PRODUCTION TECHNIQUES & SCALE-UP TECHNIQUES

INTRODUCTION:

1.       RESEARCH AND DEVELOPMENT PERSONNEL EXPAND A CONSIDERABLE AMOUNT OF EFFORT DEVELOPING DRUG DOSAGE FORMS WITH EXACTING SPECIFICATIONS (ADEQUATE PHYSICAL&CHEMICAL STABILITIES).

2.       SCALE UP TECHNIQUES MUST INCLUDE A CLOSE EXAMINATION OF THE FORMULA TO DETERMINE ITS ABILITY TO WITH STAND BATCH SCALE AND PROCESS MODIFICATION.

3.       DURING THE SCALE-UP EFFORTS IN THE PLANT PRODUCTION&PROCESS CONTROLES ARE EVALUATED, VALIDATED&FINALIZED.

4.       APPROPRIATE RECORDS & REPORTS ARE ISSUED TO SUPPORT GMP'S TO PROVIDE THE HISTORICAL DEVELOPMENT OF THE PRODUCTION FOR FORMULATION, PROCESS AND EQUIPEMENT TRAIN & SPECIFICATIONS.

GENERAL CONSIDERATIONS FOR SCALE-UP TECHNIQUES:

1. PERSONNEL REQUIREMENTS

2. SPACE-REQUIREMENTS

3. REVIEW OF THE FORMULA

4. RAW MATERIALS

5. RELEVANT PROCESSING EQUIPEMENT

6. PRODUCTION RATES

7. PROCESS EVALUATION

8. PREPARATION OF MASTER MFG PROCEDURES

9. GMP CONSIDERATIONS

10. TRANSFER OF ANALYTICAL METHODS TO QUALUITY ASSURANCE

11. PRODUCT CONSIDERATION (FOR SEMISOLIDS&STERILE PRODUCTS)

1. PERSONAL REOUIREMENTS:

1.       Persons should have a good theoretical knowledge of pharmaceutics, practical experience in pharmaceutical industry (formulation & equipment experience), good communication skills.

2.       The type & level of education is very important for pharmaceutically trained scientists have the ability to assimilate the complex interrelationship between pharmaceutical process & the potential impact on chemical, physical, biochemical medicinal attributes of dosage forms;

3.       Many of the process involve engineering principles (machinery), so some engineering capability is also necessary.

4.       An experienced scientist with a knowledgeable technician to be handle projects depending on their complexity, while at the same time providing technical support for marketing products

2. SPACE REQUIREMENTS:

There are 4 types of the space requirements

ADMINISTRATION & INFORMATION PROCESSING: 

Ø  Adequate office must be provided for both scientists & technicians. This should be adjacent to work area but sufficiently isolated to permit people to work without undue distraction.

Ø  In this office the persons (scientists, technicians) from different departments can meet & discuss subjects of mutual concern. The computer is used for the data entry.

PHYSICAL TESTING AREA:

Ø  In which samples can be laid out & examined.

Ø  In this only perform the physical tests by the equipment like balance, pH meter, viscometers etc.

STANDARD PLANT EQUIPEMENT FLOOR SPACE:

Ø  In this space the equipment for mfg all types of pharmaceutical dosage form is located.

Ø  For semisolids-millers, mixers, moulds are located

Ø  For sterile products-filters, laminar airflow bench, filling equipment, sealing equipment (bead, pull sealing), sterilization equipment

STORAGE EQUIPEMENT:

Ø  For storage of active ingredients, excipients, process materials, finished bulk products, packaging materials-bottles, closures, tubes, vials, and ampoules.

3. REVIEW OF THE FORMULA:

Ø  The purpose of each ingredient and its contribution to the final product mfg on the small-scale laboratory equipment should be understood.

Ø  Then the effects of scale -up using equipment that may subject the product to stresses of different types can be more readily predicted

Ø  This should be done as early as possible in phase-3 trails to allow time to Generate meaningful long-term stability in support of a purposed new drug application (NDA).

4. RAW MATERIALS:

Ø  One responsibility of the pilot function is the approval & validity of active ingredient & raw materials used in pharmaceutical products.

Ø  Why because the larger lots of active ingredients may change in particle size, shape, morphology, bulk density, static charges; rate of solubility, flow property, color, etc,

Ø  So quality of the active ingredient must be verified

5. RELEVANT PROCESSING EQUIPEMENT:

Ø  Based on the known processing characteristics of the product, the equipment that promises to be the most economical, simplest, most efficient, most capable of consistency producing product with in the proposed specifications should be evaluated.

