KYAMBOGO UNIVERSITY

FACULTY OF SCIENCE

DEPARTMENT CHEMISTRY

CIPLA QUALITY CHEMICAL INDUSTRIES

INTERNSHIP REPORT

1ST JAN-31ST JANUARY 2021

BY

WATALA JOHN

REG. 19/U/CTD/20322/PD

INTERNSHIP REPORT SUBMITTED TO THE DEPARTMENT OF CHEMISTRY AT

FACULTY OF SCIENCE IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE AWARD OF THE DEGREE OF BACHELOR OF SCIENCE TECHNOLOGY
CHEMISTRY AT KYAMBOGO UNIVERSITY.

i
DECLARATION

I WATALA JOHN declare that this work is original, mine and has not been submitted for any
other degree award to any other university.

Signature................................................

Date………/…........./.............................

ii
APPROVAL

This is to certify that this internship report has been approved for submission to the Department
of Chemistry and it contains the student's own work to the best of my knowledge.

Mr. Kawanga John Muwummuza (Field Supervisor)

Signature: ………………………………...

Date: ………/………/….……

Dr. Twinomuhwezi Hannington (University Supervisor).

Signature: ……………………………………

Date: ………/………/……….

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 DEDICATION.
I dedicate this report to my parents, Mr. Poma Stephene Maishye and Mrs. Mary Poma Namisi
who have endeavored to support me in my academics at all costs. My dear sister Miss.
Namusumba Joyce and my brother Ferara Yoweri who provided their unweathering support to
ensure my training is a success.

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 ACKNOWLEDGMENT.
I primarily love to thank the almighty God, for he enabled me to do my training in this state-of-
the-art facility.

Mr. Harrison Kiggundu, Mr. Jerry Kaweesi the human resource office am thankful for giving me
the opportunity to intern at CiplaQCIL.

I extend my appreciation to the institute of Kyambogo University for their recommendation and
providing ample time for training.

I would like to distinctly thank my university supervisor Dr. Twinomuhwezi Hannington who
was able to visit and inquire about my challenges, experiences state of wellbeing and if I
encounter knowledge in my field of study.

My experience at CiplaQCIL was a success with the aid of the entire Cipla team. Their ability to
willing share knowledge, job experiences life challenges was inspiring, and I am grateful.

Special thanks to my site supervisors Mr. Kawanga John, Mrs. Masika Victoria and Mrs.
Murungi Jerusha who tirelessly ensured that training schedule was kept, and we were fully
attended to in the best way possible.

Finally, to my fellow interns from different institutions of learning, am grateful for your support
during the training.

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 TABLE OF CONTENTS

DECLARATION.............................................................................................................................ii

APPROVAL...................................................................................................................................iii

DEDICATION................................................................................................................................iv

ACKNOWLEDGMENT.................................................................................................................v

LIST OF TABLES..........................................................................................................................ix

LIST OF FIGURES........................................................................................................................ix

ACRONYMS AND ABBREVATIONS.........................................................................................x

ABSTRACT...................................................................................................................................xi

CHAPTER ONE..............................................................................................................................1

1 INTRODUCTION........................................................................................................................1

1.1 Field attachment:.................................................................................................................1

1.2 Relevance of field attachment.............................................................................................1

1.3 Description of the Organization..........................................................................................1

1.4 VISION.................................................................................................................................2

1.5 MISSION..............................................................................................................................2

1.6 VALUES...............................................................................................................................2

1.7 PRODUCTS..........................................................................................................................2

1.8 BACKGROUND..................................................................................................................4

1.9 ORGANOGRAM.................................................................................................................5

1.10 Major activities of specific units.......................................................................................6

CHAPTER TWO.............................................................................................................................7

2 EXPERIENCE..............................................................................................................................7

2.1 QUALITY ASSURANCE (QA)..........................................................................................7

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 2.1.1 Functions of Quality Assurance department..............................................................7

2.1.2 Good manufacturing practices (GMPs)....................................................................10

2.1.3 Premises........................................................................................................................11

2.2 STORES..............................................................................................................................12

2.2.1 Functions:.....................................................................................................................12

2.2.2 Types of stores in CiplaQCIL.....................................................................................12

2.2.3 Receipt of materials.....................................................................................................13

2.2.4 Dispensing....................................................................................................................14

2.2.5 Finished Goods............................................................................................................15

2.3 PRODUCTION..................................................................................................................15

2.3.1 GRANULATION.........................................................................................................15

2.3.2 COMPRESSION.........................................................................................................18

2.3.3 Inprocess checks..........................................................................................................20

2.3.4 Tableting problem.........................................................................................................20

2.4 COATING...........................................................................................................................21

2.4.1 Coating process............................................................................................................22

2.4.2 Checks performed.......................................................................................................23

2.4.3 Tableting problems......................................................................................................23

2.5 PACKING...........................................................................................................................25

2.5.1 Stages of packaging,....................................................................................................25

2.5.2 Forms of product packaging......................................................................................26

2.5.3 Tablet rejects................................................................................................................28

2.6 Checks performed..............................................................................................................29

2.6.1 Initial checks................................................................................................................29

2.6.2 In process checks.........................................................................................................29

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 2.7 QUALITY CONTROL......................................................................................................29

2.7.1 Functions......................................................................................................................29

CHEMISTRY SECTION....................................................................................................30

2.7.2 Laboratory standards.................................................................................................30

2.7.3 Analysis using different equipment...........................................................................30

Stability studies.....................................................................................................................32

2.7.4 Sampling.......................................................................................................................33

2.7.5 Moisture determination..............................................................................................35

2.7.6 Water analysis..............................................................................................................36

2.7.7 MICROBIOLOGY......................................................................................................36

2.7.8 Tests on media.............................................................................................................39

2.8 WATER SYSTEMS...........................................................................................................41

2.8.1 Sources of water...........................................................................................................41

2.8.2 Types of water..............................................................................................................41

2.8.3 Process of water treatment.........................................................................................42

2.8.4 Testing for Chlorine....................................................................................................44

2.9 New knowledge and skills..................................................................................................44

2.10 Level of accomplishment.................................................................................................45

2.11 Challenges faced during the training.............................................................................45

2.12 Opportunities identified..................................................................................................45

2.13 Suggestions of how operations of the firm can firm can be improved........................45

2.14 Major benefits derived from field attachment program..............................................46

CHAPTER THREE.......................................................................................................................47

3 CONCLUSION AND RECOMMENDATIONS.......................................................................47

3.1 CONCLUSION...................................................................................................................47

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 3.2 RECOMMENDATION.....................................................................................................47

3.2.1 University.....................................................................................................................47

3.2.2 Company......................................................................................................................47

3.3 REFERENCES...................................................................................................................48

Appendices....................................................................................................................................49

Appendix A................................................................................................................................49

Appendix F.................................................................................................................................51

ix
 LIST OF TABLES
Table 1: Product name, it’s active ingredient and function.............................................................3
Table 2: Tablet problems, causes and solutions during compression............................................20
Table 3: Tablet problems, causes, solutions during coating..........................................................23
Table 4: Types of media and their functions.................................................................................36

LIST OF FIGURES
Figure 1:The organogram of CiplaQCIL.........................................................................................5
Figure 2: Equation of cation exchange..........................................................................................43
Figure 3: Equation of regeneration of resin...................................................................................43

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ACRONYMS AND ABBREVATIONS.
ACT Artemisinin Combined Therapies.

API Active Pharmaceutical Ingredient.

ARV Anti-Retroviral.

BMR Batch Manufacturing Record.

BPR Batch Packing Record.

CAPA Corrective action and Protective action.

cGMP Current Good Manufacturing Practices.

CiplaQCIL Cipla Quality Chemicals Industries Limited.

FBE Fluidized Bed Equipment.

FEFIFO First Entry First In First Out.

FIFO First In First Out.

GC Gas Chromatography.

GLP Good laboratory Practices.

GR Goods Received.

HEPA Highly Efficient Particulate Air (filter).

HMPC Hydroxyl Propyl Methyl Cellulose.

HPLC High Performance Liquid Chromatography.

IR Infrared.

LAF Laminar Air flow.

LOD Loss on Drying.

MPM Media Preparation Method.

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NDA National Drug Authority

Ppm parts per million.

SMG Saizoner Mixer Granulator.

SOP Standard Operating Procedure.

RO Reverse Osmosis.

ABSTRACT.
CiplaQCIL is pharmaceutical manufacturing company that manufactures medicine for Malaria
HIV/AIDS and Hepatitis.

The pharmaceutical products are subjected to current Good Manufacturing Practices and Good
Laboratory Practices.

CiplaQCIL obtained approval from drug regulatory authorities to manufacture and export drugs
produced.

It was established during the HIV/AIDS epidemic when the Government of Uganda reached out
to Cipla limited India to locally manufacture drugs to fight life threatening virus.

Before, during and after production, quality assurance ensures that product quality is not affected
by any factor during storage, production and packaging.

