A Report on

In-plant Training
Eskayef Pharmaceuticals Ltd.

Submitted By
Sagotom Sutra Dhar Joy
ID: UG08-33-18-033
Department of Pharmacy
State University of Bangladesh

Training Period:
(22nd August, 2022 – 11th September, 2022)
1
 LETTER OF TRANSMITTAL

Date: 11th September, 2022

Md.Abdullah Al Wahid
Executive Director - Plant
Eskayef Pharmaceuticals Limited
Murapara, Rupganj, Narayanganj-1464

Subject: Submission of Internship Report

Dear Sir,
With due respect, I like to take the opportunity to submit my internship report on In-
Plant Training program at Eskayef Pharmaceuticals Limited at your kind disposal. I
have tried to compile this internship report according to my learning that has been
obtained throughout the training period. This report has been prepared for
completing a part of my B. Pharm. program. I have put my efforts to accumulate
together, my knowledge obtained from my course works and my experience of
working at the pharmaceutical for preparing this report.
I state profound gratitude to you for examine my report thoroughly and for giving
your valuable comments. I would try with best of my knowledge to provide any
clarification regarding the report.

Sincerely yours,
Sagotom Sutra Dhar Joy
B. Pharm
ID: UG08-33-18-033
State University of Bangladesh

2
 INDEX
SL. NO. Content Page No.

1 Acknowledgement 04

2 Introduction 05

3 Warehouse 09

4 General Manufacturing Unit 16

5 Oncology Unit 27

6 Penicillin Unit 35

7 Quality Control 39

8 Quality Assurance 40

9 Microbiology 43

10 Pharmaceutical Engineering 48

11 Calibration 52

12 Validation & Documentation 53

13 HSE 55

14 Conclusion 58

3
 ACKNOWLEDGEMENT

First of all, I express my sincere and whole-hearted gratitude to Almighty Allah as I

have completed this in-plant training successfully and for giving me the opportunity
to gain knowledge and making me able to implement this knowledge for the
betterment of myself and the mankind.

Practical training is an integral part of pharmacy education for the students of

professional courses because what we learn from textbooks is not sufficient to apply
our knowledge in the practical sector. In this case, the in plant training for the
students of pharmacy in pharmaceutical industries is absolutely essential for the
fulfillment of academic knowledge.

I convey my gratitude to Eskayef Pharmaceuticals Limited authority especially to

Mr. Md. Abdullah Al Wahid, Executive Director-Plant, Eskayef Pharmaceuticals
Limited and Mr. Moniruzzaman, GM- Quality assurance, Eskayef Pharmaceuticals
Limited and Mr. Barun Kumar Roy, GM- Production and all other officers and
members of Eskayef Pharmaceuticals Limited for their permission and attention.

I wish to express my deepest sense of gratefulness to my Admin Coordinator Mr.

Md. Mizanur Rahman, Senior HR Officer and Training Coordinator Mr. Md.
Shahnewaz Khan, Senior HSE Executive for their outstanding lessons on work
ethics, and his keen supervision.

During my two weeks of training in Eskayef Pharmaceuticals Limited, I have

received lots of generous cooperation from every people at every sector. I am
extremely thankful to all the officers and staffs of the factory for treating me as part
of the Eskayef family and helping me to broaden my knowledge.

4
 INTRODUCTION

Eskayef Pharmaceuticals Ltd. is one of the largest and fastest expanding

pharmaceutical companies in Bangladesh. The company, which has its headquarters
in Dhaka (the capital of Bangladesh), is also known as SK+F and is a part of the
Transcom Group. SK+F Eskayef Pharmaceuticals Limited was born from the old
facilities of SmithKline & French in Bangladesh when the company was restructured
to form GlaxoSmithKline in 2000. Eskayef envisions a leading role for itself as a
catalyst for improvement of the healthcare environment. The company's mission is
to maintain people's health and combat disease to enhance the quality of human life
so that people may live longer, healthier and more meaningful lives. The chairman
of Transcom group planted a seed of dream in 1885. As the years went by the seed
began to grow and soon turned into a fullgrown tree with its leaves branching out in
innumerable ventures.
Today, TRANSCOM is one of the leading conglomerate companies of the country.
The dream has turned into reality by the pragmatic vision of Mr. Latifur
Rahman, the Chairman of TRANSCOM GROUP and Eskayef Bangladesh
Limited and the company proudly stands symbolizing the epic tree of the seed that
was planted 120 years ago. Eskayef’s manufacturing facility has transcended the
frontiers after the accreditation of UK MHRA (United Kingdom Medicines and
Healthcare products Regulatory Agency).
Eskayef is growing more global since 2005 and exporting bulk pellets and finished
products in Asia, Africa, Central America, Europe and Australia. The company is
also tied up with the world leader in eye care solution Allergan Inc. Ireland. The
company often manufactures insulin in a world class facility which are being
exported to Novo Nordisk. Protein-X (Hormone) prepared from Popular
Pharmaceuticals Ltd. As a tool product. Beximco Pharmaceuticals Ltd. Takes
cephalosporin from here.
The company started its production of pharmaceuticals with the manufacture of
generic products for the domestic market but has since moved into bulk products
and the veterinary market. SK+F Eskayef currently manufactures and markets 28
different animal health products in 57 different dosage forms.

5
MISSION
To manufacture & supply products with quality and excellency & to contribute to
improve the population’s health & well-being.

VISION
To lead the national pharmaceutical market, to be recognized as a multinational
conglomerate from Bangladesh and stand out as a model of efficiency & trust to our
collaborators, consumers, health care professionals & society.

FACILITIES
Eskayef is now one of the fastest growing pharmaceutical companies in Bangladesh
and is engaged in manufacturing and marketing of a wide range of therapeutic drugs,
bulk pellets and animal health and nutrition products. At present, the company has
annual sales turnover of more than BDT. 4.50 billion.

Rapid business growth since its inception has propelled Eskayef to a position of
eminence among the pharmaceutical companies operating in Bangladesh today. It
manufactures and markets 126 pharmaceutical products in 294 dosage forms and
has established 22 products as the brand leader in the market. Owing to its qualified,
trained and skilled professionals and through its unswerving standards of quality
control, Eskayef is now one of the most respected names in the pharmaceutical
industry of Bangladesh.

