Orion Laboratories Ltd. is one of the premier pharmaceutical companies of Bangladesh
COMPANY PROFILE is one of the premier pharmaceutical companies of Bangladesh with a proven track record for manufacturing and marketing branded generic pharmaceutical products. Having four decades of vast experience imbibed with technical and professional expertise, now Orion levers a wide array of therapeutic areas. Orion has now more than 70 generics in a wide range of dosage form and strengths including life-saving indictable. Orion Laboratories Ltd.
History of the Company Orion Laboratories Ltd (OLL) a member of Orion group was founded as a pharmaceutical manufacturing company in 1965 with its modest start nearly of four decades with the mission to serve the ailing humanity around the globe. OLL has today burgeoned out into one of the leading pharmaceutical company in Bangladesh among 216. It has already established itself to the doctor’s community, other health care professionals, chemists and patient as provider of quality medicines and health care services through 50 brands and 51 presentations of various formulations. Since its humble beginning in 1965, ORION has made giant strides to establish itself as one of the leading pharmaceutical companies in the intensely competitive pharmaceutical market. ORION has been able to make its very strong ethical presence felt in the community as accompany with vision. Company pursues, follow and maintain the latest World Health Organization (WHO) approved all standards of Good Manufacturing Practices (GMP), in every step, from the procurement of raw materials to the manufacturing of finished products. A highly skilled, dedicated and enthusiastic team of professionals, comprising of pharmacists, biochemists, chemists, microbiologists, engineers, doctors and other are making relentless efforts in manufacturing and marketing quality pharmaceutical products at affordable prices for the people of Bangladesh.
Leading Edge Orion has gained a leading edge in many important therapeutic groups including Antimicrobial Agents, Antihypertensive, Anti-ulcerants & Antacids, Antihistamines, Antidiabetics, Antipyretic/Analgesics, Anxiolytics, NSAIDs, Diuretics, Cardiovascular drugs, Vitamin & Mineral supplements, Hypoglycemic Agent & Tranquilizer.
Flagship Products Enliven (Imatinib Mesylate), Pep (Zinc Sulphate Syrup), Ortac (Ranitidine), Clog nil
(Clopidogrel) and EC-plus (Vitamin E and C) are the major flagship products, which are the deserving pride of Orion.
Trust to Excel Orion Laboratories Ltd. has more than just the reputation to keep up. Always "In search of excellence". 'Quality' and 'Affordability' are my major concerns while operating my business. , at Orion, refuse to settle for anything until it exceeds the existing standard and until it becomes affordable.
Iso Certification Orion has strong ethical commitment and has been awarded with the ISO-9001: 2000 Certificate in January, 2003 for serving its valued customers with products of excellent quality.
UNICEF Accreditation As recognition of high standard Quality Assurance using modem machinery, Orion has achieved the recommendation of UNICEF as a "Potential Medicine Supplier of UNICEF".
Quality Policy Orion Laboratories Ltd. is dedicated to serve its valued customers with products of excellent quality through continuous improvement in technology, process and human resources complying with the guidelines of Good Manufacturing Practice (GMP) and the requirements of 150-9001: 2000 Quality Management System (QMS).
Vision of Orion Orion believes in Quality in everything they do. Their vision is 'To be regarded as a worldclass pharmaceutical company through products and services.
Mission of Orion Their mission is to provide health care services to the ailing humanity round the globe by: • Continuous development of people competence • Recognizing individual contribution • Introducing new as well as innovative products and technologies. • Assuring quality products from advanced manufacturing facilities. • Exceeding customer satisfaction and gaining trust through quality services. • Expanding the export market.
Values of Orion In order to achieve its aspired vision, Orion Laboratories Ltd. subscribes the following values: • Quality in everything they do • Live up to my commitments • Transparent and fair in all my dealings • Take initiative to exceed standards • Trust and respect for each other • Work as a team • Share social responsibility
Talent and Resources of Orion Orion boats a team of the sharpest mindsets in Bangladesh Pharmaceutical Market backed up with an excellent group dynamics of administrative, marketing and service professionals. With its more than 500 well-motivated field colleagues and 350 Distribution Personnel in 13 distribution-cum-sales centers throughout the country, Orion has been able to promote and distribute its products as per customer need.
A Mind Set to Never Give Up
NECESSITY OF IN-PLANT TRAINING Orion believes in 'Quality never ends'. So, Orion stands for ceaseless efforts to improve its products and processes for further development. Keeping in mind of its motto "Quality in Everything I Do" Orion always hunts technological challenges presented by enterprising customers as well as leading profession. A pharmacist is the person of drugs or the expert on drugs. S/he is the only expert on drugs,
for expertise regarding drugs requires knowledge in depth in all the facts of pharmacy. It is his/her professional responsibility to know all about the drugs. No educational program other than that in pharmacy provides the background to understand completely all about drugs. Among the professions of pharmacists like community pharmacy, institutional pharmacy, whole sale pharmacy, industrial pharmacy, government service, pharmaceutical education, organizational management, in my country industrial pharmacy offers great opportunity to the pharmacists. Industrial pharmacy is a profession of unique hybrid of business and profession. So an industrial pharmacist should have proper knowledge about drugs and also about medical progress, commence marketing and technology. To be a self-sufficient pharmacist beside academic knowledge, practical knowledge is essential. This is why after appearing the Bachelor of Pharmacy examination in-plant training was arranged by the discipline in renowned ORION Laboratories Ltd.. This training has sharpened our academic knowledge what we learnt in the last few years .We have completed training in Orion Laboratories Ltd. a fast growing pharmaceutical company in Bangladesh.