Raw and packaging materials are received by store department and stored under predetermined
conditions by suppliers.

Samples are withdrawn in quarantine area for analysis to Quality Control. Approved materials
are placed on mobile ranks in approved section in preparation for dispensing following a work
order plan from production and packing.

Materials dispensed to production under goes several processes to form tablets. Granulation
where product is first sifted, then mixed either under wet granulation or dry granulation to form
granules.

xii
Granules undergo blending with their respective inactive such as lubricants, disintegrant, and
glidant to form homogeneous powder. Checks are performed on the endpoint.

Granules are moved to compression where the granules are compressed to form tablets of desired
shapes. Tablets are checked if they reach the required specifications (In process checks).

Tablets are taken for coating by adding coating solution onto the tablets. Tablets coated include:
Trioday, Duomune and Duovir. Checks are performed on the coated tablets to ensure they meet
the expected specifications.

Tablets proceed to packaging area where they might undergo blister or container packaging.

Quality control performs analysis on raw, packaging materials and finished goods to assess their
quality. It performs microbial analysis on water and air used. Stability tests are carried out on
finished products to know how the product varies under different environmental conditions.

Water systems ensures water undergoes treatment, purified and portable is distributed to various
user points.

Generally, the training skilled me with pharmaceutical knowledge and how to build quality in a
product safe for the consumers.

xiii
 CHAPTER ONE.

1 INTRODUCTION.
1.1 Field attachment:
The field attachment refers to the field based practical training course.it prepares students for the
activities and operations expected to execute at the completion of their study at the university. It
therefore, equips the students with hands on skills that are relevant in the job fields. The training
has a stipulated tenure of eight to ten weeks. It is usually done after the end of the second
academic year. My training ran from 4th June to 3rd August 2018.

1.2 Relevance of field attachment.

The field attachment training program was relevant to me as trainee in various ways, the
relevance to me was as follows;

i. It provided me with practical experience in an organizational setting.

ii. It is was an excellent opportunity to see how the theories learned in classes are integrated
into the practical world.
iii. It helped me decided if industry is the best career option to pursue.
iv. It enabled me to learn new skills and add to my knowledge base.
v. It gave me the opportunity to practice communication and teamwork skills.
vi. Allowed me to meet new people and practice their networking skills.
vii. Makes a valuable addition to my resume.
viii. Enhanced my candidacy to graduate school.
ix. Opened doors to an employment recommendation.

1.3 Description of the Organization.

Cipla Quality Chemicals industries Limited (CiplaQCIL) is pharmaceutical manufacturing
company in Uganda. The plant mainly manufactures medicine for Malaria, HIV/AIDS, and
Hepatitis.

1
The coordinates of the plant are 0°18’17.0” N, 32°38’22.0” E. The plant is located in Luzira
industrial park along port bell road, twelve kilometers east of Kampala city in Uganda. The
company is neighbored by Luzira prison (North) and Bishop Cipriano Secondary School (West).

The plant is highly regulated in order that they produce pharmaceutical products of the highest
quality that have no environment impact. Pharmaceutical products are subjected to current Good
Manufacturing Practices(cGMP) and Good laboratory Practices (GLP).

1.4 VISION.
To become a center of excellence in the manufacturing of quality, affordable and newer
medicines

1.5 MISSION.
To sustainably avail affordable and efficacious medicines to improve the quantity and quality of
life.

1.6 VALUES.
At CiplaQCIL, every decision and action taken demonstrates our values. There six core values
that create lasting benefits for the clients served. The plant basically strives to ensure the
following values are achieved;

 Quality  Accountability
 Integrity  Innovation
 Customer focus.  Teamwork
 Excellence

CiplaQCIL obtained approvals from various organizations that are nationally and internationally
recognized.

These organization include; World Health Organization (WHO) in 2008, National Drug
Authority (NDA), Kenya Pharmacy and Poison Board (KPPB), Tanzania Food and Drug
Administration (TFDA), Rwanda Biomedical Centre (RBC), Drugs for Neglected Diseases
(DUDI), South Sudan General Medical Council (SSGMC), International committee for Red
Cross (ICRC), Zambia Medicines Regulatory Authority.

Since then WHO has seen the number of access to antiretroviral drugs increase.

2
1.7 PRODUCTS.
CiplaQCIL mainly manufactures Anti-retroviral and anti-malarial drugs.

Table 1: Product name, it’s active ingredient and function.

Product name. Active Ingredients. Function.

ARV Products.

Duovir Lamivudine USP – 150mg Inhibition of replication of

HIV in cell.
Zidovudine USP – 300mg
Reduce the rate of mother
Duovir – N Lamivudine USP – 150mg
to child transmission of
Zidovudine USP – 300 mg HIV.

Nevirapine USP – 200mg

Trioday Lamivudine – 300mg, Increases the number of

infection fighting cells in
Tenofovir Disoproxil Fumarate
the body.
300mg,
Blocking the activity of a
Efavirenz – 600mg
viral enzymes.
Duomune Tenofovir Disoproxil Fumarate –
300mg, Lamivudine USP – 300mg

Efavir 600 Efavirenz 600mg Reverse transcriptase

inhibitor.

ACT Products.

Lumartem Artemether – 20mg Kills malaria parasites by

damaging the cell
Lumefantrine – 120mg
membranes of the
parasites.

3
1.8 BACKGROUND.
During the HIV/AIDS epidemic Government of Uganda reached out to Cipla limited India,
urging them to partner with local firm Quality Chemicals limited. This was to enable Uganda to
locally manufacture drugs to meet the challenges of treating HIV patients.

The sub-Saharan region showed a prevalence of 60% HIV/AIDS and 80% of malaria, yet the
region only manufactured 1% of its required Medicine.

The Trade Related Aspects of Intellectual Property Rights (TRIPS) had barred many developed
pharmaceutical manufacturing countries such as India from supplying medication until under
patent at an affordable price.

This was a challenge to supply medication to countries like Uganda. TRIPS however, provided
an agreement flexible for least developed countries to set up Pharmaceutical facilities and
manufacture medicines.

QCIL founded the step up of CiplaQCIL which now is approved by WHO

4
1.9 ORGANOGRAM

Figure 1:The organogram of CiplaQCIL

5
1.10 Major activities of specific units.
Quality Assurance.

Quality assurance department bases on quality related systems, ensuring that the product quality
is not affected by any factor during storage, production and packaging. it ensures good
manufacturing practices are enforced.

Quality control.

Department performs analysis of raw materials, Inprocess materials and packaging material to
assess their quality before they used for production. Chemistry section basically performs assay
calculations, quantify and identify actives in tablets.

Microbiology section determines microbiol load of materials and premises used.

Stores.

This department basically receives materials from suppliers, store them under their required
storage conditions, dispense them depending on the work order, and dispatch finished goods for
transportation to the respective markets.

Production.

This department basically receives the dispensed materials and organize the different cubicles for
manufacturing. These include granulation, blending, compression and coating. They also
perform inprocess checks before product proceeds to next process.

Packaging.

Packaging mainly receives both coated and uncoated tablets and enclose them in packaging
materials. The packaging can be blister or container this is dependent on the drug.

6
 CHAPTER TWO

2 EXPERIENCE
2.1 QUALITY ASSURANCE (QA)
Quality assurance is a concept which deals with all matters that collectively or individually
influence the product quality. Quality assurance department bases on quality related systems,
ensuring that the product quality is not affected by any factor during storage, production and
packaging.

2.1.1 Functions of Quality Assurance department

Validations.

The QA department performs two main validations, these include; Process validations and
Cleaning validation.

Process validations involves documented evidence that guide on one to determine a process is
performing as expected. When performing process validations, one must have a protocol,
personnel, training, tests, acceptance limits of the process being validated.

After validation, the individual ought to present their findings, draw a summary and take for
approval. During process validations, a minimum of three different batches are tested to
determine that a machine is to perform as required. A report is made, graphical representation to
perform comparisons and conclusions deduced later the report is taken for signing.

Cleaning validation involves cleaning process, being carried out to the required standards of
WHO. The essence of having cleaning validation is to ensure the product used is not carried to
next product using the same equipment. It ensures durability and maintenance of the equipment.

Validation involves the development of cleaning protocols such as the materials for cleaning
machines which concentrations are used and on which equipment require which materials.
Cleaning protocols guide the cleaner on how to handle machines in contact with the product and
those not in contact with the product manufactured. They guide on the amount of water to be
used and concentration of teepol solution (liquid detergent).

7
Standard operating procedures (SOPs).

One of the major roles of quality assurance department is to ensure that all departments have
SOPs. Each department drafts their own SOPs, then they are brought forward to the QA
department to be reviewed.

QA provides a standard format to be followed during the designing of SOPs, it makes

corrections, print, sign, approve each department SOPs. SOPs are reviewed several times to
ensure consistence of production. SOPs may be reviewed after three years. However, under rare
or demanding circumstances for the product production, they are reviewed immediately.

