A PRESENTATION ON PHARMACEUTICAL PRODUCTION AREA AND PRODUCTION PROCESSES BY KHALID MEHMOOD PHARMPHARM-D UNIVERSITY OF KARACHI

SOLID AREA: TABLET MANUFACTURING AREA: TABLET: Solid pharmaceutical dosage form containing drug substances with or without suitable diluents and have been traditionally prepared by either compression or molding methods.

METHODS OF PREPARING TABLETS:

a)

WET GRANULATION: Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture.

Equipments used in wet granulation:

1. 2. 3. 4. 5. 6. 7.

Twin shell blender Double cone blender Planetry mixer Ribbon blender Sigma blade mixer High shear mixer (diosna) Fluid bed granulator

b)

DRY GRANULATION METHOD: Create granules by light compaction of powder blend under low pressure. The compact so formed are broken up gently to produce granules (agglomerates). Equipment used in dry granulation:

1. 2. 3. c)

Roller compacter Compactor mill Tablet press using slugging tooling DIRECT COMPRESSION: Consists of compressing tablets directly from powdered material without modifying the physical nature of the material.

TABLET MACHINES:
1)

SINGLE PUNCH MACHINE: The simplest tablet machine available are those having single punch design. ROTARYTABLET MACHINE: For increased production, rotary machine offers great advantages. A head carrying a no. of sets of punches and dies revolves continuously while the tablet granulation runs from the hopper, through a feed frame in to the dies placed in a large steel plate revolving under it.

2)

3)

HIGH SPEED ROTARYTABLET MACHINE: Capable of compressing tablets at high production rate. It is modified form of rotary tablet machine having increase no. of sets of punches and dies in each revolution, improving feeding device and in some models dual compression points. MULTI LAYER ROTARYTABLET MACHINE: It is also modified form of rotary tablet machine. This machine is able to make 1, 2, or 3 layered tablets.

4)

FLOW CHART OF TABLET MANUFACTURING PROCESS: DIRECT COMPRESSION:

Material issuance & receiving

Com ression

Blistering

Weighing

Lubrication & Blending

Final acking

Sieving

Dry mixing

FLOW CHART OF TABLET MANUFACTURING PROCESS: DRY GRANULATION:

Material issuance & receiving Co ression listering

Weighing

Lubrication & blending

Final acking

Sieving

Dry screening

Mixing

Slugging

FLOW CHART OF TABLET MANUFACTURING PROCESS: WET GRANULATION:

Material issuance & receiving Drying Dry screening

Weighing

Screening of damp mass

Lubrication & mixing

Sieving

Granulation

Compression

Dry mixing

Preparation of granulating fluid

Blistering

Final packing

COATING: There are four major techniques for applying coating to pharmaceutical dosage forms
1. 2. 3. 4.

Sugar coating Film coating Micro encapsulation Compression coating SUGAR COATING: Sugar coating is regarded as the oldest method for tablet coating and involves the deposition of aqueous sucrose solution to solid dosage form may contain other functional ingredients e.g. fillers, colors etc.

1)

2)

FILM COATING: The deposition of thin polymeric film on to the dosage form from solutions that were originally organic-solvent based but now rely much more on water as prime solvent and proven to be a popular alternative to sugar coating. MICROENCAPSULATION: A modified form of film coating, differing only in the size of particles to be coated and the methods by which this is accomplished. This process is based on either mechanical methods such as pan coating, air suspension techniques, multi orifice centrifugal techniques and modified spray drying techniques or physico-chemical methods involving concervation phase-separation in which material to be coated is suspended in a solution of the polymer.

3)

4)

COMPRESSED COATING: Involves the use of modified tableting machine that allow the compression of a dry coating around a tablet core produced on the same machine. The main advantage of this type of coating process is that it eliminates the use of any solvent whether aqueous or organic in nature.

SUGAR COATING PROCESS: Sugar coating is sub divided in to six main steps
1. 2. 3. 4. 5. 6.

Sealing Subcoating Smoothing Color coating Polishing printing

FILM COATING OF DOSAGE FORM: Film coating is a very flexible process that allow a broad range of products e.g. (tablets, powder, granules, non- pareils, capsules) to be coated. FILM COATING RAW MATERIALS: The major components in any film-coating formulations consist primary of the following
1. 2. 3. 4.

Polymer Plasticizer Colorants solvents

MODIFIED-RELEASE FILM COATING: Film coating can be applied to pharmaceutical products to modify drug release. There are two types of modified release dosage forms
1.

DELAYED-RELEASE PRODUCTS: Often are designed to prevent drug release in the upper part of GI tract. EXTENDED-RELEASE PRODUCTS: Are designed to extend the drug release over a period of time.