PRODUCTION DEPARTMENT OF ORION The production area in Orion Laboratories Ltd. Can be divided into the following sections: 1. Tablet section • Granulation • Compression • Coating 2. Liquid Processing and Filling section 3. Capsule section • Manual • Auto 4. Dry Syrup section • Blending • Filling 5. Packaging section • Blister packing • Vitamin packing • DIS packing 6. Warehouse(RM & PM) 7. Maintenance 8. Finished Product Store 9. Sterile Section
TABLET SECTION
Tablet
Tablet Section Tablets may be defined as form of medicament or without suitable diluents prepared either by molding They vary greatly in shape, depend upon the amount mode of administration. diluents, binders, lubricants, sweetening coloring agents.
the solid unit dosage medicaments with or or excipients and or by compression. size and weight which of medicament and the Excipients may include disintegrating agents, agents, flavoring and
Advantage Tablets have following advantages: 1. Easy to carry. 2. Easy to swallow and may provide the greatest ease of swallowing with the least tendency for "hang-up" above the stomach, especially when coated, provided that tablet disintegration is not excessively rapid. 3. They lend themselves to certain special - release profile products, such as enteric or delay-release products. 4. Attractive in appearance. 5. Unpleasant taste can be masked by coating. 6. Do not require any measurement of dose. 7. Can be divided into halves and quarters by drawing lines during manufacturing to facilitate breakage whenever a fractional dose is required. 8. An accurate amount of medicament even if very small can be incorporated. 9. Tablets provide prolong stability to medicament. 10. The incompatibilities of medicaments and their deterioration due to environmental factors are less in tablet form. 11. Since they are generally produced on a large scale therefore their cost of production is relatively low. 12. They have the best combined properties of chemical, mechanical and microbiologic stability of all the oral forms. During training we have observed the manufacturing of the following tablets: • Nidazyl • EC Plus • Deslor • Maxical Plus Different solid manufacturing unit The different solid manufacturing units are:
Dispensing unit Granulation unit Dry granulation Wet granulation
Compression unit Coating unit Packaging unit
Dispensing Unit The manufacturing unit sends a demand paper according to their need, to the warehouse. Central Dispensing Unit weighs the required amount of active ingredient & excipients and then sends it to the manufacturing unit. Manufacturing unit received and rechecked it. Raw materials must be approved from QC department before dispensing. Granulation unit There are two types of granulation: 1. Dry granulation 2. Wet granulation Instruments / Apparatus Used in Granulation: There are various types of sophisticated instruments are used for the purpose of materials mixing. The instruments are SI No 01 02 03 04 05
Name of the machine
Source
Capacity
Horizontal Mass Mixture Planetary Mass Mixture Solace Mass Mixture Tone Mixture Double Corn Mixture
Bangladesh India India India India
120 Kg 100 Kg 50 Kg 15 Kg 20 Kg
There are various types of sophisticated instruments that are used for the purpose of granulation. The instruments are SI Name of the machine No 06 Fluid Bed Dryer 07 Fluid Bed Dryer 08 Fluid Bed Dryer Steps of Dry Granulation
Model no TR30E BF-60 TR60E
Company
Source
Capacity
Alliance Bombay Alliance
India India India
30 Kg 60 Kg 60 Kg
Raw Material (Active + Excipients) ↓ Mixing (Except Lubricant) ↓ Blending at V- shaped or Cone blender for 10-30 minutes ↓ Add lubricant ↓ Blending for 5-10 minutes ↓ Quality Control (For Approval) ↓ Compression Steps of Wet Granulation
Raw Material (Active + Excipient) ↓ Sieving with the mesh size of 24 ↓ Mixing at Horizontal Mass Mixture for 30 minutes (Dry Mixing) ↓ Wet Mixing for 80-90 minutes (Add binder and starch paste) ↓ Drying at Fluid Bed Dryer for 40 minutes to 3 hours ↓ Milling at multimill (Mesh size 3 or 5) ↓ Sieving (Mesh size 12 or 16) ↓ Final drying ↓ Loss on Drying (Consider maximum 1%) ↓ Adding lubricant (Which increase flow properties) ↓ Quality Control ↓ Compression Compression Unit After proper blending granules are stored in a container and then it is delivered to the compression unit. Before compression some parameters are checked: • Proper cleaning of machine. • Proper arrangement of die and punch. • Removal of all the material relevant to previous product • HVAC system. • Dust collecting system • Humidity • Temperature • Pressure differential • Granules are poured into hopper Tablet compression For the compression of granules in the form of tablets, various types of machines are used which are known as tablet making machines or tablet presses. Various types of machines so used are as follows: 1. Single punch machines. 2. Multi punch machines. 3. Rotary tablet machines. 4. High-speed rotary tablet machines. 5. Multilayer rotary tablet machines. During our training we have familiar with various types of machines used in tablet compression. These are as follows
Instruments / Apparatus Used In Tablet Manufacturing SI No. 01 02 03 04
Name of the Machine CADMACH-1 CADMACH-2 CLIT ZPT
Model No. CMD-3B-16 CMD-4D-27 CJD-3 ZPT-23
Punch No. 16 27 16 23
Capacity (Per Hour) 30000 100000 30000 150000
Source India India India China
Steps of tablet compression Granules or Materials (Raw Materials + Excipients) ↓ Hopper ↓ Tarat ↓ Materials in the die hole through feed fram ↓ Pressure with upper and lower punch through upper and lower roller ↓ Tablets Problems, which may arise during manufacturing • Binding in the die. • Capping and lamination • Chipping, picking and sticking • Mottling • Hardness variation • Weight Variation • Double Impression Coating Unit Coating is one of the important steps after compression. The various objectives of coating are as follows Objectives • To mask the taste, odor or color of the drug. • To provide physical and chemical protection for the drug. • To control the release the drug from the tablet. • To protect the drug from gastric environment of the stomach with an acid-resistant enteric coating. • To improve the pharmaceutical elegance by use of special colors and contrasting printing. Instruments / Apparatus Used In Tablet Coating There are various types of sophisticated instruments are used for the purpose of tablet coating. The instruments are
