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SYLLABUS : Introduction, Requirements, Formulation, Methods of preparation, Containers, Evaluation


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Presentation Transcript

Slide 1:

Pilot Plant Scale Up Techniques SHUBHRAJIT MANTRY Asst.Prof Kottam Institute of Pharmacy . A.P

Contents :

Contents Definition Objectives Steps in scale-up General considerations Advantages and Disadvantages Scale up of solid dosage forms Scale up of liquid dosage forms. Scale up of semisolid dosage forms. Contract manufacturing. References

Slide 3:


Slide 4:

What is Pilot plant : “Defined as a part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by the development of liable practical procedure for manufacture.” R & D Production Pilot Plant Scale-up : “The art of designing of prototype using the data obtained from the pilot plant model.”

Pilot Scale and Scale-Up :

Pilot Scale and Scale-Up Pilot Scale Scale-Up R & D Large Scale Production

What Do Pilot Scale and Scale-Up Mean ? :


Slide 7:

Formulation related Indentification and control of critical components and other variables Equipment related Identification and control of critical parameters and operating ranges Production and Process related Evaluation, validation, and finalization of controls Product related Development and validation of reprocessing procedures Documentation Records and reports according to cGMP Objectives of the Scale-Up


Objective To try the process on a model of proposed plant before committing large sum of money on a production unit. Examination of the formula to determine it’s ability to withstand Batch-scale and process modification. Evaluation and Validation for process and equipments


To identify the critical features of the process Guidelines for production and process controls. To provide master manufacturing formula with instructions for manufacturing procedure. To avoid the scale-up problems. Objective

Slide 10:

Bench studies (product characterization , purity) Animal studies (toxicology , pharmacokinetics-ADME , efficacy) Clinical studies Increasing compliance with regulations as product moves through testing and evaluation Increasing knowledge about the product Increasing knowledge about the possible problems, snags, pitfalls with manufacturing, processing, packing, storing (and installing) the product Ultimately facilitates the transfer of product from laboratory into production Why Pilot Scale ?

Slide 11:

Why Scale-Up ? A well defined process A perfect product in laboratory and pilot plant But may fail in QA tests Because processes are scale dependent Processes behave differently on a small scale and on a large scale Scale-Up is necessary to determine the effect of scale on product quality



Slide 13:

Should Adequately monitor the process To provide the assurance that the process is under control The product produced maintains the specified attributes originally intended Scale-Up .....

Slide 14:


Slide 15:

Pilot Plant Design Formulation and Process Development Technology evaluation, Scale-Up and Transfer Clinical supply manufacture

Why conduct Pilot Plant Studies?:

Why conduct Pilot Plant Studies? A pilot plant allows investigation of a product and process on an intermediate scale before large amounts of money are committed to full-scale production. It is usually not possible to predict the effects of a many-fold increase in scale. It is not possible to design a large scale processing plant from laboratory data alone with any degree of success.

A pilot plant can be used for:

A pilot plant can be used for Evaluating the results of laboratory studies and making product and process corrections and improvements. Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-life and storage stability studies. Providing data that can be used in making a decision on whether or not to proceed to a full-scale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant

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Slide 19:

Operational Aspects Validation Training Engineering support Maintenance and Calibration Inventory, Orders, Labeling Material control Process & Manufacturing Activities QA & QC

Slide 20:

V A L I D A T I O N Design specifications Installation Qualification Operational Qualification Performance Qualification Compliance with cGMPand FDA standards

Slide 21:

Compliance with GMP Safety and environmental responsibilities Compliance with SOPs Technical skills and knowledge TRAINING

Slide 22:

ENGINEERING SUPPORT Design of facility Construction of facility Co-ordination, scheduling, direction of ongoing operations Validation of facility

Slide 23:

To ensure data integrity and equipment reliability To meet cGMP norms Maintenance & Calibration

Slide 24:

Computerized system Material control Inventory Orders (FIFO) Labeling (GMP-GLP)

Slide 25:

PROCESS AND MANUFACTURING ACTIVITIES Formulation & Process Development studies Technology evaluation, ScaleUp, & Transfer Clinical supply manufacture

Slide 26:

QUALITY ASSURANCE Auditing pilot plant Auditing and approval of component suppliers Reviewing, approval and maintaining batch records for clinical supplies Sampling and release of raw materials and components required for clinical supplies Release of clinical supplies Maintaining and distributing facility and operating procedures (SOPs) Review and approval of validation and engineering documentation

Slide 27:

