mehdi(nub) beximco pharma 2016

Crossponding by Md. Mehdi Hasan & Mizanur Rahman;Email:[email protected]

In-plant Training

Repot

On the basis of

Observation

Beximco Pharmaceuticals Ltd.

Submitted to:

Brig. Gen. Md. Mehboobul Haque (Retd.)

GM, HR & Admin.(Factory)

Beximco Pharmaceuticals Ltd.

Submitted by

Md.Mehdi Hasan Northern University Bangladesh

Kallol Banik Stamford University Bangladesh

Md.Mizanur Rahman Stamford University Bangladesh

Mahbub Hasan Stamford University Bangladesh

Ajoy Kumar Ghosh Stamford University Bangladesh

Rozi Hasna Stamford University Bangladesh

Ms.Sumaiya Mahmud University of Development Alternative

Training Duration

1st June 2016 to 13th June 2016

Date of submission 14th June 2016

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14th June, 2016

The General Manager,

Brig. Gen. Md Mehboobul Hoque (Retd.)

GM, HR & Admin (Factory) Beximco Pharmaceuticals Ltd.

126, Kathaldia, Nishatnagar,Tongi- 1711,

Gazipur, Bangladesh.

Subject: Submission of In-Plant training report.

Dear Sir,

At first, we the trainees of Northern University Bangladesh(NUB), Stamford University Bangladesh,

and University of Development Alternative(UODA) would like to relay our deepest gratitude to you

for providing us with the opportunity to attend in our in-plant training program from 1st June 2016

to 14th June 2016 in your renowned company as per our academic requirement. We take great

pleasure in informing you that we have successfully completed the training program and as a part of

it we have tried to prepare a comprehensive report on various aspects of Beximco Pharmaceuticals

Ltd.

We therefore will be much obliged to you if you will be kind enough to accept the report and also

would be kind enough to forgive our mistakes that might have taken place unintentionally.

Yours sincerely,

Md.Mehdi Hasan , Northern University Bangladesh

Kallol Banik , Stamford University Bangladesh

Md.Mizanur Rahman,Stamford University Bangladesh

Mahbub Hasan, Stamford University Bangladesh

Ajoy Kumar Ghosh,,Stamford University Bangladesh

Rozi Hasna,Stamford University Bangladesh

Ms.Sumaiya Mahmud,University of Development Alternative

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Aim & Objectives For the last four years, we went through several courses of pharmacy to complete our

graduation. We studied many topics theoretically and also done our practical classes with

some basic equipments and machines but could not see their implementation in

pharmaceutical industries. So far the enrichment of our theoretical knowledge we are here

in your pharmaceutical industry and our objectives are,

1. For the development of our practical skills and techniques which are directly

applicable to our careers.

2. To realize and know how a pharmaceutical company runs.

3. To know how its departments are interlinked and work together.

4. To identify how GMP or cGMP is applied in the plant.

5. To have an idea about Standard Operating Procedure (SOPs).

6. To get information about how a product runs smoothly and be a quality based

product.

7. To understand how pharmacists manage the manufacturing problems.

8. To see how quality is assured as well as controlled.

9. To learn about the documentation record practices.

10. To get general ideas about corporate environment and activities of an organization.

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Acknowledgement

Internship program or In-plant training in any pharmaceutical company is an important part for the

partial fulfilment of Bachelor of Pharmacy Course (B. Pharm). We are fortunate enough to have a

chance to complete our In-plant training in Beximco Pharmaceuticals Ltd (BPL).

We would like to express our gratitude to Beximco Pharmaceuticals Authority especially to Brig. Gen.

Md. Mehboobul Haque (Retd), GM, HR, Admin (factory) and Mr. Lutfur Rahman,Director,

Manufacturers all other officers & members of Beximco Group for their cooperation and valuable

guideline.

We wish to express our deepest sense of gratitude thank to Mr. Alim Russell ,officer, HRA Factory,

who was the main coordinator of our training program specially for his friendly & affectionate

behavior.

We are extremely indebted to

1. Mr. Animesh Bhowmik (Senior Assistant Manager, Production Planning)

2. Mr. Partha Pratim Barua (Senior Manager, Warehouse)

3. Mr. Md. Ashraful Alam (Senior Manager, Solid Dosage Formulation)

4. Mr. Subodh Charndra Das (GM, Research & development)

5. Mr. Md. Abdul Mannan Miah (Senior Manager, Liquid dosage formulation)

6. Mr. Salim Hossain (DGM, Quality Control Department)

7. Mr. Md. Sazzad Hossain (Manager, Quality Assurance Department)

8. Ms. Soomna Lohani (DGM, Infusion Unit LVP formulations)

9. Mr. Yusuf Hossain (GM, Engineering Services & Utilities)

10. Ms. Saima Sultana (Senior Manager, Training Department)

11. Mr. Zakir Hossain (Manager, EHS), for their valuable instructions & information.

During our three weeks of training in Beximco Pharmaceuticals Ltd, we have got lots ofgenerous

cooperation from every people at every sector. We are really thankful to all the officers and workers

of the factory for treating us as family and helping us to widen our knowledge.

Index HRA 13

Production Planning 18

Warehouse 22

Solid Dosage Formulation 27

Research and Development 52

Liquid Dosage Formulation 61

Quality Control Department 64

Quality Assurance Department 73

Infusion Unit: Large Volume Parenteral Fromulations

78

Engineering Services & Utilities 84

EHS 91

Training Department 94

Findings 98

Introduction Medicine is directly related to human life and therefore, its manufacturers

have massive social responsibility of providing safe and effective medication.

From its very initiation, Beximco Pharmaceuticals has always highlighted the

need for rigid quality. Beximco‘s commitment to quality is clear from its

progressive use of state of the skilled manufacturing technology.

Beximco strictly follows WHO guidelines at every stage of manufacturing and

procures its raw materials from the very best sources. But what makes Beximco

a success story is its people. Beximco‘s team of highly skilled and motivated

professionals work around the clock to guarantee the safety and efficacy

ultimately the qualities of its products

In plant training is a golden opportunity for a student to transform his/her

theoretical knowledge into practical experience. That having been said,

successful interns will have a fantastic experience, one that will be most

enjoyable & rewarding .our experience at ―BEXIMCO PHARMACEUTICAL

LTD‖ was quite amazing & it is one that we will certainly never forget.

A successful in plant training is the first step towards a successful professional

life. From this point of view we can certainly say that,we have had an

interesting & educational in plant training. This internship helps us to get an

insight into procedural aspect of a pharmaceutical company & to prepare

ourselves for the existing job field.

COMPANY PROFILE

―BEXIMCO PHARMACEUTICALS LTD‖ is one of the well renowned manufacturers of

pharmaceutical products as well as Active Pharmaceutical Ingredients (APIs) in Bangladesh

and also in the global market

―BEXIMCO PHARMACEUTICAL LTD‖ is a dynamic, progressive company engaged in the

science of mankind. It proudly stands today as one of the most reputed pharmaceutical

company of Bangladesh.

―BEXIMCO PHARMACEUTICAL LTD‖ is a private limited company established in the

end of 1976 & started production in the end of 1980 with the view of formulate & supply

quality pharmaceutical products to the people of Bangladesh.

―BEXIMCO PHARMACEUTICALS LTD‖ is the first pharmaceutical company who got the

most sophisticated and sensitive approval of USFDA which brings enormous proud for

Bangladesh.

―BEXIMCO PHARMACEUTICAL LTD‖ believes quality is first & to ensure quality they

have excellent facility & number of experience 7 skilled personnel who are contributing for

that.

BEXIMCO Group is the largest private sector industrial conglomerate in Bangladesh

engaged in diverse business areas. The Group turnover in 2008 was BDT 18.5 billion.

BEXIMCO employs 35,000 people and has 230,000 shareholders. BEXIMCO‘s shares

constitute 4.73% of the market capitalization of DSE.

We have successfully completed our training in ―BEXIMCO PHARMACEUTICAL LTD‖.

We took the notes during our visit to different departments. This report will only represent

what we have seen, what we have learnt & what we have been taught during our training. We

hope this report will help us to implement our experience in our working field.

KEY COMPANY INFORMATION:

Year of Establishment : 1976

Country of Incorporation : Bangladesh

Commercial Production : 1980

Status : Public Limited Company

Business Lines : Manufacturing and marketing of pharmaceutical Finished

Formulation Products, Large Volume Parenterals and Active

Pharmaceutical Ingredients (APIs)

Main Country of operation : Bangladesh

Corporate Headquarter &

Registered Address

: 17 Dhanmondi R/A, Road No. 2, Dhaka- 1205, Bangladesh Phone: +880-2-58611891 Fax: +880-2-58613470

Email : [email protected]

Operational Headquarters : 19 Dhanmondi R/A, Road No. 7, Dhaka- 1205, Bangladesh Phone : +880-2-58611001-7 Fax : +880-2-58613888, +880-2-58614601

Email : [email protected]

Website : www.beximcopharma.com

Overseas Offices & Associates : Australia, Bhutan, Cambodia, Chile, Ghana, Hong Kong,

Indonesia, Jordan, Kenya, Kuwait, Malaysia, Myanmar,

Nepal, Pakistan, Philippines, Saudi Arabia, Singapore, Sri

Lanka, Vietnam and Yemen

Authorized Capital (Taka) : 9,100 million

Paid-up Capital (Taka) : 3,862.4 million

Number of Shareholders : Around 90,000

: Dhaka and Chittagong Stock Exchanges of Bangladesh and

Stock Exchange Listings AIM of London Stock Exchange

Number of Employees : Upper 3,063

TIDM: (Tradable Instrument

Display Mnemonic)

Date shares were admitted to

trading

: BXP

: Dhaka Stock Exchange : 3 July, 1985

Chittagong Stock Exchange : 11 June, 1995

AIM ( Alternative Investment 21 October,

Market) :

2005

ISIN : US0885792061

mailto:[email protected]

mailto:[email protected]

http://www.beximcopharma.com/

MILESTONES ARCHIVED BY BEXIMCO:

1976 Registration of the company.

1980 Started manufacturing and marketing of licensee products of Bayer AG of Germany and Upjohn Inc. of USA.

1983 Launching of BeximcoPharma‘s own brands.

1985 Listing in the Dhaka Stock Exchange (DSE) as a Public Limited Company (PLC).

1990 Commissioning of Basic Chemical (APIs) unit.

1992 Started export operation with Active Pharmaceutical Ingredients (APIs).

1993 First export market operation with finished formulations.

1996 Introduction of Sustained Release Dosage form.

1997 Introduction of Suppository Dosage form; Commissioning of Metered Dose Inhaler (MDI) plant; Introduction of Metered Dose Nasal Spray.

1998 First pharmaceutical company of the country achieving ‗National Export

Trophy (Gold)‘ for 1994-95.

1999 UNICEF approval of BeximcoPharma as an enlisted supplier.

2000 Agreement to manufacture Metered Dose Inhaler (MDI) for GlaxoSmithKline.

2001 Introduction of Small Volume Parenteral (SVP) products; establishment of Analgesic Anti-inflammatory bulk drug plant.

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®

2003

Received ―National Export Trophy (Gold)‖ for consecutive 2 years .

(1998-99, 1999-2000)

Won the Silver prize of ICAB National Awards 2003 for ‗Best Published

Accounts and Reports‘ in Non-Financial Sector Category.

Introduced Anti-HIV drugs for the first time in Bangladesh.