SI No. 01 02 03
Name of the Model Machine RAMA-1 27 RAMA-2 39 ECO COTA 900
Company
Source
N. R. Narongkarmchang. Co. Ltd N. R. Narongkarmchang. Co. Ltd FD & C Equipment (Pvt) Ltd
Thailand Thailand Pakistan
capacity (Kg) 20-30 100 100
Types of coating • Sugar coating. • Film coating. • Compression coating. • Enteric coating. During my training we observed Film coating. There are two types of film coating • •
Aqueous coating Organic solvent coating
Film coating Film coating involves the deposition, usually by a spray method, of a thin film of polymer surrounding the tablet core. Ingredients used in film coating Typically a coating formulation (solution or suspension) contains following ingredients— Polymer • Cellulose derivatives (Hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, cellulose acetate phthalate etc) • Methacrylate amino ester copolymer (Eurasia,) • Polyvinyl acetate phthalate (Opadry, Opaglos, Nutrateric, Sureteric) Plasticizer • Polyhydric alcohols (glycerol, propylene glycol, polyethylene glycol etc) • Organic esters (diethyl phthalate, triethyl citrate etc) • Oils or glycosides (castor oil, acetylated monoglycerides etc) Solvents • Water • Alcohols (methanol, ethanol, isopropanol etc) • Esters (ethyl acetate) Colorants • Iron oxide pigments • Titanium dioxide • Aluminum lakes Important critical parameters to check prior to spray coating solution • Pump speed • Pan Rotation • Bed Distance
• Negative Pressure • Inlet Air Temperature • Outlet Air Temperature • Atomizing Air Pressure • Fluid Return Volume • Nozzle to nozzole Distance • Nozzle Distance from the Tablet Bed Coating Procedure Coating solution (Aqueous or Non aqueous) ↓ Filtering (Need for only in non aqueous solution) ↓ Tablets into coating pan ↓ Dedusting ↓ Heating (For aqueous 70˚ C & non aqueous 55˚ C) ↓ Spray by spray gun ↓ Polishing (Opadry clear or PEG-6000) ↓ Drying at 40˚ C-45˚ C for 1-2 hours Problems, which may arise during coating • Sticking & Picking. • Roughness. • Orange-Peel Effects. • Color variation. • Cracking. • Edge chipping/Erosion. • Logo bridging. • Logo infilling. • Twinning. • Core erosion. IN-PROCESS QUALITY CONTROL • Weight variation • Hardness Test • Friability Test • Disintegration During tablet manufacturing, the raw materials needed for a batch of drugs are taken from the Warehouse (RM&PM) department after accurate weighing and to the production area. These materials then go for granulation, milling, blending and drying processes as required. Plain tablets and tablets cores are produced in the various compression rooms using the machinery listed previously.
After compression, many tablet cores get a coating. Products then wait in quarantine area in Finished Goods Store, until the quality control laboratory confirms their standardized quality and authorizes their release. The whole process of tablet manufacturing ensures "Good Manufacturing Practice." LIQUID PROCESSING, FILLING & PACKAGING LIQUID PROCESSING, FILLING AND PACKAGING
The oral use of liquid Pharmaceutical has generally been justified on the basis of ease of administration to those who have difficulty in swallowing solid dosage form. A drug administer in solution is immediately available for absorption and in most case is more rapidly and efficiently absorbed than the same amount of drug administered in tablet and capsules. In liquid section oral suspension, syrup etc. are manufactured. During my visit, I have observed the manufacturing of • Deslor syrup • Orioplex syrup • Pep-2 syrup Machines used • Syrup preparation vat Capacity : 400L • Process vat Capacity : 1200L • Process vat Capacity : 500L • Stirrer machine Capacity : 60 rpm • Transfer pump • Filter Machine • Colloid Mill • Liquid Filling Machine • Capacity: 30-40 Bottle/Minute. • Liquid Sealing Machine Flow diagram of liquid manufacturing Sugar syrup (Heat85-95ºC) conc.40-65%
+
Step 1: Syrup base Cooled 40-60ºC Step 1.1: Presecrutives Solution
Step 2: Filtration
Excipients
Step 2.1: Dispersed thickening
Step 2.2: Slurry of active ingredient
Agent, if necessary
Step 2.3: buffering agent
Step 2.4: Flavoring agent
PH adjusters
Step 2.5: colorants Step 3: Volume adjustment Liquid filling Flow diagram of liquid filling (a) Empty bottle supply Outer labeling
Outer making
Bottle washing
Print checking
Inserting in to outer
Section I.1
Cap wiping
Closing of outer
Cap sealing
Labeling
Inspection
Turn table
Checking & Stacking
Liquid packaging There are two type of packaging• Primary packaging Syrup/Elixir/Emulsion: These products are filled into clean glass bottle and sealed by automatic bottle filling and sealing machine • • •
Secondary packaging Cartooning/Box: After primary packing products are pack into paper/printed cartoon. In this time, Batch no. Mfg date, Exp date must be check and maintain strictly. Master cartooning: Small individual cartoons or boxes are pack into fibre board cartoon according to batch no, it is called master cartooning.
C
APSULE SECTION CAPSULE Capsules are the solid unit dosage form of medicament in which the drug(s) is enclosed in a practically tasteless, hard or soft soluble container or shell made up of a suitable form of gelatin. Gelatin shells are supplied in a number of sizes. The number varies from 000 to 5, the former being the largest and later the smallest. The exact amount of a medicament which can be filled in a particular size of capsule shell depends upon density of the material to be filled in. Generally the capacity varies from 600mg to 30mg. Advantages • Capsules are tasteless, odorless and can be easily administered. • Attractive in appearance. • The drugs having unpleasant odor and taste are enclosed in a tasteless shell. • They can be filled quickly and conveniently therefore the physician can change the dose and combination of drugs to suit the individual patient. This is an advantage over tablets. • Flexibility in onset and duration of action also contribute to the suitability of the capsule as a pharmaceutical dosage form. • Ease of formulation. • Limited potential for incompatibilities.
