A REPORT ON IN-PLANT & MARKETING TRAINING
The ACME Laboratories Ltd.
Introduction The ACME Laboratories Ltd is one of the well renowned pharmaceutical companies in Bangladesh and also in the global area. The vision of this pharmaceutical company is to be recognized as a world class pharmaceutical company by providing high standard products and services. According to the training schedule, I visited all the departments of The ACME Laboratories Ltd. The ACME Laboratories Ltd always manufactured high quality products of various dosage forms and never compromises in the name of quality. To ensure good quality products the quality assurance and quality control departments and in process control systems have been developed. During the in-plant training, the process of manufacturing and maintaining quality according to “Good Manufacturing Practice� (GMP) guidelines were observed and in this context, standard operations procedures were developed. As a result of visiting in such a reputed and well organized company like The ACME Laboratories Ltd, my theoretical concept regarding various issues has developed due to the practical view. ISO (International Organization for Standardization) Introduction: ISO is an International Organization for Standards that was formed by technical committees. They provide user-friendly guidelines for a wide range of organizations. Examples of these organizations include manufacturing, processing, servicing, printing, forestry, and electronics. The International Standards Organization represents140 countries around the globe. The Organization was founded in 1947 as a non-governmental organization to promote the development of standards in quality. ISO was established in 1947, in Switzerland, with the purpose of developing intellectual, scientific, technological, and economic corporation between member countries (Bureau of Business Practice). Later in 1979 the ISO Technical Committee (ISO/TC 176) was formed to make a set of guidelines that would bring together and standardize world industries. ISO has affiliates in more than 90 countries.
Definition: ISO comes from the Greek word “isos” which means “same as.” The words “same as” can be implied to mean the consumer gets what the consumer expects. In our quality assurance class we have learned that if the consumer gets what they expect, this is consider quality. Therefore, the root word ISO stands for quality. The International Organization for Standardization (ISO) is an international consortium (combination of some company) of representative of bodies constituted to develop and promote uniform or harmonized international standards. Among the various ISO used in the pharmaceutical industry are those in the series ISO 9000-9004. The standards are including here pertaining to – •
Development
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Production
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Quality Assurance (QA)
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Quality Control (QC)
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Detection of defective product
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Quality Management
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Other issues as product safety and liability
Our Export Markets #A Regular Export Market Myanmar Sri Lanka Afghanistan Hong Kong
Nepal Pakistan Philippines Vietnam
#B Irregular Export Market East Timor Uzbekistan Yemen Cambodia
Gambia Bhutan Malta
#C Market Development Ethiopia
Taiwan
Myanmar Cambodia Nigeria (Vet)
Yemen Kenya KSA
#D Product registration status in different countries Myanmar=29
Iraq=08
Philippines=10 Hong Kong=02 Uzbekistan=09
Nepal=36 Vietnam=01 Pakistan=50
Quality Operation Division Duration of Training: Total 8 days Quality assurance, or QA for short, is the systematic monitoring and evaluation of the various aspects of a project, service or facility to maximize the probability that minimum standards of quality are being attained by the production process. QA cannot absolutely guarantee the production of quality products. Purpose: GMP is that of quality assurance which ensures that, products are consistently producer and controlled to the quality stander appropriate to their intended use and as required by marketing authorization. A product specification this makes it clear that QA in the Generic, wider term. Once upon a time when only ultimate goal of any business company was to be beneficial but at this modern age this idea is changed. Now the vision of any company is to provide quality products to the customers and beneficial simultaneously. As The ACME Laboratories Company is the leading ethical drug producer of Bangladesh, they always try to provide quality product to the customers and this foremost effort done by Quality Assurance Department. QA may be defined as the responsibilities of an organization to determine that the system, facilities and written procedures are adequate and followed in order to assure that the products are controlled and will meat, in the final dosage form, all the applicable specifications. Thus QA is a preventive development process. The Quality Assurance Department of ACME monitors each step of manufacturing operation and adopted “Good Laboratory Practice (GLP)� to ensure reliability and accuracy of the Pharmaceutical product. The department is subdivided into different section so as to ease and facilitate documentation and proper operations. The sections are: 1. Validation and Documentation. 2. In-Process Quality Assurance (IPQA). 3. Method Development and Validation. 4. Foreign Registration and export. A. Validation Validation is defined as establishment document evidence, which provide a high degree of assurance that a specific process or system will consistently produce a result meeting its predetermined specification. Validation is normally required for processing, equipment’s service, production process and the test procedure & computer system.
The following things are validated •
Manufacturing process validation
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Critical equipment validation
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Area & facilities validation
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Cleaning & contamination validation
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Utilities validation •
HVAC system
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AHU (Air Handling Unit)
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Compressed air
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Demineralized water Plant
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Analytical method validation
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Analytical equipment validation
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HPLC
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GLC
Computer system validation
Types of validation: 1. Prospective validation: For new method, new machine, new area, new facility etc. 2. Retrospective validation: If the validation is not done properly or totally then validation is done again. 3. Concurrent validation: If there is any change in formulation, facilities etc then validation is done again. 4. Revalidation: Same as retrospective validation but in this type full specification tests are done for validation. Function of validation: o IQ ( Installation qualification) o
DQ (Design qualification)
o
OQ (Operation qualification)
o
PQ (Performance qualification)
Process Validation: Process Validation in the pharmaceutical and medical service industry is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a requirement for Good Manufacturing Practice and other regulatory requirements. Analytical tests under process validation: - Microbiological test - Lose on drying - Potency test Process Validation must have
Repeatability Reproducibility Meet pre-determined specifications.
Critical parameters are optimized before validation. Each step of the manufacturing process should be qualified to validate the complete process. Source Validation/Specimen Sample analysis: Specimen sample is a small amount of sample that shows what the rest of it is like. Various test involved in specimen sample analysis/source validation: •
Identification
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Solubility
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Appearance of the sample
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pH
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Melting point limit
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Loss on drying
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Bulk density
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Mesh size
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IR spectroscopy
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UV spectroscopy
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HPLC
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Optical rotation
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Potency determination
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Microbiological test
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Kearl fisher titration
Solubility: Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on temperature and pressure. The extent of the solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase the concentration of the solution. The approximate solubility of a compendia substance is indicated by one of the following descriptive terms: •
Very soluble – 1gm in 1ml.
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Freely soluble – 1gm in 10 ml.
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Soluble – 1gm in 30ml.
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Sparingly soluble – 1gm in 100 ml.
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Slightly soluble – 1gm in 1000 ml.
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Very slightly soluble – 1gm in 10000 ml.
Procedure: Sample Fill in vol flsak Added of water Shake + Sonicate + Shake in water bath Slightly soluble As per the BP it is slightly soluble Assay: Assay test for compounded preparations are intended to serve as the official test in the event of a question or dispute regarding the preparations conformance to official standards. Sample
Conical flask + water Boiling in water bath (For 10 mins) Added indicator (phenopthaline) Titrated in 0.1N NaOH Water bath: Water bath means a bath of boiling water unless water at another temperature is indicated. Assay = Burette reading ×Factor ×Equivalent weight as BP×100 Sample weight
= %
Instrument used in analytical test: INSTRUMENTS HPLC HPLC System 1 to 8
ORIGIN Waters, USA Shimadzu, Japan Dionex,Germany.
FUNCTION For separation, identification & assay
GLC (Gas Liquid Chromatogram) UV Spectrophotometer Fourier Transform Infrared Spectrophotometer (FTIR) Atomic Absorption Spectrophotometer (AAS) Dissolution Testing Apparatus Apparatus 1 Apparatus 2 Apparatus 3
Shimadzu, Japan
Product identification, separation & assay
Shimadzu, Japan
Product identification
Shimadzu, Japan
Product identification, mainly for raw materials
Japan.
For identification/ detection of metal (elemental analysis).
Erweka, Germany
Dissolution time determination.
Disintegration Testing Erweka, Germany Apparatus Logan,USA Apparatus 1 Apparatus 2
Disintegration time determination.
Melting Temperature Gallanhamp Testing Apparatus
Melting pint determination.
pH Meter
Mettler Teledo, Suizerland
Determination of pH.
Karl Fisher Titrator
Mettler Toledo,Germany Brookfield,UK
Determination of water content.
Viscometer
Determination of viscosity.
Method Development Method development is a part of QC department. For analysis, methods those are described in compendium, i.e., BP, USP, are followed. But in case of non-described raw materials, the methods supplied by raw materials suppliers are followed. But, in many instances, the supplied methods don’t work. In those cases, a better & compatible method is developed. Following steps are involved in new method development: •
Development protocol, method trial, recording in the book, selection of the method, opening of a new file.