Change request of SOPs.

Change requests of SOPs have procedures known as the change request procedures. These
procedures are managed by QA department. Change request involves changes and proposals of
SOPs of departments. These changes are directed to department heads with reasons

QA department provides guidelines for change requests. These include:

i. Circulation of draft SOP and change request form to applicable departments for comments.
ii. The change initiator sends the change request to QA for logging.
iii. The change request is reviewed by the department heads.
iv. The change coordinator does evaluation and impact assessment of change request and
selection of applicable departments for comments. The applicable departments do
evaluation and acceptance. If change is required, it’s sent back to change initiator for
corrections, after corrections to the department head to review.
v. If no change is required, it moves to QA head for approval.
vi. The document is taken for signing off by document author, reviewer and QA manager as
signatories.
vii. QA stamps the final SOP with date of issue and initiates training by the training
coordinator, if rejected it’s taken for further assessment by change coordinator.
viii. Finally, the SOP is implemented.

8
QA follow up the change implemented. It monitors whether the change is applicable to systems
new equipment, instruments and software used.

Deviations.

This is the temporary departure from established standard. Deviations may be planned or
unplanned. These can be categorized as minor or major based on impact. Major deviation has
impact on products quality, purity and physical characteristics. Minor deviation has no major
impact on product.

Planned deviations

Under planned deviations, the proposed departure to any approved procedure prior to execution
such as FEFIFO system not being followed, rescheduling activities due to lack of supporting
documents.

Unplanned deviations.

These deviations event resulting in departure from approved procedure such as sudden change in
temperature.

A procedure should be documented and established for review of deviation reports, the
procedure should require analysis of data assessment of whether a significant problem exists and
allocation of tasks for corrective action.

Qualifications.

During qualifications the follow factors are to be met by suppliers of the equipment of interest

 Design.
 Performance
 Installation.
 Operation

9
The buyer specifies their parameters of the equipment of interest to manufacturers which is later
shipped to the Buyers location. The equipment is installed by engineers with specific utilities
assembled, reprogrammed and calibrated.

Operations of the parts of the machine are tested such as the double rotatory is checked for its
specified speed. Other functions of the equipment are tested if they are functional. Performance
parameter is also examined by carrying out a batch test. Three different batches are tested,
summary of the findings is made, recommendations are also made. Manufacturers present
acknowledge the deviations.

Vendor management.

Vendors should be pre-qualified before settling for the quiet agreements. Requalification should
be done periodically.

Product quality reviews.

Product quality reviews should be done within a preapproved review period with use of trends to
identify product and process improvement.

Training employees.

Training employees should be done on continuous basis by employees and recruits in their job
descriptions. Training should be given to all personnel as per approved schedules. Unscheduled
training should be conducted when necessary. Only certified trainers are eligible to conduct
trainings.

Complaints and product recall.

Any product complaints from customers, medical professionals and regulatory authorities should
be recorded and investigated with pre-approved timelines. Corrective action and protective
action should be taken.

If product is suspected to be sub-standard and considered hazardous to consumers, a procedure

should be available to withdraw product/batch from markets. This should be applicable to both
local and export markets.

10
2.1.2 Good manufacturing practices (GMPs).
QA department is guided by GMP guidelines which are clearly stressed as important in
pharmaceutical industry by the National Drug Authority. GMP is part of quality assurance which
ensures that the products are consistently produced and controlled to quality standards
appropriate to their intended use and as required by marketing authorization.

GMPs eliminate possible risks such as contamination and mix-ups. Therefore, internal standards
of the organization should be more stringent than the legal requirements. They are ten basic
principles of GMPs:

i. Prevent mix-up and contamination

ii. Ensure that the equipment used for manufacturing is clean.
iii. Ensuring right equipment and material are used.
iv. Instructions should be followed as exactly stated.
v. Before any job is started instructions should be written correctly.
vi. Keep things clean and tidy including oneself.
vii. Always prevent labelling errors.
viii. Accurately document, perform checks/rechecks of carried out operations.
ix. Work accurately and precisely.
x. Lookout for non-conformances and report them.

2.1.3 Premises.
Principle on premises states that premises must be located in to minimize risk of cross
contamination. The layout and design should ensure logical flow, minimize risks of errors,
permit effective cleaning, effective maintenance and avoid any adverse effect on the quality of
products.

Design principles keep in mind material flow, people movement, and process flow should ensure
logical flow. Construction should be of suitable materials, good electrical supply, suitable
lighting for visual on-line check, temperature and humidity control, good ventilation

Storage areas should have good storage conditions which involve clean, dry and good light
system. Temperature and relative humidity conditions in defined limits.

11
Weighing areas should have a provision for dust control, smooth, durable, easy to clean, cleaning
procedures, records and documentation.

2.2 STORES
2.2.1 Functions:
 Receiving of materials.
 Dispensing of materials
 Dispatch of finished goods
 Regulation of storage conditions
 Movement of materials

2.2.2 Types of stores in CiplaQCIL.

There basically four types of stores and these include;

i. Raw material stores.

ii. Packaging stores.
iii. Rejects stores.
iv. Miscellaneous stores.

2.2.2.1 Raw materials stores

This is storage are for raw materials on receipt, in preparation for sampling and dispensing. It
consists of approved area and quarantine. Materials are placed on mobile ranks.

Raw materials in quarantine are normally awaiting sampling and are undertest. Materials in
approved area consist of containers/ canisters which have passed the tests in QC and eligible for
dispensing.

2.2.2.2 Packaging material stores.

Types of packaging material stores.

There three types of Packaging material stores.

 Primary packaging stores.

12
 Secondary packaging material store
 Tertiary packaging material store

Primary Packaging material stores.

This is an area for storage of materials in direct contact with the product such as PVC, aluminum
foil.

Secondary Packaging material stores.

This is an area for storage of materials in contact with primary materials such as cartons, stickers,
leaflets. These materials are kept under double lock system, to ensure no unauthorized access.

Tertiary Packaging material stores

This is storage area for materials in contact with secondary packaging materials of product such
as shippers and tape. All of them packaging material stores have a section of quarantine and
approved area.

2.2.3 Receipt of materials

Communication from procurement about the material being brought in. Stores officer moves to
be ready to receive materials. Once the vehicle reaches, security informs stores. Stores checks
the consignment and signs against the invoice.

The stores officer goes to the receiving bay through the change room with document for
verification. The shatter is opened, the vehicle packs and the seal of the vehicle is broken. The
cleanliness of the vehicle is checked, containers are checked for spillage and damage.

Documents verified include; invoice, purchase order document, delivery note, pack list and
certificate of analysis.

The documents of each drum are verified according to their batch number, name of item, expiry
date, storage conditions, name of manufacturer, manufacturing label.

The weight of each drum is verified by taking the weights of each drum using a weighing
balance. Materials are transported to the airlock where they are dedusted using a vacuum cleaner
or lint free clothe, then taken to quarantine.

13
In quarantine, materials are placed on an automated mobile rank. Materials are labelled as
awaiting Good Receipt (GR). GR is raised using a SAP system. GR informs Quality Control that
the material has been received and are waiting sampling.

Status label changes from quarantine to sampled. Quality Control prepares for sampling in the
sampling room. After sampling the containers are labeled with an undertest label.

An SAP batch number is generated for materials under test. The material undertest may fail or
pass the test, those that fail the test are taken to rejects room while those that pass the test are
taken to approved section.

If materials received is under cold storage, one should check on the drum and monitor the data
logger. These materials are taken straight to walk in cold chamber which are segregated as they
wait testing, approval and dispensing. Material approved are taken to approved section from
where they are issued.

During insurance, a work plan is received from production and stores personnel checks for
available material. Material are then approved by the FIFO or FEFIFO principle. If the material
is still under the stores personnel info Quality Control.

Material to be moved to prestaging area for dispensing are checked and verified by stores
personnel for material name, approved label, AR number, batch number, reanalysis date. The
material to be dispensed are passed through the pass box.

Primary packaging materials are taken to packaging stores where verification batch details are
checked. A GR is prepared and status changes to sampling. After sampling the label is added for
undertest. During the testing the materials may fail or pass the test. Approved material is insured
as per FIFO principle and are dispensed under reverse laminar air flow.

Secondary and tertiary packaging material undergo same process as primary packaging material
except they not dispensed under reverse laminar air flow.

Rejects stores.

Materials that fail the tests performed on them and receive a failed label are moved to rejects
stores.

14
2.2.4 Dispensing.
i. Only materials bearing approved label are issued for dispensing.
ii. Materials are first unloaded from mobile ranks onto pallets using stalker, cleaned and then
taken to the pre-stage area of the dispensing room.
iii. Materials are removed as per FEFIFO principle.
iv. They are passed through the pass box to the dispensing cubicle.
v. The container of the material is brought under Reverse LAF and placed in safe zone
vi. Before dispensing materials, they are weighed and checks of material name, item code is
done and recorded.
vii. Liquids are dispensed in clean stainless-steel container. Solid materials are dispensed in
double fresh polythene bug. Each material should be dispensed using clean fresh scoop.
Place container with dispensing label fastener on weighing balance and tare
viii. Transfer details of tare, net, gross weight printout one dispensing label and work order
signed and checked by production officer.