Diversification into Anti-Cancer therapeutic class.

2004 Signed contract with Novartis to manufacture their liquid, cream, ointment

and suppository products under ―Toll Manufacturing‖ agreement.

Merger of Beximco Infusions Ltd. with Beximco Pharmaceuticals Ltd.

2005 Admission to Alternative Investment Market (AIM) of London Stock

Exchange (LSE)

2006

New USFDA standard Oral Solid Dosage (OSD) Plant Commissioned

Successfully relocated/outsourced penicillin and cephalosporin

manufacturing facilities as per cGMP guidelines Introduced generic

oseltamivir in Bangladesh Launched CFC free ozone benign HFA inhalers

as the first company in Bangladesh

2007 Launches Microincapsulation

2008

Become the first Bangladeshi company to achieve GMP Clearance from

TGA Australia. Also become the first Bangladeshi company to receive

export approval to Gulf countries.

2009 Only Bangladeshi company to receive GMP approval from ANVISA, Brazil

2010 The only pharmaceutical company in Bangladesh to enter the US market

through acquisition of an Abbreviated New Drug Application (ANDA).

Received GMP accreditation from AGES, Austria (for European Union);

2011 only pharmaceutical company to win ‗National Export Trophy (Gold)‘ for

the fourth time.

2012 First Bangladeshi company to launch Salbutamol HFA inhaler (Azmasol ) in Singapore

2013 First Bangladeshi company to export ophthalmic products to Europe

2014 First Bangladeshi company to receive GMP approval from Health Canada

and Taiwan Food and Drug Administration (TFDA)

2015 Become the first Bangladeshi company to achieve USFDA approval.

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BEXIMCO consists of the following units:

TRACK - 1

Solid Dosage Formulation

QA & QC

LCO & Suppository Unit

Infusion Unit

ION( injectable, ophthalmic & Nebulizer) Unit

Power Plant

TRACK - 2

Solid Dosage Formulation

QA & QC

MDI (Under construction)

WAREHOUSE

Warehouse for LCO & Solid Dosage Form

Infusion Warehouse.

There is a Liquid Nitrogen Plant in BEXIMCO on the other side of main area.

The employees are broadly divided into two groups-

1. Management (e. g. AGM, Manager, Senior Executive, Executive)

2. Non-management (e. g. workers); however, there are some employees who work on

daily basis & some work on a contract.

In this plant, there are several departments such as-

1. HRD (Human Resource Department)

2. PPIC (Production Planning & Inventory Control)

3. Warehouse

4. Production

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5. Quality Assurance & Control department

6. Engineering Department

7. Quality Assurance & Control department

8. Accounts, Finance & Informatics etc.

REGULATORY APPROVALS

The manufacturing facilities of Beximco Pharmaceuticals have been audited and approved

by:

Food and drug administration (USFDA)

National Health Surveillance Agency (ANVISA),Brazil (MDI)

Therapeutic Goods Administration (TGA), Australia (OSD, MDI and Spray)

Gulf Central Committee for Drug Registration (for GCC member states)(OSD &

MDI)

Health Canada(Canada)

TFDA(Taiwan) AGES (EU)

Qualified by UNICEF (MDI & OSD)

Qualified by Global GlaxoSmithKline (MDI)

Qualified by Asthma Drug Facility (ADF), France (MDI)

Qualified by Global F Hoff Mann La Roche (OSD)

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HUMAN RESOURCES DEPARTMENT:

A human resources department is a critical component of employee well-being in any

business, no matter how small. A company‗s human resources department is responsible for

creating, implementing and/or overseeing policies governing employee behavior of company

toward its employees. The human resource function serves to make sure that the company

mission, vision, values or guiding principles, the company metrics, and the factors that keep

the company guided toward success are optimized.

Beximco Pharmaceuticals Limited is one of the leading corporate houses of the country and

has a handsome amount of workforce led by the HRD.

DUTIES & RESPONSIBILITIES

Organizing & controlling of routine activity in the factory. Prepare & maintain ISO-9001 documentation. Supervise shift wise sectional activities.

Shift wise manpower distribution.

No institution or workstation can run without people. BEXIMCO Pharmaceutical LTD. is one

of the leading industry of the country has a generous amount of work force led by the Human

http://humanresources.about.com/od/glossarym/g/Mission.htm

http://humanresources.about.com/od/glossaryv/g/Vision.htm

http://humanresources.about.com/od/glossaryc/g/Core-Values.htm

http://humanresources.about.com/od/glossaryc/g/Core-Values.htm

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Resource Department (HRD). Many jobs are done by this department for smooth running.

Like,

1. Recruitment of Personal:

Daily labors (DL) with appropriate qualification & experience to fill all positions that have

an effect upon quality. Different standards are considered for different positions.

2. Preparation of Monthly Manpower Statement:

HRD prepare monthly manpower statement of the plant that includes DL to Director of the

industry and also prepares the daily manpower statement.

3. Maintain & Update Personal Files:

Detailed information of each and every employee are taken and updated monthly.

Conformations of job, increment, promotion, transfer etc. are built- in the file.

4. Deal with Industrial Related Issues:

They negotiate with employees union and ensure the labor right etc.

5. Disciplinary Action:

Disciplinary action including suspension, punishment & termination are done by HRD.

6. Inform Manager & Employee:

Personnel politics & procedures of the company are informed to the Managers and

employee by HRD

7. Coordination & Monitor Performance Appraisal:

HRD evaluate the performance of the plant employees in many ways:

a) Descriptive method

b) Questioner method

c) 360º appraisal etc.

8. Assess the training

HRD assess the training needs of personnel in light with cGMP& others related to HRD

issues. The training includes:

a) GMP

b) Safety

c) Training on performance appraisal management

d) SOP for HR & Administration

e) Labor standard & work place environment in pharmaceutical industry.

9. To arrange Induction Training Program:

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HRD organize orientation program for new employees.

10.Ensure proper implementation of labor Laws:

HRD ensure proper implementation of labor Laws applicable to factory workers &

employees.

10. Prepare and arrange In-plant training program:

Arrange training program for the students of different Universities. Coordinators handle

all matters related to In-plant training program.

11. Ensure Health labor-management relationship:

Ensure Health labor-management relationship for smooth & uninterrupted production.

12. Maintain liaison with Government Regulatory bodies

HRD collaborate with the following bodies for legal aid which help in any accident or for

medical aid:

a) Ministry of industry

b) Office of Director of labor

c) Explosive department

d) Tongi Pouroshova

e) Director of fire and Tongi fire station

f) Custom & VAT, Tongi circle

g) DC office, Gazipur

h) SP office, Gazipur

i) Civil surgeon, Gazipur.

13. Supervise & Monitor employee attendance, job cards regularly & prepare monthly

summary, daily absent report etc.

14. Monitor leaves of plant employees. Each employee has a leave file which integrate the all

kinds of leaves like-

AL (Annual leave)

ML (Medical leave)

CL (Causal leave)

Other leaves-

Special leave

Maternity leave

Leave without pay etc.

15. Ensure safety of all employees and company assets.

16. Ensure proper securely management of the plant.

17. Handle external visitors & arrange necessary uniform and other accessories.

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18. Supervise overall cleaning service of the plant (housekeeping, gardening etc.)

19. Supervise washing facility to provide proper clean dress as per departmental daily

requirement.

20. Supervise transport pool (Distribution, repair, maintenance).

21. Supervise canteen management.

Others: 1. Picnic, cultural program, medical checkup, eye checkup. 2. Inform managers and employees regarding personnel policies and procedures of the company. 3. Assess the training needs of personnel in light with current GMP. 5. Daily labor recruitment, Transportation, Housekeeping and gardening

Product Planning and Inventory Control

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PRODUCT PLANNING AND INVENTORY CONTROL:

PPIC stands for product planning and inventory control. In PPIC all raw and bulk materials

first comes and stored. These materials are collected by invoice. After supplying by the

traders the PPIC checks the appearance, sealing, marking etc parameters and receives by

fixing a mark of Under Test Goods Receive Tag.

Production planning has two broad subtypes:

1. Factory based planning.

2. Planning and inventory control.

Production planning has some functions to operate in factory based planning:

Issuing BMR and BPR: Both Batch Packaging Record and Batch Manufacturing Record are

issued by the Production Planning Department. Should it consider the need to make

amendments to any of these documents, it consults with Product Development. BPR is issued

only once whilst BMR is issued for every batch.

Maintaining Monthly Plans: According to market demand, Production Planning suggests

whether or not the company should continue the manufacture of a particular product.

Ensuring The Availability of Raw and Packaging Materials: Production planning gathers

all types of raw and packaging materials under consultation of head office.

Arranging physician samples: Production unit separates physician samples from the bulk

production according to the Production planning Department. These samples are prepared at

least one month prior to dispensing and in special packages called ―Catch Covers‖.

Arranging Products for International Marketing: Having receiver information by email,

Production Planning takes necessary actions as per requirement of the buyer to meet their

demand for purpose of export.

Coordination among all sectors: Planning department aims for the highest production with

minimal costs which requires proper co-ordination among the various departments with

appropriate calculation of every aspects ranging from dispensing to final product.

Compare man hour and achievements: Production planning department determines the

actual efficiency of man and machine to give the highest production within minimum cost

and time.

Keeping daily production report and documents: Production Planning keeps all sorts of

daily production reports and it also maintains major documentation.

Submission of monthly report: Production planning department submits production reports

to Executive departments on a daily basis and maintains documents including:

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Acceptance/Rejection of raw and packaging materials.

Order paper

Delivery report

BPR

Other invoices

Production planning has some functions to operate in planning and inventory control:

Inventory control is the processes employed to maximize a company's use of inventory. The

goal of inventory control is to generate the maximum profit from the least amount

of inventory investment without intruding upon customer satisfaction levels.

Then they send samples to Q.A. Department. If the Q.A. Department approves they keep the

materials in Released area or if doesn‘t approve they keep the materials in Rejected area.

In Released Area it maintains dry and cool environment. For sensitive materials it ensures

below 8o c temperature. Explosive materials such as Methylene Chloride are preserved in

Separate Area. Narcotics such as Pseudoephedrine are saved in Safe Lock at Liquid, Flavors,

and Lab Chemical Room. The temperature of these rooms is daily recorded.

The PPIC releases the raw and bulk materials under the requisition form from Production

department. After all type of calculation Such as Final potency, Amount after drying etc they

supply necessary amounts to the production department

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Flow Chart of Working Procedure in PPIC

Requisition from production department to PM

store

Checking for availability of required material

Preparation of Formulation Order and sending it to RM store

Packaging Materials

Checking availability of materials in RM store

Dispensing of required materials to production unit

Production of drugs

Packaging of the product

Sending the finished product to FG store

Warehouse

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Warehouse: A warehouse is a large commercial building where raw materials or manufactured goods may be stored prior to their distribution for sale or for sending it to the production department for

manufacturing purpose.Warehouses are used by manufacturers, importers, exporters,

wholesalers, transport businesses, customs, etc .

The warehouse of Beximco Pharmaceutical Ltd is an enclosed building and protects the

stored goods from environment influences. They are secured against fire by the special design

of the buildings and technical facilities. The fire brigade facility also has access to enable

appropriate firefighting.