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Method writing, checking & correction.
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Method verification by analyst.
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Method approval.
After method development, it is validated. Then it is used as standard analytical procedure. Documentation The ACME Laboratories Ltd. record all the necessary information and documents in order to ensure the availability of all the data required for manufacturing, packaging, quality control and record the history of the batch. Such as raw materials analytical sheet, packaging material analytical sheet, certificate of analysis of raw materials, finished products analytical sheet, material requisition sheet. Seeing BP,USP procedure for assay PD give fix amount potency, so getting that required potency by changing procedure basis on trail and error. After get require potency than method give procedure in master formulation that is used for assay during production time validation IPQA (In process Quality Assurance)
In Process Operation: 1. QA Operation in Dispensing Area A QA officer in dispensing area monitors the dispensing process & Checks & signs the dispensing card, whether all the information’s are Mentioned & included in dispensing card.
2. QA Operation in Solid Department I.In Production Area •
Before compression starts, the machine & the rooms are checked for proper cleaning & few tablets checked for weight, hardness, thickness, friability, disintegration & dissolution time, organoleptic tests for chewable tablets & other relevant parameters. In case of capsule, initially, some capsules are filled to check weight variation. If tablets or capsules meet the specification, machines are started for operation.
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During compression or filling, the above parameters are checked at regular intervals (2 hrs).
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After compression or filling, the finished products are sent to QC department for analysis.
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On the basis of QC report, the tablets or capsules are approved for packing or rejected.
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Tablets that require coating are sending to QC for various tests before coating & during coating operation, all steps are monitored by a QA officer. II. •
In Packaging Area
Start up & IPC (in process control) in packaging, i.e., both primary & secondary packaging. •
Checking of product name, strength, batch no., MFG date, EXP date, license no., foil printing, pocket formation, sealing, cutting, slitting, MRP & leaflet etc.
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Leak test of blisters & strips.
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Release of finished products after checking all relevant documents & QC report.
3. QA Operation in LCO Department I. In Manufacturing Site •
Before starting a new batch production, room cleanliness, temperature & %RH is checked.
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Random sampling for QC test & retention sample.
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During manufacturing, filling or packaging, the products are checked for proper weight, volume, filling, sealing, clarity of solution, batch printing, both inner &shipping carton are checked at regular time interval.
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At regular intervals, bottle washing & drying are checked. II. In Packaging Site
Following parameters are checking by QA officer in case of packaging materials. •
For Bottle/ Vial -Batch no. on Label -MFG date on Label -EXP. Date on Label -MRP -Quantity of product -Print & color of Product -Cap Sealing/ security overprinting
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PVC & PVDC for Blister & Strip Packaging Color Width Thickness Weight/10 cm
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Inner Carton Product Name & Label Claim Batch no MFG date EXP. Date MRP Print & color Spoon/ cap/ actuator Leaflet
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Shipping Carton Product Name & Label Claim Batch no MFG date EXP. Date No. of packs per shipping carton Size no. & adaptability
4. Dealing of contract manufacturing
5. Product Recall 6. Artwork Approval Checking & finalizing all kinds of artwork (design) of packaging materials. 7. Issuing all kinds of certificates 8. Documentation •
SOPs (Standard Operating Procedures) Prepared by relevant department, but checked, reviewed & Approved by QA officers.
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Documents of Source Approval
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Analytical Test Report of Raw & Packaging Materials.
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Complete Batch Documents (BMR & BPR).
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Change Control Approval Change control approval is required in case of: Short batch production for exports. Change any parameters of product, i.e., color, foil etc.
Chromatography HPLC: High-performance liquid chromatography (sometimes referred to as high-pressure liquid chromatography), HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture. HPLC typically utilizes different types of stationary phases, a pump that moves the mobile phase(s) and analyte through the column, and a detector to provide a characteristic retention time for the analyte. The detector may also provide additional information related to the analyte, (i.e. UV/Vis spectroscopic data for analyte if so equipped). Analyte retention time varies depending on the strength of its interactions with the stationary phase, the ratio/composition of solvent(s) used, and the flow rate of the mobile phase. It is a form of liquid chromatography that utilizes smaller column size, smaller media inside the column, and higher mobile phase pressures. Description: The instrument contains the following parts: a) Pump b) Injector
c) Guard Column d) Column e) Detector f) Recorder g) Column Oven h) Degasser
Principle: Sample is injected to the column. Stationary phase consists of silica gel. Compounds are flowed through the column by the liquid media (mobile phase) at a different rate. During the extraction different compounds are detected by detector. Detector detects the compound and determines the amount of compound in solution . Process: In HPLC, a high backpressure is needed to pump the mobile phase through the column. Every reagent used in mobile phase and sample preparation should be highly purified or HPLC grade. The mobile phase and liquid sample is required to filter usually with 0.2µ filter paper. The sample (0.01ml) is injected with a syringe after each run the column must be cleaned. Generally 50% methanol is used for wash. Uses: •
Identification
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Qualification
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separation HPLC on QC lab:
Instrument HPLC System 1 to 8
Origin Waters, USA
Function For separation, identification & assay
Shimadzu, Japan Dionex,Germany. Parts of HPLC:
Parts
Function
Pump Injector Column
-pumping the mobile phase in the injector. -inject sample. -separate the chemicals according to its electro negativity. -detect the chemical component by using UV light. -identification and calculate potency.
Detector Software
Spectroscopy Atomic-Absorption Spectroscopy: Introduction Atomic-absorption (AA) spectroscopy uses the absorption of light to measure the concentration of gas-phase atoms. Since samples are usually liquids or solids, the analyte atoms or ions must be vaporized in a flame or graphite furnace. The atoms absorb ultraviolet or visible light and make transitions to higher electronic energy levels. The analyte concentration is determined from the amount of absorption. Applying the Beer Lambert Law directly in AA spectroscopy is difficult due to variations in the atomization efficiency from the sample matrix, and no uniformity of concentration and path length of analyte atoms (in graphite furnace AA). Concentration measurements are usually determined from a working curve after calibrating the instrument with standards of known concentration.
Fig: Schematic of an atomic-absorption experiment
Instrumentation Light source
The light source is usually a hollow cathode lamp of the element that is being measured. Lasers are also used in research instruments. Since lasers are intense enough to excite atoms to higher energy levels, they allow AA and atomic fluorescence measurements in a single instrument. The disadvantage of these narrow-band light sources is that only one element is measurable at a time. Atomizer AA spectroscopy requires that the analyte atoms be in the gas phase. Ions or atoms in a sample must undergo desolvation and vaporization in a high-temperature source such as a flame or graphite furnace. Flame AA can only analyze solutions, while graphite furnace AA can accept solutions, slurries, or solid samples. Flame AA uses a slot type burner to increase the path length, and therefore to increase the total absorbance. Sample solutions are usually aspirated with the gas flow into a nebulizing/mixing chamber to form small droplets before entering the flame. The graphite furnace has several advantages over a flame. It is a much more efficient atomizer than a flame and it can directly accept very small absolute quantities of sample. It also provides a reducing environment for easily oxidized elements. Samples are placed directly in the graphite furnace and the furnace is electrically heated in several steps to dry the sample, ash organic matter, and vaporize the analyte atoms. Light separation and detection AA spectrometers use monochromators and detectors for uv and visible light. The main purpose of the monochromator is to isolate the absorption line from background light due to interferences. Simple dedicated AA instruments often replace the monochromator with a band pass interference filter. Photomultiplier are the most common detectors for AA spectroscopy.
IR Section (Infrared Spectroscopy) What is IR? Infrared spectroscopy (IR spectroscopy) is the spectroscopy that deals with the infrared region of the electromagnetic spectrum that is light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic techniques, it can be used to identify and study chemicals. Mechanism of IR: Produce KBr disc of sample (raw materials), here very minor amount of sample is used and it must be free from moisture placed within IR spectroscopy allowed to pass IR through sample disc Show absorbance
Compare with standard
Quality Control Quality control is the part of good manufacturing practice, which is concerned with sampling, specification and testing as well as the organization and documentation and release procedure, which ensures that the necessary and relevant tests are, in fact, carried out and that materials are not released for use, non products released for sale or supply until their quality has been judged to be satisfactory. GMP Requirements of the quality control department: Normally QC laboratories should be separated from the production areas. This is particularly important for laboratories for the control of biological, microbiological and radio isotopes, which should also be separated from each other. Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid the mix-up and cross contamination. There should be adequate suitable storage space for samples and records. Separate rooms may be necessary to protect the sensitive instruments from the vibration, electrical interference, humidity etc. Special requirements are needed in laboratories handling particular substances such as biological or radioactive samples.