6
QUICK OVERVIEW

Company name : Eskayef Pharmaceutical Limited

Company slogan : Excellence through quality
Company type : Private limited company
Acquisition from : SmithKline & French
Company started : 1990
Ownership : Transcom group
Factories : Mirpur, Tongi, Rupganj, Shalna
Marketing office : Taneem Square, Banani, Dhaka
Commercial dept. : Taneem Square, Banani, Dhaka
International business : Taneem Square, Banani, Dhaka
Finance & Accounts : Gulshan tower,Gulshan 2, Dhaka
AHND office : Gulshan, Dhaka
Web address : www.skfbd.com
E-mail : info@skf.transcombd.com
Employees : 4000+
Business : Formulation, Consumer, Bulk pellets, AHND
Distribution : Transcom Distribution Company Limited
Depots : 23 depots
Regions : 26 regions

7
 Manufacturing zones of Eskayef consists of
❖ Mirpur plant
❖ Tongi plant
❖ Dedicated cephalosporin block (Tongi)
❖ Rupganj plant
❖ Shalna plant

RUPGANJ PLANT
Rupganj plant is located in Murapara, Rupganj, Narayanganj-1464
Rupganj plant is divided into five distinct unit-
● General Manufacturing Unit
● Oncology Unit
● Penicillin Unit
● Penem Unit
● Cosmetics Unit

WAREHOUSE
A Pharmaceutical warehouse is a place where raw materials (RM), packaging
materials (PM) and finished goods (FG) are kept for storage according to their
storing conditions given. To accommodate huge raw materials, Eskayef Rupganj
plant currently has seven vast warehouse namely warehouse 01,02, 03,04,05,06 and
07.

⮚ Warehouse 1: Under construction for soft gel

8
⮚ Warehouse 2: The capacity of Warehouse 01 is 7, 34,000 square feet. It
maintains a Controlled room temperature below 25 degree Celsius (15-25°C)
and used for raw materials only which includes both API and excipients which
need to be stored at this temperature range. The basic functioning of
warehouse is to receive the raw materials which include both excipients and
active ingredients, properly and store in the correct storing conditions as
required. When a raw material comes to the industry it is received in the
loading/unloading bay. Here when the raw materials are brought, the materials
are checked whether the correct materials have been brought, correct amount,
manufacturing date, expiry date and from the approved source. The source is
checked by the approved source list given. After all these checking the
material is unloaded. The sample of raw material is taken and sent to Quality
control lab for testing to ensure that the identity of the product. In case of API
all the containers that is 100% checking is done and for excipients the
checking is done by using a formula-
√n+1 n= no. of container
i.e., if 100 containers are there then sample from 11 containers will be taken
and checked. But in case of propylene glycol 100% identity test is done after
the Reed Pharma Tragedy.
After these are sent for sampling these materials and before receiving they are
given R.R no and labeled QURANTINE and kept in the warehouse. If the
materials are approved form the QC then they are labeled PASSED and if not
then they are labeled REJECT. The containers from where samples are taken
after sampling labeled SAMPLED. If the materials are purchased from a local
manufacturer then they are returned before the billing happens in case the
materials are rejected but if exported then they are kept in the reject room
(located in warehouse 1) and after 3 months with proper authorization
destroyed.
There is a cool room under construction.

⮚ Warehouse 3: Raw materials of penicillin

9
 ⮚ Warehouse 4: Packaging materials of penicillin

⮚ Warehouse 5: Under reconstruction

⮚ Warehouse 6: Raw materials of Agrovet are kept here. Ambient temperature

is maintained here.

⮚ Warehouse 7: Mixture of RM & PM (Maxi. PM). This warehouse maintains

a temperature below 45°C (Ambient temperature). It is mainly used for storing
packaging materials (shippers, bottles, vials, rubber stoppers, E-cap, foil etc.).

Different units of ware house

• Quarantine Area
• Released Area
• Dispensing Area
• Finished Product Area
• Rejected Area
• Packaging Products Area
• Special Area
• QC Sampling Room
• Change Room for Warehouse Officers & Workers
• Change Room for QC Officers

The main functions of Warehouse:

• Material Receiving
• Storing

10
• Dispensing

Materials Receiving System

❖ Upon receiving the shipment’s labeling should be carefully to make sure

that they belong to the same source approval. Only materials from the
sane batch receive the same Receiving Record (RR) number.

❖ The RR is the identification number for that raw material.

❖ The shipment should be inspected visually for damage.

❖ The materials are than carefully labeled ‘Quarantine’ with the RR

number.

❖ Rejected materials should be clearly separated from the ‘released’

materials.

❖ Rejected packaging materials containing the company’s logo are

destroyed. For raw materials that are the rejected the vendor is contacted
immediately.

Storage:

➢ Raw materials and finished products are stored according to their

chemical or physical properties.

➢ Some raw materials and finished products are kept at normal room
condition.

➢ In order to prevent mix-up of printed containers and labeling materials,

each printed packaging material is stored properly identified with the

11
specific GRN number and code number and at the time issues the
identity is checked very carefully.

Working process for Raw Material & Packaging Material:

They received materials which is purchased by purchasing department

Keep record and send Sampling booth for sampling& pass label about those
materials to QC
↓
QC collects sample
↓
Perform test and provide approval or rejected tag
↓
If QC tests are passed, then supply raw materials, packaging materials, excipients
to the concerned department according to product order sheet and product
requisition in first in first out process.
↓
Keep records about that.

Working process for Finished Goods:

After packaging of final product, QA gives the NOT RELEASED yellow tag
in the shipping carton

12
 ↓
Stored in the outer portion of the ware house-2.
↓
After all the performed tests by QC are passed, they give the RELEASED
green tag removing the previous one. (If not passed, a HOLD label is given.
↓
Then these RELEASED goods are moved to the inner portion of the ware house-2
↓
According to market demand, the released products are distributed in First in first
out process to the depots.

Conditions for storage:

Storage Freeze Cold Cool CRT
Temperature <0°C 2-8°C 8-15°C 15-25°C
Relative Humidity - 20% RH 35% RH 55% RH

There is one cool room for essence and color.

Capsule room- 15.5°C-24.4°C & RH 39-61%
Ambient temperature is set at warehouse. However, for moisture sensitive
products, specific RH and RT is maintained. Three types of areas are
maintained for storing materials:

❖ Cold temperature area (2-8°C) for storing insulin, omeprazole powder

etc.

