Presentation

on In plant training in
SQUARE pharmaceuticals ltd.
(Dhaka Unit)
 Presented by:

Robiul Hasan FH-117 Pharmacy University Of Dhaka

Kazi Aaquib Mosharraf SH-12 Pharmacy University Of Dhaka

Ataur Rahman EK-32 Pharmacy University Of Dhaka

Fairuz Zahan Piyal RK-113 Pharmacy University Of Dhaka

Nadia Tasnim Ahmed SN-02 Pharmacy University Of Dhaka

Md.Meshkat Sharif Bhuiyan FH-07 Pharmacy University Of Dhaka

Human Resource Department

A human resources department is a

critical component of employee well-being
in any business, no matter how
small. HR responsibilities include payroll,
benefits, placement, evaluation,
compensation and development of the
employees, hiring, firing.
Functions of HRD:

 Hiring.
 Promotions.
 Reassignments.
 Position classification and grading.
 Salary determination.
 Performance appraisal review and processing.
 Awards review and processing.
 Personnel data entry and records maintenance
 Provides & maintains transport.
 Maintains salary statement, increment & bonus.
 Arranges breakfast, lunch & evening snacks for employees.
 Maintains record of entrance & exit of all the management and
non-management staffs.
 Keeps the record of leave of the personnel.
 Prepares all documents for factory inspector.
 Maintains all personal files of staffs & officers.
 Disciplinary action as per labor law.
 Makes liaison with Govt. regulatory bodies.
 Recruitment of personnel at the plant.
Production Planning and
Inventory Control
PPIC was introduced in Square Pharmaceuticals in 1986.It is one of the
vital sector of SPL which is concerned with smooth production and
distribution.
Functions of PPIC

Production Requisition of Inventory

Planning. raw and Control
• Sales packaging • By 8 months rolling
Forecasting. materials. forecast by PMD.
• Determining • SCM • Supervision of
management. supply ,storage
production and accessibility.
target. • Depot Stock
summation.
Information Related to PPIC

 BOM- It refers to Bill of Materials.

 ROFO- Rolling Forecast. Production amount=Rolling Forecast*Stock.
 Lead Time- The time that requires to receive materials after requisition. It
depends on the route of shipment.
For local vendor- 45 days
For import-
By sea- 150days (1-5month)
By road- 120days (1-4month)
By air- 90days (1-3month)
For export- 25days
Warehouse

Warehouse is the place where materials for the production are stored for further use and
distribution. Good Manufacturing Practice (GMP) is followed to maintain the proper
environment for storage of drugs and some medical products in warehouse.
There are two types of ware house in SPL.
 Raw Material warehouse
 Finished Goods warehouse.
Segments Of Warehouse

Loadin Mars
g/unlo halin Quarantin
ading g ed Area
Bay Area
Raw Sam
Cold
Material pling Storage
Area Boot Area
h
Rele Finished
Rejected
Area ased Product
Area Area
Labels Used

QUARANTINED

SAMPLED

PASSED

REJECTED
Raw Materials

Materials Kept initially Sampling is

received by in the done is the
loading or Marshaling sampling
unloading bay area booth

Kept in Passed Sent to

quarantined materials are manufacturing
area for QC kept in Passed floor for
approval area production
Finished Goods Warehouse

FG are sent to
warehouse from Till QC approval
packaging area. FG samples are FG are stored
sent to QC for in quarantined
test. area.

Loaded to
Passed FG are Transferred to vehicle and
kept in Passed loading/unloading supplied to
Area. bay during supply. depots and
markets.
 GPB is the main production building of Dhaka unit.
 It started its operation in 2002.
 It is also known as FU-1.
 Only tablet & capsule dosage forms are manufactured in GPB.
 currently 120 products are manufactured in GPB.
 Capacity: 4.7 billion units per year.
Number of machineries &
equipment:

 Materials air lock - 1

 Dispensing booth - 4 (3 is operating )
 Sieving room - 1
 Slugging / milling room - 1
 Granulation unit - 5
 Blending unit - 1
 Compression unit - 6
 Coating unit - 5
 Encapsulation unit - 3 ( But only 1 is operating )
 Primary packaging line - 12 ( But 1 is non functional )
Environmental Condition in GPB:

Dispensing booth is class C but dispensing room is class D and corridor is

non classified.
Negative pressure remain inside the room and positive pressure in
corridor.
Laminar air flow
Temperature ≤ 30°C and RH ≤ 65%
 General work flow of GPB
slugging/
Warehouse Granulation
milling

pre
dispensing Sieving Blending
area

post Encapsulation
Dispensing dispensing
Compression
area

Coating packaging

packaging
Manufacturing process:

Dispensing:
Materials are dispensed in dispensing booth, then kept
in post dispensing area.