• • • •
Good stability. Easy to swallow. They are economical. They are easy to handle and carry.
Disadvantage • Capsules are not usually used for the administration of extremely soluble materials such as potassium chloride or ammonium chloride. • Capsules should not be used for highly effervescent or deliquescent materials. Effervescent materials may cause the capsule to soften. • Deliquescent powders may dry the capsule shell to excessive brittleness. • The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation in the stomach. Capsule shell has two parts: Body and cap. Several designs of locking systems in the capsule shells are available. During my visit I have observed the manufacturing of following capsules. • • • •
ORIXYL GLORY PROCAP ENLIVEN
Flow Diagram Of Capsule Processing: Process 1 (For Pellet) Weighing Dispensing Blending Encapsulation Process 2 (For Powder)
Weighing Dispensing Blending Slugging Sieving
Granulation Encapsulation Process of capsule filling: • Manual • Auto Procedure of Manual Capsule Filling Capsule shells are set into the plate through insetter ↓ Plate set into the hand filler ↓ Body and cap separated by scissor ↓ Fill the body with materials ↓ Attached body and cap ↓ Capsules Machines Are Used • Hand filling machine(300 pores per plate) • Insetter machine (India) • Balance machine (Powder wt / Capsule wt) Procedure of automatic Capsule Filling Capsule shells into the hopper ↓ Meggine ↓ Cap boos and body boos ↓ Filling materials from chemical hopper ↓ Checking ↓ Close the body and cap by closing pin ↓ Capsule open from the boos by capsule open pin ↓ Capsules Instruments / Apparatus Used In Automatic Capsule Filling There are various types of sophisticated instruments are used for the purpose of capsule
filling. The instruments areSI No. Model 01 AF25T 02
AF40T
Company PAM Pharmaceuticals & Allied Machinery Company (Pvt) Ltd PAM Pharmaceuticals & Allied Machinery Company (Pvt) Ltd
Relative merits and demerits
Source India
Capacity 25000/ hour
India
40000/ hour
of Manual filling & Auto filling:
Manual filling
Auto filling
Time consuming Repolishing necessary
Less time consuming Not necessary
More worker needed
Less worker needed
Precaution: During manufacturing time the room condition must be in control system. The room temperature should be in between 22-250c and room humidity 40 + 5%.
DRY SYRUP Section DRY SYRUP In manufacturing area, we have visited dry syrup section. During our visit, we have observed the manufacturing of – • Truso • Pedicef • Mac Instruments / Apparatus Used In Dry syrup manufacturing: Sl No 1. 2. 3.
Name
Capacity
Double cone mixture machine Filling machine: Hopper machine Sealing machine
Source
120 kg Bangladesh Delivery rate:450-500Tir Canada 3-8 Bottles /min Bangladesh
Flow chart of Dry syrup manufacturing: Material Weighing Q.C approval
Milling & drying Final Blending
Excipient Blending Blending active with Excipients
Transfer total blended material in a drum
Cartooning
Labeling
Bottle wash
Sealing
Bottle dry
Filling
Precaution Humidity & Temperature must be controlled. (Dehumidifier is necessary for that.) Worker must be well garmented.
PACKAGING SECTION PACKAGING SECTION In the pharmaceutical industry, it is vital that the package selected adequately preserve the integrity of the product. The selection of a package therefore begins with a determination of the products physical and chemical characteristics, its protective needs, and its marketing requirements. The packaging materials selected must have the following characteristics. • They must protect the preparation from environmental conditions. • They must not be reactive with the product • They must not impart to the product tastes or odor • They must be non-toxic • They must be FDA approved • They must applicable temper-resistance requirements • They must be adaptable to commonly employed high speed packaging equipment. In packaging I observed
• • •
Blister packing Vitamin packing Dry syrup packing
During my training I have seen Blister packaging of • NIDAZYL • KETORIN( INJECTABLE) • NERVEX During my training I have seen • Making catch cover for physician STIMULIN. • Making master carton of NIDAZYL NICOR • Box carton packing of SEFIN The materials used for Blister packing are Aluminum foil, PVC, PVDC. In Dry syrup bottle I have seen shrink tubing Label or box must have: • Product name • Generic name • Strength • License no • DAR No • Precaution/Handling • Address& name Manufacturing Company. Printing Text: • Batch no. • Manufacturing Date • Expiration Date • I have seen another printing machine that is Video Zet Printer Finished Products Store All the finished products are stored here with Department's desire this department delivery the produc
care.