13
❖ Cool temperature area (8-15°C) for storing coloring, flavoring material
etc.

❖ Relative humidity area for storing capsule shell and other types of
blistering material.
There are 2 refrigerators. A thermohygrometer (sensor) to detect temperature and
humidity.
Software used for warehouse: ERP- Enterprise Resource Planning
Source of raw materials: Europe (40%), India (40%), China (20%) Handling of
damage materials: Use polybag (Polyethylene up to 4mm)
Cleaning: 2 times mop with detergent, jet, savlon, IPA, Dettol etc.
Packing materials: Foil for CRT, bottle, carton, blister, ampule, vial,
aluminum tube etc.

Function of warehouse:
Check list for raw materials & excipients
↓
Materials receiving & remarks the conditions
↓
● Send to quarantine zone for QC test
↓
● QC sampling → Passed
↓ ↓
Not passed Dispense for production
↓
14
 Rejected/ Back

GENERAL MANUFACTURING UNIT

(PRODUCTION)

Different types of formulations are done:

⮚ Solid dosage form (tablet, powder for suspension)

1. Losectil 20
2. Losectil 40
3. NRG
4. Jucy
5. Neosaline
6. Ridon EG
⮚ Liquid (syrup)
1. Zinc care 500ml
2. Zinc care 1000ml

Dispensing Area:

⮚ Consists of dispensing area and booth.

⮚ Both has a laminar air flow system

⮚ In dispensing room the raw materials are brought from the warehouse in the
quantity mentioned in BMR and weighed accordingly.

⮚ The excipients are weighed first then after partial change over active
ingredient is weighed.

⮚ When dispensing of another product is to be made then full changeover is

required which is ensured by the authorized pharmacist in charge.

15
⮚ In dispensing the date, quantity, pass label of the material is seen and then
dispensing is done.

⮚ Temperature and humidity checked for every 2 hours.

Temp: 19-24°C
Humidity: 45-60%

⮚ Booth contain two types of filters-

a. Pre-Mid Filter (Range: 50-380 KPa)
b. HEPA Filter (Range: 50-450 KPa)

Process:
Components

Dry mixing

Binder solution from solution tank

Wet mixing

Mix is passed through conicall mill and rotor sieve

Transferred through Fluid bed drier (Capacity- 360-1020L)

Granules crushed in multi mill

16
 Passed through sieve to required size

Dry granules

Blending in SS Bins by blender

Compression
*For different product following items are used for cleaning process
● Potable Water
● Hot Potable water
● Purified Water
● Compressed air
● 70% IPA

Only film coating is done in Rupganj plant.

Coating machine- Sejong (Korea)
Unit 1 Unit 2 Unit 3
Capacity 500 kg 300 kg 100 kg
Pan RPM 1-10 1-12 1-14
No. of Gun 7 5 2
Solution Preparation Tank 250 kg 150 kg 80 kg

Process:
Preparation of coating solution

17
 Peristaltic Pump (20-80RPM)

Flow meter (150-350/400 gram solvent per min)

Warm up cycle for drying tablets (5-15 min)

Initial spray at temperature 45-70C (15-30 min)

Final spray until solution ends

Drying at 45-65C

Cooling at 20C

Discharge

During feeding of tablets, pan is rotated clockwise but during discharge pan is
rotated anti-clockwise
Difference between spray gun and tablets should be 8-12 inches.

Packaging
1. Blister Packaging

Process:

18
 PVC Sheet

Heat (120-150 C)

Pressure in plates with dies (6 Barr)

Blisters filled by tablet

Camera detection

Sealing with aluminum top sheet by heat (190-210)

Perforation unit

Cutting into size

Secondary packaging

Secondary packaging
• It has 24 stations. Automatically fills secondary packs with blister strips and
inserts and seals it.
• Then goes through automatic weight checker

Secondary packaging

19
Oral Liquid (Suspension, Syrup etc.)
The liquid section has got 2 levels of FAHB Unit. Level 5 is for compounding.
One part is used for the production of suspension or small volume syrup and the
other part is used for the preparation of sugar syrup. Level 6 is for filling and
packaging. This level has the following machines-
• Bottle washing machine- 24 stations
• Filling station -4
• Cap sealing station -1
• Labeling machine.
The RPM of these machines are set according to the production cycle.

Process:
Dispensed RM taken to level 5 for compounding

Compounding of suspension in different vessels

Sending of Product to level 6 for filling by positive pressure

Filling in bottles

Sealing

Shrink sleeve application

Packaging or Casing

20
Operation in Tablet Section
i. After the recommendation for the production of a batch, at first the
requisition of required raw materials is sent to ware house department.
ii. QC & QA approved required raw materials of specific amount is then sent
to the dispensing unit.
iii. A list of chemicals with corresponding specific weight is hung in
dispensing unit.
iv. Accurate weighing of chemicals.
v. Remaining materials with a document containing amount used and amount
loss is returned to ware house department. vi. Mixing and granulation
Compression
vii. Coating (if necessary) Packaging and packing
viii. Each step is carried out according to Standard Operating Procedure
(SOP)
Dispensing unit:
Dispensing unit receive required raw materials which are approved by QC for
tablet preparation. It supplies materials to the granulation and coating unit after
accurate weighing according to dispensing order sheet and return the remaining
materials to store.

Granulation unit:
Granulation is the process in which the powder particles of raw materials are made
to form larger particles in order to facilitate compression for the production of
tablet.
In SK+F. the following granulation processes are used for tablet manufacturing,

21
 Methods of tablet manufacturing

Wet Granulation Dry Granulation Direct Compression

Wet granulation
This is the most widely used and most general method of tablet preparation. Its
popularity is due to the greater probability that the granulation will meet all
physical requirements for the compression of both tablets. The wet granulation of
tablet production is essentially a process of size enlargement, sticking particles of
drug and excipients together using an adhesive to produce a granular product with
improved flow properties and increased ability to cohere under pressure.