Ø  The size of the equipment should be such that experimental trails can be run that are meaningful & relevant to the production-sized batches that will eventually be made.

Ø  If plant equipment is too small-process developed will not scale up well

Ø  If plant equipment is too large-excessive costs will be incurred

Ø  For responsible plant development process intermediate sized experimental batches should be run.

6. PRODUCTTON RATES:

Ø  The equipment & process should be chosen as so to produce batches at a frequency that takes into consideration product loss in the equipment during mfg, the time required to clean the equipment between batches & number of batches that will needed to be tested for release.

Ø  To accommodate future growth, increase Production capacity may be realized more economically through more efficient utilization of smaller equipment than through purchase of oversized equipment.

Ex: several smaller lots produced serially may be combined in a final blend to make single large batch.

7. PROCESS EVALUATION:

Ø  It includes,

·   Mixing speed

·   Time

·   Rate of addition of granulating agents, solvents, solutions of drugs, slurries etc

·   Heating & cooling rates

·   Filter sizes

·   Screening sizes

·   Drying temperature

·   Drying time

Ø  Monitoring the different measurable parameters such as content uniformity, moisture content, compressibility

Ø  Parts of the process such as milling, mixing, heating, cooling, drying, sterilization,

Ø  Compacting, filling which causes some measurable changes in the state of material being processed, need to be evaluated.

8. PREPARTION OF MASTER MFG PROCEDURE:

Ø  In which the mfg directions, the chemical weigh sheet, the sampling , directions, and the in-process and finished product specifications are very important, for the technician understands and complies with them.

Ø  The weigh sheet should clearly identify the chemicals required in a batch, with required quantities.

Ø  To prevent confusion and possible errors both names and identifying numbers for the ingredients should be used on batch records, and these should correspond with those on the bulk raw material containers.

Ø  In accord with GMP's, the batch records need to provide space to show the weighing and addition of each ingredient with appropriate counter signatures for each.

Ø  The batch record directions should include specifications for addition rates, mixing speeds; heating cooling rates, temperature and appropriate ranges should be given.

Ø  The actual time, temp, speed used should be documented, so these can be used to monitor the functioning of the equipment.

Ø  Finished product specifications set the standards by which a product is .evaluated and help ensure that each batch mfg delivers the drug in the dose specified throughout the designated shelf life of the product

9. GMP CONSIDERATIONS:

Ø  FDA guidelines describe GMP

Ø  A check list of GMP items that should be part of scale-up or new product or process introduction includes the following

·   Equipment qualification

·   Process validation

·   Regularly scheduled preventative maintenance

·   Regular process review and validation

·   Relevant written standard operating procedures

·   The use of competent, technically qualified personnel

·   A well defined technology transfer system

·   Validated cleaning procedures

·   An orderly arrangement of equipment so as to ease material flow and prevent cross contamination.

10. TRANSFER OF ANALYTICAL METHODS TO QUALITYASSURANCE:

1.       During the scale up of a new product, it must be transferred to the quality assurance department

2.       Quality assurance should review the process to make sure that the proper analytic instrumentation is available and the personnel are trained to perform the test.

11. PRODUCT CONSIDERATION:

»Solid dosage forms (Tablets)

»Emulsions

»Suspensions

TABLETS:

1. MATERIAL HANDILING:

Ø  In laboratory, materials are simply scooped, dumped or poured by hand which is suitable for small or intermediate scale of production.

Ø  But in some intermediate and large scale productions mechanical means of handling materials is necessary.

Mechanisms include:

·   Simple post hoists

·   Devices for lifting and tilting drums

·   Sophisticated methods like 'vacuum loading systems, screw feed systems, metering pumps.

Ø  Lengthy transfer lines may result in material loss for with there must be accountability and compensation.

Ø  If more than one product are to be transferred through a system, cross contamination should be prevented

2. DRY BLENDING:

Ø  Powders to be granulated prior to tableting should be well blending to ensure good drug distribution.

Ø  The dry blend should take place in the vessel in which any subsequent processing such as granulation occurs.

Ø  A larger batch may be dry blended and then sub divided into multiple sections for granulating operation.

Ø  The ingredients to be blended should be free of lumps, which cause flow problems through equipment.

3. GRANULATION:

For scaling up granulation process in an efficient manner the purposes of granulation must be known.

Ø  Some of the equipment are more suitable than other to develop desire characters of granules.

Ø  Wet granulation by sigma blade or heavy-duty planetary mixer is preferred.

Ø  The high shear forces generated by these powerful units affect both granulating time and amount granulating fluid required.

Ø  Other equipment used are:

·   Tumble blenders with high speed chopper blades.