From
the
marketing
Common Procedure of The Blister Packaging Is PVC from PVC ruler ↓ PVC passes through the heater for the softness ↓ Forming station (Pocket form by vacuum pressure) ↓ Channel or Gidel (It contains or carries the PVC with pocket) ↓ Pusher (It helps to set out the ampule or vial) ↓ Sealing station ↓
Alu Foil
PVC – Alu or Alu – Alu attached by heater ↓ Cooling the blister ↓ Draw off ↓ Cutting ↓ Storage Instruments / Apparatus Used In Blister Packaging There are various types of sophisticated instruments are used for the purpose of blister packaging. The instruments are SI No
Model no
Company
Source
01 02 03 04
VAL MINISTER-V Wider-AIII MINISTER-AV
HOONG-A Corporation HOONG-A Corporation BUCHON Machinery Company Ltd HOONG-A Corporation
Korea Korea Korea Korea
QUALITY ASSURANCE & QUALITY CONTROL
QUALITY ASSURANCE
INTRODUCTION: In pharmaceutical market few companies ensure qualitative products. ORION Laboratories Ltd is one of them. Now a days, manufacturing of quality product is quite difficult from the raw materials to the finished product in each and every step quality operation department plays a very important role. Quality Assurance Department is very important for a pharmaceutical industry to maintain G.M.P. The concept of total quality management and total quality control refers to the process of striving to produce a perfect product by a series of measures requiring an organized effort by the entire company to prevent or eliminate errors at every stage in production. Although the responsibility for assuring product quality belongs principally to Quality Assurance Department, it involves many departments and disciplines within the company. To be effective it must be supported by a team effort. The Quality Assurance Department is vital for a pharmaceutical industry since it controls and assures the quality of the products starting from the raw materials. QUALITY ASSURANCE DEPARTMENT IS CONSIST OF FOUR SECTIONS, THOSE ARE:
QUALITY ASSURANCE
QUALITY CONTROL
IN PROCESS CONTROL
MICROBIOLOGY
R&D
Functions of Quality Assurance Department • • • • • • • • • • • • • • •
Raw Material Analysis In Process Analysis Finished Goods Analysis Packaging Material Analysis Calibration and validation of Laboratory Instruments Fixation of Expiration Date (Stability test) Process Validation Product Complained analyses Investigation of Out of specification Environmental Analysis Development of New test Procedures GMP Audit New source approval Raw material validation Microbiological analysis
Quality assurance activity performs in the ORION Laboratories Ltd. Is given below a flow chart-
Visual inspection & testing for the quality of supplied
Taking sample of raw materials & packaging materials of Q.C analysis
Release or rejection based upon the quality control results
If the material passes the quality control test, the raw & the packaging materials are dispensed.
If the cleanliness of equipment & area of manufacturing are ok, giving approval.
Some parameters are checked during in plant process..
Product as taken as sample from in process product for Q.C
In process checking of packaging operation. Collection of the retention sample & transfer of finished product for distribution.
Quality Control It is the part of good manufacturing practice, which is concerned with sampling, specification and testing as well as the organization and documentation and released procedures. It ensures the necessary and relevant tests that are necessary to determine whether the products will be released or not for use, the raw materials can be used or not until their quality has been judged to be satisfactory. Quality Control Operations The Q. C. department assures manufacturing of quality product. It is completely related with production operation, mainly done in the production area to check o Dispensing of materials o Checking in pharmacy weighing
o Compounding in ingredients o Process validation o In process checking o Complains of G.M.P., mainly storage of raw materials, finished products. o Label control The objectives of quality assurance are achieved when processes have been defined which, when followed, will yield a product that complies with its specification & when the e finished product o Contains the correct ingredients in the correct proportion. o Has been correctly processed according to the defined procedures. o Is of purity required. o Is enclosed in its proper container, which bears the correct label or otherwise suitably marked or identified. o Is stored, distributed and subsequently handled in such a way that its quality is maintained throughout its designated or expected life. VARIOUS TESTS DONE IN QC Quality control department performs 3 types of assay for analysis
• • •
Chemical Assay Physical Assay Bio-Assay O FOR RAW MATERIAL Solid raw material o Identification o LOD o Bulk density o Heavy metal testing o Impurities o Melting point • Liquid raw material o Refractive index o ph o Weight per ml o Viscosity • FOR FINISHED PRODUCTS o Solid preparation Description Dissolution and Disintegration time Weight variation Assay • Liquid preparation o Weight per ml o Microbiological limit test o pH • Semisolid preparation Microscopic examination -Assay • FOR PACKAGING MATERIAL o Description
o Text o Colour o Dimension o Weight (gm/m2) o Visual inspection for defects o Adaptability In the Quality control department all the information is written in a specific S.O.P. SHEET is prepared according to ORION Laboratories Ltd, Test procedure, BP and USP procedure. Several information, included, in the SHEET is as follows. • Trade name and official name of the material • Date • Manufacturer date • Lot No. • Expiration date • Quantity • Label Potency • Test Procedure (As described before) • S.O.P. no.
Instruments in QC Department
In Quality control Department the following sophisticated instruments are used: • High Performance Liquid Chromatography (HPLC): Agilent Technologies, Australia • High Performance Liquid Chromatography (HPLC): Waters, Japan • Refract meter • Karl- Fischer Titrator: Miller • Moistureanalizer • UV visible spectrophotometer(1) • UV visible spectrophotometer(2) • Dissolution Tester • Disintegration tester • PH Meter • Electronic PH Meter • Melting point Testing Apparatus • Friabilator • Hardness tester • Fume Hood • Electric Balance • Vacuum Dryer • Heating Oven • Slide calipers • Vacuum Pump Motor (for leak test) • Humidity test chamber (for stability test) • Thermometer. • Muffle furnace system • Graphite furnace system • Water purification system • Conductivity meter
• • • • • • •
Magnetic Shaker Atomic absorption spectrophotometer Viscometer Tap density tester(USP) Polarimeter IR detector Hydraulic press
Instruments used in Microbiology Laboratory • • • •
Bacteria proof filter paper Microscope Vacuum Pump Motor Refrigerator
• • • • • • •
Sterility test Microbiological contamination test Pyrogen test Growth promotion test Media validation test
Tests in Microbiology lab
Solid media Liquid Media
o Environmental monitor
• • • • •
SWAB test Settle plate technique Contact plate technique Air bone particle count Air sampling
High-performance liquid chromatography,(HPLC) High-performance liquid chromatography, HPLC is a popular method of analysis because it is easy to learn and use and is not limited by the volatility or stability of the sample compound. The information that can be obtained includes identification, quantification, and resolution of a compound.