Wet granulation method is performed with the following steps in SK+F:

Accurate weighing of active ingredient and incipient
↓
Preparation of granulating paste/ slurry by suitable solvent with binder,
preservatives etc. and dry mixing of active ingredient(s), diluents etc.
↓
Wet mixing (Dry mixture + paste/slurry).
↓
Wet sieving (granulation).
↓
Drying (usually fluid bed dryer used and required moisture is maintained here)
↓
Dry sieving (granulation).
↓
Lubrication and blending
22
 ↓
Discharge (into double polythene bag & close lid of drum tightly and sent to
compression unit

Dry granulation
This process is applied for those drugs which are sensitive to moisture. This
process is also used for water sensitive powder that needs granule formation before
compression.
Steps applied for dry granulation are given below:
Weighing of drugs and excipients
↓
Dry mixing of drugs and diluents
↓
Slugging or precompression
↓
Milling and sieving
↓
Lubrication Discharge for compression

Direct compression
Tablets are produced directly from the powder by compression without modifying
the physical nature. It is done for only few selective drugs, which has crystalline
nature, e.g., KCl, NaCl etc.
In SK+F, we didn’t observe the production of tablet using this method.

23
Oral tablets coated with a layer of sugar or film are called coated tablet. The
application of coating to tablets, which is an additional step in the manufacturing
process, increases the cost of the product. Again, the coat must be dissolved before
disintegration and dissolution of the tablet.

Therefore, the advantage to coat a tablet is usually based on one or more of the
following objectives:
• To mask the bad taste, order, or color of the drug. To protect moisture
sensitive drugs from moisture.
• To provide physical and chemical protection of the drug. To control the
release of the drug from the tablet.
• To protect the drug from the gastric environment of the stomach with a
resistant enteric coating.
• To incorporate another drug or adjuvant in the coating to avoid chemical
incompatibilities or to provide
• sequential drug release.
• To improve the pharmaceutical elegance by use of special color or
contrasting printing.

Process employed in Eskayef pharmaceutical Ltd.

In SK+F, the following three processes are employed for tablet coating:
1. Film coating
a. Aqueous film coating
b. Organic film coating

1. Film coating

24
This process involves the deposition of a thin polymeric film onto tablets from
solutions that are organic solvent based or water based. Some substances used for
film coating in SK+F are mentioned bellow:
• Kollicoat (coating agent)
• HPMC
• PG or PEG400
• Titanium dioxide (increase shining)
• Purified talc (increase flow property)

Equipment used in GMU (production) :

Serial Instrument Manufacturer Origin
No:

1 Fluid Bed Dryer Nano Pharm Tech CHINA

Machinery Equipment
CO. Ltd
2 Multi Mill Chanzhou Jiafa CHINA

3 High Share Mixer Nano Pharm Tech CHINA

Machinery Equipment
CO. Ltd
4. Shifter Navector Screening CHINA
Technology CO. Ltd
5. Square Cone Huaxing Pharmaceutical Shanghai
Blender Equipment CO. Ltd
6. Multi Mill Gansons India

25
 7. Sachet Machine Sulpac korea

8. Sachet Machine Sunny Machinery Shanghai

9. Blister Machine Beijing Double Cane China

Equipment CO. Ltd
10. Liquid Filling Pharmapeck Engineering Bangladesh
Machine
11 Automatic Blister Double-crane India
Machine

ONCOLOGY UNIT

First time in the history of Bangladesh, ESKAYEF Oncology facility has been built
with the most advanced isolator technology. First time in Bangladesh
true OEL validated Oncology facility and in compliance with all the major global
regulatory authorities like FDA, MHRA, TGA, WHO and EUROPEAN MEDICINE
AGENCY. Isolator technology has been applied in every step of manufacturing
process of tablets, liquid injections and lyophilized Injections to ensure the safety of
people and to avoid Cross Contamination of Oncology Products.

OEL
An occupational exposure limit is an upper limit on the acceptable concentration of
a hazardous substance in workplace air for a particular material or class of materials.
It is typically set by competent national authorities and enforced by legislation to
protect occupational safety and health. It is an important tool in risk assessment and
in the management of activities involving handling of dangerous substances. There
are many dangerous substances for which there are no formal occupational exposure

26
limits. In these cases, hazard banding or control banding strategies can be used to
ensure safe handling.

ISOLATOR TECHNOLOGY
In the pharmaceutical manufacturing environment, a basic requirement is to prevent
contamination of a manufactured product by the environment.
Protect the Product and the Operator
In the pharmaceutical manufacturing environment, a basic requirement is to prevent
contamination of a manufactured product by the environment. Pharmaceutical
companies invest heavily in clean rooms of various grades, ventilation systems and
process equipment designed to maintain a clean environment. Indeed, humans are
the largest contributors of contamination in the entire process. The solution: place
the process out of reach of the operator, in an isolator. The isolator can be cleaned
and sterilized before use and the environmental conditions can be controlled during
the manufacturing process. Any manual interventions required can be through sealed
gloves or suits, and any materials required can enter via an ingenious transfer
isolation system, the rapid transfer port (DPTE).

Isolation technology also protects the operators and pharmacists from working with
toxic chemicals, drugs and manufactured substances.

LYOPHILISATION
Lyophilisation is a process by which material is rapidly frozen and dehydrated under
high vacuum. Lyophilization or freeze drying is a process in which water is removed
from a product after it is frozen and placed under a vacuum, allowing the ice to
change directly from solid to vapor without passing through a liquid phase. The
process consists of three separate, unique, and interdependent processes; freezing,
primary drying (sublimation), and secondary drying (desorption). Products are
manufactured in the lyophilized form due to their instability when in solution.
The advantages of lyophilization include:

❖ Ease of processing a liquid, which simplifies aseptic handling

27
 ❖ Enhanced stability of a dry powder
❖ Removal of water without excessive heating of the product
❖ Enhanced product stability in a dry state
❖ Rapid and easy dissolution of reconstituted product

The lyophilization process generally includes the following steps:

⮚ Dissolving the drug and excipients in a suitable solvent, generally water for
injection (WFI).
⮚ Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-
retentive filter.
⮚ Filling into individual sterile containers and partially stoppering the containers
under aseptic conditions.
⮚ Transporting the partially stoppered containers to the lyophilizer and loading
into the chamber under aseptic conditions.
⮚ Freezing the solution by placing the partially stoppered containers on cooled
shelves in a freeze-drying chamber or pre-freezing in another chamber.
⮚ Applying a vacuum to the chamber and heating the shelves in order to
evaporate the water from the frozen state.
⮚ Complete stoppering of the vials usually by hydraulic or screw rod stoppering
mechanisms installed in the lyophilizers.