2)

On the bases of these two types of modified release dosage forms film coatings are divided in to the following types
1.

ENTERIC COATINGS: Film coatings used to prepare delayed-release products are called enteric coatings. SUSTAINED- OR CONTROLLED-RELEASE FILM COATINGS: Film coating use to prepare extended-release products are called sustained- or controlled-release film coatings.

2)

ENTERIC COATING: Enteric coatings generally remain intact in the stomach but will dissolve and release the contents of the dosage form once it reaches the small intestine. The most currently used enteric coatings are weak acids that remain un dissolved in the low pH environment of the stomach but readily ionize when the pH rises to about 5. The most effective enteric polymers are polyacids having a pKa OF 3TO 5. Pharmaceutical formulators now prefer to use synthetic polymers to prepare more effective enteric coatings.These synthetic polymers are:

1. 2. 3. 4. 5. 6. 7.

Cellulose acetate phthalate (CAP) Polyvinyl acetate phthalate (PVAP) Hydroxypropyl methylcellulose phthalate (HPMCP) Acrylic polymers Cellulose acetate trimellitate (CAT) Corboxymethyl ethylcellulose (CMBC) Hydroxypropyl methylcellulose (HPMCAS) In recent years, acrylic polymers have evolved as a most preferred materials for designing enteric coating formulations in terms of performance and global acceptability.

SUSTAINED-RELEASE COATINGS: The concept of sustained release coatings was developed to eliminate the use of multiple dosage regimens, particularly for those drugs requiring reasonably a constant blood level over a long period of time. In addition it also has been adopted for those drugs that need to be administered in high doses, but where too rapid release is likely to cause undesirable side effects.

MATERIALS SUITABLE FOR PRODUCING SUSTAINEDRELEASE COATINGS:

1.

2. 3. 4. 5. 6.

Mixture of waxes (e.g. bees wax, carnauba wax) with glyceryl monosterate, stearic acid, palmitic acid, glyceryl monopalmitate, and cetyl alcohol Shellac and zein Ethylcellulose Acrylic resins Cellulose acetate Silicon elastomers

COATING PROCEDURES AND EQUIPMENTS:

1)

COATING PANS Sugar coating is historically has involved the ladling of the various coating fluids on to a cascading bed of tablets in a conditional coating pan fitted with a means of supplying drying air to the tablets and an exhaust to remove moisture and dust-laden air from the pan. In Film coating the equipment initially was completely conventional in design and was similar to that used in sugar coating with the exception of addition of spray application equipment. Spray technique use in film coating is of two types Air less (or hydraulic) spray Air spray

a) b)

Air less spray techniques typically used in large scale film coated operations employing organic solvents, while Air spray techniques are more effective in either a small scale laboratory set up or aqueous film coating operations. MODIFICATION IN CONVENTIONAL PAN EQUIPMENT:


Pellegrini coating pan: A substantial change came with the introduction of Pellegrini coating pan, a some what angular pan that rotates on a horizontal axis. Pan design and integral baffle system ensures uniform mixing. Pellegrini pan produce an enclosed system.

Further modification is done by introduction of Air plenum with perforated boot in the pellegrini coating pan to improve air exchange particularly with in the tablet beds.


side vented coating pan: It is an angular pan fitted with an integral baffle system and rotates on a horizontal axis. It provides an enclosed system. A perforated pan is there that allows drying air to pulled through a cascading bed of tablets. Side vented coating pan is successfully applied in film coating technology.

2)

FLUIDIZED-BED COATING EQUIPMENT: Based on fluid bed processing technology having a wurster concept. Fluid bed process exhibits the most effective drying characteristics of any film coating process. Fluid-bed coating equipment is applied in film coating of multi particulates( pellets, granules, powders) when producing modified release dosage forms.

RECENTTRENDS IN PHARMACEUTICAL COATING TECHNOLOGY: CONTINUOUS FILM COATING PROCESS: Current continuous process are based on the concept of stretched side-vented coating pan, where uncoated product is introduced at one end, passes by a whole bank of spray guns, and merges from the other end fully coated. The advantages of this type of process include:
1. 2. 3.

Increasing out put Reducing residence time in a process Improving uniformity of distribution of coating materials Coating process of this type are usually reserved for large-volume products.

CONTINUOUS FILM COATING PROCESS PRINCIPALLY BASED ON ELECTROPHOTOGRAPHY: It is a more revolutionary approach to film coating, based on a continuous process, involves the electrostatic deposition of powder coating systems to the surface of tablets (and fusing the coating through application of heat). It applies the principles that are based on electro photography (photocopying). In this process, tablets are coated individually one side at a time. The advantages of this type of process are:
1. 2. 3. 4.