Function of quality control department: The well equipped and sophisticated QC has been working for the day by day control of quality of products. Even real time study also done to ensure the stability announced by the company. QC also checks quality of RM, packing and finished goods. QC officers and pharmacists assesses and assures that entire production process has been completed satisfactorily and satisfied all the aspects of cGMP as microbiological tests and validation ensured Quality control is responsible for the day by day control of quality within a company. This department is stuffed with scientist and technicians who assess and assure that entire production process has been completed satisfactorily and satisfied all the aspects of GMP. Protocol for quality control assignment Sampling (A quality assurance officer does it & brings it to the Q.C department )
Supervising (A representative from the Q.C. dept. receives the sample & assign someone to analyze.) Analysis (The analyst analyses the sample according to the specification) Checking (After the tests, the results are checked) Final approval (The Q.C. manager verifies the result) Collection (A Q.C. officer collects the results of the results of the sample that was assigned previously. )
Major responsibility of QC • Sampling adequately for testing purpose. • Issuing release, reject or quarantine advice for each batch of raw, bulk and packaging materials. • Assessment of the finished products for their release, reject etc. • Maintaining batch wise full quality control test records with signature of the person(s) who performs the tests. • Batch documentation. • Performing Environmental monitoring checks. • Calibration and standardization of laboratory equipment. • Control of laboratory reagents. Packing and Packaging Section This section deals with the checking of procure packaging and packing materials as well as monitors the proper packing of finished product for the correct label, batch number, manufacture and expiry date. The tests that are exercised by this section for packing materials are: Product PVC & PVDC Cotton Shipping cartoon Inner cartoon Plastic cap Dropper Mask type Bottles, ampules, vials
Test Colour, width, thickness, weight per unit area etc. Appearance, weight, moisture content sulphated. Weight, dimensions, thickness. Height and level, description (text, colour, general appearance) weight etc. Appearance, weight, length, diameter, volume capability. Appearance, weight, length, capacity, adaptability with bottle cartoon and plastic cover Appearance, width, adhesiveness, Height, neck diameter, weight, volume capacity, light transmission test, machine acceptance.
Raw material Section The materials, which are used to prepare a dosage form, are known as raw materials except packaging materials. Raw materials may be of two types: 1. Active ingredients 2. Excipients. 1. Active ingredients: The substance or compounds that is intend to be used in the manufacture of pharmaceutical products, which is pharmacologically active, are called active ingredients. 2.Excipients: Excipients are the non- drug components of a pharmaceutical formulations, which are used as a diluents, binder, adhesive, disintegrant, lubricant, glidant, color, flavor, sweetener etc.
Sampling rule: • √N+1 (N=no. Of container), if N>5 • If N<5,then sampled all • For damaged containers, sampled all When QA department confirms the raw materials as useable then they are transferred to free stock with released tag. Tag used in warehouse: Under test: Yellow tag Sampled: White tag Released: Green tag Non-conforming: Blue tag Urgent released: Orange tag Rejected: Red tag In Warehouse raw materials are stored in different environment depending on their chemical and physical nature. The store conditions are as follows: 1. Cold store (Temperature: 02-080C) 2. Cool store (Temperature: 08-150C) 3. Penicillin store (Temperature: >250C) 4. Narcotic store (Ambient temperature) 5. Control store (Temperature: >300C) 6. Empty Hard Gelatin store (Temperature: 15-250C,RH 35-65%) The passed materials are sent to the respective production department according to their Batch Manufacturing record (BMR).
Raw Material Procurement and Analysis Demanding of raw materials (Demanded by production according to the needs through commercial dept.) Source approval Raw materials received procure by store Raw materials in quarantined area QC
sampling
(Green
tag)
Under test Rejected
QC
passed
Documentation Stored in passed area Retest Dispensed Waiting for product preparation Various test involved in raw materials analysis: ● Identification ● Solubility ● Appearance of the solution ● PH
● Melting point limit ● Loss on drying ● Bulk destiny ● Mesh size ● IR spectroscopy ● UV spectroscopy ● HPLC ● Optical rotation ● Water content or loss on drying ● Potency determination ● Microbiological test
Product Testing Section Oral liquid section the section monitors all the in-process QA process as well as thefinal clearance for the finished product to be sold in the market. In-process QC exercises by the section are: •
Potency determination
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Viscosity
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pH
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taste odor & flavor
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color
Tablet section For tablet following experiments have been done: •
Checking the cleanliness of drying and granulation area
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Determination of moisture content of granules
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Determination of harness, friability and thickness of compressed tablets
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Regular monitoring of humidity and temperature of compressed room
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Checking of weight variation, disintegration time, dissolution time and other relevant parameters
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Potency of active ingredient in tablet
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Checking the uniformity of coating coated tablets
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Finally checking the elegance of the product
Injectable section These sections monitor all the in-process QC measures in the production of injectables. This includes: •
Monitors the cleaning procedure of compounding and filling rooms according to SOP
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Checking the integrity of membrane filter by performing bubble poin test
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Potency determination
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Volume adjustment
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Maintenance of aseptic area
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Monitoring the sterilization of products
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Monitoring the pH of a product
Ointment, Cream, Dry syrup and capsule section Oinments and creams are checked for their microbiological contamination as well as to find the grittiness. Capsules are assayed as per the specification which includes parameters such as weight variation, potency, disintegration etc. dry syrups are regular checked by regular sampling of bottles, their qualitative and quantitative assayed are made and finally the proper sealing of the cap is monitored. Product testing of finished products is made in the quality control laboratories. The testing of finished product for compliance with predetermined standards is a critical factor product release. Microbiology testing section: Microbiology department is an essential part of QC. Microbiological test perform an important role to ensure the quality of the parental and non-sterile products in various steps ranging from the raw materials to finished products. Drugs like eye drops, injections must be sterile in condition. For this purpose a varity of test have done in Microbiological laboratory. The departments of Microbiology perform the role of immense importance to follow the GMP and to formulate as well as to implement the SOPs. Overall activity profile of the microbiology section of QC department of ACME is represent by following ways:
For ForSterile Sterileproduct product(Parenteral (Parenteral preparation) preparation)
Environmental Environmental Monitoring Monitoring
For Fornon-parenteral non-parenteralproduct product
Microbiological MicrobiologicalLimit Limit Test Test
Sterility Sterilitytest test Bioassay Bioassay
Bacterial Bacterialendotoxin endotoxintest test
Particulate Particulate contamination contaminationtest test
Sterility Test Filter the product with 0.45Âľ Filter paper (Nitrocellulose Nitrate or Nitrocellulose Acetate)
Cut the filter paper into two part, one part keep in fluid (thioglycolate broth) for bacteria an another part keep in Tryptone soya broth for Fungi.
Incubate at 32.5 °C for bacteria and 22.5 °C for fungi(Both for 14 days)
Observed regularly Bacterial Endotoxin Test LAL test means Limulus Ameaeobocyte lysate test. Limulus amebocyte lysate (LAL) is an aqueous extract of blood cells amoebocyte from the Horseshoe crabe Limulus polyphemus. LAL reacts with bacterial endotoxin and lipopolysecharide (LPS), which is a membrane component of Gram Negative Bacteria This reaction is the basis of the LAL test, which is used for the detection and quantification of bacterial endotoxins. Process: Test sample add in Limulus amebocyte lysate
If any types of gel is formed, then it is consider that any type of endotoxin present in sample Non-parenteral Product Limit Test •
Microbiological Limit Test of raw materials & finished products. 1. Total aerobic (bacteria & fungi) count. 2. Detection of 4 pathogens, which are Escherichia coli, Pseuodomonas aeroginosa, Salmonella species & Staphylococcus aureus.
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Bioassay of raw materials & finished products 1. Bioassay is mainly performed to detect the potency of antibiotics.