Lyophilization process flow chart

28
FINISHED PRODUCT TESTING FOR LYOPHILIZED PRODUCTS
There are several aspects of finished product testing which are of concern to the
lyophilized dosage form. These include dose uniformity testing, moisture and
stability testing, and sterility testing.

(a) Dose Uniformity

The USP includes two types of dose uniformity testing: content uniformity and
weight variation. It states that weight variation may be applied to solids, with or
without added substances, that have been prepared from true solutions and freeze-
dried in final containers. However, when other excipients or other additives are
present, weight variation may be applied, provided there is correlation with the
sample weight and potency results. For example, in the determination of potency, it
is sometimes common to reconstitute and assay the entire contents of a vial without
knowing the weight of the sample. Performing the assay in this manner will provide
information on the label claim of a product, but without knowing the sample weight
will provide no information about dose uniformity. One should correlate the potency
result obtained form the assay with the weight of the sample tested.

(b) Stability Testing

An obvious concern with the lyophilized product is the amount of moisture present
in vials. The manufacturer's data for the establishment of moisture specifications for
both product release and stability should be reviewed. As with other dosage forms,

29
the expiration date and moisture limit should be established based on worst case
data. That is, a manufacturer should have data that demonstrates adequate stability
at the moisture specification.
As with immediate release potency testing, stability testing should be performed on
vials with a known weight of sample. For example, testing a vial (sample) which had
a higher fill weight (volume) than the average fill volume of the batch would provide
a higher potency results and not represent the potency of the batch. Also, the
expiration date and stability should be based on those batches with the higher
moisture content. Such data should also be considered in the establishment of a
moisture specification.
For products showing a loss of potency due to aging, there are generally two potency
specifications. There is a higher limit for the dosage form at the time of release. This
limit is generally higher than the official USP or filed specification which is official
throughout the entire expiration date period of the dosage form. The USP points out
that compendial standards apply at any time in the life of the article.
Stability testing should also include provisions for the assay of aged samples and
subsequent reconstitution of these aged samples for the maximum amount of time
specified in the labeling. On some occasions, manufacturers have established
expiration dates without performing label claim reconstitution potency assays at the
various test intervals and particularly the expiration date test interval. Additionally,
this stability testing of reconstituted solutions should include the most concentrated
and the least concentrated reconstituted solutions. The most concentrated
reconstituted solution will usually exhibit degradation at a faster rate than less
concentrated solutions.

(c) Sterility Testing

With respect to sterility testing of lyophilized products, there is concern with the
solution used to reconstitute the lyophilized product. Although products may be
labeled for reconstitution with Bacteriostatic Water For Injection, Sterile Water For
Injection (WFI) should be used to reconstitute products. Because of the potential
toxicities associated with Bacteriostatic Water For Injection, many hospitals only
utilize WFI. Bacteriostatic Water For Injection may kill some of the vegetative cells

30
if present as contaminants, and thus mask the true level of contamination in the
dosage form.

Oncology Products in SK+F:

1. Capcitab 500
2. Carbotor 150 & 450
3. Fenitab 200
4. Meganor 160
5. Imitab 100 & 400
6. Paclitor 30, 100 & 300
7. Pemetor
8. Flurator

Equipment used in Oncology Unit :

Serial Instrument Manufacturer Origin
No:

1 Dispensing Topleader China

Machine
2 Granulation Suite Cos-Mec Milano, Italy

3 Digital Metal Cio Italy

Detector Machine

31
 4. Compression Galileo Argentina
Machine
5. Isolator Telstar United Kingdom

6. D-Duster Belgium

7. Lypholizer Shinva China

8. Coating machine Xiaolun China

PENICILLIN UNIT

In SK+F Ltd. this unit has two parts, which are-

1. Sterile: Includes vial filling and sealing. Ampoule and vial filling and
sealing are also performed in SVP section if required. Here aseptic
condition is also maintained like SVP.Ex.
● Flucloxin 500mg(IM/IV)injection
● Augment 1.2gm IV injection
● Augment Vet 1.2 & 2.4gm(IM/SC)injection
● Aject vet injection
● Aject vet DS injection

32
2. Non-Sterile (oral): Includes tablet, dry syrup(Powder for suspension) and
capsule filling and sealing. Ex-
Tablets:
● Augment tablet (Amoxicillin+Clavulanic Acid-500mg+125mg)
● Augment Vet bolus
Dry Syrup (Powder for suspension)
● Flucoxin PFS
● SK-mox PFS
● SK-mox DS
● SK-mox PD
● Augment PFS
● Augment oral powder vet-100gm/500gm
● Eskamox-300(vet)

Capsule:
● Flucloxin 250 & 500mg
SK-mox 250 & 500mg

Tablets formation flow chart:

Weighing/Dispensing
↓
Sieving/Milling
↓
Dry powder mixing
33
 (API+Excipients)
↓
Roller compaction
↓
Milling/sizing
↓
Mixing /lubrication
↓
Compression

Dry Syrup (Powder for suspension):

This is a powder dosage form of oral drug used because the drug is unstable
in solution. It must be reconstituted before use. It is mainly sugar based
preparation. We observed the preparation of SK-mox PFS

Process:

Milling and drying of sweetener

↓
Transfer to a drum blender
↓
Sieving and addition of active ingredients and other excipients
↓
Proper mixing

34
 ↓
Bottle filling and sealing
During dry syrup preparation of moisture sensitive products, the humidity and
temperature is maintained up to 39 % and 25°C respectively if needed.