·   High shear mixer - dandifies light powders but limited load size.

·   High shear mixer with chopper - uniform distribution of granulating fluid.

Ø  Recent advances include processors which are able to perform all functions to prepare finished granules in a continuous process.

Ø  Closed continuous system - reduce the danger of personnel expose to potent materials.

Ø  Binders used in tablet formulation are used either in dry form or along with granulating fluid.

Ø  Binders when incorporated in granulating fluid increases the viscosity and may offer difficulty in pumping and pouring

Ø  During scale-up this can be avoided by dispersing some or all of binding agent in dry powder prior to granulation.

Ø  The granulation liquid having any remaining binder can then be easily pumped and metered in to the batch.

Ø  Some granulations when prepared in production-sized equipment, take dough like consistency and may have to be subdivided to a more porous mass to facilitate drying. This can be accomplished by passing the wet mass through oscillating granulator.

Drying

Ø  The conventional method of drying is by hot air oven.

Factors to consider as part of scale-up oven drying includes

1. Air flow

2. Air temperature

3. Depth of granules on tray

4. In case of soluble dyes migration effect is considered.

Ø  The drying process is monitored by use of moisture and temperature of probes or frequent multipoint sampling of granulation.

Ø  Fluidized-bed dryer is alternatively widely used because

·   Reduction in drying time

·   Dry blending, granulation can also be performed.

Ø  Scale-up of a FB dryer must establish:

·   Optimum load

·   Rate of airflow.

·   Inlet air temperature and humidity.

Reduction of particle size

Ø  Particle size and size distribution are important to the compression characteristics of granules.

Ø  In lab scale, hand screening or small-scale milling equipment are sufficient where as in production size high speed presses with elaborate feed systems are required.

Ø  Both oversized and undersized granulations adversely affect the content uniformity.

Ø  Particle size reduction of dried granules of product-sized batches can be carried by oscillating granulator, a hammer mill, a mechanical sieving device.

Ø  The oversized portion must be milled and then returned to the batch.

Ø  Compressibility of the milled samples is used to ascertain the milling .conditions and target mesh pattern for subsequent batches.

Ø  As a part of scale-up, lubricants and glidents are added to the dried granules during the sizing process, because some additives like magnesium stearate, tend to agglomerate when added in large quantities to the granules. Sizing operation does preliminary dispersion.

Blending:

Ø  Type of blending equipment often differs from that using in laboratory.

Ø  In any blending operation both segregation and mixing occur simultaneously are a function of particle size shape, hardness, and density, and of the dynamics of the mixing action.

Ø  Particle abrasion is more likely to occur when high-shear mixers with screws or blades are used.

Ø  When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender.

Dry blending and direct compression:

Ø  Scaling up of a dry blending operation for a directly compressible formulation requires attention to blender loads, optimum mixing time and speed such that drug distribution is uniform with in a batch and is consistent from batch to batch.

Ø  When wet granulation is prepared, complete distribution of the active ingredient is achieved through a series of operations and if anyone step in the operation is inadequate to achieve content uniformity, the other processing steps often compensate where as this is not possible in single dry blend for a directly compressible formula. Therefore optimization of the process and validation of its performance are important.

The following aspects of dry blending are can be adjusted to optimize the process.

1.       The order of addition of components to the blender

As an example, a low-dose active ingredient is placed between 2 proportions of directly compassable excipients in the blender to improve dispersion and to avoid loss to the surface of blender

2.       Mixing speed:

Blade rotation speed for planetary speed mixer, and mixer tumbling or rotational speed for a twin shell, cone type mixer.

3.       Mixing time:

The mixing time can be increased or decreased based on the available data of the material used. Excessive mixing time may fracture fragile excipients and ruin their compressibility.

4.       Use of auxiliary dispersion equipment:

Intensifier bar or chopper blade in a twin shell mixer increases efficiency of dispersion of liquids and solid ingredients and also reduce agglomerates present in the mixture.

5.       Mixing action:

It is determined by mechanics of mixture can be changed by converting form one blender to another blender and by introduction of baffles or plates, which would alter the mixing characters.

6.       Blender load:

The amount of material volume to total mixer volume affects the efficiency of the blender.

Slugging:

Ø  A dry powder that cannot be directly compressed can be processed using slugging.

Ø  The tablet press used for slugging operates at a pressure of 15 tons .and have tablet punches with greater diameters.

Ø  The process is slow, as slower press speed are required slugs range from 1 inch diameter (easily slugged material) to ³/₄ inch(material difficult to compress)

Ø  After compaction, hammer mill or an oscillating granulator breaks down slugs.