Principle A liquid mobile phase is pumped under pressure through a stainless steel column containing particles of stationary phase with a diameter of 3-10 um. The analyze is loaded onto the head of the column via a loop valve and separation of a mixture occurs according to the relative lengths of time spent by its components in the stationary phase. It should be noted that all components in a mixture spend more or less the same time in the mobile phase in order to exit the column. Monitoring of the column effluent can be carried out with a variety of detectors.
Applications • •
The combination of HPLC with monitoring by UV/visible detection provides an accurate, precise and robust method for quantitative analysis of pharmaceutical products and is the industry standard method for this purpose. Monitoring of the stability of pure drug substances and in drugs in formulations with
• •
quantization of any degradation products. Measurement of drugs and their metabolites in biological fluids. Determination of partition coefficients a pKa values of drugs and of drug protein binding.
Advantages • • •
Easily controlled and precise sample introduction ensures quantitative precision. HPLC is the chromatographic technique, which has seen the most intensive development in recent years leading to improve columns, detectors and software control. The variety of columns and detectors means that the selectivity of the method can be readily adjusted.
Instruments used in Microbiology Laboratory • • •
Microscope Vacuum Pump Motor Refrigerator
Tests in Microbiology lab • • • • • • •
Sterility test Microbiological contamination test Pyrogen test Growth promotion test Media validation test Solid media Liquid media.
Environmental monitor • • • • •
SWAB test Settle plate technique Contact plate technique Air bone particle count Air sampling
In Process Quality Control To assure batch-to-batch uniformity and integrity of the products, written procedures describing sample taking, the controls and tests or examinations is conducted on in process products of each batch should be established and followed. Such control is intended to monitor the product yield and validate the performance of the production process that may be responsible for causing variability in the characteristics of in process products. The following in process quality control procedures are adopted
IPC for Manufacturing Section: Product Tablet
Tests performed Wt. Variation Friability Disintegration Dissolution Hardness Thickness
Capsule
Wt. variation Moisture content Sealing Bottle volume Over all supervision for all steps performed by the operators whether they complies or not with the SOPs.
Liquids Sterile products
IPC for Packaging Section • The quality control/ quality assurance officer checks the packets • The labels are checked by the officer to the standard labels • The cartoons are checked randomly whether they contain specific no. Of packs or not. • The blister and the sealing of the finished product are checked. DOCUMENTATION Introduction
Documentation is a prime necessity in quality assurance. Its purpose is to define the system control, to reduce the risk of error, so that personnel are instructed in details of and follow the procedures concerned and to permit investigation and tracing of detective products. To facilitate proper and effective use of documents these should be designed and prepared with care • The title, nature and purpose of the document are to be clearly stated. • The way of using the document and by whom should be clearly apparent from the document itself. • Where documents bear instruction these should be written in the imperative. These should be clear, precise and in language so that the user can understand easily. • Documents, which require the entry of data, should provide sufficient space for the entry. • Reproduced documents should be cleared and legible.
RESEARCH & DEVELOPMENT
RESEARCH AND DEVELOPMENT R&D deals with some important functions: • • • • • •
Pre formulation study Process validation-Prospective process validation, Retrospective process validation, Concurrent process validation, Revalidation Incompatibility study of active with excipients Trouble shooting & Packaging material specification Preparation of B.M.R. & B.M.R. for a new product.
• Evaluation & Development of existing product. Development of a new product Step 1: Product information from marketing department along with .necessary attributes such as: • Source • Sample • Q.C test (potency. LOD etc) Step-2: • Pre-formulation study of the active drug and excision: • Chemical activity • Function o Interaction o Boiling point o Contraindication o Moisture content etc. Step-3: Collection of raw material of active drug ingredients and excipients. Step-4: Different trials for development of a stable, effective and active Formulation. Step-5: Drug administration formalities include: • • • • • • • •
• •
a) Submission of recipe to drugs administration which contains Strength Dosage form Contraindication Dosage form Dissolution Description Precaution -Side effect
-M.R.P Indication b) Sample submission (if INN product) c) Approval of sample from drug administration and inclusion of D.A.R. and license no. d)
Submission of Inclusion Dossier.
e) Final approval for commercial production. Step-6: Pilot trial and accelerated stability testing.
Step-7: Readjustment If necessary. Step-8: BPR preparation if every aspect is satisfied which • • •
Product name Code Size
contains
• • • •
Batch no Theoretical yield Batch size Annexure etc.
Step-9: Transfer to commercial production. Development of existing product Product development department also deals with the development of existing product formulation.
Objective • • • •
Increasing the quality of the product. Prevention of any type of problem existing in the product. To save time and cost. Increasing the patient acceptance.