Cleaning
Complete Cleaning
Back to Back Cleaning

Sieving:
It is done to get particle of uniform size.
RUSSELL sieve ------------------USA
Milling:
Kevin Roller compactor------------------UK
Cosmec Hammer compactor ----------Italy
Fitz mill --------------------------------------USA

Granulation:
For suitable granulation, 30---40% powder & 60—70% granules and 1—5%
moisture is required.
There are two type of granulation-
1. Dry granulation
2. Wet granulation

Machines :
EUROVENT------------------->UK
GEA---------------------------->UK
Yenchen----------------------->Taiwan
Blending:
It is done to distribute the API & excipient uniform. During blending,
Lubricant is mixed with granules.
Matcon-----------------UK

Compression:
It is the process of forming tablet by applying pressure.

Machines:
KORSCH XL , KORSCH Pharmapress 300, BOSCH ----------------
Germany
UNIPRESS-------------------------------------------------------------------
UK
PTK Pharmatach ----------------------------------------------------------
South korea
In process quality control test:
 Friability
 Weight variation
 Disintegration test
 Hardness test
 Moisture content
Coating :
Two type of coating observed in SQUARE –
1. Film coating
2. Enteric coating

Machines:
Gansons1200, Gansons 1500 -----------------India
IMA--------------------------------------------------Italy
PAM GLATT ---------------------------------------Germany

Encapsulation:
The capsule shells are made of gelatin. The active are given in
the form of powder or pellets.
Parameters to be considered during encapsulation: Weight variation ,
capsule length , capsule diameter etc.
 Packaging:
There are two type of packaging-
1.primary packaging
2. Secondary packaging

1.Primary packaging:
Which is directly in contact with product is called primary packaging.

 Blister packaging
 Strip packaging
 Container or Bottle filling & sealing

Equipments : HOONGA , NOACK , HEINO ILLSEMANN.

2.Secondary packaging:
 Leaflet ,
 Inner carton ,
 shipper carton ,
 Labelling ,
 Inspection slip,
 PVC gum tape,
 Large volume Parenteral (LVP)

 Large volume parenterals are preparation containing 100 ml or more volume .

 LVP Unit is also called formulation unit 4 (FU-4) or New parenterals unit.
 It is a linear manufacturing facility ( I shape )
 It is the biggest sterile facility in South Asia.
 This unit consists of double door facility and pressure increase deep in the facility
.

The products made there are –

 Infusion
 Vials
 Ampoules
 Facilities:
Class of clean room that is maintain by following rules –
> Class-A for filling
> Class-B for dispensing booth
> Class-C for dispensing and formulation room
> Class-D for washing & autoclaving

Cleaning process :
Manufacturing lines:

There are following manufacturing lines in LVP building:

1. Manufacturing floor 1:
a. BFS extension line
b. BFS existing line
c. PVC bag Infusion line
d. Glass bottle Infusion line
e. Nasal spray line
2. Manufacturing floor 2:
a. ampoule extension line
b. Ampoule existing line
c. Vial line
d.
1. Blood and plasma derivative products line
2. Pre fill syringe line
3. BFS dispensing materials being washing and drying line
4. BFS formulation line
Machines available in LVP:

Type of machine Name

Autoclave Fedegari Italy
Ampoule washing and Tofflon Chine
depyrogenation tunnel
Ampoule filling and Tofflon Chine
sealing machine
Ampoule inspection Spami Italy
machine
BFS filling machine Rommelag Switzerland
De-flashing machine Rommelag Switzerland
Cap welding machine Rommelag Switzerland
Vial filling and labeling Trueking Chine
machine
Packaging machine HOONGA Korea
In process control (IPC) tests :
 Leak test
 Appearance check
 Tip seal check ( for ampoule)
 Volume /Fill check
 White particle check
 Black particle check

