PROJECT REPORT ON

Equipment familiarization and Management overview involved with the

production process of pharmaceuticals.

Submitted in Partial fulfilment of the Requirement for the award of Degree of

BACHELOR OF TECHNOLOGY
IN
BIOTECHNOLOGY
Submitted By
K.L.N.GOUTHAMI SUMA
Roll No. 16311A2325
(2016-2020)

Under Esteemed Guidance of

Dr. G. MALLIKARJUNA

From
HETERO LABS LIMITED
SANATH NAGAR, 500 018

Submitted to

Department of Biotechnology
SREENIDHI INSTITUTE OF SCIENCE AND
TECHNOLOGY
Yamnampet, Ghatkesar – 501301

1
S.NO CONTENTS PG.NO
1 INTRODUCTION 3
2 OBJECTIVES 4
3 EQUIPMENT USED 4-5
4 1. TABLET SECTION 5-18
BLENDING
COATING
2. CAPSULE SECTION
3.QUALITY CONTROL
4.SAMPLING
5 CONCLUSION 19
6 REFERENCES 20

2
 INTRODUCTION

COMPANY PROFILE:

HETERO DRUGS LIMITED is an organization engaged in the development, manufacturing and

marketing of high-quality Chemical and Biologic Drugs across diverse therapeutic areas.globally

renowned vertically integrated pharmaceutical organization engaged in the development,

manufacturing and marketing of high-quality Chemical and Biologic Drugs across diverse

therapeutic areas.

Hetero is one of India’s leading generic pharmaceutical companies and the world’s producer of

anti-retroviral drugs for the treatment of HIV/AIDS. Backed by over 25 years of expertise in the

pharmaceutical industry, Hetero’s strategic business areas spread across APIs, Generics,

Biosimilars, Custom Pharmaceutical services and Branded Generics. The company is globally

recognized for its strengths in Research and Development, manufacturing and commercialization

of a wide range of products.

Hetero has 36 state-of-the-art manufacturing facilities strategically located worldwide, audited and

approved by stringent regulatory authorities like US FDA, EU, TGA-Australia, MCC-South Africa

and others. Our portfolio includes 300 plus products encompassing major therapeutic categories

such as HIV/AIDS, Oncology, Cardiovascular, Neurology, Hepatitis, Nephrology, Urology,

Diabetes, Ophthalmology, Hepatology and Immunology etc.

Hetero has a strong global presence in over 126 countries and focusses on making affordable

medicines accessible to patients worldwide.

3
OBJECTIVES:

Familiarization to equipment and their operations and process and management overview involved
with the production process of pharmaceuticals.
EQUIPMENT USED:

1. Sifter:
An instrument used to sieve the ingredients of a tablet with a replaceable mess ware. In this
technique, particles of power mass are placed on a screen made of uniform aperture. The sifter is
attached with a vibrator that helps in sieving the materials through the meshwork. The mechanism
of action is to loosen the packing of the particle in contact with screen surface, permitting
entrapped sub sieve particles to the screen surface.
2. Planetary Mixer:
For wet granulation a planetary mixer is used. Solutions of the binding agent are added to the
mixed powders with stirring. The powder mass is wetted with the binding solution until the mass
has the consistency of damp snow. The planetary mixer can mix a material of 100kg. The beater
of
the planetary mixer revolves 2-4times for each revolution of the head, providing double mixing
action.
3. Mass Mixer:
This is also mixing equipment used to mix dry as well is wet ingredients. The mixer has blades
that are alternately arranged and is allows uniform mixing. The mass mixer is emptied by inverting
it and scrapping off its ingredients. The planetary mixer can mix a material of 100kg.
4. Multi-mill:
This is a hammer mill that uses a high speed rotor to which a number of swinging hammers
are fixed. The unit is enclosed with chamber containing a grid or removable screen through which
the material can pass. The material is fed from the top and ground by impact of hammers or against
the plates around the periphery of the casing. The materials are enough pass through the screen
that forms the lower portion of the chamber. The fragments are swept downward against the
screen where they undergo additional hammering action until they are reduced to a size small
enough to pass through the openings and out. Oversize particles are hurled upwards into the
chamber where they also undergo further blows by the revolving hammers.