There are 4 types of warehouse in Beximco Pharmaceutical Ltd:

1. Central warehouse: Central warehouse houses about 1000 types of raw materials such as

paracetamol, ranitidine HCI etc. and 7000-8000 types of packaging materials such as Blister

foil, PVC film, Inner carton. It also stores shipping carton, Alu-Alu foil. It has product

receiving area, approved area, and quarantine area. Materials enter from the log in area &

release from the log out area. It has a platform balance in the dispensing area & its capacity is

up to 300 kg. This area is also called weighing area.

It maintains-

Temperature: 22°C Humidity 48%

2. Infusion warehouse:100 types of packaging materials, 16 types of raw materials

(Calcium chloride, Calcium carbonate, Calcitrol) and some finished products

(Dexaque-100ml, Irigon – 100ml, Lactoride-1000ml) are stored.

3. Pharmatek warehouse

4. Track-2 warehouse- There is a Liquid Nitrogen Plant in BEXIMCO beside the warehouse.

AREAS OF WAREHOSE:

1. Quarantine Area

After receiving, raw materials and packaging materials are kept for QC approval in a yellow

marked area

a. Materials come through a covered van and unloaded and cleaned to make it dust free.

b. Then these materials are checked individually and information like name,

manufacturer, manufacturing date, expiry date, quantity and etc are recorded in the

checklist.

c. They are weighed and crosschecked whether they contain the same material and

quantity as mentioned in the container or not.

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d. If it is found to be up to standard then MMR (material receiving report) is prepared

and materials are kept in the quarantine area for QC (Quality Assurance Department)

approval.

2. Released Area

QC approved raw materials and packaging is generally stored in the central place of

warehouse with great safety and with controlled temperature and humidity.

a. MMR is sent to the Quality Control Department; officer comes for sampling after

receiving the MMR and sampled sticker are sealed. [If the receiving material is an

active ingredient then 100% sampling is necessary but if it is, an excipients then (n+1)

is done.

b. If the sample is found to be standard by the Quality Assurance department then

released sticker is sealed and stored in the central place of the warehouse with great

safety.

3. Dispensing Area

One dispensing officer always responsible for dispensing the materials to the production and

packaging materials to the packaging areas, following things must be checked by the

dispensing officer

a. Only released (green tag) materials are brought to the dispensing area.

b. The dispensing area is completely free from materials of other products.

c. Correct quantity and approved qualities of materials are being dispensed as per

requisition. d. Materials that expired first are being dispensed first i.e. to follow FIFO. e. Documentation of dispensing

4. Finished Product Area

a. Finished products are also stored here for delivery. b. Warehouse deliver the finished products as per asked by the planning department.

5. Rejected Area

a. If the materials fail to pass QC test, QA give rejected tag (red tag) on each and

individual container or box.

b. Rejected materials are placed in the rejected area until further decision for final

disposition is made (official letter is sent to respective department).

6. Packaging Products Area

Imported packaging products are stored in a separate room beside the raw material storing

room in the warehouse with great care.

7. Special Area:

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This is a special room or area for stored light & heat sensitive materials like colors, flavors,

vitamins poisonous materials, flammable materials etc. in maintaining temperature in

between 20-25ºC.

8. QC Sampling Room:

In this separated and lab- based room, when a new material arrives in the warehouse QC

officer comes here for sampling test.

9. Change Room for Warehouse Officers & Workers:

When any officer or worker works in the warehouse, before entering in the warehouse, he or

she change his/her cloths here & wears apron, shoe cover and head cover.

10. Change Room for QC Officers:

When any QC officer comes warehouse for sampling a material, he or she change his/her

cloths here and wears apron, shoe cover and head cover before entering into sampling room.

The main functions of warehouse are given below: Receiving in-voice and purchase order from material management Receiving materials Cleaning of received materials

Weighing of received materials and compare with purchase order

Dispensing of materials according to DOS for production

Receiving of finished goods from production

Inventory of tool manufacture also maintains by warehouse

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ACTIVITY OF WAREHOUSE

Arrival of Materials In Voice Checking

Quarantine Storage Physical Inspection &

Receipt

LOG Book Entry MRR for Inspection &

Receipt

QC for Analysis & Report

Q.A. Sampling

QA Release QA Reject

MRR Failed MRR

Disposition Released

Materials

Disposition Rejected Materials

Distribution Dispensing

Computer Entry of

Requisition Monthly Inventory Report

SOLID DOSAGE FORM

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TABLET:

Tablets are solid single unit pharmaceutical dosage forms containing one or more active ingredients with or without auxiliary substances and prepared either by molding or by compression.

Types of tablet according to BP

Conventional/Uncoated tablet

Coated tablet

Effervescent tablet

Soluble tablet

Gastro-resistant tablet

Modified-release tablet

Tablet for using in the mouth

Production department has the following units:

Dispensing

Granulation

Compression

Coating

Encapsulation

DISPENSING OF MATERIAL FOR PRODUCTION

One of the most vital steps in pharmaceutical manufacturing is dispensing. This is the first

step that needs to be done during the process of manufacturing. Dispensing area dispenses

only those materials which are released or approved by the QC. After dispensing, products

should be used within 7 days as stated in the SOP. Here, the appropriate weight of each

ingredient is measured according to the dose present in the BMR. Then it is kept in the

desired pallet and a tag is added to it which contains different information. Throughout the

process a log book is maintained.

Manual Dispensing:

By hand scooping from primary containers and weighing each ingredient by hand on

a weigh scale

By manual weighing with material lifting assistance like vacuum transfer and Bag

lifters.

Criteria of dispensing:

Record the reading from the booth magnehelic gauges in the logbook before commencing dispensing.

Do not start dispensing if readings are in orange zone-report to executive.

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Verify that the balances to be the used are clean and within their calibration period.

Record the temperature and relative humidity of the area before dispensing using hygrometer.

Weighing area also contains HEPA filter and Dual filter.

Dispense the RM in the order standard on dispensing page.

Dispense each material of one batch at the same time.

Bring only one raw material into the booth at one

Dispense each material into sealed containers or polythene bags. Seal the polythene bag properly with plastic wire ties. Complete and attach a dispersed label to each container or polythene bag

When batch is fully dispensed, transfer the packets cage trolley to the holding area for further processing.

There are two dispensing booths in solid dosage form of BeximcoPharma

one for weighing under 5 kgs

another for weighing above 5 kgs

Cleaning Specifications in the Dispensing Area:

In the dispensing area, the operator and his helper is cleans the balances and cleaners cleans

the floors, corridors and other areas. These operators and cleaners have their training records

documented.

Dispensing area contains two booths which are facilitated with –

Avery Balance.

Sartorius Balance.

Temperature & humidity detector.

Different filters:

Pre filter

Fine dust filter

HEPA filter

Dual filter

A negative pressure is always maintained inside the booth. In addition, there is a vertical

laminar air flow inside the booth to prevent the entry of dust.

Equipment and Reagents Used For Cleaning In Dispensing Area

Vacuum cleaner

Clothes

Water (hot, purified)

Isopropyl Alcohol (70%) solution as disinfectant.

Virocid (as disinfectant for floor cleaning only)

Savlon antiseptic lotion.

30

Process of dispensing:

Receive the raw material issue requisition and record the serial number, material code and

date of receipt

Check for the batch size, batch no., R no. and signatures for requisite by and authorizes by

From raw material stock register, check the quantities of material available and quantities

requested for.

Issue the materials that are approved by QC

Check the tare weight of the empty container and note down on the dispensed label

Select the bulk raw material container of appropriate R no.

Carefully transfer the material into the dispensing area and then transfer the required

quantity into the container

Calculate the net weight and record on dispensing label and sign for issued by

Close the bulk raw material container and transfer back the bulk raw material container to

the original space

Repeat the steps for remaining raw materials needed for the specific drug formulation

31

GRANULATION

In the pharmaceutical industry, granulation refers to the act or process in which primary

powderparticles are made to adhere to form larger, multiparticle entities called granules. It is

the process of collecting particles together by creating bonds between them. Bonds are

formed by compression or by using a binding agent. Granulation is extensively used in the

manufacturing of tablets and pellets (or spheroids).The granulation process combines one or

more powder particles and forms a granule that will allow tableting or the spheronization

process to be within required limits. This way predictable and repeatable process is possible

and quality tablets or pellets can be produced using tabletting or spheronization equipment.

The pharmaceutical granules regularly have a size reach between 0.2 to 4.0mm, contingent

upon their ensuing user.

Necessity of granulation

Improve flow

Densify materials

Improve content uniformity

Improve compression characteristics

Control the rate of drug release

Facilitate metering or volume dispensing

Decrease dust generation and reduce employee exposure to drug product

Improve the appearance of the tablet

Granule properties

Controlled Size Distribution

Specific Granule Voidage-Intragranular Porosity

Specific Bulk Density

Suitable Structural Stability and Physical Strength

Types of granulation performed in this unit are:

Dry Granulation

Wet Granulation

Direct compression

https://en.wikipedia.org/wiki/Powder_%28substance%29

https://en.wikipedia.org/wiki/Powder_%28substance%29

https://en.wikipedia.org/wiki/Granular_material

https://en.wikipedia.org/wiki/Tablet_%28pharmacy%29

https://en.wikipedia.org/w/index.php?title=Spheronisation&action=edit&redlink=1

32

Wet Granulation:

In wet granulation, granules are formed by the addition of a granulation liquid onto a powder

bed which is under the influence of an impeller (in a high-shear granulator), screws (in a twin

screw granulator) or air (in a fluidized bed granulator). The agitation resulting in the system

along with the wetting of the components within the formulation results in the aggregation of

the primary powder particles to produce wet granules. The granulation liquid (fluid) contains

a solvent which must be volatile so that it can be removed by drying, and be non-toxic.

Typical liquids include water, ethanol and isopropanol either alone or in combination. The

liquid solution can be either aqueous based or solvent-based. Aqueous solutions have the

advantage of being safer to deal with than solvents.

During wet granulation, liquid binders or adhesives are added to the lactose and active

mixture, usually by blending. The mixture is then dried and sized, and compressed into

tablets. There by producing a dust free formula plus improving flowability, eliminating poor

content uniformity and the ability to encapsulate a poorly soluble API.

Mechanisms of wet granulation by Fluid Bed:

33

Steps of wet granulation: Key process stages include blending the dry powder mix, wet granulation with water or another binder solution, adding any additional components, further lubrication and final

compaction. Excipients used in wet granulation typically include diluent, binder, disintegrant

and lubricant, while other stabilizing agents and pigments may also be included.

Process parameters

Impeller Speed

Chopper Speed

Water Addition Rate and Method

Massing Time

Load of the Mixer

34

Dry Granulation: The dry granulation process is used to form granules without using a liquid solution because the product granulated may be sensitive to moisture and heat. Forming granules without

moisture requires compacting and densifying the powders. In this process the primary powder

particles are aggregated under high pressure.