2.2.5 Finished Goods.

Goods are received through a lift on pallet with Daily Product Record having details of the
product.

The vehicle for transportation is notified and moves closer to dispatch bay where its inspected.
The finished goods are moved to through the airlock to the dispatch bay where the details of
batch record are verified.

Material and its documents are loaded onto the vehicle under security monitoring.

2.3 PRODUCTION.
2.3.1 GRANULATION
Types of granulation.

There two types of granulation;

 Wet granulation which requires binder solution.

 Dry granulation where a compaction force is used

Granulation process.

15
Sifting.

Materials dispensed from stores are cross checked for labels of all materials, weight verification,
and visual verification of materials.

Actives and inactives are transferred to the sifting room. At the sifting room, an equipment
known as a vibratory sifter is used to separate foreign materials from raw materials.

Vibratory sifter has a mesh whose size is determined by the number of holes per linear inch. This
equipment creates vibrations which separate and removes foreign particles. The integrity of the
sieve is checked before and after sifting using an inspection kit or dyanascan.

Sifted materials are transferred through the pass box to granulation hall to enable unidirectional
flow of materials.

Wet granulation.

Under wet granulation, binder solution preparation is essential. Binder is prepared using steam
kettle. Specified amount of water is weighed and poured into binder vessel. Water is heated to a
particular temperature and polysorbate 80 is added. Maize starch is first mixed with water before
it’s added into hot water.

Actives and inactives are loaded into SMG machine with the aid of LPD. The SMG has two
moving parts, agitator which rotates horizontally, and chopper rotates vertically. Materials are
mixed as per batch formula.

The binder is added as agitator keeps running with continuous addition of binder. Liquid-liquid
bonds are formed which are weak. During the agglomeration process, granules start forming
lamps which are chopped by a chopper to smaller size.

Two parameters are monitored at the end point;

 Amperage
 Visual inspection.

Granules are released into FBE bowl, as the granules are released the co-mill breaks down any
remaining lamps. Granules are moved to the FBE machine, where the granules are fluidized by
passing a stream of air upward through a specially designed perforated sheet.

16
This motion can be utilized to bring about mixing as well as forward movement of solid
particles. The air is heated to form hot air which evaporates the fluid and dries the solids. Solid
bonds are formed when moisture is removed. Fines get agglomerated to larger granule particles.

Fluid bed with spraying system;

In this process fluid beds form granules from fine powder. The powder is wetted with binder
using a spray gun connected to peristaltic pump.

The powder is wetted until liquid bridges are formed between particles. The granules are then
dried in the equipment using hot air. The end point is determined by loss on drying.

Dry granulation.

This process is used to form granules without using liquid solution because the product
granulated may be sensitive to moisture and heat.

First ingredients are weighed and combined in the required proportions and then the resulting
mixture is compressed by roller compactor.

Roller compaction facilitates the agglomeration of dry powder particles. This results in sheets of
compressed material which are then milled into granules of exactly the agreed density before
being lubricated and compressed into desired tablet.

Sizing.

Size reduction(milling) is an impotent step (unit operation) involved in the tablet manufacturing.
In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of
pharmaceuticals is easier and more uniform if the ingredients are approximately of same size.
This provides a greater uniformity of dose. A fine particle size is essential in case of lubricant
mixing with granules for its proper function. Advantages associated with size reduction in tablet
manufacture are as follows:

i. It increases surface area, which may enhance an active ingredient’s dissolution rate and
hence bioavailability.
ii. Improves the tablet-to-tablet content uniformity by virtue of the increased number of
particles per unit weight.

17
 iii. Controlled particle size distribution of dry granulation or mix to promote better flow of
texture in tablet machine.
iv. Improved flow properties of raw materials.
v. Uniformly sized wet granulation to promote uniform drying.

Blending

During blending, granules are mixed with their respective ingredients to form a homogenous
powder. Conta blender is used for small volumes and the octagonal blender is used for large
volumes. Inactives such as magnesium stearate (lubricant), microcrystalline cellulose
(disintegrant), and Talc (glidant) are added.

During co-sifting, a mixture of microcrystalline cellulose and artemether is known as premix is

done under sodium vapor lamp because it suitable for artemether bond formation.

Inprocess checks

In process checks done during granulation. These checks performed to ensure the product
conforms to the limits specified in the BMR. Usually carried out at specified intervals during the
process and at the end.

Loss on drying; LOD essentially determines moisture content of granules and lubricated
granules done by use of a moisture analyzer. This ensures that the moisture content levels are
within limits to avoid product defects during compression.

Percentage fines; This is done by use of Sieve shaker to establish the percentage of fine
particles in a given mass of granules by separating fine particles and determine its mass. The
mass of fine particles is expressed as percentage of the sum of fines and granules. Low
percentage fines prevent dust production and improve flow properties in compression.

Bulk density; This is done by use of Weighing balance and measuring cylinder by dividing a
measured mass of granules by volume they occupy in a measuring cylinder. Bulk density should
be within range to avoid compressibility problems during tableting.

18
Tapped density; this is done by use Tapped density machine. This is the bulk density after
tapping a known mass of granules.

2.3.2 COMPRESSION
Issuance and receipt of product in blend store

Production office(compression) verifies batch details and sign in the blend issue log while
receiving lubricated granules.

Before entering the blend in the compression cubicle, production officer and operator should
verify the batch details and sign on back side of the labels.

During compression, MIPC is loaded onto the LPD. The granules are loaded into the hopper. The
MIPC has a knob that can be fully open or closed. The knob is controlled in the way that the
follow of granules is by gravity.

Compression cycle.

Compression cycle basically consists of three phases which include. Filling, compression and
ejection.

Filling:

During filling, the fillomatic controls the number of granules flowing to the die bore. Before the
die is filled, the lower punch us lowered its lowest point and it’s filled.

It is then raised to predetermined point so as the excess granules are scrapped off. The die bore
provide the shape of the tablet, the die bore is in the turret.

Compression of granules occurs at the compression phase. This phase is divided into pre-
compression and main compression.

Pre-compression.

During pre-compression, the upper punch enters the die bore, the granules undergo tamping
where most of the air entrapped in the granules is removed.

Main compression

19
Under main compression, a hydraulic force is applied, and powder is fully compressed. The
force used determines the hardness, thickness, weight variation of tablets.

Ejection.

At ejection, the lower punch is raised until it levels with the top of the die. The tablet is scrapped
off the punch face by takeoff blade. The lower punch moves to the lowest point in preparation
for the next filling.

Tablets move to the tablet take off plate and proceed to the deduster that removes any dust
powder left on the tablet. Deduster vibrates and the tablet obtain kinetic energy and move
upwards along a helical coil.

Tablet from the deduster proceed to the metal detector which traps tablet containing metal pieces
that are attracted by a very strong magnetic field. Metal free tablets proceed and are dropped into
the material tablet intermediate container.

2.3.3 Inprocess checks.

The in-process checks carried out include Hardness test using hardness tester, friability using
friabilator, disintegration using are disintegration test apparatus, weight (individual and group
weight), diameter, length, and breadth.

20
2.3.4 Tableting problem.
Table 2: Tablet problems, causes and solutions during compression.

Problem Causes Solution

Thickness  Upper punch height  Reduce machine speed.

variation. inconsistent.  Provide uniform granules.
 Non-uniform granules.

Weight variation  Lower punch working height  Obtain standard heights

inconsistent.  Improve lubrication.
 Granules not flowing freely.  Provide uniform granules.
 Non-uniform granules

Collar formation  Too much fines  Improve granules.

on tablets.  Worn out punches and dies.  Replace defective tools.

Black marks on  Oil may be contaminating  Reduce lubrication for

tablets powder. upper punches.
 Oversized granules an  Improve granules quality.
excessive moisture.

Picking/sticking.  Excessive moisture and  Improve granulation

insufficient lubrication.  Check LOD of granules.
 Less compression pressure  Increase pressure
and too much heat generation
due to wrong settings.
 Punching face having pitting
marks.

Types of machines used include Fette, Kilian, and Cadpress. Stations are categorized into 45, 49,
and 55. Tooling types include B, D, BB, DB.

21
During cleaning of machine s all machines should be cleaned as per SOP. Before cleaning of the
cubicle all record labels, material, container of the previous product should be removed. All
equipment and panel boards should be covered with Virgin polybags.

2.4 COATING.
Tablet coating is the application of a coating composition to moving bed of tablets with
concurrent use if heated air to facilitate the evaporation of the solvent. The equipment used
involves the Neocota or the Autocoater.

There three types of coating which include;

 Sugar coating.
 Film coating.
 Enteric coating.