4
5. Fluidized bed dryer:
In a fluidized bed dryer, the fluidized air stream is introduced by a fan or blower mounted at
the top of the apparatus. The air is heated to the required temperature in an air heater and flows
upwards through the wet materials, which remains in a drying chamber fitted with a wire mesh
supported at the bottom. By this process, the material is suspended and agitated in a warm air
stream while the granulation is maintained in motion.
6. Tray dryer
It consists of a chamber, containing horizontal arrangements of trays on which granules are
dried. The drying process is accomplished by a gust of hot air driven by or blower through an
electric heater and heat exchange. In this method, the wet materials are placed over paper sheets
and finally placed over the trays and the drying operation is carried out. These dryers are mainly
useful for materials that contain alcoholic solutions and where slow drying for better granule
characteristic is necessary.
7. Compressor:
For increased production, Rotary machines offer a great advantage. A head carrying a
number of sets of punches and dies revolves continuously while the tablet granulation runs from
the hopper, through a feed frame and into the dies placed in a large, steel plate revolving under it.

PRODUCTION SECTION:

TABLET SECTION:
A tablet is a mixture of active substances and excipients, usually in powder form, pressed or
compacted into a solid.

UNIT OPERATIONS:
There are three methods of preparing tablet granulations. These are
(a) Wet granulation,
(b) Dry granulation (also called "slugging"), and
(c) Direct compression.
Each of these methods has its advantages and disadvantages. The first two steps of milling and
mixing of the ingredients of the formulation are identical, but thereafter the processes differ.

5
Steps in Different Methods of Tablet Manufacture (Unit Operations)
A. Wet granulation:-
Wet granulation is a process of using a liquid binder or adhesive to the powder mixture. The
amount of liquid can be properly managed, and over wetting will cause the granules to be too
hard and under wetting will cause the granules to be too soft and friable. Aqueous solutions
have the advantage of being safer to deal with than solvents.
1. Milling of drugs and excipients
2. Mixing of milled powder.
3. Preparation of binder solution
4. Mixing binder solution with powder mixture to form wet mass
5. Coarse screening of wet mass using 6- to 12- mesh
6. Drying moist granules
7. Screening dry granules with lubricant and disintegrants
8. Mixing screened granules with lubricant and disintegrants
9. Tablet compression
EQUIPMENT USED IN WET GRANULATION:

6
B.Dry granulation:-

This process is used when the product needed to be granulated may be sensitive to
moisture and heat. Dry granulation can be conducted on a press using slugging tooling or
on a roller compactor commonly referred to as a chilsonator. Dry granulation equipment
offers a wide range of pressure and roll types to attain proper densification. However, the
process may require repeated compaction steps to attain the proper granule end point.
Also called as “Pre-compression” or “Slugging” method.
1. Milling of drugs and excipients
2. Mixing of milled powders
3. Compression into large, hard tablets called slugs
4. Screening of slugs
5. Mixing with lubricant and disintegrating agent
6. Tablet compression

C.Direct compression:
Tablets are compressed directly from powder blends of the active ingredient and
suitable excipients.
No pretreatment of the powder blends by wet or dry granulation procedures is
necessary.
1. Milling of drugs and excipients
2. Mixing of ingredients
3. Tablet compression

Blending:
Powders to be used for encapsulation or to be granulated must be well blended to ensure good
drug distribution.
Inadequate blending at this stage could result in discrete portion of the batch being either high
or low in potency.
Steps should also be taken to ensure that all the ingredients are free of lumps and

7
agglomerates.
For these reasons, screening and/or milling of the ingredients usually makes the process more
reliable and reproducible.

Equipment used for blending

V-blender.
Double cone blender.
Ribbon blender.
Slant cone blender.

-EQUIPMENT USED FOR BLENDING

Sieving
Separation of a mixture of various-sized particles, either dry or suspended in a liquid, into
two or more portions, by passing through screens of specified mesh sizes.
Importance of sieving
The sieving process gives three fractions of granules:
Very coarse granules, which return back to the milling process.
Very fine fraction, which return back to the compaction.

8
 Fraction with optimal dimensions for following manufacturing steps.

Equipment used for sieving

Industrial Sifter and Sieving Machine
Specifications:
Model Capacity Power
Sifter-20 100-120 Kg./Hr 1.0 HP
Sifter-30 150-180 Kg./Hr 2.0 HP
Dryer
In the pharmaceutical sector the fallowing dryers are use:
1. Static Oven,
2. Rotary Drier,
3. Fluidized Bed Dryer etc.

Tablet presses:
The basic unit of any tablet press is a set of tooling consisting of two punches and a die which is
called a station. The die determines the diameter or shape of the tablet; the punches, upper and

9
lower, come together in the die that contains the tablet formulation to form a tablet. There are two
types of presses: single-punch and rotary punch. The single-punch press has a single station of one
die and two punches, and is capable of producing from 40 to 120 tablets per minute depending on
the size of the tablet. It is largely used in the early stages of tablet formulation development. The
rotary press has a multiplicity of stations arranged on a rotating table in which the dies are fed the
formulation producing tablets at production rates of' from a few to many thousands per minute.
There are numerous models of presses manufactured by a number of companies, ranging in size,
speed, and capacity.
Tablet presses consist of:
1)Hoppers, usually one or two, for storing and feeding the formulation to be pressed
2)Feed frame(s) for distributing the formulation to the dies
3)Dies for controlling the size and shape of the tablet
4)Punches for compacting the formulation into tablets
5)Cams (on rotary presses) that act as tracks to guide the moving punches
All other parts of the press are designed to control the operation of the above parts.