Dry granulation can be conducted under two processes; either a large tablet (slug) is produced

in a heavy duty tabletting press or the powder is squeezed between two counter-rotating

rollers to produce a continuous sheet or ribbon of material

Steps in Dry Granulation:

Direct Compression This is another method of tablet manufacturing. The materials are directly compressed to form tablets.Direct compression is a popular choice because it provides the shortest, most

effective and least complex way to produce tablets. The manufacturer can blend an API with

the excipient and the lubricant, followed by compression, which makes the product easy to

process. No additional processing steps are required

35

Machines used for granulation:

Granulation Unit #1

Sl. Name of Instrument Manufacturer/

Supplier

Origin Capacity

1 High Speed Mixer Granulator

(HSMG)

Thailnd 60 Kg

2 Fluid Bed Dryer Saphire India 60 Kg

3 Multi Mill Gansons India 100 Kg/h

4 Vac-U-Max Belleville USA 2000 Kg/h

Granulation Unit #2

Sl. Name of Instrument Manufacturer/ Supplier

Origin Capacity

5 High Speed Mixer Granulator (HSMG)

India 120 Kg




Granulation Unit #3


Origin Capacity


Thailand 250 Kg



12 Multi Mill Mark Bangladesh


14 Lift Lever (Stacker) Toyota Tuscho Corp.

Japan 650 Kg

36

Granulation Unit #4


Origin Capacity

15 Solace Aero Dryer Solace India 120 Kg


Thailand 250 Kg



Blending:

Blending, one of the most basic of pharmaceutical unit operations, can also be one of the

most challenging to control. Solid formulations contain multiple ingredients beyond the

active pharmaceutical ingredients: fillers, tableting agents, disintegrants, and absorption

enhancers or agents that slow down and control absorption. Ingredients from different

vendors may behave differently due to their particle size and shape and other factors, and

their tendency to form aggregates.

Materials must be chosen to ensure the desired flow characteristics, potency, proper

dissolution profile, and absorption of specific formulations. Proper particle size grades of the

ingredients must be selected to produce an optimum blend for capsule filling.

For granules containing active ingredient/s the following procedure is used in the blending

units of BEXIMCO Pharmaceutical Limited;

Remove the blender cleaned label & update the logbook with product detail.

Display a product identification label at the display board.

Verify that the instruments to be used are within their calibration period Matcon IBC blender process timer. Blend Speed Indicator.

Check that the lid is securely fitted to the IBC.

37

Blend the IBC for 20 minutes at 15 rpm

Include the blender printout in the batch wallet.

Verify that the balances used for the IBC weighing are within their calibration period.

Weigh the IBC to determine the granules yield.

The weight of granules should be between 309.054 kg to 312.176 kg (99- 100%).Notify Executive if the yield is outside the limits. Executive to investigate and provide a reason.

Blending critical parameters

Blending time

RPM (Rotation Per Minute)

Sieving:

A sieve, or sifter, is a device for separating wanted elements from unwanted material or for

characterizing the particle size distribution of a sample, typically using a woven screen such

as a mesh or net

Steps for sieving:

Record temperature and relative humidity of the area before sieving.

Remove the equipment-Cleaned label. Update the log book with product details and display a product identification label at the room entrance.

Check that the raw materials are correctly labeled and sealed and have been weighted.

Transfer the following raw material into 1000 L IBC

Sieve the following raw materials through the Russell Finex Sieve fitted with 630 μm pore size screen into a labeled poly bags.

Compression:

Following granulation is compression where the granules are compressed to form tablets of

distinct shape, size, hardness, weight & thickness. BEXIMCO Pharmaceutical has 8

compression machines in the compression unit of the solid department in which the highest

punches station is 55 and the lowest is 18.

38

Compression is the method where force or pressure is applied to the granules or powders (in

case of direct compression) to produce tablets of desired shape and size with the help of tablet

press machine.

There are two types of compressions as seen in the tablet press units of the factory. These

includes:-

1. General Compression (Of previously made granules)

2. Direct Compression

Criteria to be followed in the compression process:

Verify that the machine is properly cleaned

Verify that no previous materials are present in the compression unit.

Remove the equipment cleaned label and set up the compression machine.

Update the logbook with details of the product and display a product identification label

at the production display board.

Fit new flat tubing to the IBC discharge cone.

Verify that the instrument to be used is within their calibration period.

Ensure the compression machine is set up with the following tooling

39

General Compression:

Granules (previously made)

Transfer granules in the hopper from intermediate bulk container on the

MATCON discharge station

Rising of upper punch & dropping of lower

Filling of die cavity through feed

Removal of extra granules by scrape off

Coming down of upper punch for Compression to produce

Raising of both upper & lower punches to certain

Pre-turret punch

Main compression

Ejection of tablet with the help of take out

Inner chop to outer chop and then pass through the de-duster and metal detector

Obtain conventional Uncoated Tablets of desired shape and size

40

DIRECT COMPRESSION:

Milling & Screening of active ingredients & the excipients

Mixing of the active ingredients along with excipients including lubricants & disintegrates in the IBC

Transfer mixture in the hopper from intermediate bulk container on the MATCON

discharge station

Rising of upper punch & dropping of lower punch

Filling of die cavity through feed frame

Removal of extra granules by scrape off plate

Coming down of upper punch for compression to produce tablet

Raising of both upper & lower punches to certain extent

Pre-turret punch compression and main compression

Ejection of tablet with the help of take out plate

Inner chop to outer chop and then pass through the de-duster and metal detector

Obtain conventional Uncoated Tablets of desired shape and size

Compression machines:

Seri

al

Name of the

machine

Machine ID Producer No. of

station

No. of

channel

Capacity Model

of

punch

1. Bosch

xpress300

Sld-M-EQ -13-

51

MANESTY

Machineries

Ltd.

Liverpool,

England.

30 1(with

deduster)

200000

tablets/hou

r

D type

2 MANESTY BB4

Sld-M-EQ-93- 018

MANESTY

Machineries

Ltd.

Liverpool,

England

35 2(with deduster)

240000tab lets /hour

B type

3 Fette-1200 Sld-M-EQ-

97025

Germany 30 1(with

deduster)

220000

tablets

/hour

BB

type

4 Fette-

3100(most

high speed

machine)

Sld-M-EQ-

97026

Germany 55 2(with

deduster)

594000

tablets /

hour

BB

type

5 Sejong 45 Sld-M-EQ-

06034

South Korea 45 2(with

deduster

400000

tablets /

hour

BB

type

6 Sejong -18 Sld –M-EQ-

09637

southkorea. 18 1(with

deduster

30000

tablets /

hour

B type

7 SEJONG-49 Sld-M-EQ-

09038

South Korea 49 2(with

deduster

150000

tablets /hour

B type

8 IMA active

kilian

Sld-M-EQ-

011062

Germany 37 1(with

deduster

200000tab

lets/hour

B type

41

42

COATING: A coating is a covering that is applied to the surface of an object, usually referred to as the substrate. The purpose of applying the coating may be decorative, functional, or both. The coating itself may be an all-over coating, completely covering the substrate, or it may only cover parts of the substrate

Reasons for coating:

To mask the taste, odor or color of the drug

To provides physical and chemical protection for the drug

To control the release of drug from the tablet

To protect the drug from the gastric environment of the stomach with an acid resistant enteric coating

To incorporate another drug or formula adjuvant in the coating to avoid chemical incompatibilities

To improve the pharmaceutical elegances by use of special colors and contrasting printing

CLASSIFICATION OF COATING:

Coating is of two types:

1. Film Coating o Aqueous coating o Organic coating o Enteric coating

2. Sugar Coating

In BEXIMCO Pharmaceutical Limited only film and enteric coating are done. Sugar coating

is not performed in the coating units of the factory. For enteric coating, the coating solution is

sprayed into 2 parts.

Part-I is sprayed to form a film on the surface of the tablet

Part-II solution is sprayed on the previously formed film so that the enteric coat can retain of

the film coat.

CRITICAL PARAMETERS OF COATING

Atomization pressure

Steam pressure

Spray pattern

Gun to bed distance

Spray rate

Pan depression

Program parameter

Height of core sample after pre-jag drying cycle.

43

STEPS OF COATING:

Suspension making for about 45-60

Compress tablet core in feeding

Pre jag warm up for about 30 min at 40®C

Drying + Spraying

Drying

Cooling

Unloading of coated tablet

Film coating Defects

Sticking & Picking -It is defect where isolated areas of film are pulled away from the surface when the tablet

sticks together and then apart.

-Insufficient drying and higher rate of application of coating are the main causes.

Remedies:

-Use optimum and efficient drying conditions or increase the inlet air temperature -Decrease the rate of application of coating solution by increasing viscosity of coating

solution.

Roughness It is the defect of spray coating process, where some of the droplets dry too rapidly before

reaching the tablet bed, resulting in deposits on the tablet surface of ‘spray dried’ particles

instead of finely divided droplets of coating solution.

44

Higher distance of nozzle from tablet bed or increase polymer concentration /pigment

concentration are the main cause.

Remedies: -Moving the nozzle closer to the tablet bed or reducing the degree of automization of

spraying

-Decrease the polymer concentration Orange peel effects

It is related to the inadequate spreading of the coating solution before drying. Appearance

similar to orange feel.

Rapid drying and high solution viscosity are the causes. Use mild drying conditions and use additional solvents to decrease viscosity of solution can

remedy

Bridging and filling

It is defect that renders the monogram or bisect indistinctness. During drying the film shrink and pull away from the sharp corner of a bisect, resulting in a

bridging of the surface depression. This mainly represent a problem with formulation.

Increasing the plasticizer or changing the plasticizer can decrease the incidence of bridging.

Filling is caused by applying too much solution or too fast solution, resulting in a thick film

that fills and narrows the monogram or bisect.

Carefully monitoring of the fluid application rate and through mixing of the tablets in the pan

prevent filling

Blooming It is defect where coating becomes dull immediately or after prolonged storage at high

temperature.

Blooming or dull film is generally because of higher concentration and lower molecular

weight of plasticizer. So use lower conc. And higher mol.wt grades of plasticizer.

Blistering It is local detachment of film from the substrate forming blister.

It is related to entrapment of gases in or underneath the film due to overheating.

Too rapid evaporation of solvent from the core and the effect of high temperature on the

strength, elasticity and adhesion of the film may result in blistering.

Milder drying conditions are way of elimination.

45

Cracking /splitting It is defect in which the film either cracks across the crown of the tablet(cracking) or splits

around the edges of the tablet (splitting)

Cracking occurs if internal stress in the film exceed the tensile strength of the film. The tensile strength of the film can be increased by using high mol.wt. polymers or polymer

blends.

Colour variation.

This can be caused by processing conditions or the formulation. Improper mixing, uneven

spray pattern, and insufficient coating may result in colour varistion.. The migration of soluble

dyes, plasticizers, other additives during drying may give the coating mottled or spotted

appearance

Encapsulation:

In the manufacture of pharmaceuticals, encapsulation refers to a range of

dosage forms—techniques used to enclose medicines—in a relatively stable

shell known as a capsule, allowing them to, for example, be taken orally or be

used as suppositories.

According to World Health Organization, capsules are solid dosage forms with

hard or soft shells. They are of various shapes and sizes and contain a single

dose of one or more active ingredients. They are intended for oral

administration.

When excipients are used it is necessary to ensure that they do not adversely

affect the stability, dissolution rate, bioavailability, safety or efficacy of the active

ingredient(s); there must be no incompatibility between any of the components of the dosage

form.

46

The different categories of capsule include:

Hard capsules;

Soft capsules;

Modified-release capsules

The active is filled in the empty the hard gelatin capsule shell in the form of

Powder

Pellets

There are 4 different sizes of empty hard gelatin capsule shells used in

BEXIMCO Pharmaceuticals Ltd. for general production, which include-

Capsule shell size 0




BEXIMCO Pharmaceuticals Limited encapsulated only hard gelatin capsules.

Process of encapsulation:

Polishing of capsules, when needed, is done first by Capsule Polishing machine which

removes dust, adherent powder and gives a shiny appearance.