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Environmental Monitoring. 1. Monitoning of Particulate Contamination And air flow in clean room Particle counter 2. Monitoring of settle plate exposure. 3. Monitoring Personal Hygiene Contact Plate Method 4. Monitoring Surfaces Contact Plate Method Swab Test 5. Monitoring of Airborne Microorganisms. Air Sampling by RCS Sampler
Instruments used in microbiology department: • • • • • • • • • • • • •
Sterility Testing device Autoclave / Steam steriliger Laminar air flow Oven PH meter Incubator Refrigerator Air supplier for air sampling Microscope. Colony counter. Liquid particle analyger Air borhe particle counter. Water bath
Product Development Department
Duration of Training: One day
INTRODUCTION Product development department is the core & heart of a pharmaceutical industry. Product development as the name implies, is responsible for the development of a new product. This department formulates new drugs & plays key role for the development & improvement of the quality of the existing drugs & for the establishment of new drugs. Moreover, this department fix ups any market complain of an existing product in the market, troubleshoots any problem arising during manufacturing the product & last, but not the least, documentation (preparation of BMR & BPR, i.e., Batch Packaging Record). Functions of product development •
New product formulation
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Preparation of recipe or drugs
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Development of packaging materials for new product.
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Development of existing product with cost effective formulation.
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Source approval work for existing materials both active ingredients and exipients
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Preparation of master formulation and analytical procedure for new product
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Reformulation
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Reprocess
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Trouble shooting
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Handling market complain
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Preparation of BMR/BPR
NEW PRODUCT DEVELOPMENT 1. Selection new product for product development by CPM of marketing department according to the demand of the market. 2. Collection of raw material (both excipient & active ingredient) to be developed. 3. Preformulation study. Checking of following parameters for active drug or excipients: •
Solubility.
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Water content.
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Particle size.
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Bulk / tapped density.
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Flow properties.
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Melting point.
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Crystal properties.
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Biological properties.
4. Recipe Preparation. 5. Lab scale trial batch for stability studies. 6. Analytical method development & validation. 7. Preparation of stability study protocol & stability study as per (International Conference on Harmonization) guideline
ICH (30°C±2°C &
65%±5% RH, 40°C±2°C & 75%±5% RH, 25°C±2°C & 60%±5% RH ). 8. Evaluation of stability study test result after 03 months & 06 months (Accelarate) & 03 months , 06 months & 12 months (real time). 9. Preparation of master formulation an procedure. 10. Preparation of BMR (Batch Manufacturing Record) & BPR (Batch Packaging Record) for small scale commercial batch, i.e., pilot batch. 11. Pilot batch production (at least 3 consecutive successful batches). 12. Preparation of BMR & BPR for routine commercial production.
Launching a new product involves a lot of work
Market study of the new product by PMD
Proposal from Product Management Department (PMD)
Feasibility study and evaluation of existing facilities.
Feasibility study by PMD
Cost Evaluation
Proposal Approved
Product File Open
Raw materials procurement requisition according to QA specifications
Lab batch produced by PD
Stability testing for shelf life
Galenical and Analytical method development and validation REPROCESS If the chemical assay for QC for a particular batch donâ&#x20AC;&#x2122;t comply the standard then PD will check the batch & take necessary action accordingly. REFROMULATION Selection of product for reformulation to improve the product quality, product stability, manufacturing process, organoleptic properties of the product and to change elegance & packaging mode of the product. TROUBLESHOOTING
During manufacturing of a new product in pilot 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 on 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. DOCUMENTATION •
Preparation of product dossier for regulatory purpose.
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Preparation of export document (e.g. manufacturing process, batch formula, and stability data) as per requirement of respective countries.
AREAS •
Formulation Section. 1. Tablet Compression room. 2. Coating room 3. Granulation, Drying & Milling Room.
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Analytical Section 1. Stability study room 2. HPLC Room. 3. DT, Dissolution analysis room.
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Documentation Room
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Official Room
Product Shelf-life determination If meet all specifications, then the shelf-life of products is given according to the following table: Accelerated stability test time Equivalent life time 6 months 2 years 3 months 1 years Stability Test There are two methods by which stability is tested: Real-time stability study, and Accelerated stability study. Products are kept in the stability chamber at three different conditions: 25°C, 60% Relative Humidity (RH) a) Real time stability 30°C, 65% RH b) Accelerated Stability: 40°C, 75%RH
The product stays in the stability chamber for 6 months. If the degradation of the product is less than 5% in 6 months then the shelf life is 2 years The Analytical method development requires demonstration of suitable • Accuracy • Precision • Specificity • Sensitivity • Ruggedness Machineries and Materials used in PDD: 1. Balance 2. Oven 3. Stability chamber 4. PH meter 5. Stirrer Propeller 6. Coating machine (NEOCOTA) 7. Disintegration, Dissolution tester, Refrigerator,Friability tister 8. The several tester which are used for a variety of purpose in PDD are given below: 9. Excipients 10. Lubricating agent -e.g. providone, purified talc etc. 11. Disintegrating agent –Crospovidone, Na-starch Glycolate etc. 12. For flow property –Mg stearate, Colloidal SiO2 etc. 13. Suspending agents 14. Sweetening agents 15. Flavor 16. Coating materials 17. Coloring agent.
Mechineries should be included: • • • • • •
Granulator (singma bladed) Compression machine (Rimek Mini Press- 2 MT) Blending machine. Milling machine Silverson stirrer Osmo meter.
Marketing and Sales Division
Duration of Training: One day Product Management Department Introduction: Pharmaceutical industry is one of the largest sectors of business in Bangladesh. More than 300 pharmaceutical firms fight for a significant amount of market share in the pharmaceutical market. The importance of this industry in the total economy can easily be understood by the fact that pharmaceutical industry is the second highest tax payer to the Government of Bangladesh after the tobacco industry. On the other hand they employ a generous amount of professionals from the field of Pharmacy, Chemistry, Engineering, Health and Business. About 95% demands of pharmaceutical products are met up locally in this country. Therefore pharmaceutical industry as a whole entitles for a great deal of importance in the economy of Bangladesh. Name of the Company: The ACME Laboratories Ltd. Location Corporate Head Office:
The ACME Laboratories Ltd. Court De La ACME 1/4 Kallayanpur, Mirpur Road Dhaka – 1207
The Heart of the Company The ACME Laboratories Ltd. stands out among pharmaceutical companies worldwide for the expertise, commitment and diversity of its people. Its strong, multicultural team brings innovative thinking and customer-oriented service to The ACME Laboratories Ltd. ACME’s values The following are the views of the ACME on the Values: Respect for people Respect is best demonstrated by developing people. It is the opposite of protectionism, which only serves to disempowered and restrict people. But respect also means creating a meritocracy in which performance is rewarded. An integral feature for Acme and its business is respect for people of different national, cultural, racial and corporate backgrounds. Integrity Integrity allows us to reach the right decisions faster, giving us the speed we need to be competitive. At the heart of integrity is transparency in our actions, motives and intentions. “We the talk” and resist politics. Sense of Urgency Fundamental to our sense of urgency is the endeavor for speed and simplicity in everything we do. It means being goal oriented and focusing on delivering results. The critical point is not that we do the same thing faster but that we think about our own processes and change the barriers and structures to reduce friction. It also involves fighting bureaucracy – if a superfluous, extra level of approval exists, get rid of it. Networking
Effective networking means reaching out beyond boundaries not just to get information and ideas, but also to share our ideas and information with colleagues. Positive networking involves breaking down silos. This demands courage, discipline and integrity. Creativity Being creative calls for innovations in all processes and in everything we do. It is not always easy, and it involves “embracing” the discomfort we all feel when we are moving into uncharted territory. Our aim is to reach a point where we find this satisfying and rewarding. Empowerment Empowerment is very closely related to other Acme’s Values. It means using transparent processes to create a clear understanding of a mission. But a significant element of empowerment is also to create an environment in which people know we expect them to have the self-confidence to show initiative. It is about seizing the initiative and being accountable for the result. Courage Courage is an essential value for creativity and innovation. Furthermore, without courage, open and challenging discussion would not be possible. It is about getting things on the table and discussing them upfront to reach a timely decision; but courage is also about setting ourselves demanding targets, which help us to advance more rapidly. This division has mainly the following departments: • National Sales Department • Marketing Department • Export Department • Training Department • Research Department Sales (National) • Headed by National Sales Manager; Regional Sales Manager (RSM) works under him. • About forty six Area Sales Manager (ASM) report to Regional Sales Managers. • About 300+ Medical Representatives report Area Sales Managers • Each of the Medical Representatives covers about 125 doctors on average. • Other than this Sales Manager Institution also report to National Sales Manager.