QUALITY CONTROL Release Testing of finished product Physical, Chemical and Microbiological testing of finished clinical products, components required for clinical supplies Testing for validation and revalidation programs QC in-process testing during development, Scale-Up and Technology transfer activities

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Slide 29:

Requirements for Pilot scale and Scale-Up Personnel Requirements Equipment Requirements Space Requirements Process Evaluation Preparation of Master Manufacturing Procedures GMP Considerations

Slide 30:

PERSONNEL REQUIREMENTS Theoretical Knowledge of Pharmaceutics Ability to communicate Practical experience in pharmaceutical industry Engineering Capability Knowledge of electronics and computers

Slide 31:

EQUIPMENT REQUIREMENTS Equipment selected based on processing characteristics of product Most economical, simplest and efficient The size should be relevant to production sized batches Ease of cleaning Time of cleaning

Slide 32:

SPACE REQUIREMENTS Administration and Information Processing Physical Testing Area Standard Pilot Plant Equipment Floor Space Storage Area Separate for API and Excipients and further segregated into area for approved and unapproved materials Inprocess materials, finished bulk products, retained samples, experimental production batches, packaging materials Controlled enviornment space for Stability Samples

Slide 33:

Process parameters should be evaluated and optimized. For example : Mixing Order of addition Mixing speed Mixing time Rate of addition etc., PROCESS EVALUATION

Slide 34:

Chemical weigh sheet Identify the chemicals Its quanitity The order of using The sampling directions Process specifications Should be in understandable language In process and finished product specifications Proper documentation required MASTER MANUFACTURING PROCEDURE

Slide 35:

Process Validation Regular process review and revalidation Relevant written Standard Operating Procedures Equipment Qualification Regularly scheduled preventive maintenance contd ….. GMP CONSIDERATIONS

Slide 36:

Validated cleaning procedures An orderly arrangement of equipment so as to ease material flow and prevent cross-contamination A well defined technology transfer system The use of competent, technically qualified personnel Adequate provision for training of personnel

Slide 37:

General considerations

Slide 38:

GENERAL CONSIDERATION CONSIST OF:- Reporting Responsibility Personnel Requirement Space Requirements Review of the formula Raw materials Equipment Production Rates Process Evaluation Master Manufacturing Procedures Product stability and uniformity

General considerations:

General considerations Reporting Responsibility R & D group with separate staffing The formulator who developed the product can take into the production and can provide support even after transition into production has been completed

Slide 40:

Scientists with experience in pilot plant operations as well as in actual production area are the most preferable. As they have to understand the intent of the formulator as well as understand the perspective of the production personnel. The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles. 2. Personnel Requirement

Slide 41:

3. Space Requirements Administration and information processing Physical testing area Standard equipment floor space Storage area

Slide 42:

Administration and information process: Adequate office and desk space should be provided for both scientist and technicians. The space should be adjacent to the working area.

Slide 43:

Physical testing area:- This area should provide permanent bench top space for routinely used physical- testing equipment.

Slide 44:

Standard pilot-plant equipment floor space:- Discreet pilot plant space, where the equipment needed for manufacturing all types of dosage form is located. Intermediate – sized and full scale production equipment is essential in evaluating the effects of scale-up of research formulations and processes. Equipments used should be made portable where ever possible. So that after use it can be stored in the small store room. Space for cleaning of the equipment should be also provided.

Slide 45:

It should have two areas divided as approved and unapproved area for active ingredient as well as excipient . Different areas should provided for the storage of the in-process materials, finished bulk products from the pilot-plant & materials from the experimental scale-up batches made in the production. Storage area for the packing material should also be provided. Storage Area:-

Slide 46:

4. Review of the formula: A thorough review of the each aspect of formulation is important. The purpose of each ingredient and it’s contribution to the final product manufactured on the small-scale laboratory equipment should be understood. Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized.

Slide 47:

5. Raw materials:- One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients raw materials. Raw materials used in the small scale production cannot necessarily be the representative for the large scale production Why?

Slide 48:

6. Equipment:- The most economical and the simplest & efficient equipment which are capable of producing product within the proposed specifications are used. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. If the equipment is too small the process developed will not scale up, Whereas if equipment is too big then the wastage of the expensive active ingredients.

Slide 49:

7. Production Rates:- The immediate as well as the future market trends/requirements are considered while determining the production rates.