Film and enteric coating are carried out at CiplaQCIL. Film costing is the addition of thin
polymer-based coat applied to the tablets.

Sugar coating is form of coating where a sugary substance is added onto the tablets. Enteric
coating is the addition of polymer on oral medication that prevents its dissolution or
disintegration in the gastric environment.

During Trioday coating. There two sets of coating Trioday which include seal coating and film
coating. Seal coating involves a mixture of HMPC, Isopropyl Alcohol and water. HPMC is first
mixed with Isopropyl Alcohol and then added to water.

Film coating uses a premixed material known as Opadry of different colors such as opadry
yellow (Trioday) while for, Opadry white (Duomune) is used.

2.4.1 Coating process.

The coating process occurs as follows;

Coating solution is added into solution preparation tank. The solution is pumped into tubes made
of silicon by peristaltic pump. The pump is controlled by motor which causes a sanction force for
the tubes to draw the solution from the tank to coating pane.

22
The coating pane is cylindrical in nature with a retractable arm which enters the coating pane.
The retractable arm has five spray guns with four connections on each gun, on each gun has one
tube which provides coating solution and other three provide different types of air.

As the retractable arm rotates the guns spray the tablets placed on the coating pane. Layers of the
coating pane are perforated to allow free air flow. Air is from service floor which is first filter by
10-micron filter, dehumidified, the filtered by an intermediate filter and HEPA filter.

Baffles in the coating pane help to change the tablets and ensure uniform movement of tablets to
ensure proper spraying. Air enters through the inlet air entry and outlet through which it escapes
and moves in unidirectional flow.

In the coating pane, there is generation of powder which is removed by the exhaust air. Before
the air is passed to environment, is moved to scrubber unit that reduces the powder content in the
exhaust air. Fresh water is pumped from the tank that traps the powder.

There three different types of compressed air used, and these include; Atomization air, Pattern
air, Controlled air.

Controlled air blows the solution through the gun nozzles. Atomization air exerts pressure that
changes the liquid into droplets that accumulate onto the tablets. Pattern air determines the shape
of fine mist as conical, single or fan type.

2.4.2 Checks performed.

Initial checks
Inlet air and exhaust temperature are recorded. The relative humidity (45-60)%, differential
pressure, and spray pump speed.

Spray pump speed is determined by the spray test which includes the spray rate and spray
uniformity.

Spray rate is determined by first obtaining the tire weight of sample bag. The sample bug is used
to cover each spray gun. Using controlled air, the spray gun is run at given time, the weight of
solution is taken.

For the spray uniformity, a comparison is made between the guns. The difference is obtained
which should not exceed a particular value as compared to the average.

23
In process checks:
Disintegration test, Tablet hardness, Thickness, Loss on drying

2.4.3 Tableting problems.

Table 3: Tablet problems, causes, solutions during coating.

Problem. Causes. Solution.

Edge chipping  Low tablet hardness  Increase solid content of

 Excessive pan speed. coating liquids.
 Increase compaction force

Sticking/  Inadequate drying  Improve drying conditions.

picking. conditions  Increase atomizing air pressure.
 Poor distribution of
coating liquid.

Core erosion.  Inherent softness,  Increase compaction force to

excessive pan speed improve mechanical strength of
core.
 Reduce pan speed.

Logo bridging.  Inappropriate design of  Opadry II improved adhesion

Logo characteristics.
 insufficient plasticizer in  Use logo design with increased
film. area.

Orange peel  Viscosity of the coating  Reduce solids content of

roughness. liquid to high and the coating liquid.
stimulation of coating  Increase atomization air.
liquid.

Peeling  Poor adhesion of coating  Use Opadry II with improved

to tablets surface. mechanical strength and

24
  excess lubricant usage in adhesion characteristics.
formulation.  Orange peel roughness
 Reduce solids content of
coating liquid.
 Increase atomization air.

Cracking.  Inadequate plasticization  Use formulation (Opadry II) of

causes low mechanical improved mechanical strength
strength of coating and elasticity
 Improve film plasticity

Twinning  Spray rate too high, pan  Reduce spray rate.

speed to low,  Increase pan speed.
inappropriate tablet  Use tablets whose shape
shape, tacky coating minimizes chances of coming
formulation. into contact.

Tablet-tablet  Too little coating applied  Tablet-tablet variation.

variation. insufficient number of  Increase quantity applied.
spray guns, poor spray  Increase pan speed.
pattern, low pan speed,  Increase number of spray guns.
inadequate mixing of  Ensure gun position is correct
tablets. and provide optimum bed
coverage.

Logo infilling.  Logo disappearance due  Reduce spray drying potential

to erosion of tablet by increase spray rate.
surface around logo,  Reduce inlet air temperature.
infilling of logo with
spray dried coating
material.

25
2.5 PACKING
Packing is the process of enclosing or protecting products for storage, distribution, and sale.

2.5.1 Stages of packaging,

There three stages of packaging;

 Primary packaging.
 Secondary packaging.
 Tertiary packaging.

Materials used for each stage of packaging.

Primary packaging Secondary packaging. Tertiary packaging.

 Containers. Leaflets. Shippers.

 PVC. Ink. Bopp Tape.
 Aluminum foil. Cartons.
 Silica gel. Glue.
 Cotton. Stickers.

2.5.2 Forms of product packaging

There two forms of product packaging at CiplaQCIL. These include:

i. Blister packing
ii. Bulk/container packing.

Principle operation of each form of packing.

2.5.2.1 Bulk packing.

This type of packing is common for tablet which are enclosed in container. Some of tablets
include Duomune, Trioday.

During bulk packing the product move through several steps before it's full closed. These are the
steps and their respective equipment and function.

26
Primary packaging.

Containers are loaded in the hopper of the unscrambler machine and moves along the conveyor
belt. The unscrambler cleans containers using deionized and compressed air. It also arranges
containers on the conveyor.

Containers proceed to the Silica gel inserted machine. The silica gel inserted inserts silica gel.
Silica gel absorbs any moisture in the container.

The containers proceed to the tablet counting filling machine. This machine counts the number
of tablets to be placed in the container. It has a camera to detect tablet defects.

The product in its containers proceed to the checkweigher. Checkweigher determines the weight
of each container to ensure that they lie within the tolerance limits. Those out of the limits are
rejected.

Cotton is inserted into the container using cotton inserted. Cotton insert cuts the preset length of
cotton and inserts it into the container.

Container proceeds to the rotatory packing machine. This machine arranges caps, fixes caps
onto the container. It tightens the caps and records the torque force applied.

Secondary packaging

Containers proceed to the induction sealing machine which seals aluminum foil on the container.
It has an aluminum foil sensor (no foil sensor).

The container proceeds to retorque machine. This tightens the container and measure torque
applied. It has three sensors: no cap, no foil, and cap level sensor.

Labelling is done the containers using labelling machine. It wraps the label around the container.

Product details such as batch number, manufacturing date, expiring date are printed onto the
sticker labels using thermoprinter.

Pack I camera checks for over printing and verify pharmacode.

Topserter is used to apply glue on the container. Glue is heated at 100 ºC in a tank then pumped
through hose pipes and applied using glue gun.

27
Booklets are put onto the glue area of the container using the booklet pick and place machine.
Container proceeds to buffer conveyor which delay movement of the containers.

Bottles are picked and placed using bottle pick and place that uses compressed air to sack and
pick three containers.

The containers are placed into the cortonater. The machine detects the product, releases cartons,
opens, erects, cartons, inserts products into cartons, closes cartons and discharge for the next
process.

Embossing of stereos on cartons is done by the coding unit. Pack I check for the pharmcode and
cartons and product weighed using checkweigher.

Tertiary packaging

Cartons are placed in shippers sealed both at top and bottom using tapping machine to apply
tape.

2.5.2.2 Blister packing.

The machine used during primary packing is known as B-max. Consist of several equipment
which perform various functions.

An LPD uses hydraulic pressure to lift intermediate product containers (IPC) and positions it
above the hopper.

Hopper is connected to linear vibratory and rotary vibrator. Tablets are released into the hopper
which are released into the feeder station.

The forming station consists of forming dies (top and bottom plates). During the formation of
cavity using compressed and chilled water aid in cavity formation.

Tablets are added into the blister cavity at feeder station. Tablets proceed to the camera area
which detects defects on the tablet.

Tablets move to sealing station which consists of top and bottom sealing plate. Top sealing plate
is connected to heater and bottom sealing plate is connected to chilled water. Sealing occurs
(170-200) ºC. Cooling station cools the blisters.

28
Blisters are pulled by subjecting a tensile strength at pulling station. Blisters proceed to the
indexing station where the coding is done by adding stereos.

An I mark is added onto the e blisters by punch tool. Blisters move to the non-field station where
rejects are detected.

Tablets proceed to the ejection point. At injection point, a sanction pressure is applied on to
blisters, blisters are accepted at 90 º and rejected blisters at 45 º.