Marketing
Headed by Manager Marketing Major Function: • Offer International Business (routine products & unmet medical needs) • In house promotion through clinical meetings • Sales promotion through Doctors and promotional materials. • Budgeting short term, mid term and long term marketing plans Export Headed by manager Export
Major Functions: • Export (LC and non LC i.e. purchase order) • Tender Based Export • Registration of new products to the potential countries • Registration of new products in the existing operating countries. • Do oversee marketing operation for export growth. • Attend international fair for the market expansion. • Forecast the targeted goal for the next year sales. Training Headed by Manager Training Major Functions: • Selling Skill • Product Induction • Refresh Course • PPP • APILP On the Job Trainings include the following: • Guideline are provided in field • Evaluation done • Team wise detailing Regulatory Affairs: Major Functions: • Product Registration • Attaining Govt. Approval for literature and packing manuals. Regular Export Market
Market Development
Myanmar Sri Lanka Afghanistan Hong Kong
Ethiopia Myanmar Cambodia Nigeria (Vet)
Nepal Pakistan Philippines Vietnam
Taiwan Yemen Kenya KSA
Production Department Duration of Training: Total 11 days
There are seven Departments of Production Divisions of Human. These are Tablet Section Capsule Section Liquid Section Cream & Ointment Section Injection Section Inhaler & Suppository Section Dry Syrup Section Tablet Section Tablets are solid dosage forms with or without suitable excipients, which are prepared by sweetening agents, f compression or by molding method. Excipients may include diluents, disintegrating agents, lubricants, flavoring and coloring agents. The tablets in The ACME Laboratories Ltd. are produced only by compression method. Operation on Tablet section ● After the recommendation for the production of a batch, at first the requisition of required raw materials is sent to ware house department. ● QC & QA approved required raw materials of specific amount is then sent to the dispensing unit. ● Accurate weighing of chemicals. ● Mixing and granulation ● Compression ● Coating (if necessary) ● Packaging and packing Each step is carried out according to Standard Operating Procedure (SOP) Excipients used for tablet formulation
• • • • • • • • • • • •
Diluents: Maize starch, Calcium hydrogen phosphate, pregelatinized starch. Lactose. Lubricants: Polyethylene glycol, purified talc, Mg-stearate, Aerosil-200. Glidants: Colloidal silicon dioxide, talc. Disintegrants: Starch-1500, Aerosil-200. Coloring agents: Allura red lake. Sweetening agents: Granulated sucrose, saccharine-Na. Flavoring agents: Orange flavor, Anise oil, vanilla, perfume rosa. Humectants: Glycerin, sorbitol, ethylene glycol. Binder:Starch paste,Povidone Preservatives: Methyl paraben, propyl paraben. Shining agents: Tritanium dioxide, Mg-stearate. Dissolution rate enhancer: Na-lauryl sulfate.
Precautions taken during manufacturing of tablet in The ACME Laboratories Ltd. • Room, floors, machineries and other tools involved in manufacturing are checked for proper cleanliness everyday. • During changeover, floor of every area in this section are cleaned properly by a vacuum cleaner. • Then it is washed with savlon water using cloth. • Wall, door, glass and other furniture etc. are cleaned with savlon water using a clean cloth. • After completion of daily work, each area of this section is cleaned in the same process. • After cleaning, the machineries are labeled as “clean”, which is confirmed by the QC personnel. Only after confirmation, these are used for next production. Process of flow of tablet: Raw Material Dispensing Raw material receiving by production officer Blending / mixing Wet mass/Dry granulation Preliminary drying Crushing Final drying Blending Compression
Coating Blistering Packing of finished goods Distribution of depots In The ACME Laboratories Ltd. the following granulation processes are used for tablet manufacturing:
Method of tablet manufacturing Wet granulation
Dry granulation
Direct compression
Wet Granulation : In this method purified water is used as granulating agent. This is the most popular way to form tablet granulation. Steps in wet granulation: Accurate weighing of active ingredient and excipients . Dry mixing of active ingredient and excipients except lubricant. Wet mixing (Dry mixture + purified water). Wet mass pass through multi mill through 10 mm screen. Drying (usually fluid bed dryer used and required moisture is maintained here) Dry sieving (granulation). Mesh 20 is used here Lubrication and blending Discharge (into double polythene bag & close lid of drum tightly and sent to compression unit for compression)
Dry Granulation : In this method larger tablets are formed and then they are crushed to form granules. This granules are used to form tablets. Steps applied for dry granulation are given below: Weighing of drugs and excipients Dry mixing of drugs and diluents Slugging or precompression Milling and sieving Lubrication Discharge for compression Direct compression: In this method no granulation is required. The materials are directly compressed to form tablets. Steps of direct compression: Weighing of drugs and excipients Sieving Mixing of all ingredients Discharge for compression Machine used for granulation : Table-4 Name of machine Manufacture Planetary mixture Ganson – India Rapid mixer granulator Sainath & Saizoner mixtureIndia Multi mill Ganson – India Drum blender Bangladesh Roller compactor CLIT- India Fluid bed dryer Alliance and Ganson – India Fray dryers Bangladesh
Purpose To mix the ingredients. To mix the ingredients. To reduce the size of granules. To blend. For slugging. To dry the granules. To dry the exicipent.
Compression: Compressed to form tablets of specified weight, hardness and thickness, the process of compression is preformed in nine (9) separate rooms, each room equipped with compression machine, weighing balance , batch production record sheet, wet bulb and dry bulb hygrometer, dust extractor and dehumidifier. During and after compression, following tests are preformed: • Hardness • Thickness and diameter
• • • • •
Moisture content of tablet Friability Temperature Disintegration time Relative humidity
Problem may be arising during tablet manufacturing: •
Capping: It is the partial or complete separation of top or bottom layer from the main body of the tablet.
Cause: •
Problem of formulation
•
•
o
Entrapped air
o
Excess powder
o
Over drying granules
o
Elastic compression of tablet
Problem of punch o
Claw formation
o
Deep concave punches
Problem of die o
• •
Ring formation
Incorrect setting of tablet machine
Chipping: It is breaking of edge of tablet during compression
Cause: •
•
Problem of formulation o
Excess moisture
o
Lack of lubricant
Problem of punch o
•
Problem of die o
•
Rough surface of the upper punch
Serious sticking of granules with die wall
Incorrect setting of tablet machine o
Improper setting of fed frame
o
Incorrect adjustment of sweep off blade
o
Improper setting of ejection knob
•
Lamination: It is separation of a tablet into two or more distinct layers.
•
•
Entrapped air
•
Excess powder
•
Insufficient & poor quality of binder
Picking: It is the removal of granules from the surface of tablet during compression.
•
Cause:
Cause: •
Excess moisture in the granules
•
Due to the rough faces punch
•
Lack of binder
Sticking: It is the adhesion of granules to the die wall.
Cause: •
Excessive moisture in the granules
•
Low melting point substance
•
Molting: Unequal or heterogeneous distribution of color on the tablet surface.
•
Double impression: Twice impression of the letters on the tablet.
•
•
Uncontrolled free rotation of the lower punch
•
Unequal size distribution of granules
•
Poor flow property of granules
•
Poor mixing
•
Amount of binder
Weight variation:
•
Cause:
Cause:
Hardness:
Cause:
Tablet coating unit: Oral tablets coated with a layer of sugar or film are called coated tablet. The application of coating to tablets, which is an additional step in the manufacturing process, increases the cost of the product. Again the coat must be dissolved before disintegration and dissolution of the tablet. Therefore, the advantage to coat a tablet is usually based on one or more of the following objectives: 1. To mask the bad taste, order, or color of the drug. 2. To protect moisture sensitive drugs from moisture. 3. To provide physical and chemical protection of the drug. 4. To control the release of the drug from the tablet.
5. To protect the drug from the gastric environment of the stomach with an acid resistant enteric coating. 6. To incorporate another drug or adjuvant in the coating to avoid chemical incompatibilities or to provide sequential drug release. 7. To improve the pharmaceutical elegance by use of special color or contrasting printing.
Classification of Coating: Mainly three types of coating are performed in the solid section. They are as follows: Coating Sugar coating
Film coating
Enteric coating
Aqueous coating Organic coating Coating process employed in The ACME Laboratories Ltd. In ACME, the following three processes are employed for tablet coating: 1.Film coating a. Aqueous film coating b. Organic film coating 2.Enteric coating a. Liquid enteric coating b. Powder enteric coating
General flow chart of coating of tablets:
Compressed tablets in feeding pan
Spray of coating solution
Complete procedure of tablet coating: Coating solution Proper setting of inlet & outlet Temperature, pan speed, Air pressure distance of gun to the tablet bed
Simultaneo us drying
Coated tablets
Place the compressed tablet in feeding pan Dedusting Spray of coating solution by nozzle Turning of the exhaust an & glower Rolling the tablet Simultaneous drying Fig- Flow chart of tablet coating
Coating agents: For enteric coating: 1. Cellulose acetate phthalate. 2. Hydroxy propyl methyl cellulose phthalate 3. Diethyl phthalate For film coating: 1. Hydroxy propyl methyl cellulose 2. Polyethylene glycol 3. Methylene chloride Solvent: Acetone, Ethanol, Methylene chloride recently H 2O is used as solvent coating of Ecosprin tablet. (Sugar coating is not used in Acme Laboratories.)