Encapsulation of fine powder:

Blending
↓
Slugging
↓
Granulation
↓
Sieving
↓
Encapsulation

Three types of packing materials are involved:

1. Primary packaging materials (in contact with products)which are
● For Blister packing Aluminum foil and PVC film
● For Strip packing Aluminum foil only
● Ampoule
● Bottle
35
 ● Vial
2. Secondary packing materials which are
● Label
● Inserts
● Inner cartons
3.Master shipper

Equipment available at Penicillin Unit :

Serial Instrument Manufacturer Origin
No:

1 Compression Shinva CHINA

Machine

2 Coating Maachine Xiaolun CHINA

3 High Share Mixer Nano Pharm Tech CHINA

Machinery Equipment
CO. Ltd
4. Shifter Navector Screening CHINA
Technology CO. Ltd
5. Square Cone Huaxing Pharmaceutical Shanghai
Blender Equipment CO. Ltd
6. Multi Mill Gansons India

7. Sachet Machine Sulpac Korea

8. Sachet Machine Sunny Machinery Shanghai

36
 9. Blister Machine Beijing Double Cane China
Equipment CO. Ltd
10. Liquid Filling Pharmapeck Engineering Bangladesh
Machine
11. Bottle Drying East China China
Pharmaceutical
Company Ltd.
12 PFS filling Shanghai East China China
machine Pharmaceutical
Machinery Co. Ltd.
13 Foiling Machine Ganson India

QUALITY CONTROL

Quality control is an essential operation of the pharmaceutical industry. Drugs

must be marketed as safe and therapeutically active formulations whose
performance is consistent and predictable. New and better medicinal agents are
being produced at an accelerated rate. At the same time more exciting and
sophisticated analytical methods are being developed for their evaluation.

According to GMP (Good Manufacturing Practice), Quality control can be defined

broadly as the regular control of quality, ensured by pharmacists and technicians,
responsible for the acceptance or rejection of incoming raw materials, packaging
components and finished products. Quality control for in process tests and
inspections to assure that systems are being controlled and monitored, are also
important. Moreover, it is the crucial part of Quality Assurance (QA).

37
Quality Control Department mainly checks the quality of 3 types of materials:
• Raw Materials (RM)
• Packaging Materials (PM)
• Finished Goods (FG)

The basic goal of quality control is to ensure that the products, services, or
processes provided meet specific requirements and are dependable, satisfactory at
the end of the operations process. In case of packaging material physical checking
is done by matching the carton size, length, width, height etc .

There are three main points during the production process when inspection is
performed:
● When raw materials are received prior to entering production

● Whilst products are going through the production process

● Before releasing finished goods

Equipment used in Quality Control lab:

Seria Instrument Manufacturer Origin
No:

1 Analytical Sartorius Germany

Balance
2 HPLC Dionex , Water USA

3 Muffle Fussace Nabertherm Germany

38
 4. Gas Parkinelmer USA
Chromatography
5. Disintegration Erweka Germany
Test
6. Tap Density Wincon Company Ltd China

QUALITY ASSURANCE

Quality Assurance department is responsible for assuring that the quality policies
adopted by a company are followed and, in most organizations, it serves as the
contact with regulatory agencies and are the final authority for product acceptance
or rejection. It also helps to prepare the standard operating procedures (SOP)
related to the control of quality
Quality assurance means the sum total of the organized arrangements made with
the object of ensuring that products will be at the quality required by their intended
use. It is thus GMP plus factors outside the scope of ISO guidelines.
The function of QA starts from raw materials and continues up to released
products. The function of QA in a pharmaceutical is given below.

39
Environment of the suppliers are also sensitive for purchasing of raw materials.
QA checks the environment before purchasing the active pharmaceutical
ingredients (API). In ware house
• Identification of raw materials (RM / PM)
• Check the quality by QC
• Orientation of raw materials.
• Orientation of packaging materials.
• QA inspection and report submission to the head of QC.
• Sampling for,
• Lab sample
• Microbiological sample.
• Retention sample.
• Released and rejection works of raw materials and packaging materials
In production area
• Before starting of manufacturing the cleaning operation or changeover
of machineries is cheeked by the Q.A.
• Line clearance.
40
• In process QC.
For solid production the following tests are done –
• Weight variation
• Hardness
• Thickness
• Diameter
• Friability
• Disintegration Test for L.C.O.-
• Weight
• Volume checking.

In aseptic area
Air particle monitoring, microbiological tests (swap test), water test and treatment
are done by microbiological department under the supervision of QA.

In packaging area
QA officer give the line clearance for starting of packaging operation after assuring
the following points:
• Absence of product of previous order.
• Absence of packaging material belonging to the previous order.
• Cleanliness.
• QA officer check the batch no. Mfg. & Expiry date.
• Random checking of blister & strip.
• Random wt. checking for cream and ointment.
• Random volume checking for liquid during filling.

41
• Check of inner and shipping cartoon.
• Evaluation and repacking of accidental damaged goods.

Equipment used in Quality Assurance for IPC test:

Seria Instrument Manufacturer Origin
No:

1 Analytical _ Mettler Toledo Switzerland

Balance
2 Friability Tester Pharma Test Germany

3 Leak Tester Pharma Test Germany

4. Hardness Taster Erweka Germany

5. Disintegration Erweka Germany

Test
6. Karl – Fisher Methrom Switzerland

7. DHS Machine Shinva China

Quality Management System

For complain handling part is based upon three areas minor, major and critical.
Depending upon the criticality of the complaint it is decided that who shall handle
the situation QA, GM or Head of Eskayef.
The Quality management system reviews documents through four areas-

42
• Assesses Deviation- When an established process is given but cannot be
followed and this comes from the production, warehouse, calibration etc. Depending
upon the criticality of the deviation it is decided who to handle it.
• Out of specification -This comes from the QC when any product shows result
out of the specification stated.
• Change Request- The change request if needed comes from production, QC,
calibration, warehouse and accordingly done after proper justification that why the
change is needed.
• CAPA (Corrective action and preventive action)- This includes immediate
action or an alarm type system is made via documentation for future perspective.

MICROBIOLOGY

Microbiology department checks for mainly microbial contamination inside the

plant. Their area of inspection includes every possible source of microorganism such
as raw materials, air, water, environment etc. They check for the source and after
identification suggest for the preventive measures. Even before any contamination
they also suggest precautionary steps that should be taken.

There are some limits defined in the compendia for micro-organisms in every place
inside the plant. Microbiology department checks for the presence of micro-
organisms if they are above this limit. Checking is done at different interval in
different conditions. If the limit is crossed abnormally, they investigate and try to
find the source. Then they give corrective measures.