List of products :
 Solo IV 0.9% Infusion
 Solodex IV Infusion
 Neotack Injection
 Water for injection 10 ml
SFrL
Square Formulations Limited
 SFrl is the newest solid oral dosage form plant of Square Pharmaceuticals
Limited.
 Started commercial manufacturing in November, 2013.
 Equipped with latest state-of-art technology.
 US-FDA compliance plant.
 10 billion units capacity per year.
Exterior view of SFrL
SFrL
Square Formulations Limited
 Features-
 Production building is based on steel
structure
 3 floors -
 1st floor for warehouse
 2nd floor for production area
 3rd floor for technical area

 1,60,000 square feet per floor

SFrL
Square Formulations Limited
 Currently manufacturing about 50 products including tablets and capsules
 Separate material and personnel flow in production floor
 Separate area for each manufacturing step
 Manufactured dosage forms are-

Tablet
Capsule
Powder for suspension
SFrL
Square Formulations Limited
Available Process Line Total Currently
Operating
Dispensing Booth 6 2

Granulation Line 7 5

Sieving 2 2

Blending 3 1

Compression Line
Tablet 11 6
Encapsulation 4 3

Coating 7 4
SFrL
Square Formulations Limited
Available Process Total Currently
Line Operating
Packaging

Blister 9 5

Strip 3 3

PFS 1 1

Effervescent 1 0

Bottle filling line 1 1

(tablet)
SFrL
Square Formulations Limited
 A dedicated 24/7 manufacture line for –

Cap. Seclo 20 & 40 mg

Cephalosporin Unit

 Why we need a separate unit for cephalosporin

drugs ?

The main reason is “Cephalosporin drugs are highly sensitive drugs. They can
cause hypersensitivity reaction in sensitive persons.”

Another reason is to minimize the chance of cross contamination as they can

develop resistance property in bacteria at sub-therapeutic dose.
Cephalosporin Unit

Features:
 Dedicated plant for cephalosporin production
 Fully separated, well established and isolated manufacturing area
 Highly sophisticated HVAC system and AHU are used
 More precautions are maintained in each and every step during production,
filling, Sealing and packaging to prevent cross contamination.
Cephalosporin Unit

Products of Cephalosporin unit:

1. Tablets
2. Capsules
3. Dry powder for syrup/suspension
4. Powder for injection
Cephalosporin Unit

Production of dry powder for syrup/suspension

Dispensing

Sieving & mixing

Blending
Bottle washing
Filling

Sealing

Final packaging
Insulin and MDI:

 Insulin: a protein pancreatic hormone secreted by the beta cells of the islets
of Langerhans that is essential especially for the metabolism of carbohydrates
and the regulation of glucose levels in the blood and that
when insufficiently produced.

MDI: A device that delivers a measured amount of medication as a mist the

patient can inhale. A MDI consists of a pressurized canister of medication in a
case with a mouthpiece.
The infrastructure of Insulin Manufacturing Facility
has been established by Tpro (Telster Projects)

For filling of insulin products, SQUARE brought IMA-

MAC vial washing, filling machine from Italy.

The CFC free MDI (Metered Dose Inhaler) project of

SQUARE Pharmaceuticals had been started in
September 2008 and finally ready for Qualification
(IQ, OQ, PQ) for HVAC system and process
machineries on mid of April 2010.
Insulin products of SPL:

 Ansulin R (40IU, 100IU)

 Ansulin N (40IU, 100IU)
 Ansulin 30/70 (40IU, 100IU)
 Ansulin 50/50 (40IU, 100IU)
 Ansulin R pen cartridge
 Ansulin N pen cartridge
 Machines available in the insulin department:
SL. NO. INSTRUMENT NAME ORIGIN

1. Autoclave celester ( freezer ) Spain

2. Fixed reactor (cold chamber) Spain

3. Mobile reactor ( pH meter ) Spain

4. Mobile reactor ( conductivity meter ) Spain

5. Mobile reactor ( Large stirrer ) Spain

6. IMA-MAC filling & washing machine Italian

7. Dabrico prefilled syringe & stopper insertion machine. USA

8. Bausch+strobel cartridge filling & washing unit. Germany

Facility:
The area for MDI manufacturing is maintained at
clean room status. The area can be classified as –
Area Clean room class