Problems of coating: (1) Logo bridging. (2) Edge chipping or erosion. (3) Picking or sticking. (4) Cracking. (5) Blocking.
(6) Poor erosion. (7) Loss of logo definition. (8) Orange peel roughness. (9) Twining. (10) Mottling.
Packing Area Packaging: The concept of pharmaceutical packaging developed stage by stage with the objectives of presenting a product with physical protection, environmental protection, dosage information, regulatory complies, perceived quality and pack security. So, the drug quality is dependent on the packaging quality. Drug quality + Packaging quality
Product quality
Purpose of packaging: • • • • • •
To increase the acceptability of the drug To increase the stability of the drug To minimize the transport/shipping hazards To improve patients compliance To improve the pharmaceutical elegance by use of special color or contrasting printing
Two types of packing materials are involved1. Primary packaging materials (in contact with products) which are 2. Secondary packing materials which are There are two types of packing: •
Blister packing
•
Strip packing
Procedure of Primary Packaging: 1) Formation of pockets for tablets/capsule using a heat softened plastic film. 2) Introduction of product in to the pockets, manually. 3) Sealing of product by covering material 4) Cutting 5) Conveying to the secondary packaging section via the convey belt.
Blister Packing: Usually tablets and most of the capsules is blister packed in this case, at first the PVC/PVDC /Aluminum foil is heated by heating plate. The packets are produced by the air pressure and immediately cooled. At the next stage tablets/capsules are filled into the pockets are pockets and the aluminum foil is sealed over the PVC/PVDC/ALU film by heating. Finally the blister pack cut into suitable size.
There are 3 types of Blister: 1. Alu-PVC blister 2. Alu-Alu blister 3. Alu-PVDC Secondary Packaging Room: There is another room beside the blister packaging room where the secondary packaging of bottles is done manually. After completion of blistering, the finished strips are then sent to the packing lines. There the following steps are doneo
Feeding
o
Laying
o
Visual checking
o
Cartoon making
o
Inserting
o
Flap closing and Tapping
o
Outer making and filling
o
Outer closing.
o
Finally the finished packets are sent to warehouse after Quality Assurance approval
In-Process Control (IPC) for Secondary Packaging • •
Packaging Test — Leak Test (methylene blue vaccum test) Machine Performance test- Blank foil test
•
Line Clearance Monitor
•
Packaging area temperature and humidity test (50%RH and 25° C)
• • •
Visual inspection of Secondary Packing. Number of finished products checked Quality and identity of components complient slip/labels/cartons/leaflets/outer labels/outer box/ spoon Identity and appearance of product in packs Quantity: No./volume/weight Overprinting/embossing: batch no./MFD/Exp date/MRP Label/carton with product name, batch no., Mfg date, and price. Exp date.
• • • •
Process of blister packing: Blister formation in PVC either by hydrolic or pressure and temperature Feeding of tablets in the blister manually or mechanically
Scanning of empty blister and sealing with Al foil at 1650 c Code embossing and cooling Rejection of empty blister Perforation Cutting Product (Blister pack) Fig: Flow chart of the process of blister packing Strip package: A strip package is a form of unit dose packaging which is commonly used for the packing of tablets and capsules. Striping materials: Polyethylene laminated aluminum foil.
Process of strip packing: Aluminium foil
Aluminium foil
Batch printing Dropping table in the pocket of two molded hot rollers Fill the product into strip Cutting Collected Fig: Flow chart of the process of strip packing
Liquid Section
Oral Liquid Section
Compounding area
Filling &Sealing area
Antacid area
Packaging &packing area
Other Liquid Area
Antacid Total product:4 1. Oxycone Suspension 2. Oxycone –S Suspension 3. Oxycone-M Suspension 4. Oxycone- MS Suspension 5. Milk of Magnesia 114ml 6. Milk of Magnesia plus 120ml In cleaning process the following materials are used: • Tape water, Purified water,UV treated water •
JET
•
70% IPA (Iso-propyl alcohol).
FUMIGATION: • Na-Nitrite 100mL (6.9%W/V). It is given to the pipe line. •
250 mL formalin sprayed in the whole room for whole night.
ROOM CONDITION: Double door system, positive pressure in the room, temp28
0
C.
Manufacturing Flow Chart of Oxycone Suspension: Hydrated Al, Mg dried gel (paste) are taken into the charge vat Hydrated suspending Agent Addition of sweetening agent Continuously stirring by silverson stirrer Addition of preservatives Addition of colouring ,flavoring,buffering agent
Addition of monochloramine water 10ppm for Prevention of microbial action. Stirring cotinuously Volume adjustment Sample-1 Send to microbial section
Sample-2 Send to QC dept.
If the result is ok Then the product send to Filling and sealing unit labeling packaging
Manufacturing Flow Chart of Syrup: Preparation of syrup (hot water+sucrose) Addition of preservatives. Cooling at 400 C Addition of wetting agent (when temp. goes to 100째C) Transfer the sucrose solution into the vat by transfer pump Addition of active ingredient Addition of co-solvent, buffering agent Addition of color/flavor
Volume adjustment Filling Sealing Labeling Packing
Machineries used for Compounding (For Syrup and For Antacid): The machineries and utensils that are used for compounding are listed below: 1. Compounding vessels (capacity: 500L, 250L, 210L,1000L,2500L,3000L) 2. Silverson stirrer 3. Homogenizer 4. Filter press pump 5. Colloid mill 6. Transfer pump and 7. Storage vessels Bottle washing and drying: The bottle are washed both internally and externally with DM water. The washed bottles are dried at 130oC. For antacid preparation, bottles are passed through CL-water . Name Bottle washing machine
Capacity 100-1 20 bottle/mm
Manufacturer India
6 channels,100 India Bottle filling & Cap bottles\min locking machine
Machineries used for Filling and sealing: The machineries used for this purpose are; 1
Automatic filling, sealing and labeling
2
Semi-automatic filling and sealing machine
PROBLEMS ASSOCIATED WITH ORAL LIQUID DOSAGE FORM : • Microbial contamination • Sedimentation • Phase separation
• •
Cake formation Color may be changed
OBSERVATION : • Cleanliness & environment are strictly maintained. • Temperature, humidity aqurately maintained. • Water purity aqurately maintained • Purified water are used. • Microbial contaminations are maintained. • Separate bottle washing and drying room. • All machines are operated according to standard operating procedure (SOP). • Machines are calibrated timely. Dry Syrup Department Introduction: Dry syrup is the preparation that is formulated as dry powder but administered orally as liquid dosage form. They are prone to hydrolysis during extended exposure of moisture. They are to be reformulated by mixing with certain amount of boiled water and should be use up within certain periods (5 days at normal temperature). Types: The ACME Laboratories Ltd. produces three different formulations for Dry Syrup – 1.Powders for suspension 2.Powders for syrup 3.Powders for paediatric . Physical plant design: It is divided into two areas Manufacturing area (blending or mixing area) Filling and Sealing area Manufacturing Flow Chart Weighing of all ingredients Sieving of ingredients with different sieve size All ingredients Blending/mixing Bottle washing and Drying at 140oC Filling of dry syrup in dried bottle
Sealing of Bottles Checking Packing
In process control 1
Manufacturing: Relative Humidity ≤ 50% and temperature ≤ 28oC.
2
Filling/Sealing: Weight variation, relative humidity, temperature and sealing check.