Slide 50:

8. Process Evaluation:- PARAMETERS Order of mixing of components Mixing speed Mixing time Rate of addition of granulating agents, solvents, solutions of drug etc. Heating and cooling Rates Filters size (liquids) Screen size (solids) Drying temp. And drying time

Slide 51:

Why to carry out process evaluation? The knowledge of the effects of various process parameters as few mentioned above form the basis for process optimization and validation.

Slide 52:

9. Master Manufacturing Procedures:- The three important aspects Weight sheet Processing directions Manufacturing procedure

Slide 53:

The weight sheet should clearly identify the chemicals required In a batch. To prevent confusion the names and identifying nos. for the ingredients should be used on batch records . The process directions should be precise and explicit . A manufacturing procedure should be written by the actual operator . Various specifications like addition rates, mixing time, mixing speed, heating, and cooling rates, temperature, storing of the finished product samples should be mentioned in the batch record directions. Master Manufacturing Procedures

Slide 54:

10. Product stability and uniformity:- The primary objective of the pilot plant is the physical as well as chemical stability of the products. Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability. Stability studies should be carried out in finished packages as well.

Advantages :

Advantages Members of the production and quality control divisions can readily observe scale up runs. Supplies of excipients & drugs, cleared by the quality control division, can be drawn from the more spacious areas provided to the production division. Access to engineering department personnel is provided for equipment installation, maintenance and repair.

Disadvantages :

Disadvantages The frequency of direct interaction of the formulator with the production personnel in the manufacturing area will be reduced. Any problem in manufacturing will be directed towards it’s own pilot-plant personnel's.

Slide 57:


Pilot Plant design for Tablets:

Pilot Plant design for Tablets The primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale . The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness . If possible, it should be located on the ground floor to expedite the delivery and shipment of supplies .


MATERIAL/POWDER HANDLING Two primary concerns : Achieving reliable flow and maintaining blend uniformity. Segregation leads to poor product uniformity. Handling system : - Must deliver the accurate amount of the ingredient - Material loss should be less - There should be no cross contamination

Material handling system:

Material handling system In the laboratory, materials are simply scooped or poured by hand, but in intermediate- or large-scale operations, handling of this materials often become necessary . If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination . Any material handling system must deliver the accurate amount of the ingredient to the destination . More sophisticated methods of handling materials such as vacuum loading systems, metering pumps, screw feed system .

Slide 63:

Vacuum loading machine


DRY BLENDING Dry blend should take place in granulation vessel Larger batch may be dry blended and then subdivided into multiple sections for granulation. All ingredients should be free of lumps otherwise it causes flow problems. Screening and/or milling of the ingredients prior to blending usually makes the process more reliable and reproducible.

Slide 65:

The equipment used for blending are: V- blender Double cone blender Ribbon blender Slant cone blender Bin blender Orbiting screw blenders vertical and horizontal high intensity mixers . SCALE UP CONSIDERATIONS Time of blending . Blender loading. Size of blender .

Slide 66:

V – cone blender Double cone blender

Slide 67:

Ribbon blender


Granulation The most common reasons given to justify granulating are: To impart good flow properties to the material , To increase the apparent density of the powders , To change the particle size distribution , Uniform dispersion of active ingredient . Traditionally, wet granulation has been carried out using, Sigma blade mixer , Heavy-duty planetary mixer .

Slide 69:

Sigma blade mixer Planetary mixer

Slide 70:

Wet granulation can also be prepared using tumble blenders equipped with high-speed chopper blades.

Slide 71:

Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling . In sometimes the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult . This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation. Binders:



Hot Air Oven:

Hot Air Oven Air flow Air Temperature Depth of the granulation on the trays Monitoring of the drying process by the use of moisture and temperature probes Drying times at specified temperatures and air flow rates for each product

Fluidized Bed Dryer:

Fluidized Bed Dryer Optimum Load Air Flow Rate Inlet Air Temperature Humidity of the Incoming Air

Drying :

Drying The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity. The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays . If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load.

Slide 76:

Fluidized bed dryers are an attractive alternative to the circulating hot air ovens. The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity.

Reduction of Particle size:

Reduction of Particle size Compression factors that may be affected by the particle, size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness and tablet color uniformity . First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings. Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device.

Slide 78:

Oscillating type granulator Hammer mill


BLENDING Blender loads Blender size Mixing speed Mixing time Bulk density of the raw material (considered in selecting blender and in determining optimum load) Characteristics of the material


SPECIALISED GRANULATION PROCEDURES Dry Blending and Direct Compression Slugging (Dry Granulation)

Dry Blending and Direct Compression:

Dry Blending and Direct Compression The order of addition of components to the blender The blender load The mixing speed The mixing time The use of auxiliary dispersion equipment within the mixer The mixing action Compression force

Slide 82:

Equipments used for mixing Sigma blade mixer. Planetary mixer. Twin shell blender. High shear mixer

Slugging (Dry Granulation):

Slugging (Dry Granulation ) A dry powder blend that cannot be directly compressed because of poor flow or compression properties. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less. Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts. If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation.