Machine used for encapsulation

Encapsulation Unit Name Capacity Supplier

01. MG-2 Futura 50000 capsules/hour MG America

47

Packaging

Pharmaceutical packaging has to be carried out for the purpose of the safety of the

pharmaceutical preparations in order to keep them free from contamination, hinder microbial

growth, and ensure product safety through the intended shelf life for the pharmaceuticals. A

product is packaged for its safe delivery to the target customers. It should be safe, compatible

to the product contained and robust enough to resist the hazards met during the overall

transaction and shell-life. Packaging is a critical tool in the pharmaceutical industry for

product delivery and regulatory compliance; many pharmaceutical companies will do all their

packaging within a contamination free environment or Cleanroom.

Packaging materials are of two types:

Primary Packaging materials (PVC, Aluminum foil, PVDC)

Secondary Packaging Materials (Printed cartoon, Liner, Labels, Leaflet, Printed tape)

Primary Packaging

Packing Forms

The following forms of packs available in this company:

Blister pack, used for tablet, capsule,

Strip pack, used for tablet and capsule

Primary Packaging Machine

Packaging unit Machine Supplier/origin

Blister 085 Klockner Hansel Germany

Blister 042 Otto Hansel Germany

Blister 043 Otto Hansel Germany

Blister 074 Klockner Hansel Germany

Blister Elmac Elmac India

Blister Pampac Pampac India

Blister Hoong A Hoong A Korea

Strip Packaging Gansons Strip Packaging India Machine 1

Gansons Strip Packaging India

Machine 2

48

Blister Packaging

The primary component of a blister pack is a cavity or pocket made from a formable web,

usually a thermoformed plastic. This usually has a backing of paperboard or a lidding seal of

aluminum foil or plastic. A blister that folds onto itself is often called a clamshell. After

packaging the strips is tested I leak Test apparatus and then passed on to the secondary

packaging area through conveyor belt

Blister packs are useful for protecting products against external factors, such as humidity and

contamination for extended periods of time. Opaque blisters also protect light-sensitive

products against UV rays.

Steps of Blister Packaging

Strip Packaging The tablets formed by compression are enclosed in strip packages. The strip utilizes the rolls

of aluminum foils which are scaled together tablet with little application of heat, the coding is

done stereotypically. After the strip packing the strips are checked for leak in leak test

apparatus. The strips are then passed on to the secondary packaging area through conveyor

belt. Roller heating temperature limits -1200c-1400c.

49

IPC for packaging

Leak test

Coding

Appearance

Stoppages/Adjustments

color

flavor

Bottle filling area for solid product: Bottle filling machine

Producer:Tiwan

ID:SLd-P-EQ-89011

Cap sealing o2

ID:Sld-p-EQ-03012 Station :6

Bottle Washing machine Name :pharmalab

Producer :India

Channel-64

Water spray station:28

50

Bottle dryer Name: Kilburn oven ID;SLd-P-EQ-78023

Temp.-150c

Capacity :7200

Labelling machine

Name:Autolabelling

ID:Sld-P-EQ-95014

Producer:England

Secondary Packaging Secondary packaging is the middle layer of packaging Here different packaging line area assigned differently i.e. one packaging line comes from

each strip packaging area, one from blister packaging and one from bottle packaging area. All

materials received through conveyor from the primary packing area are suitably checked and

boxed which are packed in cartons and cooled sealed. Then operate the machine for

packaging.

Roller forming temperature – 140 ⁰C Sealing roller temperature – 220 ⁰C Perform leak test on 10 strips at a time

Final packaging The stripped capsule arrived at the secondary packaging area through the conveyor belt from primary packaging area. Stripped capsules undergo manual inspection for any irregular

printing or sealing or any damage. Then they are packed in cartoon which are subsequently

packed in specified corrugated boxes and sealed. The boxes are then to the finished goods

storeroom.

51

Problems that may arise during packaging are:- 1. Empty pocket 2. No pocket

3. Damage of tablet/capsule

4. Printing mistake

5. Unclear printing

52

RESEARCH

&

DEVELOPMENT

53

Pharmaceutical companies generate innovation in health care by inventing and developing

new treatments for previously untreated health problems (radical innovation) and also

developing improved versions of existing medicines or new indications for them e.g. to treat

diseases other than those for which the medicines were originally invented (incremental

innovation). Often underestimated, these incremental innovations significantly improve

health and quality of life, by providing patients with more choice, better risk tolerance, easier

dosing and administration.

R & D deals with the following functions

a. Formulation of new product

b. Reformulation (where required)

c. Reprocessing (if required)

d. Problem solving related to manufacturing/formulation when required (Trouble shooting )

e. f.

Preparation of B.P.R/B.M.R for a new product. Development of existing products.

g. Development of manufacturing procedure.

h. Analytical method development

i. Selection of packaging mood.

j. Stability study and determination of product shelf life.

Development of new product

Product development department is responsible for the establishment of formulation and for

the preparation of technical part of recipe of drugs. Steps involved in new product

development

Step-1: Product information from marketing department along with necessary attributes such

as

Dosage form Strength

Step- 2: Pre formulation study of the active drug and excipients

Chemical activity Function Interaction Boiling point Contraindication Moisture content, etc.

Step-3: Preparation of technical part of recipe for registration which include,

54

Formulation Manufacturing procedure Product specification & Acceptance criteria

Step-4: Requisition to purchase department for new material to give laboratory trial.

Step-5: Collection of raw material of active and excipients with necessary documents. (COA,

MOA, MSDS, stability report etc.)

Step-6: Product development (PD) laboratory trial batch production.

Step-7: Checking of physical and chemical parameters of PD lab trial batch.

Step-8: Selection for trial batch for stability study and prepare at least three batches for

stability study.

Step-9: Conduction for stability at three conditions,

Room temperature 300C ± 20C, RH 65% ± 5%. 400C ± 20C, RH 75% ± 5%.

Step-10: Preparation for stability study report and determination for product shelf

Step-11: Preparation for provisional product data sheet.

Step-12: BPR/BMR preparation for pilot come commercial batch if every aspect is satisfied

which include -

Product name Code Batch no Theoretical yield Batch size

Step-13: Production of at least three successful pilot come commercial batches.

Step-14: Finalization for formulation.

Step-15: Preparation for final BPR/BM for commercial production.

REFORMULATION

It is done for three reasons:

For farther improvement for product quality. For increase productivity (by working on process). For more cost effective formulation maintaining quality.

55

DEVELOPMENT OF EXISTING PRODUCTS

Product development department also deals with the development of existing product formulation.

Objective

Increasing the equality of the product. Prevention of any type for problem exiting in the product. To save time and cost. Increasing the patient acceptance.

STABILITY TESTING (AST)

Stability testing is done in following conditions:

400C ± 20C, RH 75% ± 5%. 300C ± 20C, RH 65% ± 5%. At room temperature

TROUBLE SHOOTING

During manufacturing of a new product in pilot come commercial batch many problems may arise. In

that case personnel from product development department (PDD) investigate the problems and take

necessary steps and remedies to minimize those problems and carry the manufacturing process

successfully.

Such as sudden capping of tablet or denting incase of capsule or may be pH imbalance in case of

liquid may occur. These types of problems are investigated by PD personnel and take necessary

actions to solve these problems immediately.

STABILITY

Stability test is done for a finish product to predict whether the product be stable for sufficient time to

ease marketing of the product. For stability test ICH guideline (International Conference on

Harmonization) is followed. Stability test is done for any new drug, change in the formulation, change

in primary packaging material, for change in the source of raw material and for registration purpose.

PURPOSE OF STABILITY TESTING

1) For the required condition of the product 2) Increase the Shelf-life 3) Retention sample analysis

4) Fixation of expiry date

There are two type of stability testing,

A) Long term/ Real time stability test

B) Accelerated stability test

56

A) Long term/ Real time stability test

In real time stability test, the product is kept up to one year more than predicted expiry date

i.e. shelf life. The storage condition is-

Temperature: 30 ± 2oC Relative humidity: 60 ±5oC

B) Accelerated stability test

In accelerated stability products are kept for short life (3or 6 month) in accelerated condition.

Upon the stability over this condition, shelf life is predicted.

Temperature: 40 ± 2oC Relative humidity: 75 ±5oC

STORAGE CONDITION AND SAMPLING INTERVAL

Study Storage Condition Sampling intervals

Long term 300C 20C &

65% RH 5% RH

3,6,9,12,18,24,& 36 Month

Accelerated 400C 20C &

75% RH 5% RH

0,1,2,3,8,6 Month

PREDICTION OF SHELF LIFE

If a product is stable over 1 year real time stability test, then 2 year of shelf life can be predicted

for the product. If a product is stable over 3 months accelerated stability test, then 2 year of shelf life can be

predicted for the product. If suppository is stable over 1 year real time stability test, then 1.5 years of shelf life can be

predicted for the product. Accelerated stability test can‘t be done for suppository, as it tends to melt on body temperature.

MICROBIOLOGY

Microbiology division of QC performs microbiological tests. A microbiological test

determines the potency of products as well as the presence or absence of microbes in

products Microbiological tests relates to potency determination includes the following

products of Beximco: Azithromycine, Azithrocine capsule, etrocine dry suspension, etrocine

tablet, Gentocep cream, Anustant ointment, Genlomycin, Neomycin, Nystatin.

The microbiology department of BEXIMCO pharmaceutical Limited works with the QA

department. For implementation of GMP microbiology department is very important.

Microbiology section will just determine the microbial contamination monitoring.

57

The function of microbiology laboratory can be presented as follows,

Microbial count

Water, raw materials, bulk

samples, finished products,

packing containers

LAL test sterility test

Water, indictable, raw

materials, other sterile

products

Environmental study

All manufacturing & filling

area including aseptic filling

room

Validation Steam & dry heat sterilizer,

oven & cleaned equipment

Personal hygiene test Aseptic production area

operators

Bio- assay Antibiotic raw materials &

finished products

Major tests are performed by microbiology department

Bioburden test (microbial count) Bioassay Sterility test Test for water

Microbial count

These tests are performed for

Raw material (Active pharmaceutical ingredient & excipients)

Water (PRW & WFI)

Finished dosage form

Pre-sterilized

58

Required media

TSA (Trypton soya agar) SDA (Sabourauds dextrose agar)

Flow chart for microbial count

For solid take 10mg & for liquid take 10ml of sample

Add 90ml of PBPS (Phosphate buffer peptone salt)

From these solution taken 1ml in to TSA media for bacterial growth & 1ml in SDA mediafor

fungal growth observation.

STERILITY TEST

Sterility test is an important test for sterile product. All product labels sterile must pass the sterility test, having been subjected to an effective process of sterilization.

Media

TSB TGM

Process

Collect sample according to sample volume and dissolve into a suitable solvent and passed through the filter paper

This filter paper is cut into 2 pieces then one was taken into TSB media & another was taken

into TGM media

Incubation for 14 days then visual inspection done (if the microorganism present the media

will becomes turbid)

59

LAL TEST

The meaning of LAL is LimulasAmoebocyte Lysate. This test is performed to identify the presence of

pyrogen. The procedure of the test involves taking 100 ml of product and 100 ml reagent in a small

tube. The mixer is then keeping into incubator for 1hr for incubation. After incubation the tube is

inverted to check whether the gel is formed or not. Generally 0.125EU/ml is present then gel is

formed. If gel is formed there is the presence of Pyrogen and if not the solution is liquid the product

satisfied the test and ready for use.