Manufacturing procedure Step-1: Dried sucrose powder + Dried Cefradine (micronized) powder. Seieve with 20 mesh screen. Transfer into cone blender. Step-2: Sodium benzoate + Banana trusil flavors + Raspberry trusil flavors + Aerosit-200. Seieve with 20 mesh and transfer into cone blender. Step-3: Finally, Raspberry red color (40 meshes) is transferred into cone blender. All ingredients are blending for one hour. Production through sampling advice sheet to QC & QC sampled for released tag. Step-4: Bottle filling and sealing. Average fills wt. 60.29 gm. Then checking and final packaging. Cream & Ointment Department Pharmaceutical creams are semi-solid preparations containing one or more medicinal agents dissolved or dispersed in either a water-in-oil or an oil-in-water emulsion or in an other type of water washable base. After application of the cream, the water evaporates, leaving behind a thin residue film of stearic acid or other oleaginous component. Instruments used for preparing cream and ointments: • Charge vat (Jacket vessel). • Oil charge vat • Water charge vat • Storage vat (non-jacketed) • Vacuum emulsifier • Colloidal mill. • Semi-auto filling and sealing machine.
Observed Product: Bet-A Cream 15 gm Composition of Bet-A Cream 15 gm Active: Betamethasone valarate Micronized as base Liquid paraffin Excipients:
Oil phase
Aqueous phase
White soft paraffin
Chloresol
Cetostearyl alcohol
Glycerin
Cetomacrogol
Sodium dihydrogen phosphate DI water
FLOW CHART OF CREAM PRODUCTION PROCESS:
0 0 Aqueous Aqueousphase phasemixing mixingatat70 70C C inina aStainless Stainlesssteel steeljacketed jacketed vat vat
Oil Oilphase phasemelt meltininStainless Stainless steel steeljacketed jacketedvat vatand andmelt meltatat 0 0 70 70c c
Stirring Stirringwith with stirrer stirrer
Stirring Stirringwith with stirrer stirrer
Oil Oilphase phaseisistransfer transfertotothe the content contentofofaqueous aqueousphase phasetoto vacuum vacuumemulsifier. emulsifier. Stirring Stirringwith withSilverson Silverson 0 stirrer stirrerand andcool cooldown downatat45 450 c c
Add Addthe theactive activeingredients ingredientsdirectly directlytotovacuum vacuum emulsifier emulsifierand andmix mixthe theproduct productfor for30 30min. min.
Send Sendthe thesample sampleadvice advice sheet sheettotothe theQC QCfor for sampling. sampling.
Filling Filling,sealing ,sealing and andPacking Packing
Fig: Flow chart of production (Cream) Manufacturing of ointment:
All Allingredients ingredientsblending blending
Homogenizing Homogenizing
Aluminum-tubes Aluminum-tubesFilling Fillingand andSealing Sealing
Checking Checking
Packing Packing Fig: Flow chart of production (Ointment) Special care for eye-ointment:
1. 2. 3. 4.
Tubes for eye ointment are sterilized. The room is sterilized with UV radiation and fumigation is performed with formalin. Ointments must free from gritty particles. PH viscosity and consistency is strictly maintained (Monitored by Q.C).
Machineries Observed: Name of the machine Jacketed S.S “MONITA”
Planetary
Manufacturer Purpose mixer/vat Italy
To mix the active ingredients with excipients
Homogenizer/colloid mill ‘GANSONS” India
To prepare homogenize mixture.
Semi auto tube filling and sealing India machine
For filling and sealing purpose.
Preparation of NEOBET Cream 10gm: Active Ingredient: Neomycin Sulfate Oil phase: Liquid paraffin, white soft paraffin, cetomacgrol, cetostearyl alcohol, polyethylene glycol. Water phase: Tween 80, Butylated hydroxyl toluene, Formalin. Room condition: Relative humidity-Not exceed 50%. Temperature- Not more than 25oC.
Manufacturing process: Step-1: All oil phase ingredients in 5.5 jacketed planetary mixer using high temperature. Keep for one hr. at that temp. Cool down to about 40oC with slow stirring. Step-2: All water phase ingredients in 5.5 jacketed planetary mixer. Heating at temp. 90 oC and then cool down with slow stirring. Step-3: in a S.S bowl Neomycin Sulfate, Betamethason valerate and oil phase and water phase solution mix manually until homogenous. Step-4: Pass the product through homogenizer for two times to get smooth mass. Then transfer to the storage vat. Cleaning of ointment room, vat, utensils etc: The remained ointment to the vat and floor is cleaned with clean cloth. Isopropyl alcohol is taken in clean cloth and then charge vat, utensils, homogenizer, storage vat etc. 200 ppm chlorine water is used to clean up the whole room, wall etc.
Capsule Department
Capsule may be defined as solid pharmaceutical dosage form in which medicinal and/or nonmedicinal inert substances are enclosed within a tasteless, hard or soft soluble small shell or container made up of a suitable gelatin. The ACME Laboratories Ltd. Produces almost 32 types of capsules, most of them are antibiotics, and others are hematinic vitamins, antidiarrheal etc. The ACME Laboratories Ltd. use only hard gelatin capsule for their production.
Capsule shell size Capsule shells are supplied as a number of sizes. The number varies from 000 to 5, the former being largest and later the smallest. The exact amount of medicament which can be filled in a particular size of capsule shell depends upon the density of the materials to be filled in. Generally capacity varies from 600mg to 30mg. We know that, Capsule filled weight=Tapped bulk density Ă&#x2014; capsule volume. Then, Capsule volume=Tapped bulk density/weight of capsule Most widely used capsule sizes are 0,1 and 2. The largest capsule shell 000 is used for veterinary purpose.
Capsule Sizes (In Theory): Empty gelatin capsules are manufactured in various sizes, varying in length, in diameter and in capacity. The size selected for use is determined by the amount of material to be encapsulated.
Sizes
Volume(mL)
000
1.4
00
.95
0
.68
1
.50
2
.37
3
.30
4
.21
5
.13
Capsule Filling Areas There are three distinct areas for encapsulation in The ACME Laboratories Ltd. 1
Penicillin area 2 3
Cephalosporin area
Non-penicillinand non-Cephalosporin area
Filling room condition 1
Temperature: must kept at 20 to 25oC 2
Relative Humidity: not exceed 50%
Filling the capsule shell First, the weighed amount of active ingredients and additives filling operation. Now the empty capsule shell are taken to separate them into cap and body. The body is taken filled with the prepared powder mixer or granules. Now the cap is pressed in the body to close it. Finally the filled capsule shells are ejected for cleaning and polishing.