Ø  During scale-up of such an operation, attention should be paid to forces used for slugged operation.

·   Diameter of punches

·   Sizing and screening

Ø  Granulation by dry compaction by using a roller compactor. This is widely used for the very low density makes them achieve a bulk density sufficiently.

Example: densification of aluminium hydroxide.

Granulation handling and feed systems:

Ø  The handling of finished granules during compression can be Simple operation-hands scooping the materials into the press hopper large operation-sophisticated automated handling systems that is vacuum or metallic systems.

But in these systems segregation due to static charges occur leading to the problems with the material flow to press hoppers and feed frames and resulting in finally poor content uniformity.

A well-documented and validated cleaning procedure is essential for such systems.

Compression:

Ø  The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press.

Ø  During compression, the tablet press performs the following functions.

Ø  Filling of empty die cavity with granulation.

Ø  Precompression of granulation (optional).

Ø  Compression of granules.

Ø  Ejection of the tablet from the die cavity and take-off of compressed tablet.

Ø  When evaluating the compression characteristics of a particular formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be tried.

Ø  Only then are potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected.

Ø  High-speed tablet compression depends on the ability of the press to interact with granulation.

Ø  Following are the parameters to be considered while choosing speed of press

Ø  Granulation feed rate.

Ø  Delivery system should not change the particle size distribution.

Ø  System should not cause segregation of coarse and fine particles, nor it should induce static charges.

Ø  The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame.

Ø  The smaller the tablet, the more difficult it is to get a uniform fill a high press speeds.

Ø  For hi-speed machines, induced die feed systems is necessary.

Ø  These are available with a variety of feed paddles and with variable speed capabilities.

Ø  So that optimum feed for every granulation can be obtained.

Ø  After the die cavities are filled, the feed frame to the center of the die table removes the excess.

Ø  Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers.

Ø  This cause the punches to the penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between the punches.

Ø  The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers.

Ø  Larger the compressions roller, the more gradually compression force is applied and released

Ø  Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation.

Ø  The final event is ejection of compressed tablets from die cavity.

Ø  During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking.

Ø  High level of lubricant or over blending can result in a soft tablet, decrease in wettability of the powder and an extension of the dissolution time.

Ø  Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the center in order to relieve pressure during ejection.

Suspensions:

Ø  These are the biphasic dosage forms in which solid particles are uniformly distributed in the liquid phase by the aid of suspending agent.

Suspending agent:

Ø  The dispersion of the suspending agent in laboratory scale involves sprinkling the materials into the liquid vortex which requires use of a vibrating feed system in case of large production scales novel approaches are required.

Ø  A powder eductor facilitate the addition of a materials which tend to clump during the process.

Ø  Making slurry with a portion of a vehicle can disperse suspending agent. This concentrated slurry can be more completely dispersed using high shear mixture and also resulting rapid hydration of suspending agent when added to large portion of vehicle.

Ø  The time and temperature required to hydrate suspending agent is often critical unless the hydration of suspending agent is completed the other ingredients should not be added to the formulation as it affects the quality of final product.

Active ingredient:

Ø  The dispersion procedure of active ingredient depend upon its physical characteristics

Ø  If API is wetted easily, dispersed readily-a simple addition of chemicals at convenient state is appropriate.

Ø  If API is difficult to wet and agglomerate-

·   Prepare a slurry with wetting agent

·   Blending the active ingredient in high shear blender using . some of the liquid ingredients possibly with surfactant.

Ø  During the scale-up of suspensions the performance of mixers, pumps, mills and horsepower of the motors should be selected.

Ø  The equipment must be selected based on size of the batch and viscosity of the product.

Ø  Mixing speed should be optimum

·   Low speed-uninformed distribution of ingredients

·   High speed-entrapment of air in product, which result in physical and chemical stability of the formulation.

Ø  If any air bubbles are present they can be removed by using vacuum unit such as versator

Ø  Unwanted and discolor particulate matter material is removed by filtration of final formulation using screens of 150 mesh having an opening of 100 microns.

Emulsions

Ø  Emulsions are dispersion systems in which dispersed phase is finely divided immiscible liquids dispersed in oils or waxes.

Ø  Processing parameters and procedures that must be adjusted and control for various types of emulsions include

Temperature, mixing equipment, homogenizing equipment, in process or final product filters, screens, pumps and filling equipment

Ø  The degree of reduction of globule size affects the physical properties of the emulsion.

Ø  Use of results that are operated with vacuum avoids the problem of unwanted aeration.

The unwanted particulates are efficiently removed by filtering the separate oil and water phases before emulsification.