The project file It contains project related every papers such as • • • • • • • • •
Recipe Product attributes Lab tried process records Stability study protocol and report Approved product data sheet Sales forecast Standard packaging material sample Process validation protocol record Related correspondence
STERILE SECTION
STERILE SECTION Sterile products are doses form of therapeutic agents that are free of viable microorganisms. Principally these include parenteral ophthalmic and irrigating preparations. Equipment commonly used for parenteral division:
For washing area: • • • •
Ampoule/vial washing equipment—washing of ampoule /vial Distilled water and holding tank-washing and rinsing Drying oven (thermostatic control)—drying components Laminar airflow system-- components collecting and storage
Sterilizing equipment: • • •
Autoclave (double ended)—moist heat sterilization Membrane filtration units—liquid sterilization by filtration Oven (double ended)—dry heat sterilization
For bulk preparation area: • • • • •
Bubble point testing equipment—testing filter integrity Double distilled plant (pyrogen free)—liquid preparations Filtering device (bacterial grade membrane)—filtration Measuring equipment—volume measurement Mixing vessels/glass jars—collecting filtrate
For Aseptic filling area: • • •
Conveyor—filling line Filling and sealing machine—filling and sealing of products Laminar air bench—clean air protection
For Inject able section including dry vial An area of about 550 square feet is recommended for basic installation. This area shall be in conformity with the clean room standard of A & B depending on the nature of the injectable preparation. Dry vials are filled in sterile area under laminar air flow as the products can not be sterile after filling. Dry vial filling room must be ascetically clean with class A (or 100) with double door entry system. • • • • • • • •
Distilled water plant for inject able grade water Ampoule /vial washing machine Drying oven SS production and mixing vat Filter equipment for bacteria proof filter Autoclave Ampoule vial filling, sealing machine Ampoule leak testing equipment
Clean Area An area with environmental control of particulate and microbial contamination constructed
and used in such a way as to reduce the introduction generation and retentions of contaminants within the area. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. The at–rest state is the condition where the installation is completer with production equipment installed and operating but with no operating personnel present. The in-operation state is the condition where the installation is functioning in the define operating mode with the specified number of personnel working. For the manufacture of the sterile medicinal products normally 4 grades can be distinguished: At rest(b) In operation Grade Maximum permitted number of particles/m3 equal to or above 0.5mic.m 5mic.m 0.5mic.m 5mic.m A 3500 0 3500 0 B 3500 0 350000 2000 C 350000 2000 3500000 20000 D 3500000 20000 not define(c) not define(c)
Instrument Used In Sterile Section SI No 01 02
Name of the Machine
Model
Boiler Machine DM Water Plant
03
WFI Storage Tank & Distribution System DM Storage Tank & Distribution System Multi Coloumn Distilled Water Still Pure Steam Generator Steam Sterilizer Dry Heat Sterilizer Multi jet Ampoule & Vial Washing Machine Ampoule Filling and Sealing Machine Automatic Single head Alluminium Cap Sealing Machine Automatic Injectable Powder Filling with Rubber Stoppering Machine Mixing Vessel Filtration Unit Inspection Table Blister Packaging Machine Pressure Vessel Conveyer Belt Laminar Air Flow
04 05 06 07 08 09 10 11 12
13 14 15 16 17 18 19
Source
Capacity
ICS-30 C4-33/1MB-300
India India
M-1000
India
470kg/hr 2500lit/hr &1000lit/hr 1000 liters
India
2000 liters
India
80 lit/hr
India India India India
200 lit/hr
KAVW-240
Pharmalab Pharmalab Pharmalab Pharmalab
AFS-100
Pharmalab
India
KNCS-80
Pharmalab
India
NKPF-125
Pharmalab
India
M-50 GMP
Pharmalab Pharmalab
India India
2KLDWST
Company
Pharmalab
WS-80 PSG-200
50 liters
Singapore
20
Dispensing Both
Singapore
Flow Chart of Dm Water Water pump ↓ Water ↓ Charcoal filter ↓ Anion bed ↓ Cation bed ↓ Mixed bed ↓ DM water
CREAMS & OINTMENTS CREAMS AND OINTMENTS Creams are semi-solid emulsion systems with opaque appearances, as contrasted with translucent ointments. Their consistency and rheological character depend on whether the emulsion is a water-in-oil or oil-in-water type and on the nature of the solids in the internal phase. Required Room Condition • • •
Temperature : 18-25oC Relative Humidity : 40-65% Pressure difference : Not less than 2.5 Pascal
Flow chart on emulsion manufacturing
Preparation of oil phase in one vessel
Preparation of water phase in another vessel
Storage vessel
Addition of oil phase into water phase using centrifugal pump Filtration with filter
Flow chart of cream manufacturing WATER PHASE Collect purified water in jacketed vessel
OIL PHASE Collect base in jacketed vessel & melt at 7580oC
Addition of water phase and boiled at 75-80oC with stirring
Addition of other oil phase with continuous stirring
(Add slowly aqueous phase to the oil phase with stirring) Using negative preessure Main vessel
Add slurry when reduce the temperature
Continuous stirring for 45minutes(milk like look) Cool the system to 30-40oC
Make slurry of active ingredient and rest of ingredients.