10
Coating
Tablets may be coated for a variety of reasons, including protection of the ingredients from air,
moisture, or light. Tablets are also coated to protect the drug against decomposition or to disguise
or minimize the unpleasant taste of certain medicaments. Coating also enhances the appearance of
tablets and makes them more readily identifiable. In addition, coatings can be resistant to gastric
juices but readily dissolve in the small intestine. These enteric coatings can protect drugs against
decomposition in the acid environment of the stomach.
a. Sugar Coating
The sugarcoating process involves building up layers of coating material on the tablet cores as they
are tumbled in a revolving pan by repetitively applying a coating solution or suspension and drying
off the solvent. Before sugarcoating, the core is coated with a sealing coat of shellac, PVP*-
stabilized types of shellac, or other polymeric materials, such as cellulose acetate phthalate and
polyvinyl acetate phthalate. The next stage is to build up a subcoat that will provide a good bridge
between the main coating and the sealed core, as well as round off any sharp corners. This step is
followed by smoothing or grossing. The finishing stage is accomplished by again applying one or
two layers of clear syrup. The tablets are then left for several hours before being transferred to the
polishing pan. The polish is a dilute wax solution (e.g., carnauba or beeswax in petroleum spirit)
applied sparingly until a high luster is produced.
b. Film Coating
Film coating has increased in popularity for various reasons. The film process is simpler and,
therefore, easier to automate. It is also faster than sugarcoating, since weight gains of only 2 to 6%
are involved, as opposed to more than 50% with sugarcoating. Two major groups of film coating
materials may be distinguished: (a) those that are nonenteric and, for the most part, cellulose
derivatives, and (b) those that can provide an enteric effect and are commonly esters of phthalic
acid. Films may contain a plasticizer that prevents the film from becoming brittle with consequent
risk of chipping. Until recently, alcohols, esters, chlorinated hydrocarbons, and ketones have been
among the most frequently used types of solvents. However, because of increasing regulatory
pressures against undesirable solvents, there has been a pronounced trend toward aqueous film
coating.

11
c.Modified-Release Coatings
c. A coating may be applied to a tablet to modify the release pattern of the active ingredient.
Two general categories, enteric coating and controlled-release coating, are distinguished.
The former are insoluble in the low pH environment of the stomach but dissolve readily in
the small intestine with its elevated pH. They are used to minimize irritation of the gastric
mucosa by certain drugs and to protect others that are degraded by gastric juices.

Capsule Section:
Capsule is the most versatile of all dosage forms. Capsules are solid dosage forms in which one or
more medicinal and inert ingredients are enclosed in a small shell or container usually made of
gelatin.
There are two types of capsules, “hard” and “soft”. The hard capsule is also called “two piece” as
it consists of two pieces in the form of small cylinders closed at one end, the shorter piece is called
the “cap” which fits over the open end of the longer piece, called the “body”. The soft gelatin
capsule is also called as “one piece”. Capsules are available in many sizes to provide dosing
flexibility. Unpleasant drug tastes and odors can be masked by the tasteless gelatin shell. The
administration of liquid and solid drugs enclosed in hard gelatin capsules is one of the most
frequently utilized dosage forms.
Industrial filling of hard gelatin capsules:
a) Removal of caps
b) Filling of the bodies,
c) Replacement of caps, and
d) Ejection of filled capsules
Capsules are delivered into the perforated capsule filling ring. The ring is rotated on a
turntable, and a vacuum pulls the bodies into the lower half of the ring, leaving the caps in the
upper half of the ring.
The top & bottom halves of the filling ring are separated manually, and the cap half of the ring
is set aside.
The body half of the ring is then moved to another turntable where it is rotated mechanically
under a powder hopper.
The hopper contains an auger which feeds the powder into the bodies.

12
 When the capsule bodies are filled, the cap and body rings are rejoined.

Specifications of the Capsule Filling Machines

Output 5000 to 6000 capsules per hour.
Capsule Combinations Size 00/0, Size 0/1/2, Size 3/4 and Size 5.
Machine Dimensions 395 X 240 X 500 MM
Machine Weight 45 KG
Shipping Dimensions 533 X 400 X 609 MM
Shipping Weight 70 KG

Process Capsule Filling

1. Milling /Sieving of all Ingredients.
2. Blending Powder Blender / Empty Capsules.
3. Capsule Filler.
4. Capsule cleaner.
5. Capsule injection screen.
6. Capsule check-weighing system/reject.
7. Finished capsules.
Finishing:-
The filled the sealed capsules necessitate finishing operation before inspection, bowling or
packing in strips and labeling. The following steps are involve in the finishing process-
Pan polishing.
Cloth dusting.
Brushing.
Sealing.
Inspection (ROTOSORT).
Evaluation of capsules:-
1. Uniformity of weight.
2. Content of active ingredients in capsules.
3. Disintegration.
4. Dissolution.