No solvents (aqueous or organic) are used The coating is deposited on to tablets in a much more precise manner than any other coating process Novel imaging can be achieved Tablet surfaces can be only partially coated, thus facilitating applications involving novel drug delivery

CAPSULE FILLING AREA: CAPSULES: Solid dosage forms in which the drug substance is enclosed in either a hard or soft, soluble container or shell of a suitable form of gelatin.

FLOW CHART OF CAPSULE FILLING:

Material issuance & receiving Mixing Sieving

Blistering

Filling

Lubrication & mixing

Final packing

LIQUID AREA (PARENTERAL): PARENTERALS: Dosage forms injected directly in to the body tissue through primary protective system of the human body, the skin, and mucous membrane. WATER FOR INJECTION: Water for injection can be prepared by distillation or by membrane technologies( reverse osmosis or ultra filtration) DISTILLATION: Two basic types of water for injection distillation units: a) Vapor compression still b) Multiple effect still

a)

COMPRESSION DISTILLATION: The vapor compression still is primarily designed for the production of large volume of high-purity distillate with low consumption of energy and water. Operation: The feed water is heated from an external source in the evaporator to boiling. The vapor produced in the tube is separated and conveyed to a compressor that compresses the vapor and raises its temperature to approximately 107. It then flows to the steam chest where it condenses to the outer surfaces of the tubes containing the distilland; the vapor is then condensed and drawn off as a distillate, while giving up its heating to bring the distilland in the tubes to the boiling point.

b)

MULTIPLE EFFECT STILL: The multiple effect still also is designed to conserve energy and water usage. In principle, it is simply a series of single-effect stills or columns running at different pressures where phase changes of water takes place. A series of up to seven effects may be used, with the first effect operated at a highest pressure and the last effect at atmospheric pressure. Operation: Steam from an external source is used in the first effect to generate steam under pressure from feed water; it is used as a power source to drive the second effect condenses as it gives up its heat of vaporization & forms a distillate. This process continuous until the last effect, when the steam is at atmospheric pressure and must be condensed in a heat exchanger.

REVERSE OSMOSIS: As the name suggest, the natural process of selective permeation of molecules through a semi permeable membrane separating two aqueous solutions of different concentrations is reversed. Pressure is applied to overcome osmotic pressure and force pure water to permeate through the membrane. Membrane usually composed of cellulose esters or polyamides, are selected to provide an efficient rejection of contaminant molecules in raw water.

FLOW CHART OF WATER FOR INJECTION SYSTEM:

City water Sand filter(s) Primary softener (cation softener, resin banks)

Reverse osmosis system (several stages)

Dechlorinator (sodium metasulfite or carbon banks)

Polisher (secondary softener)

Storage tank

Multiple effect still

Cool loop

Clean steam generator

Hot loop

TYPES OF CONTAINERS:
1)

GLASS: Composed principally of silicon dioxide with varying amount of other oxides such as sodium, potassium, calcium, magnesium, aluminum, boron and iron. Types:

a) b) c)

Type I, a borosilicate glass Type II, a soda lime treated glass Type III, a soda lime glass (not suitable for parenterals for containers)

2)

RUBBER CLOSURES: To permit introduction of a needle from a hypodermic syringe in to a multiple dose vial and provide for resealing as soon as the needle is withdrawn. Each vial is sealed with a rubber closure held in place by an aluminum cap. Rubber closures are made up of multiple ingredients. The elastomer primarily used in rubber closure, plungers and delivery system is synthetic butyl or halo butyl rubber.

PYROGENS: Are products of metabolism of microorganisms. The most potent pyrogenic substance (endotoxins) are constituents (lipopolysacharides, (LPS) of the cell wall of gram negative bacteria. Pyrogen when present in parenteral drug products and injected in to the patients, can cause fever, chills, pain in the back and leg and malaise. TEST FOR PYROGENS:


Amebocyte lysate (LAL) test: The limulus Amebocyte lysate (LAL) test, can only detect the presence of lipopolysacharides (LPS).

Monocyte activation test: It is a new test that replace LAL as the official Pyrogen test because of its greater sensitivity to all agents that include the release of cytokines that cause fever and a potential cascade of other adverse physiological effects.

CONTROL OF PYROGENS: Pyrogen van be destroyed by heating at high temperature. A typical procedure for depyrogenation of glass ware and equipment is maintaining a dry heat temperature of 250C for 45 minutes.