Preserve the prepared bulk cream in containers with proper tagging Packing Filling and Sealing Machine: AXOMATIC (Italy)
Flow chart of filling and sealing
Loading the tube Set the tube Backside of the tube fit for filling by air pressure Filling Heat (hot tap) Look the product for go out Cut the back side of the tube Pressure by pin to come out for ejection Exit
WARE HOUSE (RM & PM) WARE HOUSE (RM&PM)
INTRODUCTION
The Ware House of ORION Laboratories Ltd is more or less well organized. Various Tags with different colors are used to identify the materials easily in the storage area in specific space. Raw Materials Storage Area • Quarantine area -To be truthful it is so called in ORION Laboratories Ltd. After receiving of raw materials they are stored first in the quarantine area. Then Q.C. sampling and checking is approved and then shifted to the main storage area, which is escorted by grille. • Rejected Materials area- Here, the rejected materials • Main storage area- Here raw materials are stored. There is another isolated storage
area for sophisticated materials maintaining temperature and humidity in side the main storage area named cooling room. The storage department performs some important functions such as a) Specific raw materials are stored in specific mentioned area with proper documentation. Capsule shells are kept in 150c & aluminum foil in 00 to 250 c. b) According to monthly program, this department has the responsibilities to get final Q.C. approval for raw materials. c) According to plan and recovery maintenance, the raw materials are supplied to the production area for required batch size. d) There is another room in second floor of Orion where various stationary & gift items are stored. Storage Area for Packaging Material Packaging material including master pack, carton, foil, inner pack, catch cover etc are stored here. Weighing area: There is an isolated area with humidity & temp control for weighing. From here materials are supplied to the production area by accurate weighing in presence of Q. C. officer. Storage Area for rejected Samples Some samples are unfortunately rejected; these are stored in this section with red color tag. Viewing this tag someone understands products are rejected will go further to Q. C. department. OPERTIONAL SCHEME (From sampling to finished product)
Material receive by primary checking ‘Quarantine’
QC department takes sample QC fixes ‘Approved’ tag if tests are passed Approved material goes to Production Department
Manufacturing Packing Finished product come to store again
‘Rejected’ tag is given if materials fail to pass the tests
Quality Inspection on finished products are done by QA department Goes to depot for distribution
MAINTENANCE
INTRODUCTION Maintenance may called The Engineering Department, in one sense, is the heart of the plant since it is the department which ensures all the functions of the machineries and electrical facilities as well as different types of air and water through out the plant.Thus the production at the factory can run on smoothly only if engineering department maintains the environment of the plant properly. Maintenances can be classified in 3 classes. These are as follows• Preventive maintenance • Breakdown maintenance • Daily checking Maintenances Daily checking maintenance Preventive maintenance Record for daily Breakdown maintenance Preventive maintenance Machinery Work request from production programme of machinery Repairing & servicing files & equipments. Annual preventative programme of machinery preventative & equipments. Advice form Record preventative & servicing Repairing & servicing files
Maintenance Department provides the following facilities:
• Electricity • Central air conditioning • Repairing machineries • Compressed air • Water supply HVAC (Heating, Ventilation, and Air Conditioning): Controls for heating, ventilation, and air conditioning (HVAC) traditionally mostly consist of dedicated systems that are limited to standard functions. In the pharmaceutical sector, however, HVAC is a critical factor affecting the reliability of analysis results, experiments, and production systems. Pharmaceutical manufacturers require precise, critical control over temperature, humidity levels, and air-flow patterns. The flexibility and level of customization required to achieve this cannot be found in traditional HVAC control systems but requires an industry-specific approach. The HVAC system in ORION Laboratories Ltd. helps maintain the environmental conditions required in the BMR and is vital for GMP. Different specifications of humidity and temperature are needed for different product and here HVAC comes into play. Steam is used to heat up while air condition ducting used to cool down certain parts of the plant; the
humidity is maintained using filters and dampers along the different HVACs handling different parts of the production facilities. THE HVAC CONSISTS OF: • Heating coil and steam • Air handling units • Automated PLC • Dehumidifiers and filters THE HVAC SYSTEM IS DIVIDED INTO 4 MAJOR ZONES COVERING THE ENTIRE PLANT • The normal area (packaging area) • Outside environment or the general area • Production area (manufacturing area) • The blister packing area; and • The sterile facility.
FINISHED PRODUCT STORE All the finished products are stored here with care. From the marketing Department's desire this department to delivery the product. Heat sensitive finished products are placed inside the 1st floor of this department. Then all the finished products goes to CDC ( City Distribution Centre).
PRODUCT MANAGEMENT DEPARTMENT
PRODUCT MANAGEMENT DEPARTMENT (PMD) Marketing is the process of planning & executing the conception, pricing, promotion, & distribution of ideas, goods & services to create exchanges that satisfy individual & organizational objectives. Typical Marketing Activities • To develop the product • To fix up the product • MPO training • Marketing plan • Relation to commercial • Distribution • Collect market information • To test market products • Select brand names • Package Products • Pricing • Establish price objectives
• • • • • • • • • • •
Analyze competitor’s prices Set actual prices Promotion Determine type of promotion (advertising, personal selling sales promotion, publicity.) Design and advertising message Selection of advertising media (print, radio, television, billboards, specialty items.) Making schedule of the advertisements. Distribution Select wholesalers and retailers Establish procedures for handling and moving products (transportation, storage, inventory control.) Find the best locations for plants, warehouses and retail outlets
Marketing Research Research provides a bridge to customers. Marketing research a procedures to gather and analyze new information to help marketing managers make decisions. One of the important jobs of the marketing researchers is to get the facts that are not currently available in the marketing information systems. Five steps application of the scientific method that includes: o Defining the problem o Analyzing the situation o Getting problem specific data, o Interpreting the data, o Solving the problem.
CONCLUSION Although the four weeks time of my training in ORION Laboratories Ltd. flew very quickly, with the co-operation of the authority and all the personnel, have learnt a great and gathered a lot of experience which will be helpful for future practical purposes. In every section, the respective authority cordially received. They initiated curiosity and interest regarding the relevant subjects. Pleased with the behavior of every person involved in the factory. Thus, have completed training with great satisfaction and hope that the feeling is mutual. Some of the technical aspects of ORION Laboratories Ltd, which found very admirable, are as follows: The plant layout of the ORION Laboratories Ltd. plant at Tejgaon is in a word, excellent. It was, no doubt, a very well planned layout that provides an optimum use of space and ease of operation and thus contributes highly towards optimum productivity. Furthermore, there is ample opportunity for expansion when the need will arise. The plant area is also very nice and, having its own Prayer room. The plant is very well organized and the internal environment is very supportive to the
employee, which is very nice since a congenial atmosphere increases the productivity of a company. The canteen is also very nice and the food menu was found to be very good, although there is always room for improvement in this regard. One of the impressive things about ORION Laboratories Ltd. is its wide range of products and its quality. also very impressed with the maintenance of GMP and the extensive documentation of all the works kept in the company, complying with the ISO 9001 requirements. Another most impressive things about ORION Laboratories Ltd is that they are trying to commence such kind of product which are valuable and they are marketing it in lower price. For example the anti-cancer drug Enliven. Would like to end with a note of thanks, again, to Almighty Allah, and to everyone involved, for successful completion of this training and hope that ORION Laboratories Ltd will continue its co-operation to allow In-plant Training in future.