Tests done by Microbiology department:

There are several tests that are done by the microbiology department- • Sterility test

43
• Limit/ Bio-burden test
• Environmental Monitoring
• Total Organic Carbon (TOC) test
• Heavy Metal Test
• Conductivity test
• Total dissolved solid test (TDS)
• Nitrate test
• Endotoxin test

Equipment used in Microbiology Department :

Seria Instrument Manufacturer Origin
No:

1 Analytical Balance _ Mettler Toledo Switzerland

2 Analytical Balance Sartorius Germany

3 Airborne Particle Counter PMS USA

4. Bacterial Memmart Germany

Incubator
Germany
5. Colony Counter Biocote UK

6. Conductometer Methrom Switzerland

44
 7. Dynamic Passbox Hiclean China

8. Heating Block Daihan Korea

9. Laminar Airflow Cabinet ESCO Singapore

10. Media Dispenser Interscience France

11. Microscope Carl Zeiss Germany

12 P H meter Metrohm Switzerland

13 Shaking Water Memmart Germany
Bath
14 DHS Memmart Germany

Sterility test
A thermostable gram negative bacteria Geobacillus stearothermophilus is used in
the sterility test to ensure that an autoclave is finely working. If this bacteria is killed
in the autoclave at 121°C after 15 minute time then autoclave is confirmed as
functioning.

Endotoxin removal
Endotoxin is inactivated by sterilizing the sample at 230°C temperature for 2 hour
Liquid Particle Count
Acceptable range- 10µ= 6000 and 25µ= 600 for small volume parenteral
10µ= 25 and 25µ= 3 for LVP

Environmental Monitoring

45
In this test organisms in air, room, ceiling are checked by introducing a plate of
medium to 1000L of air from the room.I. Monitoring of airborne microorganism
(Settle Plate, Mechanical sir sampler)

II. Monitoring of surface (Contact plate method, Swab method)

III. Monitoring of personnel hygiene (Gloves or hands, Garments)

Water Purification
Water from all the point of use is tested for microbial contamination. It can be
divided in three different phases-
Phase 1= Daily checked every point for 14 days
Phase 2= Every point for 14 days
Phase 3= Alternatively tested every point for 1year

Media:
• Fluid Thioglycolate (FTG) is used for bacterial growth at 30 – 35 °C
• Tryptone Soya Broth is used for fungal growth at 20 – 25 °C
• There are other medias like MacConkey Agar, Cetrimide etc.

Basic responsibilities
1. Sampling and microbiological monitoring of raw materials, finished products,
purified water.
2. Microbiological monitoring of aseptic area, other clean areas, sterility testing
area and non-sterile area.
3. Effectiveness of media, growth promotion test and validity of microbial tests.

46
 PHARMACEUTICAL ENGINEERING

SK+F Limited has a strong engineering department, which rendering their services
to act as a supportive hand for smooth production. The engineering department of
Eskayef Bangladesh Limited consists of a team of dedicated engineers, pharmacist,
technicians and workers responsible for facilitating production.
The following wings are included under this department.
1. Project
2. Project Maintenance
3. Calibration
Project
Project means planned set of interrelated tasks to be executed over a fixed period
and within certain cost and other limitations.
Project Maintenance
Project Department planned, designed a new task and finally implement it then
they handover it to project maintenance department. The maintenance department
is actually a helping department of project department that helps to maintain the
particular project such as the air, water, electricity, machines and equipments in the
industry identify any technical problem and solve it promptly. It deals with
procurement, installation, and renovation of machines. This department is
responsible for maintenance of machines and equipment and it checks instruments
at varying intervals depending on class of instrument.

Project maintenance department usually deals with the following system:

Power house
● Heat, ventilation and air conditioning system (HVAC system) ➢ Water
plant

47
● Air Compressor
● Chiller system
● Steam generation in a boiler and supplied plant.
● Effluent Treatment Plant (ETP)
HVAC system: The HVAC system means “Heating Ventilation and Air
Conditioning system”. The total system is an automatic process and is maintained
by a software system named “metaris”. The process is maintained in the different
area by controlling the air pressure (positive and negative).
Function of HVAC in pharmaceuticals:
In pharmaceutical industry the importance of HVAC system can not be described
in words as it helps to maintain different classes of clean room (i.e class A, B, C, D
and so on). HVAC system main performs the following function in
pharmaceuticals:
● To maintain specified temperature (i.e-24℃)
● To maintain specific relative humidity
● To remove dust particles from production area
● To hold the air contamination within acceptable limits.
● To maintain proper air flow to the ensuring cross contamination does not
occur.
● To prevent microbial contamination in some area using HEPA fil

Zoning concept: Zoning concept is properly maintained in SK+F plant by HVAC

system. There are mainly five zones

48
Water System

Effluent treatment plant:

Effluent treatment plant (ETP) alongside insures treatment of toxic chemicals and
proper disposal of used water in the entire plant.

49
The waste water is brought in the equilisation tank and stored. In the flash mixer
tank there is a level which when crossed water is brought up into it by centrifugal
pump. In the meantime the chemicals required to treat waste water is dosed.There
are five chemicals needed to do so-
• Alum 2.5kg per 1000L
• Lime 3.125kg per 1000L
• Polymer 37.5g per 1000L
• Urea 500g per 1000L
• DAP (Diammonium phosphate) 500g per 1000L

SK+F has an effluent treatment plant having capacity of 2.5 L/hr Effluent
Treatment plant consists of:
● Collection tank
● Coagulation and sedimentation tank
● Aeration tank
● Neutralization and disinfectant tank.

Process of ETP :

Water in collection tank

Alum, lime water, polymer, urea +DAP are added in mixing tank

Coagulation and sedimentation occurs

Decantation

50
 Aeration

Again decantation

Filtration by sand filter (20µ)

Disinfection

CALIBRATION

Calibration is a comparison between measurements – one of known magnitude or

correctness made or set with one device and another measurement made in as similar
a way as possible with a second device.

The device with the known or assigned correctness is called the standard. The second
device is the unit under test, test instrument, or any of several other names for the
device being calibrated.

Calibration may be called for:

❖ A new instrument

❖ After an instrument has been repaired or modified

❖ When a specified time period has elapsed

51
❖ When a specified usage (operating hours) has elapsed

❖ Before and/or after a critical measurement

❖ After an event, for example after an instrument has had a shock, vibration, or
has been exposed to an adverse condition which potentially may have put it out
of calibration or damage it o sudden changes in weather

❖ Whenever observations appear questionable or instrument indications do not

match the output of surrogate instrument.