Dispensing booth B

Dispensing area D

Formulation area C, D

Filling area A
Machines available in MDI:

Name of the machine Origin

Cansorter Switzerland

Micronizer Germany

Mixing vessel (Iprocomsa) Spain

Valve sorter Switzerland

Sessions of York UK

OCS weightchecker UK

Shrink wrapper -
Stability

Stability testing is very important part to establish expire date and shelf life of
the product .
Instructions followed to Stability testing are--
1.ICH guidelines.
2.WHO guidelines.
  Parameters Studied in Stability are-
Appearance Change.
Dissolution and disintegration test.
Water Content(LOD).
Purposes of Stability Testing
Microbial Test.
Shelf life Impurity Test.
determination.
Hardness.
Shelf life
extension. Potency Test.

Impurity growth
testing

PD trial batch
analysis.
Types Of Stability Testing

Stability study protocol & stability study is done as per ICH

(International Conference on Harmonization) & WHO (World
Health Organization) guideline in three types.
They are-
1. Long term.
2. Intermediate term .
3. Accelerate term.

In SPL(Dhaka Unit) only Long term Accelerate term testing is

done.
 • Temp → 250c ± 20c
long term • RH → 65% ±5%
• Frequency of the test : After every 3 months gap
stability test →1st year, then after every 6 months gap
→second year and lastly with 1 year gap.

• Temp → 300c ± 20c

Intermediate • RH → 65% ±5%
stability test • Frequency of the test : 0,3,6,9 months

• Temp → 400c ± 20c

Accelerated • RH → 75% ±5%
stability test • Frequency of the test : 0,1,2,3 and 6th month
Regulatory Affairs

Regulatory affairs is a profession which acts as the interface between

pharmaceutical industry and Drug Regulatory authorities across the world.
 RA professionals are the liaison between the pharmaceutical industry and
worldwide regulatory authorities.
 Their target is to maintained with laws, regulations, guidelines and guidance
of regulatory authorities.
 To give an assurance that the process is under required regulation.
The activity is divided into 5 modules
 Module 1: Administrative Information and Prescribing Information

 Module 2: Common technical Document

 Module 3: Quality

 Module 4: Nonclinical Study Reports (toxicology study)

 Module 5: Clinical Study Reports

Dossier

Create ,assamble ,update and publish a composit

documents.
Assembly of elementary documents monitored by
structuring and publishing agent. This may be
heterogenous type.
Each document or sub dossier follows its own
lifecycle.
Dossier combines varity of same content in order to
adapt different targets.eg FDA approval, Audit
purpose etc.
Common Technical Document

 The Common Technical Document (CTD) is a set of specification for application dossier
for the registration of Medicines and designed to be used across Europe, Japan and
the United States.
Quality Control
Definition:
ISO 9000 defines quality control as "A part of
quality management focused on fulfilling quality
requirements".

Quality control emphasizes testing of products to

uncover defects and reporting to management who
make the decision to allow or deny product release.
Organization
Raw
Materials

QC
Packagin
Water
g
Analysis
Materials

Finished
Products
 Functions and responsibilities

Sampling the new raw & packaging materials arriving at the

factory premises
Issuing release, reject or quarantine tag for each batch of raw
material & final product
Assessment of intermediate products & bulk products for further
processing
Performing all test procedure for all incoming samples according
to the schedule
Maintaining batch wise full quality control tests records &
signature of the persons who perform the test
Calibrations and standardization of laboratory equipments
Ensuring precision & accuracy of all testing methods
Testing of any return goods
Control of laboratory reagents
Analysis of complicated samples with their corresponding
retained samples
 Raw material testing:

Receiving materials with a full

certificates of analysis(CoA) If n≤10 then it
forms a composite
API is sampled from Otherwise, while
each container n n>10 then every 10
containers will
form a sub
Sampling materials in sampling composite
booth and it is done from three
positions : top, middle and Excipients are
bottom of the container sampled from 1+√n
containers, here
n=total number of
container received