Dry Compaction:

Dry Compaction Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide. Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties.


COMPRESSION Press speed Handling and compression characteristics (in the selection of a tablet press) Die filling rate Flow rate of granules Induced die feed systems (for high speed machines) – speed of feed paddles The clearance between the scraper blade and the die table Design and condition of the punches

Compression :

Compression During compression, the tablet press performs the following functions: Filling of empty die cavity with granulation. Precompression of granulation (optional). Compression of granules. Ejection of the tablet from the die cavity and take-off of compressed tablet .

Slide 89:

High-speed tablet compression depends on the ability of the press to interact with granulation . Following are the parameters to be considered while choosing speed of press: Granulation feed rate. Delivery system should not change the particle size distribution. System should not cause segregation of coarse and fine particles, nor it should induce static charges.

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Slide 91:


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Slide 93:


Tablet Coating:

Tablet Coating Sugar coating is carried out in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations. The conventional sugar coating pan has given way to perforated pans or fluidized-bed coating columns.

Slide 95:

The development of new polymeric materials has resulted in a change from aqueous sugar coating and more recently, to aqueous film coating. The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column.

Slide 96:

A film coating solution may have been found to work well with a particular tablet in small lab coating pan but may be totally unacceptable on a production scale. This is because of increased pressure & abrasion to which tablets are subjected when batch size is large & different in temperature and humidity to which tablets are exposed while coating and drying process.


TABLET COATING (FILM COATING) Pan Coating Fluidized Bed Coating

Pan and Fluidized Coating:

Pan and Fluidized Coating Optimum tablet load Operating tablet bed temperature Drying airflow rate and temperature The solution application rate The size and shape of the nozzle aperture (for airless sprayer) The atomizing air pressure and the liquid flow rate (for air atomized sprayers)

Pan Coating:

Pan Coating Fixed Operating Parameters Variable Operating Parameters Other Parameters Pan Loading (kg) Solid content of coating suspension (%w/w) Spray gun dynamics Drying Air (cfm) Inlet air temperature ( ْ C ) Gun to tablet bed distance Coating System Spray rate (g min -1 ) Quantity of coating applied (%w/w) Atomizing air pressure (psi, bar) Air Pressure (psi, bar) Pan speed Number of spray guns

Fluidized Bed Coating:

Fluidized Bed Coating Batch size Drying/fluidizing air volumes Spray nozzle dynamics Spray evaporation rate



Compression rates of typical production presses:

Compression rates of typical production presses

Pilot Plant scale-up techniques for Capsule:

Pilot Plant scale-up techniques for Capsule Capsules are 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. Steps in capsule production Mixing of ingredient Granulation and lubrication Making of capsules Filling of capsules Uniformity testing Packing and labeling

Slide 105:

Both tablets & capsules are produced from ingredients that may be either dry blended or wet granulated to produce a dry powder or granule mix with uniformly dispersed active ingredients. To produce capsules on high speed equipment ,the powder blend must have the uniform particle size distribution, bulk density & compressibility required to promote good flow properties & result in the formation of compact of the right size and sufficient cohesiveness to be filled in to capsule shells.

Manufacture of Hard Gelatin Capsules:

Manufacture of Hard Gelatin Capsules Shell composition : Gelatin : Prepared by the hydrolysis of collagen. Gelatin in its chemical and physical properties, depending upon the source of the collagen and extraction. There are two basic types of gelatin: Type – A and Type – B. The two types can be differentiated by their isoelectric points (7.0 – 9.0 for type A and 4.8 – 5.0 for type B) and by their viscosity and film forming characteristics.

Slide 107:

Combination of pork skin and bone gelatin are often used to optimize shell characteristics. The physicochemical properties of gelatin of most interest to shell manufactures are the bloom strength and viscosity. Colorants : Various soluble synthetic dyes (“coal tar dyes”) and insoluble pigments are used. Not only play a role in identifying the product, but also may play a role in improving patient compliance. E.g., white, analgesia; lavender, hallucinogenic effects; orange or yellow, stimulants and antidepressants.