Machines/ Equipments present in R&D department:

In formulation sector:

High speed mixing granulator made in Thailand.

Film coating machine- NR cota, Thailand.

Fluid bed dryer- Sapphire, India.

16 station compression machine- Manestry, England.

USP Dissolution tester- Erweka, Germany.

Tap density tester (USP) - Electrolab.

Moisture analyzer- Sartorius, Japan.

Hardness tester- Erweka, Germany.

Multimiller- India.

Oven.

Dehumidifier.

Rapid dryer- Retsch.

Weighting balances- Sartorius, Japan.

In Analytical sector:

HPLCs

USP Dissolution tester

UV Spectrophotometer

Potentiometer

Balances

Viscometer

MP apparatus

Shieve shaker

Tap density tester

DT machine

Hardness tester

60

Fume hood

Dryer

FTIR

Hot stage microscope

Vacuum oven

Moisture analyzer

TOC analyzer

Refrigerators

AAS

GC

Malvern particle size analyzer

Polarimeter

Climate zone:

To store a drug in suitable storage conditions and to export drugs to foreign countries, the

knowledge of climate zone is very important fact. According to ICH (International

Conference on Harmonization), the whole world is divided into five following climate zones

on the basis of environmental conditions:

Climatic Zone Temperature Relative Humidity

Zone I 21ºC ± 2ºC 45% ± 5%

Zone II 25ºC ± 2ºC 60% ± 5%

Zone III 30ºC ± 2ºC 35% ± 5%

Zone IV 30ºC ± 2ºC 65% ± 5%

Zone IVb 30ºC ± 2ºC 75% ± 5%

Bangladesh is in the Zone IVb. So the environmental factors must be considered to ensure

proper storages of drugs.

LIQUID DOSAGE FORMATION

61

62

The production unit of BEXIMCO Pharmaceuticals Limited is highly maintained to minimize

the risk of serious medical hazard due to cross-contamination , dedicated and self contained

facilities are available for the production of Pharmaceuticals products ,

There are adequate working and in-process storage space to permit the orderly and logical

positioning of the equipments and materials to minimize the risk of confusion between

different pharmaceutical products and their components. To avoid cross-contamination and to

minimize the risk of omission or wrong application of any of the manufacturing or control

steps.

Pipe works, light fittings, ventilation points and other services are designed, and sited to

avoid the creation of recesses that difficult to clean.

The area is effectively ventilated, with air control facilities appropriate to the products

handled, to the operations undertaken and to the external environment. These areas are

regularly monitored during both production and non-production period to ensure compliance

with their design specification.

Premises for the packaging (Both primary and secondary) are specifically designed and laid

out to avoid mix-ups or cross contamination.

Production equipments are thoroughly cleaned on schedule basis they are cleaned as back to

back cleaning and complete cleaning.

Function:

Commercial batch production Readjustment of instruments and facilities according to the instruction of QA department Small - scale experimental production of newly developed product according to the

instruction of PD department.

Supervision of raw materials and packaging and final products in connection to QC

department

Supervision of packaging process

Calibration and maintenance of the production unit‘s machinery.

Objectives:

Fulfill the market demand High productivity Reproducibility Quality production

The oral use of liquid pharmaceuticals has generally been justified on the basis of

administration to those who have difficulty in swallowing solid dosage form. A drug

administered in solution is immediately available for absorption & in most cases is more

rapid in action.

63

LCO Department of Beximco Pharmaceuticals Limited produces about 84 products of

various dosages form including .

(i) Syrup (example: Napa, Aristoplex)

(ii) Suspension (example: Lactameal, Flatameal DS)

(iii) Nasal spray (example: Decomit)

(iv) Drops (Example: DefluxPed. Drop)

(v) Suppositories (example: Napa, Ultrafen)

(vi) Cream, Ointment, Gel (example: Neostin cream, Anustat ointment, Ultrafen gel)

LCO Department of BPL consists of following seven lines:

Line I: Syrup, Suspension

Line II: Antacid preparation

Line III: Small volume oral liquid preparations

Line IV: Cream, Ointment

Line V: Suppository manufacturing, filling & packing

Line Vl: syrup manufacturing

Line Vll: export packaging

INSTRUMENTS USED IN LIQUID SECTION

Name of machine Manufacturer/supplier Capacity

Automat Filling & Sealing Machine India 5000 bottles/hr

GreatidOinment Filling & Sealing Machine

Taiwan 2400 tubes/hr

Pharmalab Bottle Filling & Sealing Machine

India 5000 bottles/hr

Gansons Bottle washing Machine India 240 bottles/hr

Manufacturing & storage jacketed vessel Australia 5000 liter

Manufacturing & storage jacketed vessel Australia 3000 liter

Manufacturing vessel India 1000, 500, 2000 liter

QUALITY CONTROL DEPARTMENT

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65

QUALITY CONTROL:

Quality control department is a set of procedure which is performed to ensure that the raw

materials , finished products and packaging materials adheres to defined set of quality

criteria or meets the requirements of the clients or customer at an economical level. ―Keep the

quality up‖ with that slogan Quality Control Department of BEXIMCOPHARMA performs

its day-to-day duties. This department is stuffed with pharmacist, chemist and microbiologist

who assess and assure that entire production process has been completed satisfactorily and

satisfied all the aspects of GMP.

Objectives,

Ensuring quality and stability Reducing product loss Personnel train up Better interdepartmental and employee relation GMP practice

QC is responsible for,

1. Analytical testing of RM 2. Inspection of PM 3. In-process control (IPC)

4. Testing of finished products

Quality control units:

Central quality control lab(Track-1)

Quality control lab (Track -2)

Quality control lab (infusion)

Requirements of Quality Control Department:

Laboratory

Manpower

Machine

Method

Material

Quality control activities,

Having equipped and supported with trained with analytical staff the QC laboratory

has to perform the following major responsibilities:

Assessment of microbiological quality of raw material

Assaying potency of antibiotic

Assessment of the intermediate products for further processing Assessment of the bulk products for their release, Reprocess, reject, etc. Assessment of the finished products for their release, reject, etc,

66

Storing retention samples from each hatch

LOT of raw materials

Maintaining batch wise full duality control tests records, signature of the person who

performs the tests.

Batch documentation and batch sentencing

Ensuring precision and accuracy of all testing methods

Performing environmental monitoring checks

Calibration and standardization of laboratory equipment.

Control of laboratory regents

Testing of any return goods

Analysis of complaint samples with their corresponding retained samples.

Prepare QC related documents for DTL.

Management of stability study program.

Method development of new drug substances/products.

Good Manufacturing Practice (GMP) in QC:

GMP provides basic standards for the manufacture of drugs and from the basis on which each

company build its own system procedures to ensure the product quality. GMP ensures that

products consistently produced and controlled to the quality standards appropriate to their

intended use .There are number of national & international GMP regulatory boards

WHO

PIC

FDA

MHRA

TGA

Types of assay done by quality control

1. GENERAL:

Orientation of QC laboratory

GMP and GLP

Documentation

Raw/packaging material and finished product sampling

Packaging material

Microbiology

Stability study

2. ANALYTICAL

Chemical and physical analysis

Analytical development

67

3. INSTRUMENTAL

A) High performance liquid chromatography(HPLC)

B) Gas chromatography(GC)

C) Fourier transform infrared spectrophotometer(FTIR)

D) Partical size analyzer(Malvern)

E) Atomic absorption spectrophotometer(AAS)

F) UV visible spectrophotometer

G) Dissolution tester

H) Disintegration tester

I) Suppository testing apparatus

Disintegration tester

Softening time determination apparatus

Melting time determination apparatus

J) Karl Fischer titrator

K) Polarimeter

L) Potentiometric tritator

M) Other instruments

pH meter

Melting point testing apparatus

Viscometer

Refractometer

Stampfvolumeter

Table top centrifuge

Muffle furnage

Vaccum oven

Sonicator

Ultrasonic bath

Water bath

Centrifuge machine

Microscope

Packaging material

A,B,C class are classified according to vendors quality

Highest rating vendor is selected

But if source is changed then a new parameters are set for the new parameters

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Packaging materials

Tests

Carton Appearance, weight, moisture content, sulphated

ash

Shipping carton Weight, dimension, thickness, appearance

Plastic cap Weight, appearance, length, diameter, volume,

capacity

Dropper Weight, appearance, length, diameter, volume,

capacity, adaptability with bottle, carton, and

plastic cover.

Musk tap Appearance, width, adhesiveness

Water measuring flask. Weight, appearance, length, diameter, capacity

5ml spoon (plastic). Weight, appearance, length, diameter, capacity

Blisters Height, neck diameter, body diameter, weight,

overflow capacity,

machine acceptance, and light transmission

Inert cartoon Height & level, description, weight, dimension

MICROBIOLOGY

Microbiology division of QC performs microbiological tests.

A microbiological test determines the potency of products as well as the presence or

absence of microbes in products.

Microbiological tests relates to potency determination include the following products

of BEXIMCO Pharmaceutials –

1. Azithromycine

2. Azithrocine capsule

3. etrocine dry suspension

4. etrocine tablet

5. Gentocep cream

6. Amustant ointment

7. Gentomycine

8. Neomycine

9. Nystatin etc.

69

Function of microbiology section

Microbial count- Water, raw materials, bulk samples, finished products, packing

containers.

LAL test/sterility test- Water, raw materials, parenteral products, other sterile

products.

Environmental study- All manufacturing &filling area including aseptic filling room.

Validation- Steam &dry heat sterilizer, oven & cleaned equipment.

Personnel hygiene area- Aseptic production area operators.

Bio-Assay- Antibiotic raw materials &finished products.

Activities of microbiological section

Microbial limit test of raw materials and finished products-

Total aerobic bacterial and fungal count

Detection of pathogens like E.coli, Salmonella sp, Staphylococcus, Pseudomonas

aeruginosa.

Microbial assay of raw materials and finished products

Environmental monitoring

Test for water

Bioassay.

Equipment in Microbiological section

Laminar air flow

Hot air Oven

Autoclave

Incubator

Rota mixer

STABILITY STUDY

Climatic zone According to ICH (International conference on Harmonization), whole world is divided into

following climatic zones in considering the environmental conditions.

Zone-1 (cool & cold country, 8-15 0C)

Zone-2 (cold country)

Zone-3 (hot country)

Zone-4 (Hot &humid country)

According to ICH guideline our country fall in zone 3&4. Stability study is performed

according to ICH

70

Stage Tests

Raw Materials a. Assay

b. Description

c. Solubility

d. Identification

e. Optical Rotation

f. Purity

g. Water content Determination etc.

In Process Quality a. Disintegration Time b. Quantitative Assay c. PH

d. Identification

e. Weight variation Test

f. Dissolution Test

Finished Products a. Assay b. Description

c. Identification

d. DT

e. Weight variation test

Packaging Material a. Visual inspections b. Weight

c. d. Size and Diameter

e. Dimention

f. Adaptability

g. Adhesiveness

Types of study Experimental condition Testing frequency

Long term 25⁰c temperature , Done in every 3 months for

60%relative humidity 1st year

Intermediate 30⁰c temperature , Done in every 6 months for

65%relative humidity 2nd year Done only once for 3rd year

Accelerated 40⁰c temperature , Done initially.