Manufacturing Flow Procedure Weight of raw materials Sieving of all raw materials All Ingredients blending (Drum mixing) Empty capsule
Filling Checking Polishing Blister/Strip Sealing
Checking
Packing Machineries Observed Name of the machine Drum mixer Semi-automatic
Purpose To mix the active ingredients with excipients To fill capsule shell with
capsule India
filling machine “SCORPIO” Strip sealing machine “GANSONS” Blister sealing
Manufacturer Bombay
medicaments To seal
India
machine Germany
To seal
“HORN NOACK”
Injection Department Injection (vials): Injectables are sterile and pyrogens free products that intended to be administered in the body with the help syringe and needles through various routes such as intravenous (IV), intramuscular (IM), intrathecal (IT), intraperitoneal (IP) etc. The ACME Laboratories Ltd. produces 39 categories injectables in vials and ampoules meant for administration in the body through IV or IM routes and The ACME Laboratories Ltd. has separate for Injectables which consists of several sub units: o Compounding area o Aseptic rooms for filling and sealing o Sterilization room (autoclaving and terminal sterilization) o Vials and ampoules washing and sterilizing room o Packaging and packing room. Injection (vials) Vials are sterile glass containers whose volume up to 15 ml. This volume also may be up to 30 ml. usually vials are widely used for injectable preparations. Instruments used for injectable vials: 1.Washing machine. 2.Dry heat sterilizer. 3.Autoclave. 4.Auto filling and sealing machine. 5.Semi-auto labeling machine. 6.Semi-auto vial blistering machine. Types of packaging materials: Primary packaging materials: it includes1.Glass vials (7.5 ml or 15 ml) 2.Rubber stopper 3.Flip off seal Secondary packaging materials: It includes-
1.Combipack 2.Leaflet 3.Disposable syringe 4.Baby needle 5.Butterfly syringe 6.Inner cartoon 7.Master cartoon
Classification of Aseptic Room A-class zone: Filling area under laminar air flow. Particle count of this area must be below 100. B-class zone: Other portion of filling room except A-class. Particle count of this zone is usually above 100. Buffer zone or C-class zone: It consists of cooling room, sealing room and third change room. Criteria of A-Class zone: Air flow must be 60 meter/ sec to maintain positive air flow. Moisture must below 50% Temperature must below 25 ยบC Particles count must below 100 Sterilization process: Vials are usually sterilized or depyrogenation by using dry heat sterilizer at 220 ยบC for 2.5 hrs. Garments, gloves, machine parts or equipments are sterilized by 121 ยบC for 15 mins. Ampoules (Injection): Ampoules are special type of container used for WFI or injectable preparations. Instruments used for injections (ampoule manufacturing): 1. Auto ampoule filling and sealing machine. 2. Ampoule washing machine 3. Autoclave 4. Dry heat sterilizer 5. Charge vat 6. Cartilage filter unit
Flow chart of production (liquid Injectable) Solution preparation Empty ampoules washing, sterilization and cooling
Filtration
Filling and sealing (class 100) Terminal sterilization (if necessary)
Visual inspection Blister sealing Packing Inhaler Department Among three MDI & DPI producer of Bangladesh ACME is of them.Inhaler (MDI) may be defined as pressurized packaging system that depends on the power of a compressed or liquefied gas or any other mechanical stress to expel the contents from the container. The ACME Laboratories Ltd. produces two different types of Inhaler system 1. Metered Dose Inhaler (MDI) 2. Dry Powder Inhaler (DPI) Meter Dose Inhaler Metered dose inhalers are a special type of drug delivery systems, by which, a predetermined dose is released as a spray on actuation of a metering valve present in a special type of device named inhaler, which makes possible of the administration of an inhalant into the respiratory tract. In MDIs, drug is either dissolved or suspended in liquid propellant mixture together with excipients, including surfactants & presented in a pressurized canister fitted with metering valve. When released from the canister, the formulation undergoes volume expansion in the passage within the valve & forms a mixture of gas & liquid before discharge from the orifice. The high speed gas flow helps to break up the liquid into a fine spray of droplets When we are in the Inhaler department, there was no production of MDI. So, we missed the operation. Dry Powder Inhaler observed product: Topium Bromide Dry Powder Inhaler (DPI) Active Drug: Tiotropium Bromide Receiving of raw & primary packaging materials Acclimatization (for 3 hours) of R/M Mix accurately Lactose inhalac and lactose sorbolac for 10 min in a container Mix the API (10min max)
Seiving (40 mesh) Mix for 15 min
Keep it Container
Filling Container Filling Packaging Suppository Department This dosages form especially designed for those patient who unable to take solid, liquid and parental drug forms. This form also suggested for those patient who are in serious condition and need immediate action. Suppository is as medicated solid dosage from generally intended for use in the rectum, vagina and to a laser extended, the urethra. Rectal and vaginal suppositories usually employ vehicle that melt or softened at body temperature. In The ACME Laboratories Ltd. We observed the manufacturing of rectal & vaginal suppositories. we observed the manufacturing process of fast suppository (paracetamol). Manufacture of suppositories: In The ACME Laboratories Ltd. an automatic machine is used for the manufacture of both rectal & vaginal suppositories. By this machine, mixing, pouring, cooling and ejection is performed in a single preparation. The machine contains a rotary cooling chamber to cool and solidify the suppository. Machine observed:-Automatic suppository machine-“SARONG” (Italy) Function: Suppository compounding, filling and sealing
Some other suppositories of ACME: Rectal: •
A-Fenac-50
•
A-Fenac-12.5
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Indo-A
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Fast 500
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Fast 250
•
Fast 125
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Dirozyl 500
Vaginal: •
Cinoplus
•
Tycon
PROCESS FLOW OF SUPPOSIORY PRODUCTION PROCESS
Compounding Vessel
50°C
Melting
Addition of active ingredient
Cooling (40°C)
Sieving 40 mesh screen Filling tank (40°C)
Mouth sealing & batch coding (115°C120˚C) Compounding vessel (40°C) Cutting Packaging & send to warehouse
Warehouse Department
Duration
of
Training:
One
Day
Ware house section can be considered as an input and output section simultaneously .As a vast drug producer company ACME has a spacious well arranged ware house. The ware house is an essential part of pharmaceutical industry. Here raw materials, packing and packing materials as well as finished products are stored in specified condition and then are distributed. Various Tags different colors are used to identify the materials. The storage department of The ACME Laboratories Ltd. includes the following sections: Raw materials store Packing material store and Finished product store. Areas of Ware house: Quarantine area: Purpose of Quarantine area: • To receive the raw materials • To store the material before pass the QA test • To store the material before the decision is taken whether it is passed or rejected. • To manage the materials properly and systemically. Released area: Purpose of released area 1. To store the approval materials 2. To store the approved materials in different conditions as specified by the manufacture. Dispensing area The area from where raw materials,packing materials are dispensed according to the requisition sheet for the production. Raw materials, packing and packing materials and finished products kept in different places should be labeled properly. Only the approval (green tagged) materials are brought to the dispensing area. Materials that come first are dispensed first according to the FIFO (first in first out) rule. Finished product area This is the area where the finished products are stored after the total manufacturing process. Special area: It includes cold room(refrigerate condition), cool room and room for flammable materials.
Overall working procedure of Warehouse
Good Received Note (GRN) number receiving (Imported/Local) for each RM & PM RM & PM receiving At receipt the shipment inspected visually for labeling & damages any. Containers of materials are stored in quarantine labeled “Quarantine”
Required amount of Released by Q.C samples taken by QC dept. for testing Approved by Q.A. Dispensing of RM with inspection of QA dept.
“Rejected” by Q.C Materials rejected Destroyed or Returned
Flow Chart of Handling of finished goods by Warehouse Receiving finished products Stored with records Distribution order from head office Dispatch from the store with proper documents.
Comments: 1. All materials are properly labeled 2. Documentation system is excellent 3. Here first in, first out principle is strictly followed 4. If Q.A. Department releases any material, release label should be attached with the container and it is followed here properly. 5. Here all material is high quality & high effective 6. Calibaration is performed in proper time 7. Handelig system is well 8. Narcotics act also maintained here 9. In ware house all personnel also have a friendly relation & friendly behavior
The ACME Laboratories Ltd. maintains the following storage conditions: Table-10 Area Cold store /Cool store Empty Gelatin shell store RM store (without A/C) RM store (with A/C) Flammable materials store Suger store Dedicated penicillium area(separated from main ware house storage)with sampling & dispensing containment
Temperature (oC) 2-8, 8-15 Below 25 Ambient Below 25 Ambient Below 25 Below 25
Relative Humidity Below 70% Within 45%-65% Below 76% Below 70% Not necessary Within 45%-65% Within 35%-65%
Conclusions
Pharmaceutical Industry has grown in Bangladesh in the last two decades at a considerable rate. Pharmaceutical companies are either directly or indirectly contributing largely towards raising the standard of healthcare through enabling local healthcare personnel to gain access to newer products and also to latest drug information. Following the Drug (Control) Ordinance of 1982, some of the local pharmaceutical companies improved range and quality of their products considerably. The national companies account for more than 65% of the pharmaceutical business in Bangladesh. However, among the top 20 companies of Bangladesh 6 are multinationals. Almost all the life saving imported products and new innovative molecules are channelled into and marketed in Bangladesh through these companies. Multinational and large national companies generally follow current Good Manufacturing Practices (cGMP) including rigorous quality control of their products. The objective of the plant training was the partial fulfillment of our Pharmacy Courses and for the achievement of practical experience about manufacturing of quality drugs. During the In-plant training the process of manufacturing and maintaining quality according to GMP guideline were observed. The function and performance of quality assurance and production department are unique and appreciable. By the overall performance of all sections, Acme Laboratories Ltd. is producing quality products and thus serving the nation. Under all circumstances Acme Laboratories Ltd. meets the local regulatory quality standard, which even is higher or more rigorous. Always its journey is to excellent.
Acme Laboratories Ltd. besides providing local pharmaceuticals need has been exporting its product to various countries. Again the fact, The Acme Laboratories Ltd. is recognized as an ISO-9001: 2008 certified company. The 30 days in plant training has been completed successfully by the help of all the employee of The Acme Laboratories Ltd. Our achievement during this training will eventually help us in our professional life.
References •
http://acmeglobal.com/acme_laboratories.htm
•
http://www.acmeglobal.com/AcmeLabs/Products/Human/prod_human1100.htm
•
Briefings obtained from different department of ACME.
•
Remington-The Science and Practice of Pharmacy (Vol. I & II): Mack Publishing Company, Pennsylvania.
•
L. Lachman, the Theory and Practice of Industrial Pharmacy.
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Cooper and Gunn, 12th Edition, Dispensing for Pharmaceutical Students.
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Pharmaceutical Excipients- Raymond C Rowe.
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www.pharmacybd.com
•
British Pharmacopoeia BP
•
United State Pharmacopoeia USP