Slide 108:

Opaquing agents : Titanium dioxide may be included to render the shell opaque. Opaque capsules may be employed to provide protection against light or to conceal the contents. Preservatives : When preservatives are employed, parabens are often selected.

Slide 109:

Shell manufacture :

Slide 110:

Dipping : Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The pins are at ambient temperature; whereas the dipping solution is maintained at a temperature of about 50 0 C in a heated, jacketed dipping pan. The length of time to cast the film has been reported to be about 12 sec. Rotation : After dipping, pins are elevated and rotated 2-1/2 times until they are facing upward. This rotation helps to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends.

Slide 111:

Drying : The racks of gelatin coated pins then pass into a series of four drying oven. Drying is mainly done by dehumidification. A temperature elevation of only a less degrees is permissible to prevent film melting. Under drying will leave the films too sticky for subsequent operation. Stripping : A series of bronze jaws strip the cap and body portions of the capsules from the pins.

Slide 112:

Trimming : The stripped cap and body portions are delivered to collects in which they are firmly held. As the collects rotate, knives are brought against the shells to trim them to the required length. Joining : The cap and body portions are aligned concentrically in channels and the two portions are slowly pushed together.

Slide 113:

Sorting : The moisture content of the capsules as they are from the machine will be in the range of 15 – 18% w/w. During sorting, the capsules passing on a lighted moving conveyor are examined visually by inspectors. Defects are generally classified according to their nature and potential to cause problems in use. Printing : In general, capsules are printed before filling. Generally, printing is done on offset rotary presses having throughput capabilities as high as three-quarter million capsules per hour.

Slide 114:

Size Volume Fill weight(g) at 0.8 g/cm 3 powder density 000 1.37 1.096 00 0.95 0.760 0 0.68 0.544 1 0.50 0.400 2 0.37 0.296 3 0.30 0.240 4 0.21 0.168 5 0.15 0.104 Sizes and shapes : For human use, empty gelatin capsules are manufactured in eight sizes, ranging from 000 to 5. Capsule capacities in table:

Slide 115:

The largest size normally acceptable to patient is a No: 0. Three larger size are available for veterinary use: 10, 11, and 12 having capacities of about 30, 15, and 7.5 g, respectively. The standard shape of capsules is traditional, symmetrical bullet shape. Some manufactures have employed distinctive shapes. e.g. Lilly’s pulvule tapers to a bluntly pointed end. Smith Kline Beacham’s spansule capsules taper at both the cap and body ends.

Slide 116:

Sealing : Capsules are sealed and somewhat reshaped in the Etaseal process. This thermal welding process forms an indented ring around the waist of the capsule where the cap overlaps the body. Storage : Finished capsules normally contain an equilibrium moisture content of 13-16%. To maintain a relative humidity of 40-60% when handling and storing capsules.

Filling of hard gelatin capsules:

Filling of hard gelatin capsules Equipment used in capsule filling operations involves one often of two types of filling systems. Zanasi or Martelli encapsulator : Forms slugs in a dosatar which is a hollow tube with a plunger to eject capsule plug. Hofliger-Karg machine : Formation of compacts in a die plate using tamping pins to form a compact.

Slide 118:


Slide 119:

In this both system, the scale-up process involve bulk density, powder flow, compressibility, and lubricant distribution. Overly lubricated granules are responsible for delaying capsule disintegration and dissolution.

Slide 120:


Manufacture of Soft Gelatin Capsules:

Manufacture of Soft Gelatin Capsules Composition of the shell: Similar to hard gelatin shells, the basic component of soft gelatin shell is gelatin; however, the shell has been plasticized. The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for very hard shell to 1.0-1.8 for very soft shell. Up to 5% sugar may be included to give a “chewable” quality to the shell. The residual shell moisture content of finished capsules will be in the range of 6-10%.

Slide 122:

Formulation : Formulation for soft gelatin capsules involves liquid, rather than powder technology. Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness and manufacture efficiency. The liquids are limited to those that do not have an adverse effect on gelatin walls. The pH of the lipid can be between 2.5 and 7.5. Emulsion can not be filled because water will be released that will affect the shell.

Slide 123:

The types of vehicles used in soft gelatin capsules fall in to two main groups: Water immiscible, volatile or more likely more volatile liquids such as vegetable oils, mineral oils, medium-chain triglycerides and acetylated glycerides. Water miscible, nonvolatile liquids such as low molecular weight PEG have come in to use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs. All liquids used for filling must flow by gravity at a temperature of 35 0 c or less. The sealing temperature of gelatin films is 37-40 0 C.