Secondary packaging

Blisters are inspected for defects at the conveyor belt and inserted in cartons.

Printer prints the product details. Pack i camera checks for over printing and verify pharmacodes.
Checkweigher determines weight of each carton.

2.5.3 Tablet rejects

o Missing tablets o Embossing rejects o Torn pockets
o Broken tablets o Blackspot on o Burnt tablets
o Blister not formed tablets o standing tablets
o Powder spillage o Chipped tablet o Improper knurling
o Black spot on PVC o i-mark rejects o Double tablets
o Pin holes on PVC o Improper sealing

2.6 Checks performed.

2.6.1 Initial checks.
 Temperature (19-25) ºC
 Relative humidity (45-60) %
 Differential pressure (0.25-2) mm of water

2.6.2 In process checks

 Camera challenge. Checks for overprinting and pharmacies.
 Leak test. Tests for the dealing integrity of containers and blisters using the leak test
apparatus containing a violet solution, running for 2 minutes at 520 ml bars.
 Checking tapping quality.

29
  Checking of packing codes such as item codes.

2.7 QUALITY CONTROL

This department performs analysis of raw materials and packaging material to assess their
quality before they used for production.

Quality Control Consists of two sections;

i. Chemistry section.
ii. Microbiology section.

2.7.1 Functions
i. Analysis of finished goods.
ii. Analysis of packaging goods
iii. Analysis of raw material
iv. Calibration of all instruments
v. Sampling of material both packing and raw materials.
vi. Water analysis

Quality Control Utilizes SAP software for notification of receipt for samples. Some of the
samples that come to Quality Control include raw materials, finished goods, and stability
materials.

Every analyst is given a work allocation book. Each is assigned a section. The book is section
into pending area, allocation area and completed are to fill.

Materials that are sampled by Quality Control are often labelled with undertest label (yellow in
color), passed label(green), and for failed label(red).

Quality Control uses machines such as HPLC, GC, UV, IR, Dissolution machine, polarimeter.
The reagents used by these machines are prepared using a pharmacopoeia book which include
the British pharmacopoeia, US pharmacopoeia, international pharmacopoeia.

CHEMISTRY SECTION
2.7.2 Laboratory standards
Types of laboratory standards

30
These include:

 Reference standards.
 Test standards.
 working standards.

Reference standards are substances of high purity with critical characteristics suitable for
analysis purpose supplied by official pharmacopoeia bodies.

Test standards are primary standards which are characterized as suitability as standards. It is
applicable to official standard which are not yet available or difficult to make.

Working standards are secondary reference standards which act as substitutes for reference
standards or test standards are qualified for suitability use.

QC under chemistry section does quantification and identification of actives, related substances
and organic impurities. This identification can be done by chromatography by gas
chromatograph, HPLC. During chromatography there is preparator and chromatographer. The
preparator prepares solution why the chromatograph performs analysis on the samples.

During preparation, some substances are light sensitive, so they prepared under amber glassware
so that they don’t degrade.

2.7.3 Analysis using different equipment.

2.7.3.1 Analysis under the HPLC.

The HPLC uses basically the mobile phase and stationary phase. some of liquids used under the
liquid phase may be solvents or buffers which include; acetonitrile, isopropyl alcohol, methanol.
The stationary phases utilize are column.

Substances are placed in vessels which are degassed to remove any bubbles that may affect
chromatogram. The delivery to machine may be isocratic or gradient. HPLC consist of pump,
autosampler, column compartment, and detector.

The substance moves first through the pump to the autosampler where its mixed with analyte and
it proceeds to column where the API is detected. On detection it’s sent to software known as
chameleon.

31
Before carrying out your experiment you must ensure that it’s clean depending on what analysis
was made and which solvent should clean. This prevents carryover of previous components.

First clean the system with hot water a process known as purging, to remove buffers. During
purging, the pump is opened, and nothing goes through the column since it’s by passed. When
the pump is closed it passes through the column this is after purging.

Post flashing also cleans column after analysis column storage have different packing. The
column is stored in specific solvent to reserve column. Cleaning is important to prevent
extraneous peak on chromatogram.

Cleaning the column using 50% of mobile phase without buffer close the pump so as it flows
through the column for approximately 30 min.

It follows the path of injection. Stationary phase is affected by hot water, so a column removed,
and union is added which metallic in nature.

Loop flashing does strings rinse of the autosampler and cleans the injector.

Pre-flashing with 50% acetonitrile, we put the column and clean the instrument and column
removing traces of the previous test.

Pre-circulation runs the mobile phase without injection. Circulate column and equilibrate so that
by the time we inject everything normal, then follow the guidelines with sequence of injection
which include blank, standard and sample. Monitor on the computer incase the blank
chromatogram has peaks it’s an indication of poor cleaning of the column.

Pre-evaluation help to ensure that your system is okay to establish stability of system

For unknown impurities there is a range of acceptance. A single maximum determines the limit
of acceptance of the unknown impurity.

2.7.3.2 Gas chromatograph

This technique requires a mobile and stationary phase. The mobile phase consists of inert gases
while the stationary pass consists of packed column. GC uses capillary column where the
stationary phase consists of packed column that coats the walls of small diameter tube directly.
Separation depends on the retention time.

32
2.7.3.3 Dissolution machine

This equipment mimics the human to analyze the behavior of drug in different digestive areas
with their specified conditions such as PH, temperature, time. Parts of the machine include;
vessels, jar, pedal, heater, water bath.

Stability studies.

Is evidence of how the quality of an active pharmaceutical ingredients of finished pharmaceutical

product varies with time under the influence of variety of environmental factors such as
temperature, humidity, and light. They also shown how they vary in different types of climates
such as temperate, Mediterranean, hot dry, hot humid/tropical, hot/higher humidity (ASEAN).

2.7.3.4 Types of stability testing

There three different types of stability testing and these include:

i. Long term studies.

ii. Intermediate term studies.
iii. Accelerated stability studies

Long term studies.

Indicate how a drug must remain potent and safe for long after it leaves the manufacturing
facility. The product in subjected to the following: temperature of 25ºC ± 2 ºC and 60% ± 5 %
Relative humidity for 12 months.

Accelerated Stability tests.

A product is stored at an elevated stress conditions such as temperature, relative humidity, to

increase the rate of product degradation in terms of activity and performance. The product in
subjected to the following: accelerated ambient temperature of 40ºC ± 2 ºC and 70%± 5 %
Relative humidity for 6 months. Accelerated frozen temperature 5 ºC ± 3 ºC and no humidity for
6 months

33
Intermediate stability studies.

Temperatures for 30ºC ± 2 ºC and relative humidity 65% ± 5 % for 6 months.

2.7.3.5 Process of testing.

Identify the components before and after the different term storage conditions. Start by
dissolving the drug while make sure it dissolves thoroughly in solution and take for analysis to
HPLC, mass spectroscopy or GC for I dentification and quantification. After the getting the data
before and after different stability test compare the data to determine the stability in different
storage conditions.

2.7.3.6 Importance.

i. It necessary step for drug approval.

ii. Stability test asses how the quality of drug substance varies under influence of
environmental factors.
iii. This process determines whether any physical, chemical or microbial changes affect the
efficiency and integrity of the final product.
iv. Establishes shelf life and recommend storage conditions of finished pharmaceutical
products.

2.7.4 Sampling
Involve obtaining a preventative sample from large quantity of materials for testing for testing.

Various sampling equipment are used depending on the sample, these include:

Filter paper, conical flasks, forceps, water sample kit, sample bag, butter paper.

Materials in quarantine, on the mobile ranks are removed using a stacker machine and are passed
through a pass box to sampling booth.

Before any sampling is done, initial checks relative humidity (45-60) %, temperature (19-25) ºC,
differential pressure (0.5-2.0) mm of water, calibration is done and zero check.

2.7.4.1 Types of samples.

There three types of samples.

34
 i. Composite sample.
ii. Reserve sample.
iii. Identification sample.

Composite sample consists of several different quantities of the same type of material.
Identification sample is obtained randomly and transferred in a sample bag for testing. Reserve
sample is kept for future reference.

2.7.4.2 Sampling of actives and inactives.

All actives are sampled; therefore, samples are taken from all the containers. Inactive are in large
numbers, their containers are obtained using a formula ( √ n + 1) to obtain randomly the number
of containers to be sampled.

Micro tests are done under aseptic conditions. The containers under test are labelled with the
undertest label.

Primary, secondary and tertiary packaging sampling material are taken and subject to various
tests in Quality Control.

Tests performed on packing materials.

Primary packing materials.

o Test bottles: Mouth diameter, color, grammage.

o Aluminum foil; Printed codes, Visual inspection.

Secondary packaging materials.

o Leaflets; Grammage, dimensions (length, width, height, thickness), printed details.

o Stickers; Grammage, sticking.
o Cartons; Grammar, dimensions.

Tertiary packaging materials.

o Shippers; Dimensions, bursting strength.

o Tape; Sticking and thickness.