Releasing materials in a batch Approved raw materials are marked

fashion and with proper status green
of labeling. raw materials which do not comply with
specifications are rejected and marked
red label.
For a composite both assay and identification tests are
performed

But in case of sub composite assay tests are performed for

any one of the sub composite but identification tests will be
done for all of them
Tests those are performed on raw materials

•Appearance
•Solubility
•Identification by IR and HPLC
•Water content by Karl Fischer titrimetric method
•Ordinary impurities (instrument: TLC analyzer)
•Assay and limit for Guanine by HPLC
•Related substances by HPLC
•Residual solvents by GC
•Sulphated Ash/Residue on Ignition
Packaging material testing:

Packaging material
are sampled from 1+√n containers, here n=total
number of container received

Both types of packaging materials(primary and

secondary) are tested by QC. Two types of primary
packaging materials exist, which are printed and
unprinted
Quality Assurance
 • Quality assurance is a wide ranging concept covering all matters that
individually or collectively influence the quality of a product.

• It is the totality of the arrangements made with the object of ensuring that
pharmaceutical products are of the quality required for their intended use.

• QA is the heart and soul of quality control

QA = QC + GMP/Other Quality Systenm

Quality Assurance is a
dynamic process

It is a journey towards
the destination
The function of QA:
1. The suppliers’ approval and vendor rating

2. Line clearance

3. Documentation and data control

4. Check the over printing of packaging materials

5. Internal quality audit

•Facility •Building
•Room temperature •Skill people Personnel qualification
•SOP check •Documentation
•Safety •Cleanliness
•Health check up
6. Packaging Material Specification(PMS)
7. Quality Investigation Report
8. Quality Risk Management(QRM)
9. Export dossier: It means documentation need for export countries
10. Market complains and approval
11. Preparation of certificate of analysis(CoA) for finished formulation
and API

12. Out of Specification(OOS) Management

13. Taking Corrective action and preventive action(CAPA)

14. Establishing manufacturing methods and SOPs covering entire

operations and their regular updating

15. Overall documentation control (-SOP,-BMR/BPR,-protocols etc)

16. Communication of every aspects relating to quality to all relevant

persons for early positive action

17. Ensuring product stability

18. Annual product quality review: Quality review of batch is performed

at least once a year. It is carried out not for each and every batch but for
some selective batches

19. Ensuring adequate training program (GMP training, SOP training)

Microbiology

 Microbiology department performs various microbiological tests to kill, free,

count or suppress the microorganism.
 Microbiology department plays an important role in producing a quality
products as it checks all the parameters related with manufacturing a quality
product in both classified and non-classified area.
 The tests which cannot be performed chemically and the products, which are
biologically synthesized, go through microbiological test.
Tests According to Products

In parenteral products: Following tests are done.

• Bacterial endotoxin test.
 Sterility test.
 Liquid particle count test.
 Air velocity measurement of laminar flow and HEPA filter.
Non-parenteral products: Limit test
Microbiological Limit Test of raw materials & finished products.

 Total aerobic bacterial & fungal count.

 TAMC test: total aerobic microbial count
 TYMC test: total combined yeast and mold count
 Detection of pathogens -7 specifies organisms

1. S. aureus
2. E. coli
3. Pseudomonas aeruginosa
4. Salmonella species
5. Clostridium spp.
6. Candida arbicans
7. Bile tolerant gram-ve bacteria
Environmental Monitoring:
1. Monitoring Personal Hygiene
i. Contact Plate Method

1. Monitoring Surfaces
i. Contact Plate Method
ii.Swab Test

1. Monitoring of Airborne Microorganisms.

i. Air Sampling by Sampler
Validation
Validation

According to FDA Validation is,

“Establishing documented evidence that
provides a high degree of assurance that a specific
process will consistently produce a product meeting
its pre-determined specifications and quality
attributes”
What does this mean?

 An quantitative approach is needed to prove quality,

functionality, and performance of a
pharmaceutical/biotechnological manufacturing process.

 This approach will be applied to individual pieces of

equipment as well as the manufacturing process as a
whole.

 Guidelines for validation are set by the FDA, but the

specifications of validation are determined by the
pharmaceutical/biotech company.
Phases of Validation

Validation is broken down into 5 main

phases,
1. Design qualification (DQ).
2. Installation qualification (lQ).
3. Operational qualification (00).
4. Performance qualification (P0).
5. Maintenance Qualification (MQ)
1. Design Qualification (DQ) defines the functional and
operational specifications of a balance or instrument.

