreign companies.
In sterile manufacturing, environment plays a key role in production of quality
ophthalmic products. ARISTOPHARMA maintains a strict aseptic environment
conforming to the WHO cGMP guidelines and other international regulatory
requirements. ARISTOPHARMA is proud to having an international standard sterile
manufacturing zone and backup utilities with fully automated machineries. The facilities
include laminar air flow module, microbial monitoring device, automatic cleaning
machine, automatic filling machine, double door autoclave for sterilization, continuous
data monitoring device etc. Most importantly it has a state-of-the-art plant for WFI, the
injectable grade water since most of the eye formulations require quality of water that
can only be made by this type of special & high tech WFI plant of European origin.
Aristovision has the facility to manufacture all types of ophthalmic products like Drops,
Gel, Solution, Emulsion & Ointment for treating ocular infections, inflammation, allergy,
dry eye, glaucoma, age related macular degeneration and other eye diseases and
disorders.

Salient Features of ARISTOPHARMA's Ophthalmic Products:

 Largest portfolio: ARISTOPHARMA has the largest range of ophthalmic products

among all ophthalmic companies in Bangladesh. Currently it has around 80
products in its portfolio, which cover almost all therapeutic categories of
ophthalmic medications.

 Manufacturing facilities: Ophthalmic products of ARISTOPHARMA are

automatically filled, sealed and labeled up to ensure world-class standard. This

75
 high precision ophthalmic unit makes ARISTOPHARMA distinctive and enviably
proud.

 Vanishing preservative & preservative free formulation: Considering the safety

issue ARISTOPHARMA has taken an initiative to manufacture some of its
products with vanishing preservative like Sodium Perborate, Ascorbic Acid etc.
for the first time in Bangladesh. Some products are also manufactured as
preservative free.

 Imported bottles: ARISTOPHARMA uses high quality imported bottles for its eye
drops. These bottles are easy to squeeze & ensure uniformity of dosing in each
drop.

 Buffer system & pH: ARISTOPHARMA ophthalmic products are manufactured

with appropriate buffering agent to maintain pH similar to ocular pH and stability
of the drug.

 Osmotic pressure: ARISTOPHARMA ophthalmic products ensure exact degree of

osmotic pressure to minimize stinging, burning sensation, itching which are
common in conventional eye drops.

76
 LYOPHILIZED PRODUCT
________________________________________________________________________

Lyophilization is a process which extracts the water from foods and other
products so that the products remain stable and are easier to store at room
temperature (ambiant air temperature).

Lyophilization is carried out using a simple principle of physics called sublimation.

Sublimation is the transition of a substance from the solid to the vapor state, without
first passing through an intermediate liquid phase. To extract water from products, the
process of lyophilization consists of:

 Freezing the product so that the water in the product becomes ice;
 Under a vacuum, sublimating the ice directly into water vapor;
 Drawing off the water vapor;
 Once the ice is sublimated, the products are freeze-dried and can be removed from
the machine.
Lyophilization process is also known as freeze-drying process. The
freeze-drying process typically, the lyophilized product is frozen at
a temperature well below the eutectic p o i n t . There are four

77
stages in the complete drying process: pretreatment, freezing,
primary drying, and secondary drying. The machine in
ARISTOPHARMA is from Tofflon, USA.

Lyophilized products manufactured at Aristopharma plant are:

 Omep 40 IV injection - Omeprazole 40 mg

 Emep 40 IV injection - Esomeprazole 40 mg

 Proton P 40 IV injection - Pantoprazole 40 mg

 Asimax Injection

L YOPHILIZATION PROCESS
1. Pretreatment
Pretreatment includes any method of treating the product prior to freezing. This may
include concentrating the product, formulation revision (i.e., addition of components
to increase stability and/or improve processing), decreasing a high vapor pressure
solvent or increasing the surface area Methods of pretreatment include: Freeze
concentration, Solution phase concentration, Formulation to Stabilize Reactive
Products etc.

2. Freezing

Freezing is usually done using a freeze-drying machine. In this step, it is

important to cool the material below its triple point, the lowest temperature at which
the solid and liquid phases of the material can coexist. This ensures that sublimation
rather than melting will occur in the following steps. Freezing is done rapidly, in order to
lower the material to below its eutectic point quickly, thus avoiding the formation of ice
crystals. Usually, the freezing temperatures are between −50 °C and −80 °C. The freezing
phase is the most critical in the whole freeze-drying process, because the product
can be spoiled if badly done.

78
3.Primary drying

During the primary drying phase, the pressure is lowered (to the range of a few

millibars), and enough heat is supplied to the material for the water to sublime. In this
initial drying phase, about 95% of the water in the material is sublimated. This
phase may be slow (can be several days in the industry), because, if too much heat is
added, the material’s structure could be altered.

In this phase, pressure is controlled through the application of partial vacuum.

Furthermore, a cold condenser chamber and/or condenser plates provide a surface(s)
for the water vapor to re-solidify on. Condenser temperatures are typically below
−50 °C (−60 °F).

3. Secondary Drying
The secondary drying phase aims to remove unfrozen water molecules, since the ice
was removed in the primary drying phase. In this phase, the temperature is raised
higher than in the primary drying phase, and can even be above 0 °C, to break any
physico-chemical interactions that have formed between the water molecules and the
frozen material. After the freeze-drying process is complete, the vacuum is usually
broken with an inert gas, such as nitrogen, before the material is sealed

At the end of the operation, the final residual water content in the product is
extremely low, around 1% to 4%.

4. Filling
Lyophilized products are filled by three stages. One stage has included filling of vials
and stoppering on line; another stage included filling of vials, transportation to the
lyophilizer and then stoppering; a third stage included the filling of vials, loading in
the lyophilizer, and exposure to a portion of the nitrogen flush and then
stoppering. Since lyophilizer sterilization and sterilization of the nitrogen system
used to backfill require separate validation, media fills should primarily validate the
filling, transportation and loading aseptic operations.

79
T ESTING OF L YOPHILIZED P RODUCTS

There are several aspects of finished product testing which are of concern to the
lyophilized dosage form. These include

 Uniformity of dose
 Moisture and stability testing
 Sterility testing of the product.

T HE ADVANTAGE OF L YOPHILIZATION

 Ease of processing a liquid, which simplifies aseptic handling

 Enhanced stability of a dry powder
 Removal of water without excessive heating of the product
 Enhanced product stability in a dry state

D ISADVANTAGES OF L YOPHILIZATION

 Increased handling and processing time

 Need for sterile diluent upon reconstitution

 Cost and complexity of equipment

Process of lyophilization

Shelf pre-cooling

Pre-cooling

Condenser cooling

80
 Chamber evacuation

Primary drying

Pressure rise test

Vac breaks stopped

Shelf cooling

MACHINERIES USED IN LYOPHILIZATION PROCESS

Machine Name Capacity Origin

Insert Folding Machine 1000/hr. China

Automatic Labelling 3000-3500/hr. India

Machine

Blister Machine 2160/hr. Korea

Automatic eye drop filling, 4000/hr. India

overcaping machine

Automatic filling machine 2000/hr. Korea

Insulin filling and sealing -

machine

Lyophilizer 10,000 vessel China

Ampoule filling machine 4200/hr. -

81
Liquid vial filling and sealing 4300/hr. China
machine

AXOMATIC eye gel filling 2200-2500/hr. Korea

machine

Figure: Lyophilization machine

82