AIR CLEANING: Since air is one of the greatest potential sources of contaminants in clean rooms, special attention must be given to air being drawn in to clean rooms by the heating, ventilating, and air conditioning (HVAC) system. In one such series air from outside first is passed through a prefilter, usually of glass wool , cloth, or shredded plastic, to remove large particles then it may be treated by passage through an electrostatic precipitator such a unit induces an electric charge on particles in the air and remove them by attraction to oppositely charged plates. The air then passes through the most efficient clean device, HEPA filter.

HEPA filters are defined as 99.99% or more efficient in removing from the air 0.3 m particles generated by vaporization of hydrocarbon. The clean aseptic air is introduced in to the class 100 and maintained under positive pressure which prevents outside air from rushing in to the aseptic area through cracks, temporarily open doors or other openings. LAMINAR AIR FLOW ENCLOSURES: Laminar air flow, originating through a HEPA filter occupying one entire side of the confined space thus bathing the total space with very cleaned air, sweeping away contaminants. The orientation for the direction of air flow can be horizontal or vertical. Plastic curtains are installed to maintain the unidirection of air flow to below the filling line and to circumscribe the critical filling portion of the line.

AREA CLASSIFICATION SYSTEM FOR MANUFACTURING OF STERILE PRODUCTS:

Max. no. of particles permitted per m3 (0.5-5m) Max. no. of particles permitted per m3 (>5 m) Max. no. of viable microorganisms permitted per m3

European grades

United states classification

A
(laminar-air flow work station)

100 100 10000 100000

3500 3500 350000 3500000

None None 2000 20000

Less than 1 5 100 500

B C D

MAINTENANCE OF CLEAN AREA: Liquid disinfectants (sanitizing agents) should be selected carefully because of data showing their reliable activity against inherent environmental microorganisms. They should be rotated with sufficient frequency to be avoid the development of resistant strains of microorganisms. FUMIGATION: Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places, if required.

PERSONNEL IN STERILE AREA: The uniform usually consists of coveralls for both men & women, hoods to cover the hair completely, face masks, and Dacron or plastic boots. Sterile rubber or latex free gloves are required for aseptic operations. Dacron or Tyvek uniforms are usually worn, are effective barrier to discharge body particles (viable or noneviable). ENVIRONMENTAL CONTROL EVALUATION: To measure the particle content in air sample, electronic particle counters are available. Viable particles are only detected by sampling consists of exposure of nutrient agar culture plates to the settling of microorganisms from the air & identifying colony-forming units (CFU) after a suitable incubation period at, for example, 30 to 35 for up to 48 hrs.

MEDIA FILL (PROCESS STIMULATIONTESTING): The media fill or process stimulation test involves preparation and sterilization (often by filtration) of sterile trypticase soy broth and filling this broth in to sterile containers under conditions used normally for filling process for a product. The entire lot is introduced at temperature verified to support microbial growth and examined for the appearance of growth of microorganisms. To pass the test 95% confidence, not more than 0.1% of the challenged units show growth. This test is a very stringent evaluation of the efficiency of an aseptic filling process and is considered to be the most evaluative test available.

MANUFACTURING OF STERILE PRODUCTS: Component preparation, product preparation, filling and sealing and sterilization is carried out in separate areas. Clean areas are classified according to the required characteristics of air in grade A, B, C, D as described previously. Manufacturing operations are classified in to three categories:
a)

TERMINALLY STERILIZED PRODUCTS: Solution is generally prepared in a grade C environment in order to give low microbial and particulate counts, suitable for immediate filtration and sterilization. After preparation the product is sealed in its final container and terminally sterilized.

b)

PRODUCTS STERILIZED BY FILTRATION: The handling of starting materials and the preparation of solutions is done in a grade C environment. After sterile filtration, the product must be handled and dispensed in to containers under aseptic conditions in a grade A or B area under a blanket of HEPA filtered laminar flow air. PRODUCT MANUFACTURED UNDER ASEPTIC CONDITIONS: The handling and starting of materials and all further processing is done in grade A or B area. This is for those products which can neither be sterilized by filtration nor terminally be sterilized.

c)

FILTRATION OF PHARMACEUTICAL PRODUCTS: Certain solutions and liquids that can not be sterilized in the final container can be filtered through a sterile filter of nominal pore size 0.22 m or less. Owing to the potential additional risks of the filtration method as compared to other sterilization processes, a double filter layer or second filtration via sterilized filter immediately prior to filling may be advisable. CHECKING INTEGRITY TEST OF FILTERS: The integrity test of filter is performed by an appropriate method such as Bubble point test immediately after each use. It may be also useful to test filter in this way before use. The same filter should not be used for more than one working day unless such has been validated.