75%relative humidity Then in 3rd month and 6th Month

ANALYTICAL ANALYSIS

Tests Done for Quality Control:

Instruments which are in use in QC departments

Name of instrument Model Manufacturer Origin Use

Electronic analytical BP 210s Sartorious AG Germany Analytical weighing

precision balance

Electronic balance PT 310 Sartorious AG Germany Weighing

Electronic balance EL300 Shimadzu Japan weighing

Electronic BD 120L Mettle tiedo AG USA Do

balance(Top balance)

IR Moisture analyzer MA 30 Sartorious AG Germany Moisture determination

Disintegration test ZT3/6 Erweka,GmbH Germany Disintegration testing

apparatus

Dissolution tester DT 6L Erweka,GmbH Germany Determination of dissolution

Dissolution tester DT 700 Erweke, gmbh germeny Determination of dissolution

Rotating bottle none Fabricated in Germany Do disintegration tester BPL

Suppository ST 30 Erweka,GmbH Germany DT of suppository

disintegration tester

Suppository melting SSP Erweka,GmbH Germany Determination

point apparatus of melting point

Suppository softening PM3 Erweka,GmbH USA Determination

time tester of softening time

Humidity control NEC-234R Newtronic India Drying oven equipment

Incubators Kottermann Germany Incubation

Jolting Stan PF STAV2003 Karl-Kolb Germany Tapping volumeter Scientific

Supplies

Atomic absorption Ice 3000 Thermo scientific USA Metal detection

spectrophotometer(AAS) series

Gas chromatography 2010 Shimadzu Japan Volatile compounds potency

HPLC(high performance

liquid chromatography)

E 2695 Water USA

Sample potency

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HPLC SPD-20 A Prominence, Japan Sample potency

Shimadzu determined

HPLC Ultimate Dionex Germeny do 3000 autosampler

UPLC(ultra Waters Usa Detect the unknown performanceliquid material in short time

chromatography)

UV spectrophotometer UV 1800 Shimadzu Japan UV spectrum

Potentiometer 888 titrando Metrohm UAE Potentiometric titration

Karl fisher 890 titrando Metrohm UAE Water content determination

Karl fisher DL 18 Mettler Water content determination

Particle size analyzer AP2000 Malvern UK Particle size determination

Polarimeter H 532 Schmidt+ Optical rotation halensch

Refractometer AR 600 Leica Refractive index

Infrared spectro Prestige - 21 Shimadzu Japan Identification of raw

photometer material

FTIR Prestige-21 Shimadzu Japan do

Tap density tester Tap21 LOGAN USA Determine bulk density instruments corp of raw material

Viscometer DV–I Brookfield USA Viscosity determination PRIME

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74

QUALITY ASSURANCE DEPARTMENT:

Quality assurance is the heart of the pharmaceutical company because in this section quality

of the production is assured. To maintain cGMP quality assurance department is the most

important sector for any company. The system of QA appropriate for the manufacture of

medicinal products should ensure that medicinal products are designed & developed in a way

that takes the account of requirements of GMP &GLP (good laboratory practice). The quality

measured physically, chemically or microbiologically. The quality assurance ensure the

quality of the product this department inspected the quality is maintained or not. A

pharmaceutical product must satisfy certain standards to claim its quality. The main

characteristics of any drug, in dosage form are- safety, potency, Efficiency, stability,

Acceptance, regulatory compliance. To produce quality drug product, quality must be

ensured in:

Every step in the production In maintaining environment Personnel Equipment Operating procedure

Quality Assurance (Definition according to DIN ISO 8402)

All planned and systematic actions necessary to provide adequate confidence that a product

or service will satisfy given requirements for quality.

The impact of total quality maintenance is-

Improved operating procedure.

Greater customer satisfaction.

Increased financial performance.

Quality Assurance- Its importance creates its need. Quality assurance is a broader concept

ranging from development, quality control, production, distribution, and inspections that

individually or collectively influence the quality of a product. Quality assurance department

does hold an important responsibility of making sure effective quality control tests are

included at right stages and executed perfectly at proper stages of product life cycle. Quality

Assurance applies for both drug substances (APIs) and medicinal products, and includes

current Good Manufacturing Practices (cGMPs), as well as any necessary analytical testing

and stability studies. Quality assurance (QA) is a vital as well as a very organized department

in Beximco pharmaceuticals. It helps in ensuring the quality of a product till the hands of

consumers.

75

Quality assurance activities:

Validation of three consecutive batches. Training of GMP and SOP Audit - vendor audit and

Internal audit i.e. self inspection

Stability testing

IPC

QC

Quality incident report - corrective action, preventive action (CAPA)

Change Control Request

Out of specification

Customer complain handling

Regulatory activities

Certificate of Analysis (CO A) generation

Release for sale certificate.

Orientation

Product recall

Product quality review etc.

76

Functions of QA department

1. Warehouse:

Visual Inspection of incoming raw materials and packaging materials

Sampling of raw and packaging materials for Amoy, Microbial and Retention

test.

On the basis of the analytical results, release or rejection of raw and packaging materials are

done.

2. Dispensing area:

The QA dispensing officer monitors dispensing process thoroughly and attaches dispensing

cards to materials.

3. In- process checking

Solid Department

Granulation area

a) Machine cleanliness and room conditions are checked and line clearance is permitted

b) LOD (loss on drying) of granules measured

c) Compression Area

Machine cleanliness and room conditions are checked and line clearance is permitte

Qurantine area

On the basis of QC reports tablets are released for packaging.

Packaging area

Before packaging starts, the room and machines are checked for cleanliness.

LCO department

Before starting a new batch production room‘s cleanliness, manufacturing tank

cleanliness, room temperature and %RH are checked.

After preparation of the product in manufacturing tank, the following are checked by

QA department.

PH of preparation

Viscosity

Assay

Filling and sealing:

During filling and sealing, the following parameter are checked

77

o Proper weight

o Proper volume

o Cleanliness

o Microbial test of sealing preparation

o In case of suppository teak test is done

In packaging area:

QA officer checks the following-

o Batch printing

o Inner and shipping carbon at regular time interval

In Suppository section

Before start up of manufacturing or filling machines/rooms are checked for

proper cleaning and good house keeping.

During manufacturing room temperature, vessel temperature, pump

temperature, congealing temperature, room humidity, hardness, weight etc.

are checked.

In Inhalation section

The manufacturing vessel and area are checked properly before start up of

manufacturing.

During manufacturing weight of the ingredients, mixing time, temperature,

rpm etc. are checked.

During packaging the containers are checked for leak, total actuation no.,

dose/actuation, batch printing etc.

Sampling and approval/disapproval is done like other section.

Documentation:

The basic rules in any good manufacturing practice (GMP) regulations specify that the

pharmaceutical manufacturer must maintain proper documentation and records.

Documentation is most important task of the quality assurance department. The purpose of

documentation is to record import information with evidence. GMP requires that a complete

and accurate records of all raw/packaging materials, finished product, BMR, BPR, have to

maintain for any necessary forcing back of any time.

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.

INFUSIONS UNIT

79

INFUSIONS UNI: Infusion is a very sophisticated product where highest purity & quality is maintained because

this is introduced into patient‘s systemic circulation. A micro corruption may lead to death. In

BEXIMCO Pharmaceuticals the quality & purity of infusions products are maintained

strictly. They mainly produce dextrose saline.

The infusion preparation involves 2 main operations-

1. Preparation of WFI

2. Preparation of solution.

Followed by 2 operations like-

I. Bottle preparation & Autoclave

II. Packaging.

A. Preparation of WFI:

WFI means water for injection. It is used for injectables. It has some specific criteria like-

Totally pyrogen free.

Free from all ions & minerals.

Steps of preparing WFI in BEXIMCO-

Step 1: Natural water collection

Step 2: Removal of iron

Step 3: Chlorination

Step 4: Removal of bad odor &pyrogen

Step 5: Removal of minerals.

Step 6: Removal of Pyrogen

Step 7: Temperature minimizatio

Process of Preparation:

80

Aeration Chamber (Compressed

air supply)

Sand & Gravel Filter

Raw water Over Head Tank (Capacity 5000L)

Pre-filter 15µ

Charcoal bed

Chlorine dosing

Filter

Raw

Water

Tank

(2000L)

2.5

µ

Filter

.22

µ

C A C A

A N A N

T I T I

Filter

MULTI

BED

Distillate Tank

(6000L)

Temp. 80-900C

Steam distillation &

Condensation

DM Water

storage

Tank(4000L

)

.22

µ

2.5

µ

Filter

Heat Exchanger

WFI for Consume

81

AREA CLASSIFICATION

Class BIL Classification

Location Specification 0.5 µm 5.0 µm

Clean Grade D Class Personal air lock, 100000 700

class 100000 material air lock,

bottle pack area. Grade C Class Injection, molding 10000 70

10000 room, solution

preparation room,

clean corridor,

weighing room

Grade A Class Under laminar air 100 None

100 flow

Manufacturing and Packaging Steps for LVPF:

82

Different section of infusion unit:

Production: Solution preparation and packaging

Engineering: Bottle pack, injection moulding, autoclave, utility.

QA and QC: Quality of the product.

Warehouse: Quarantine approval and reject materials.

Quality Control Department QC performs physical, chemical and microbiological test

Physical test

This is mainly done for packaging materials

o Dimensions o Weight o Adaptability

Chemical test

This is done for raw materials, finished product and wfi

o pH value o Density o Solubility o LOD o Optical rotation o Acidity/Alkalinity

Quality Assurance Department The following activities are performed by QA

Inspection Raw materials Packaging materials

Minerals status

Label

Sampling Raw materials Packaging materials

Bulk solution minerals

Cleaning sampling

Finished product

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In process control IPC of raw materials IPC of bulk solution

IPC during bottle pack

Microbiology Department Microbiology test perform an important role to ensure the quality of the parenteral products

in the various steps ranging from raw materials to finished product.

In microbiology laboratory contains the following rooms

o Testing and incubation o Media preparation room

The total testing procedure can be summarized as follows

o Sample collection o Media preparation o Culture preparation o Incubation o Colony count

The microbiological test procedure includes

o Test of raw materials and packaging materials o Test of finished products o Environmental control o Purified wateriest o Monitoring of surfaces o Personnel hygiene

ENGINEERING SERVICE & UTILITIES

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85

ENGINEERING SERVICE & UTILITIES:

BEXIMCO pharmaceutical Ltd. has a complete and sound Engineering department for

supporting the frequent production. The engineering department provide production

environment. The manufacturing of various products require cleanliness, machine in order.

Different type of water supply, the controls of air, ventilation of the company, control of the

temperature, control of the RH test of the new machine, repairing machines etc are most

important concern for the pharmaceutical industry. All of those are maintain by the

engineering department.

Function of Engineering Department

The function of the department is divided into two types

1. Maintenance or Utility service

2. Process

3. Power supply

Maintenance of existing system

The function of this section is to separate the utilities and services in the plant. They also

perform maintenance function. The utilities and service handled by this section are given

below-

Electricity Boiler Compressed Air HVAC system Potable / drinking water and purified water Central vacuum system Hot water Cold water Chill water

Maintenance of production machinery

Engineering department is also responsible for proper maintenance of production machinery.

This function is performed by the following two ways:

a) Scheduled maintenance

b) Troubleshooting or Breakdown maintenance

Compressed Air System

Compressed air is provided by compression unit. Compressed air required for

Driving portable tools, driving machinery, transmitting control signals and actuating

pneumatic control devices and is not expected to have an impact on product quality.