35
2.7.5 Moisture determination
Moisture is determined using the principle of Karl Fisher titration. This is method of determining
water content of any substance.

Water basically reacts with iodine and endpoint of the rotation is reached when all the water is
consumed.

The process involves an organic base, Sulphur dioxide and alcohol. Organic bad used is known
as Imidazole while alcohol used is ethanol. These reagents are less toxic and provide faster
reaction.

Iodine is added to sample and amount used to consume all the water contained in sample is
calculated.

There two ways to add iodine to sample:

i. Volumetric.
ii. Coulometric.

In volumetric, a known concentration of iodine added to sample using an electric burette. The
amount of iodine is calculated from volume of iodine solution used.

In coulometric, iodine is electronically generated, and its amount is determined by measuring the
current needed for the electrochemical generation of iodine.

Hybrid is a combination of both volumetric and coulometric. Iodine is electronically generated

and if the moisture content of the sample exceeds a certain level a solution with an exactly
known concentration of iodine is added at same time.

Endpoint detection.

When all water is consumed the color of solution increasingly turns from yellow to brown.

Coulometric is suitable for samples with low water content (10-100) µg.

Volumetric is suitable for samples with higher water content (0.1-500) mg.

36
2.7.6 Water analysis
Samples retrieved from sampling points in water supply points both portable and purified water
sample are taken to QC for analysis.

The following parameters are tested for;

i. Water should be colorless, adourless.

ii. pH of water which should between 5-7
iii. Total organic carbon should be less than 500ppb
iv. Heavy metals should be less or equal to 0.1ppm
v. Chloride ions levels at some sample points vary, however, those of purified and portable
water should be zero. Ammonium levels should be less than 0.2ppm
vi. Other parameters checked for include; carbon dioxide, sulphate, water conductivity.

2.7.7 MICROBIOLOGY
2.7.7.1 Tests monitored

i. Environmental monitoring using settle plates.

ii. Surface monitoring by obtaining swabs.
iii. Water analysis from different user points
iv. Compressed air testing
v. Sub-culturing of standards cultures

2.7.7.2 Media.

Table 4: Types of media and their functions.

Media. Purpose.

Mannitol salt agar. Isolation of pathogenic staphylococci from pharmaceutical

products

Agar medium s(R2Agar) For heterophobic plate count of treated portable water
sampling using longer incubation period in accordance to

37
 European pharmacopoeia.

Peptone water. All-purpose growth medium and as base for carbohydrate

fermentation media

MacConkey agar. Isolation and identification of E. coli and enteric bacteria in

accordance with microbial colony counter unit testing by
harmonized methodology.

Yeast malt Agar. Isolation and cultivation of yeasts moulds and other acidic
microorganisms.

Triple sugar iron agar Identification of gram negative enteric bacilli on basis of
medium. dextrose lactose and sucrose fermentation and hydrogen
sulphide.

Dey Engley neutralizing Disinfectant testing where neutralization of the chemicals

agar. important for determine its bacterial activity.

Fluid thioglycolate For sterility testing of biological and for cultivation of

medium anaerobes and microaerophiles.

Cetrimide agar. A selective medium for isolation of pseudomonas

aeruginosa

Enterobacteria selective enrichment of Enterobacteriaceae from pp

enrichment broth Mossel

Soya bean casein digest General purpose medium for cultivation of a wide variety
medium (tryptone soya of microorganisms and sterility of moulds and lower
broth) bacteria.

Violet red Bile glucose Detection of enumeration of enteric bacteriaceace from pp

Agar.

MacConkey Broth purple For presumptive identification of coliforms from a variety

w/BCP of specimen such as water

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 Xylose lysine Cultivation of yeasts and moulds.
deoxycholate agar with
chloramphenicol

RZA broth for cultivation and maintenance of heterophilic bacteria

from portable water.

Media Preparation.

During media preparation a calibrated balance with appropriate weight range should be used for
weighing the media. If the media of double strength must be prepared, dispense double the
quantity mention in MPM in same volume of water.

Rehydrate the media as given in the MPM and dispense the media in validated quantities into
suitable glassware. When heating is required to dissolve the media ensure that the media is
removed from the heating device after it has dissolved. Check the pH of the media before and
after sterilization.

Adjust the pH with HCL/NaOH before sterilization if required. Record the pH after sterilization.
if pH after sterilization is not in range, the prepared media should be discarded. An immersion
probe may be used for liquids and a flat probe can be used for agar surfaces as well as for
liquids.

Agar sterilization, agar in its glassware is placed in a suitable container covered in flasks and
covered with double layer butter paper. A validated autoclave should be used for sterilization and
storage of the media in autoclave is not recommended.

All media dispensed from single weighing activity should be autoclaved in single load. Separate
labels should be given for the autoclavable and non-autoclavable media.

The prepared media should be checked by appropriate inspection of plates, tubes, containers
after preparation and before use for cracked, unequal filling of containers.

Preparation of poured plates

39
Rehydrate the medium heat and dispense validated quantity. Unload the media flask from the
autoclave and keep in thermostatically controlled water bath for at least 45 min not more than 8
hours. Cool to about (40-45) ºC.

Clean the exterior surface prior to pouring to prevent water from the bath from mingling with the
poured sterile agar.

Petri plates should be labelled. Media is poured to about 20ml in sterile Petri plates. Allow the
plates to solidify in a closed condition under LAF.

Check visually for the presence of raised agar surface in case of contact plates. Store the plates
after preincubation between (18-24) ºC in an incubator.

Preparation of slants.

After rehydrating the medium boil to digest and cool to (45-50) ºC. Pour out 10ml in test tube.
Plug the tubes with cotton and cover with double layer of butter paper.

Label the tubes and sterilize, then unload the tubes from the autoclave.

Place the tubes in slanting position so as to achieve 3/4-inch butt.

Ensure the top of the slant does not touch the cotton plug and allow to solidify in slanting
position. Preincubate, check visually for imperfections or contamination. Store the slants after
preincubation between 18-24 hours.

Preparation for broth

Prepare broth culture of bacterial and fungal cultures in soybean casein digest medium and
Sabouraud’s dextrose broth respectively. Incubate bacterial cultures at 30 and fungal culture at
(20-28) ºC for18-48 hour. Broth cultures should be labelled.

2.7.8 Tests on media

2.7.8.1 Growth promoting properties for liquid and solid media.

Add 20ml of media into petri plate and allow to solidify. Perform a surface spread method.
Inoculating each plate with small number of not more than 100cfu. Visible growth of the

40
microorganisms comparable to previously obtained.

2.7.8.2 Inhibitory properties liquids and solid.

Add 20ml of media into Petri plate and allow to solidify. Perform a surface spread method.
Inoculating each plate with small number of not more than 100cfu. Growth of the test
microorganisms occurs.

2.7.8.3 Indicative properties.

Add 20ml of media into petri plate and allow to solidify. Perform a surface spread method.
Inoculating each plate with small number of not more than 100cfu. Colonies are comparable in
appearance and indication reactions to those previously obtained and approved

Add 20ml of media into Petri plate and allow to solidify. Perform a surface spread method.
Inoculating each plate with small number of not more than 100cfu.

2.7.8.4 Inspection done on dehydrated media

Hemolysis, excessive darkening or color change, crystal formation from possible freezing,
excessive number of bubbles, microbial contamination, status of redox indicators, lot number
and expiry date checked, sterility of media, presence of moisture, integrity of containers. If any
of these is present, discard the media. New released dehydrated media should be subjected to
growth promotion, indicative and inhibitory properties test and preincubate.

2.7.8.5 Detection of microorganism.

These are the main microorganisms that are detected for in samples;

Detection of Escherichia coli.

MacConkey's agar incubates at (30-35) ºC for 18-72 hours. Examine the plates for surrounding
zone of precipitated bile is observed. The test is confirmed by carryout gram staining

Detection of Salmonella.

Streak out a loopful on the surface of xylose lysine deoxycholate agar plate incubate the plate at
(30-35) ºC for 18-48 hours. The presence of salmonella is indicated by growth of well-developed

41
red colonies with black centers. This is confirmed by carryout gram staining.

Detection of Pseudomonas aeruginosa.

Streak out a loopful of solution on the surface of cetrimide agar plate at (30-35) ºC for18-72
hours. Check for microbial growth.

Detection of Staphylococcus aureus.

Streak out loopful of solution on the surface of mannitol salt agar medium. Incubate (30-35) ºC
for 18-72 hours. If there is microbial growth on the agar.

2.7.8.6 Disposal of microbial cultures

Media plates used.

The petri plates are collected in a disposal bag after observation and polybags are sealed with the
help of fastener. They are transferred into a metal container. The metal container is partially open
and autoclaved at 15lbs 121 ºC for 30min.

For culture media tubes.

Autoclave 15lbs pressure 121 ºC for 30min, drain the contents of tubes into the sink under
running tap water. Wash thoroughly and dry.