13
QUALITY CONTROL SECTION:

Quality control is the part of GMP concerned with sampling, specification and testing and
with organization; documentation and release procedures which ensure that necessary and
relevant tests are carried out and that materials are not released for sale or supply, until their
quality has been judged satisfactory.
Quality Control (QC) laboratory, ensures that the products are pure, safe and effective and are
released only after thorough analysis as per stringent specifications, methods and procedures
developed according to international guidelines viz. EU cGMP, MHRA, WHO, TGA, etc.
The QC department performs following activities:
RM/PM analysis Finished Products analysis

In-process Checks
The quality control section performs different control measure and test procedures to verify the
product and material quality. The tests are performed by the QC personnel and the results are
matched with a reference standard.

14
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
exacting and sophisticated analytical methods are being developed for their evaluation.
Requirements governing the quality control of pharmaceuticals in accordance with the Canadian
Food and Drugs Act are cited and discussed.
Different types of test are performed for different material. The types of test performed for
each material are as follows
1. Testing Purified water
2. Testing Water for Injection
3. Testing Uniformity of Weight of Tablets
4. Disintegration Test
5. Dissolution Test
6. In Process Quality Control
7. HPLC – An Introduction
8. Assay of different tablet.

Quality Control work (Summary)

Sampling of active pharmaceutical ingredients, Excipients, finished product & packing
material etc.
1. Testing of API (Active Pharmaceutical Ingredients).
2. Testing of excipients.
3. Testing of sample process.
4. Testing of finished products.
5. Testing of packing material.
6. Stability studies of finished product.
7. Maintenance and calibration of instruments.
8. Procurement of chemicals and glass ware.
9. Procurement of reference standard.
10. Procurement of maintenance of clusters for microbiological testing.
11. To certificate analysis.

15
12. To study products complaints.
13. To destroy the control sample after six month of the date of expiry.
Quality control department
1. Quality control sampling section:
Responsibilities:-
To draw the sample of RM from store.

To draw the samples of F.G. from production department.

To keep control sample for reference & for stability studies.

Final inspection of each batch.

2. Quality control chemical section:
Responsibilities:-
Complete analysis of all RM/ process & F.G. sample as per prescribed standard.
To send report to production, store, Q C office.
To carry out stability testing etc.
Instrument maintenance and calibration.
3. Quality control microbiology section:
Responsibilities:-
Microbiological analysis of RM/process/FG/sample.
To send report to production, store, QC office.
Quality control packaging material test.
To carry out stability testing.
4. Quality control office:
Responsibilities:-
To make certificate of analysis of R.M. &finished products

To maintain & keep records of analysis & certificate of analysis.

16
Sampling
The process of sampling is done by the QC dept. after raw material enters the store and
‘UNDER TEST’ label is pasted on it by the officials in the raw material store.
For Active Pharmaceutical Ingredient (API), 100% sampling must be done.
For Inactive Pharmaceutical Ingredient sampling is done on the basis of the following
formulae:-
No. of containers to be sampled = Total no. of containers + 1

17
CONCLUSION:

This industrial training provided a valuable learning experience in the carrier exploration
process and gave us unexpected benefit. HETERO DRUGS LIMITED lab helped us to imbibe the
detailed information about tablet section,capsule section & packaging section. Many things
such as the GMP (Good Manufacturing Process), the Current Good Manufacturing Process
(CGMP).the basic laboratory requirement for product validation, the variety of machine used
in the large scale industries of medicine etc. are known. lots of experiences in Pharmaceutical
Production and Production management are aquired.

18
REFERENCES
1. Tablet-
Pharmaceutics. The science of dosage forms design. (M.E. Aulton)
The theory and practice of industrial pharmacy.
Pharmaceutical Manufacturing Handbook Production and Processes.
2. Capsule-
L. Lachman, H.A. Lieberman, J.L. Kanig (1986). The Theory and Practice of
Industrial Pharmacy (Third Ed.). Lea & Fibiger, Philadelphia.
http://www.wikipedia.org.
3. Quality control-
Ashutosh kar, Pharmaceutical analysis, theory, methodology and drug assay, volume
www.ich.org
www.fda.gov

19
20