VALIDATION AND DOCUMENTATION

Validation is establishing documented evidence, which provide a high degree of

assurance that a specific process will consistently produce a product meeting with
its’ pre-determined specifications and quality characteristics. There are four types of
validation-
• Process Validation- to prove that the process is continuously producing the product
intended and have to prove for consecutive three batches and if not then a deviation
comes and have to go for change request.
• Packing Validation- mainly primary packing validation is done and done at
maximum, within range and minimum conditions to set the optimum condition.
Like sealing temperature, pocket forming temperature.
• Equipment Validation – to prove that whether the desired functioning of equipment
is achieved or not and is based on four qualifications-
1. Design Qualification
2. Installation Qualification

52
3. Operational Qualification
4. Product Qualification
• Cleaning Validation- to see whether the equipment is properly cleaned or not and
whether it will make an impact on the product or not. Sometimes even if the
equipment is not properly cleaned it is seen that whether it is making an impact on
the product or not, if not then no further validation is done, as it is not needed.
There are four ways of validation-
1. Prospective (Before Commercialization, for new product )- at the beginning
that is before manufacturing product
2. Concurrent (Market and validation concurrently) - during the product
marketing process
3. Retrospective (After Commercial data, existing data analysis)- when batch is
large or when there is criticality then the data is taken analyzed and reviewed.
4. Re-validation (Again validity check) -revalidated when there is any major
change like formulation change (otherwise will make an impact on the
product). Otherwise revalidated after three years and if major change needed
then not waited for 3 years.

Documentation
Documentation is the vital part for a pharmaceutical company. It is necessary to
document each and every process and methods used in manufacturing as it acts as
an indicator whenever any problem occurs with the product. Good Documentation
Practice (GDP) describes standards by which documents are created and maintained.
Documentation is strictly maintained in ESKAYEF. Everything is well documented
here, because it follows this concept that without having documented you did
nothing. Each and every stage of the process and method is documented and also
validated which ensure the EU-GMP.

Features of documentation include—

53
• It should be contemporaneous with the event they record.
• It should not be hand written.
• When electronically produced it should be checked for error
• It should be free from errors.
• It should be approved, signed and dated by authorized personnel.

Document approval- Approved, signed, and dated by appropriate authorized

personnel. The documents which are reserved in SK+F are following-
• Site master file
• Validation master plan
• S.O.P
• Validation protocol
• Specification
• Batch documentation.
• Q.M.S documentation
• Others
Specification contains-
• R.M. specification
• Packaging material specification.
• In process specification
• Finished product specification
Batch Document contains-
• BMR
• COFA
• Line clearance
• Cleaned tag

54
• BPR
• Print outs

HSE MANAGEMENT

A health, safety and environment management system has been established in

Eskayef Pharmaceuticals Ltd. It covers all Healthcare operations carried out at any
locations in factories, offices and warehouse. This system is designed to ensure
health and safety of each employee working at Healthcare, to develop safe industrial
processes, and to limit the environmental impacts of Healthcare activities and
products and through all these to ensure sustainable development.

Health Safety and Environment (HSE) Policy

● To become one of the leading companies with regard to Environment, Health
and Safety performance
● Committed to increase awareness and motivate employees on EHS culture
through training at all levels
● To respect local laws and regulations to conduct EHS activities
● Committed to provide a safe and healthy working environment to ensure the
health and safety of our employees, contractors, visitors and neighbors
● To avoid all the risks related to occupation by identifying and evaluating in
time and take necessary preventive measures at an early stage
● To identify all environmental hazards utilizing qualitative and quantitative
analysis, assess and reduce the corresponding risk to an acceptable level
● To identify and assess potential exposure to chemical, physical and biological
stressors utilizing qualitative and / or quantitative evaluation
● To ensure continuous development of EHS standards

55
 ● To maintain good relation on EHS issues with neighbors, authorities,
customers and suppliers

The main functions of the HSE department are:

● Waste Management

● Fire Fighting

● Training on earthquake

● Health Check ups

Waste Management
One of the main functions of EHS is waste management. As this is a pharmaceutical
plant there are various forms of toxic wastes produced every day and if they are
passed onto the nature without any treatment this will lead to serious consequences.
The wastes can be categorized as:
1. Non- chemical solid waste
This type of waste can include the packaging materials, the API containers, the vials,
glass containers, plastic containers, papers and so on. They are passed to Prism
Bangladesh Foundation for incineration. Some of the containers which are not
contaminated can also be recycled.
2. Chemical waste
Managing chemical wastes are more challenging than the solid one. Again, they can
be categorized as Flammable and Inflammable Chemical. Under flammable waste
there can be liquid, solid and gaseous wastes. Gaseous wastes are managed through
GHS.
The liquid chemical wastes are treated through Biological ETP (Effluent Plant
Treatment) and exposed to the environment.

56
This is called as biological ETP because here bacteria are being used for equalizing
the chemicals.

Fire Fighting
Another important function of EHS is to train on fire-fighting issues. There should
be fire fighters who have at least 6 years of experience. Every employee is trained
on what to do if there is a fire occurrence. The fire-fighting aids are checked on
regular intervals and employees are trained on what to do if there is a fire breakout,
where to assemble, how to avoid the smoke and call out rolls to find out of there is
a missing person.

Training on Earthquake
Employees are trained on what to do if there is an earthquake and how to evacuate
themselves in this kind of situations.

Health Check-ups
● Employees are tested to ensure they do not carry any contagious disease
● A physician is assigned in the for-emergency situations
● First aid facilities are ensured
● For ensuring safety employees are provided with PPEs
● Employees are being trained on good ergonomics

CONCLUSION

The opportunity we were provided in this in plant training program helped us in

understanding how a pharmaceutical manufacturing plant works and how its quality
can be maintained rigorously. Eskayef strictly abide by the established law for
57
maintaining GMP regulations and hold on to the standardized quality of
manufactured products. Being one of largest pharmaceutical company of the
country, it surely has a bright future ahead. The core competency of Eskayef is that
it possesses an effective and efficient human resource who motivate fresher like me
to aim to be a part of this team. In order to stay ahead of the competition, the
company employs excellent marketing strategies. I feel privileged to be able to
complete my training from such an organization where there was a lot to learn.
Hopefully I will be able to implement the knowledge gathered from Eskayef
Pharmaceuticals Limited in future to do some good for my country and the people
in it.

58