Terminal filters are also used before the user points of the machines where the products

come in direct contact with the compressed air.

86

Capacity is 10000 lit/min.

Chiller system

This system is involved in the production of chilled water which supplied through pipe to

produce air conditioning system. BEIMCO Pharmaceuticals has both compression &

absorption type chiller of which one in new solid & another is in old solid area.

Power supply

BEXIMCO Pharmaceutical Ltd. has its own complete power supply plant, which is

considered as the heart of the factory. They do not use PDB electricity. This power plant is

divided into two sections Low Tension (LT) & High Tension (HT). About 4000 kw power is

produced from LT sector & 1950 kw power is produced from HT sector.

QUALITY OF COMPRESSED AIR

The quality of clean compressed air is monitored and required to meet the clean

com air specifications. GPF (General Purpose Filter) and DRF (Dust Removal Filter) are used to remove

particle size down to 1µm. OVF (Oil Vapor Filter) are used to removal of particle size down to 0.01µm. Mirror test performed to check whether any water or oil exists in the compressed

air. Maximum oil remaining 0.01ppm.

HVAC SYSTEM

The simultaneous control of various parameters of air to the specific limit as required for the

manufacturing of quality medicine is known as air conditioning. BEXIMCO dedicated Air

Handling Units and other building service systems installed in the mezzanine floor with a

focus to prevent cross contamination.

HVAC system is required for

To maintain specified temperature (Here 240C)

To maintain specific relative humidity ( Less than 40% for some hygroscopic material

like ranitidine)

To remove dust particle from production area

To maintain proper airflow to the rooms ensuring that cross contamination does not

occur. To prevent microbial contamination in some area by maintaining particle size within the

tolerance range (using HEPA Filters etc).

87

Laboratory

Manufacture HVAC

Primary Production

area

DIFFERENT HVAC SYSTEM

HVAC Systems

Production Area

Warehouse

Secondary Production

Area

Dust Collect

Microbiology Lab

AN &Inst Lab

Raw material HVAC

PG HVAC

WATER TREATMENT PLANT

In BEXIMCO pharmaceuticals, raw water is treated in different stages to meet criteria

specified for various applications. Process water should meet USP pacification for purified

water. Besides soft water is used for boiler feed water and generator cooling tower. Pre-

treated water is used for drinking, sanitary, washing applications etc.

Water Treatment Plant

Iron removal

plant

Pre-treatment plant

Soft water plant

Purified water plant

Iron Removal Plant

Bore whole water is passed through deep tube well to Iron removal plant. Iron is removed

here with the help of sand filter. Alum is dosed to the raw water prior to entrance to the sand

filter. Required iron concentration is less than 0.1 ppm.

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Pre-treatment Plant

This consists of tank, pumps, sand filters, activated carbon filters and dosing systems. Raw

water pump takes water from the tank and force through the filtration media of the

Omnifiltration system. Flocculants such as alum is dosed to destabilize the colloidal particles

and to give rise to insoluble compounds before entry to the filtration media. Omnifiltration

system consists of two filters installed in series and controlled by diaphragm valves. Water

passes downwards through the filtering layers in the two units and flows out of system free of

particulate material or undesirable elements. Sodium hypochlorite is dosed for oxidization as

well as for minimizing microbiological contamination. Activated carbon filters remove color,

odor and free chlorine.

Softened water plant

Water from the pretreatment plant is stored in a 8000 liter storage tank from where it is

pumped through the treatment stages. Firstly water is pumped through a sand filter which

removes suspended solids. Sodium Metabisulphate is dosed into the filtered water to

neutralize any residual chlorine that could be harmful to the softener resin. Water is then

passed through a duplex softener to remove most of the calcium and magnesium, ions. The

softening system is operated in duty/standby mode. Regeneration of the water softener is

initiated automatically after a preset volume of softened water has been produced. Then

softened water is passed through a 10 micron cartridge filter to remove any resin particles.

The softened water is split to a 12500 liter soft water tank and a 2000 liter softened water

tank. The 2000 liter softened water tank provides a buffer for the soft water that is fed to the

purified water plant. Water from this tank passes through a UV sterilizer to control

microbiological contamination. An anti-scalent chemical compound is dosed into the

softened water to remove any excess dissolved silica that could damage the reverse osmosis

membranes. Caustic is dosed to increase the PH of the softened water. This plant produces

soft water with hardness less than 5 ppm.

89

PURIFIED WATER PLANT

5 micron filter

Duplex softener

Activated carbon filter

Buffer tank

PUMP (Reverse osmosis)

Pure water

CDI

Anode

Cathode

Feeding water system (<0.2 u filter)

UV sterilizer

Purified water tank (10,000 liter)

1st& 2nd Heating and cooling exchanger

Final UV sterilizer (254 nm Intensity)

User points

Recycle to purified water tank

Flow 11.4 m3/hr

Calibration section

This section is responsible to calibrated all the instrument and machines to ensure

performance & effectiveness. The general process is to calibrate the instruments and

machines against a standard which is also standardized against international standards.

Waste chemicals cause environmental pollution by decreasing dissolved oxygen by oxidation

The oxygen demand is maintained by the following method-

Waste Chemical in

ETP

Add nitrifying bacteria that

cause breakdown of

chemical

Oxygen penetration in

water from outside

Urea supply in ETPfor

nitrifying bacteria

Maintaining normal limit

of dissolved oxygen

No environmental

pollution

FLOW CHART OF CHEMICAL WASTE MANAGEMENT

Chemical waste

Liquid waste Solid waste

Treatment

Effluent treatment plant Alkali/ ammonia treatment in case

of antibiotics

Disposed outside Incineration 90

TRAINNG DEPARTMENT

91

92

BEXIMCO Pharmaceutical Ltd. arranges training for new employees to introduce with job

responsibilities & to comply with rules and regulations as well as to make them competent

with their respective job in the company. BEXIMCO also arranges training for existing

employees to update information to the point.

BEXIMCO provides 2 types of training generally-

a) In house training

b) External training.

In house Training: Beximco Pharmaceutical Ltd.

Training Procedure:

Training Need Analysis

Select ‗Resource Person‘.

Preparing training calendar.

Conducting training session.

Evaluation.

Documentation.

Re-training.

Training Type:

Class room training.

Audio visual training.

Interactive training.

On the job training.

Group exercise.

93

Training Applies To:

Manager

Officer

Workmen

Training for new employees:

Basic GMP

Safety overview.

On the job training

SOP

For existing employees:

GMP

Safety

Utility system

On the job training

SOP

95

The EHS department of Beximco Pharmaceuticals Limited (BPL) is concerned with the

disposal of waste in a way that does not damage the environment, safety of the personnel as

well as their health, for instance by arranging annual checkup for the existing employees and

pre medical check-up for the newly joined employees

Water pollution can be controlled by:

Physical treatment:Methods employed are-

Sedimentation and gravity settling methods

Adsorption process using activated carbon

Chemical treatment:Such a treatment is generally brought out by-

Coagulation,

Flocculation,

Emulsion Breaking,

Precipitation And

Neutralization.

Biological treatment: This is another treatment process which consumes oxygen dissolved in water.

Dust explosions

In pharmaceutical industries, a large number of grinding operations is employed. If iron

or stone pieces get into the disintegrator or other similar girding mills, sparks are emitted

which might bring about explosion with some easily combustible materials.

It has been found that in pharmaceutical and ancillary factories, dust of starch and dextrin

besides organic substances are extremely hazardous.

Suitable precautions against accumulation of dust should be taken.

The methods used for controlling dust in pharmaceutical industries are-

Filtration

Inertial separation

Electrostatic precipitation

Activities of Safety Department: First Aid Measures (Chemical):

Eye Contact:

Flush eyes with plenty of water for at least 15min, lifting lower and upper eyelids

occasionally.

Do not rub eyes

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Move away from exposure to fresh air

Get medical attention if symptom remains

Skin Contact:

Flush skin with plenty of water for at least 15 minutes.

Remove contaminated clothing and shoes

Wash affected areas thoroughly by washing with mild soap and water until no

evidence of chemical remains

Inhalation:

Move away from exposure to fresh air

Keep affected person warm at rest

Allow patient to assume most comfortable position

If breathing is difficult, get medical attention

Ingestion:

Wash mouth and throat with plenty of water

If vomiting occurs, give water to drink to assist dilution

Never give anything by mouth to unconscious person

Get medical attention show the label of chemical to doctor.

Action on hearing the fire alarm: The plan should instruct all personnel upon on hearing the fire alarm to act in accordance

with the agreed FEEP strategy and if a fire warden‘s scheme is in force they, on hearing the

alarm, should proceed to pre-determined positions to assist members of the public and staff to

leave the building by the nearest safe route.

Lifts and escalators should not be used due to possible electrical failure unless they are part of

a Personal Emergency Evacuation Plan.

Personnel should not re-enter the building with the possible exception of the Fire Team

Protocol followed by Beximco Pharmaceuticals:

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RECOMMENDATION

It is true that Beximco Pharmaceutical Ltd. never compromises regarding quality of products.

BPL strictly complies with the every aspect to ―Good Manufacturing Practice‖ (GMP) and

―current Good Manufacturing Practice‖ (cGMP) and maintain in process quality of a product

consistently. Moreover, personnel directly or indirectly involved in manufacturing have made

GMP as a culture in job responsibility. Though it is too much tough to find out any

suggestion for further modification, some recommendations are pointed below

I. LCO department lacks sufficient space and building facilities are not GMP standard.

That‘s why it is urgent to shift the department or to upgrade the facilities.

II. Environmental facilities and GMP regulations in TRACK-I should be increased.

III. As soon as possible, To start insulin manufacturing

IV. Antibiotic facilities is not enough so it should be increase

V. Principles followed for the products that are exported in foreign countries, should also

be followed for local or domestic products.

VI. MDI plant should be revealed to the trainee.

VII. There should be an audio visual round system for the trainee before starting their

action.

VIII. Central warehouse of Beximco pharmaceutical is very large but the location is not

well arranged.

IX. Spacing problem in compression unit. So, space should be wider than present.

X. New machines should be installed for getting more output.

XI. Emphasis should be given in newer drug formulations.

XII. Research and Development can work on noble molecules. With the help of computed

drug designing BPL can find a new molecule without going for screening of

numerous raw materials. This will further extend their authority over the current

market. BPL can have their patent molecule. For doing this work BPL can collaborate

with various universities research center.

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CONCLUSION

We enjoyed our in plant training in BPL. We found very friendly environment here. In every

section the respect authority cordially received us. They initiated our curiosity & interest

regarding the relevant subject. We are pleased with the nice behavior of the personnel in the

plant.

The management & personnel relationship in BPL is very good .Here the inter department

communication is excellent. They safety measure is of high standard.

We have observed various latest technology applied valuable machines and large industrial area in

BPL containing own power stations and liquid nitrogen plant. During our observation it is found

that BPL follows SOP ,GMP ,cGMP in every sphere of manufacturing. To uphold this

country, immediately a new dry policy should be announced in favor of the public & our

pharmaceutical industry.

At last we would like to give hearty thanks to BPL and our gratitude goes to its all personnel.

We wish better cooperation between our Department and BPL day by day.

We wish BPL always keeps process in competitive drug market

mehdi(nub) beximco pharma 2016

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