For glass cultures media plates.

Wear rubber hand flies and nose mask. Remove the contents of the petri plates with the help of
spatula into metal container containing disinfectant.

2.8 WATER SYSTEMS

2.8.1 Sources of water.
CiplaQCIL has two sources of water which include;

i. National water and sewage corporation.

ii. Bore hole water.

2.8.2 Types of water.

However, there three types of water utilized;

42
 i. Purified water.
ii. Portable water.
iii. Underground water.

Purified and portable water are the main forms of water that are utilized. Underground water is
rarely utilized though it can be used for watering plants.

2.8.3 Process of water treatment.

Under water systems there three units;

i. Pretreatment
ii. Generation
iii. Storage and distribution

2.8.3.1 Pretreatment

During pretreatment water moves to raw water tank (10000L). This water is always dozed with
sodium hypochlorite. The chlorine concentration is 100ppm.

Water from the raw tank is pumped to the Multigrade filter (MGF) to remove large particles.
Water from MGF is pumped to the overhead tank. Water that is pumped to MGF is first dozed
with Sodium hypochlorite.

Water that is pumped to the overhead tank (75,000 L) is dozed with sodium hypochlorite. The
overhead is placed up for easy flow of portable water and to increase its pressure.

At the recirculation line there is a chlorine sensor which is determines the concentration of
chlorine which should not be more than 7ppm. Water is then pumped for filtration.

2.8.3.2 Filtration

During filtration, water is filtered using cartridge filters of 5 µ. From filtration, water proceeds to
the softening,

Under water softening hardness of water is removed. There two types of hardness;

 Permanent hardness.
 Temporary hardness.

43
 Temporary hardness is removed by boiling while permanent hardness is removed by ion
exchange.

There two softener tanks, when one is under service the other is on standby mode.

During the cation exchange mechanism, as water flows through the filter column, cations such as
Magnesium and Calcium in water are exchanged for Sodium.

 Cation exchange process.

RNa + CaCl2/ Mg Cl2 RCa/Mg + NaCl.

Hard water exhausted resin soft water

Figure 2: Equation of cation exchange.

 Regeneration of resin.

The exhausted resins can be regenerated by administration of sodium chloride solution which
reverses the above equation.

R Ca/Mg + NaCl R Na+ CaCl2/ Mg Cl2.

Regenerated Resin Draining

Figure 3: Equation of regeneration of resin.

In process checks are made which include; flow rate (1000L), hardness at the inlet should be
300ppm and at the outlet it should be 4ppm and outlet pressure.

Water moves to the tank and from the tank to Ultra filtration.

2.8.3.3 Ultra-filtration unit.

Ultrafiltration unit has two filters of 0.02 µ filters, there is 5 µ filter before the two filters to
reduce the workload of the 0.02 µ filters.

After an hour of service, there is backwashing and after every 30 cycle of backwash there is
disinfection using sodium hypochlorite. Chlorine levels are sensed and should not be more than
250 milvo.

44
Sodium metabisulphate is used to breakdown chlorine before it moves to generation unit. The
temperature of water is monitored, and it should be 25 ºC. other parameters monitored include;
flow rate, pressure, and silt density index (SDI).

2.8.3.4 Generation unit

Water is pumped to the septron unit which consist of the Reverse Osmosis (RO) and Electrode
Deionization (EDI).

RO requires a force because the movement of water is against water gradient. There three RO
semipermeable membranes of 0.01 µ. Water from RO unit is known as Permeate water.
Permeate water move to EDI.

At EDI, ions are removed from water using electrodes. Current is passed through water to split
NaCl and water to form sodium ion, chloride ions, hydrogen ions, and hydroxyl ions. The
sodium ion is attracted to the cathode while chloride ions are attracted to the anode. After EDI
process purified deionized water is formed.

Parameter monitored; temperature, conductivity, flow rate, pressure.

2.8.3.5 Storage and distribution unit.

Water is moved to the storage tanks which is connected to the distribution pump which
distributes to user points. Water is first pumped to UV unit to destroy any microbes. Microbes
absorb the UV rays which damage DNA structure preventing replication.

The recirculation pipe ensures that there is continuous flow of water through the tank into the
water treatment system and back into the tank to avoid stagnation.

Parameter monitored: intensity of UV, running time of UV, burning hours of UV.

2.8.4 Testing for Chlorine.

Testing for chlorine in Raw water and portable water using free chlorine kit. Sample for raw
water should be collected from inlet of the MGF after dosing. Sample for portable overhead tank
should be collected from the outlet of the recirculation line or from the inside tank.

45
 2.9 New knowledge and skills
During the training I encountered new sectors enriched with knowledge and these include;

i. Good Manufacturing Practices which are carried out throughout the plant.
ii. Process of obtaining purified water.
iii. Process of dissolution and disintegration of tablets in the human body.
iv. Gowning process in preparation for activity.
v. Operations of boilers in preparation of steam.
vi. Waste management and treatment at Effluent Treatment Plant.
vii. Granulation process and different types of granulation

2.10 Level of accomplishment

During the course of the training, I was able to participate actively in;

i. Running project to improve on production at the plant and minimize product loss to improve
total yield of the product.
ii. Performing inprocess checks on intermediate process products such as LOD, weight, length,
thickness variations of tablets.
iii. Obtaining samples from quarantine section and moving them to quality control section for
analysis.
iv. Preparation of sample for chromatography
v. Performing a Karl fisher titration for determination of moisture in tablets.
vi. Obtaining work order from production to stores for dispensing.
vii. Inspecting of packaged tablets for defects.
viii. De-blistering of defected tablets
ix. Collecting samples for microbial analysis.
x. Autoclaving media in preparation for culture media.

2.11 Challenges faced during the training.

Training program was designed in a way that denied students to have sufficient time in their
fields of interest in the facility.

Inability for having a field experience on operating software based high-tech machines.

46
 2.12 Opportunities identified.
a. Students can venture in quality control section.
b. Biotechnology knowledge can greatly contribute to field such as Biopharmaceuticals.

2.13 Suggestions of how operations of the firm can firm can be improved.
i. In the production sector, operations should be carried out in better closed systems to
minimize product loss rather the open systems regularly used.
ii. In compression sector due the presence of better and more efficient compression machines,
the sector should do without the old machines which normally reduce product yield.
iii. Microbiology department should improvise a mechanism of analyzing microbial load on
people's hands to reduce contamination.

2.14 Major benefits derived from field attachment program.

During the training, I was able to acquire, improve and learn essential skills necessary to
improve life skills and work oriented operations such as;

i. Networking skills and group dynamics Improving on presentation skills.

ii. Social conduct when in facility.
iii. Correct response to alarms.
iv. How to aid a rescue in case of danger.
v. Essence of having standard operating procedures.
vi. Operating some equipment for analysis of materials.
vii. Improved on my interpersonal communication skills.
viii. Critical thinking and problem-solving skills.
ix. Ability to become self-learner

47
 CHAPTER THREE

3 CONCLUSION AND RECOMMENDATIONS

3.1 CONCLUSION.
Training was highly educative and skilling with pharmaceutical knowledge from entry of raw
materials, storage, production and packaging of final product. The training showed how quality
is built in a product to ensure that the final consumer is safe.

3.2 RECOMMENDATION.
3.2.1 University.
University should ensure that the coarse program related with laboratory work, students should
have ample time with practical experience in established laboratories in their respective colleges.
The available laboratories should be fully equipped with equipment such HPLC which are vital
for analysis in quality control of pharmaceuticals companies.

The course program should introduce course units which associate biotechnology with
pharmaceutical sciences in relation to manufacturing of medicine and enable students design
drugs.

3.2.2 Company.
Company should generate schedules which enable students to have ample time in their field of
interests. Company should design a logbook for trainees that eases monitoring of what activities
students learn.

Trainers should provide user manuals for software related operations to enable trainees learn
software-based operations.

Company should regularly organize career guidance programs for students who intern in the
facility guide trainees on their career choices.

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3.3 REFERENCES
1. British Pharmacopoeia Commission (2016). British Pharmacopoeia. London,England:
Stationary Office.
2. CiplaQCIL training modules (Granulation, Compression, Quality Control, and Coating).
3. Company SOPs: Documentation Number; 1035-L-0005, 1035-L-0027, 1035-L-0014,
1035-G-0027, 1035-MM-005-INH, SOP Number: MT-29
4. United States Pharmacopeia National Formulary (2016). United States Pharmacopeia.
Rockville, Md: United States Convention.
5. Who we are (2018) (retrieved on 29th July 2018). http://www.ciplaqcil.co.ug/company-
profile
6. World Health Organization (2011).WHO Good Manufacturing Practices for
Pharmaceutical Products: main principles. WHO Technical Series No.961, Annex 3

49
 Appendices
Appendix A
A photograph of the High-Performance Liquid Chromatographer.

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 Appendix B

Process flowchart.

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 Appendix F
A map of location of CiplaQCIL

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