2. Installation Qualification (IQ) ensures that a balance or

instrument is received as designed and specified. It
documents the installation in the selected user
environment.

3. Operational Qualification (OQ) demonstrates that a

balance or instrument will function according to its
operational specification in the selected environment.
4. Performance Qualification (PQ) demonstrates that a balance or instrument
consistently performs according to a specification appropriate to its routine
use.

5. Maintenance Qualification (MQ) describes and documents any maintenance

required on the equipment.
Validation Time Line
Process Validation
Establishing documented evidence which produces a high
degree of assurance that a specific process will consistently
produce a product meeting its predetermined specifications
and quality attributed.
Types of process Validation
The guidelines on general principles of process validation
mentions four types of process validation:
•Prospective validation
•Retrospective validation
•Concurrent validation
•Re-validation
Prospective Validation
Establishing documented evidence prior to process
implementation that a system does what it is proposed to do
based on preplanned protocols.

This approach to validation is normally undertaken for a new

formula or a new facility must be validated before routine
pharmaceutical production commences.

Retrospective Validation
Retrospective validation is used for facilities, processes and
process control in operation that have not undergone a formally
documented validation process.

This approach is rarely been used today because it is unlikely

that any existing product hasn’t been subjected to the
prospective validation process. It is used only for audit of
validated process
Re-validation
Re-validation means repeating the original validation effort
on any part of it and includes investigative review of existing
performance data

Possible reasons for revalidation include

1. The transfer of a product from one plant to another

2. Change of the product, plant, manufacturing proves, the
cleaning process or other changes that could affect product
quality
3. The necessity of periodic checking of the validation results
4. Significant(usually order of magnitude) increase or
decrease in batch size
5. Sequential batches that fail to meet product and process
qualification
Analytical Method Validation
Method validation can be defined as process of demonstration
through documentation procedure confirming that the
process, piece of equipment, procedure and facilities will
consistently produce a product or result that meets
predetermined specification.

The parameters for method validation can be as follows

Specificity(interference by impurities or excipients)

Method precision
Accuracy
Linearity test
Intermediate precision/Ruggedness(Variation in system)
Robustness(variation in the composition)
Calibration
Calibration refers to the act of evaluating and
adjusting the precision and accuracy of measuring
equipment. Instrument calibration is intended to eliminate
or reduce bias in an instrument’s readings over a range for
all continuous values.

Calibration

Equipments)parts of Apparatus(Measurement Machines(complex

machinaries) and process) machinaries)
Precision is the degree to which repeated measurements under
unchanged conditions show the same results

Accuracy is the degree of closeness of measurements of a quantity to its

actual true values

All the measuring equipment such as gauges, balances and weights are
calibrated routinely by this dept. in order to restore the accuracy of
these equipments

Small balances are calibrated as a 3 months interval internally

Large balances are calibrated at a 4 months interval internally
Gauges(temperature, humidity and all the gauges of different
machines) are calibrated at a 12 months interval internally
All equipment for calibration are calibrated from abroad
All the weights are calibrated annually by B.S.T.I(Bangladesh Standard
Testing Institute)
Product Development

Galenical
Wing
Product
Development
Analytical
Wing
Product Development

 Functions:

 1. Research for and development of new products

 2. Quality and regulatory compliance
 3. Reformulation (if required)
 4. Reprocessing
 5. Problem solving related to manufacturing (Troubleshooting)
Product Development

 6. Preparation of B.M.R, B.P.R for a product

 7. Development of manufacturing procedure
 8. Selection of packaging materials and mode
 9. Stability study and determination of product shelf-life
Analytical Wing

Main function:
Develop and validate standard operating procedures (SOP) based on which QC
department will perform its function.

Methods can be developed by two ways-

 compendial methods
 In-house methods
Engineering Department

 Functions-
1. Providing electricity
2. Providing HVAC and other environmental
control over manufacturing
3. Providing water treatment
4. Maintaining ETP.
5. Addressing any problems of manufacturing
equipments and machines etc.
THANK
YOU… 