FILLING OF LIQUIDS: There are three methods for filling of liquids in to containers:
1. 2. 3. 1)

Volumetric filling Time/pressure filling Net weight filing VOLUMETRIC FILLING: Volumetric filling machines employing pistons or peristaltic pumps are most commonly used. When high-speed filling rates are required then multiple filling units often are joined together in an electronically coordinated machine.

2)

TIME-PRESSURE FILLING: Time pressure or time gravity filling machines are gaining popularity in filling sterile liquids. A product tank is connected to the filling system that is equipped with a pressure sensor. The sensor continuously measures pressure and transmits value to the PLC system that controls the flow of product from tank to filling unit. The main advantage of Time-pressure filling operations is that these filling apparatuses do not contain mechanical moving parts in the product stream.

FILLING OF SOLIDS: The rate of flow of solid material is slow & often irregular. Even though a container of large diameter opening is used to facilitate filling. Some sterile solids are subdivided in to containers by individual weighing but the quantity filled in to the container is finally weighed on a balance.

SEALING: AMPOULES: Two types of seals are employed normally:

1. 2.

Tip seals (bead seals) Pull seals

Tip seals: Tip seals are made by melting enough glass at the tip of the neck of an ampoule to form a bead and close the opening. These can be made rapidly in a high temperature gas-oxygen flame.

Pull seals: Pull seals are made by heating the neck of the ampoule below the tip, leaving enough of the tip for grasping with forceps or other mechanical devices. Powder ampoules or other types having a wide opening must be sealed by pull sealing. VIALS AND BOTTLES: These are sealed by closing the opening with a rubber closure (stopper). Rubber closures are held in place by means of aluminum caps. The caps cover the closure and are crimped under the tip of the vial or bottle to hold them in place.

STERILIZATION: Sterilization can be achieved by moist or dry heat, by ethylene oxide or other suitable gaseous sterilizing agent, by filtration with subsequent aseptic filling of sterile final containers, or by irradiation with ionizing radiation. STERILIZATION BY MOIST HEAT: Sterilization by moist heat is suitable only for water- wettable materials and aqueous solutions, both temperature and pressure is used to monitor the process. Autoclave is used for moist heat sterilization.

STERILIZATION BY DRY HEAT: The process used for sterilization by dry heat include air circulation within the chamber and maintenance of a positive pressure to prevent the entry of non-sterile air, if air is supplied , it must be passed through a microorganismretaining filter. STERILIZATION BY RADIATION: Radiation sterilization is used mainly for the sterilization of heat sensitive materials and products. Ultra violet radiation is not acceptable method for terminal sterilization. STERILIZATION BY ETHYLENE OXIDE: Various gases and fumigants may be used for sterilization, ethylene oxide shall be used only when no other method is available.

INSPECTION OF FILLED CONTAINERS: Filled containers of parenteral products is inspected normally against white and black background. Other methods of inspection are also used such as optical inspection machines, the process of which should be validated and performance should be checked at intervals.

FLOW CHART OF PARENTERAL MANUFACTURING PROCESS:

Material issuance & receiving Ampoules/ vials washing & sterilization Cleaning of closures (for vials)

Area preparation

Terminal sterilization ( for terminally sterilized product)

Filtration Filling & sealing (if product is not to be terminally sterilized)

Solution (product) preparation

Optical inspection

Final packing

LIQUID AREA (ORAL): SYRUP: Syrups are concentrated, viscous, aqueous solutions of sugar or sugar substitute with or without flavors and medical substances.

FLOW CHART OF SYRUP MANUFACTURING:

Material issuance and receiving

Solution preparation

filtration

Packing

Filling

ORAL ANTIBIOTIC SUSPENSION AREA: ANTIBIOTIC: A drug used to treat infections caused by bacteria and other microorganisms. Originally, an antibiotic was a substance produced by one microorganism that selectively inhibits the growth of another. Synthetic antibiotics, usually chemically related to natural antibiotics, have since been produced that accomplish comparable tasks. SUSPENSION: Suspension is a two phase system consisting of an un dissolved or immiscible materials dispersed in a vehicle (solid, liquid or gas). ANTIBIOTIC AREA: Dedicated and self contained facilities for the production of antibiotic is provided in addition to general facilities such as penicillin in order to minimize the risk of serious medical hazards due to cross contamination.

FLOW CHART OF PREPARATION OF ORAL ANTIBIOTIC SUSPENSION:

Material issuance and receiving

Pulverization of sugar

Mixing of ingredients including (active) & pulverized sugar

Packing

Filling

Lubrication & blending