Slide 124:

Manufacture process : Plate process : The process involved Placing the upper half of a plasticized gelatin sheet over a die plate containing numerous die pockets, Application of vacuum to draw the sheet in to the die pockets, Filling the pockets with liquor or paste, Folding the lower half of gelatin sheet back over the filled pockets, and Inserting the “ sandwich” under a die press where the capsules are formed and cut out.

Slide 125:

Rotary die press: In this process, the die cavities are machined in to the outer surface of the two rollers. The die pockets on the left hand roller form the left side of the capsule and the die pockets on the right hand roller form the right side of the capsule. Two plasticized gelatin ribbons are continuously and simultaneously fed with the liquid or paste fill between the rollers of the rotary die mechanism. As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules.

Slide 127:

Accogel process: In general, this is another rotary process involving A measuring roll, A die roll, and A sealing roll. As the measuring roll and die rolls rotate, the measured doses are transferred to the gelatin-linked pockets of the die roll. The continued rotation of the filled die converges with the rotating sealing roll where a second gelatin sheet is applied to form the other half of the capsule. Pressure developed between the die roll and sealing roll seals and cuts out the capsules.

Slide 128:

Bubble method: The Globex Mark II capsulator produces truly seamless, one-piece soft gelatin capsules by a “bubble method”.

Slide 129:

A concentric tube dispenser simultaneously discharges the molten gelatin from the outer annulus and the liquid content from the tube. By means of a pulsating pump mechanism, the liquids are discharged from the concentric tube orifice into a chilled-oil column as droplets that consists of a liquid medicament core within a molten gelatin envelop. The droplets assume a spherical shape under surface tension forces and the gelatin congeals on cooling. The finished capsules must be degreased and dried.

Slide 130:

Soft/Liquid-filled hard gelatin capsules: Important reason: the standard for liquid filled capsules was inability to prevent leakage from hard gelatin capsules. As banding and of self-locking hard gelatin capsules, together with the development of high-resting state viscosity fills, has now made liquid/semisolid-filled hard gelatin capsules. As with soft gelatin capsules, any materials filled into hard capsules must not dissolve, alter or otherwise adversely affect the integrity of the shell. Generally, the fill material must be pumpable .

Slide 131:

Three formulation strategies based on having a high resting viscosity after filling have been described. Thixotropic formulations, Thermal-setting formulations, Mixed thermal-Thixotropic systems. The more lipophilic contents, the slower the release rate. Thus, by selecting excipients with varying HLB balance, varying release rate may be achieved.

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LIQUID ORALS Liquid dosage forms may be dispersed systems or solutions. In dispersed systems there are two or more phases, where one phase is distributed in another. A solution refers two or more substances mixed homogeneously.

Steps of liquid manufacturing process:

Steps of liquid manufacturing process Planning of material requirements: Liquid preparation: Filling and Packing: Quality assurance:

General flow chart :

General flow chart Raw Materials Measured and weighed Mixing Filling Packing Distilled water Finished products storage Quality Assurance

Quality assurance:

Quality assurance Dissolution of drugs in solution Potency of drugs in suspension Temperature uniformity in emulsions Microbiological control Product uniformity Final volume Stability

Critical aspects of liquid manufacturing:

Critical aspects of liquid manufacturing Physical Plant: Heating, ventilation and air controlling system: The effect of long processing times at suboptimal temperatures should be considered in terms of consequences on the physical or chemical stability of ingredients as well as product.

Formulation aspects of oral liquids:

Formulation aspects of oral liquids Suspensions: Purpose Agent Facilitating the connection between API and vehicle -wetting agents Salt formation ingredients Protecting the API - Buffering-systems, polymers, antioxidants Maintaining the suspension appearance Colorings, suspending agent, flocculating agent. Masking the unpleasant taste/smell Sweeteners, flavorings

Formulation aspects of oral liquids:

Emulsions: Purpose Agent Particle Size Solid particles, Droplet particles Protecting the API Buffering-systems, antioxidants, polymers Maintaining the appearance Colorings, Emulsifying agents, Penetration enhancers, gelling agents Taste/smell masking Sweetners , flavorings Formulation aspects of oral liquids Emulsions:

Formulation aspects of oral liquids:

Solutions: Protecting the API Buffers, antioxidants, preservatives Maintaining the appearance Colorings, stabilizers, co-solvents, antimicrobial preservatives Taste/smell masking Sweeteners, flavorings. Formulation aspects of oral liquids Solutions:

Layout of the pilot plant:

Layout of the pilot plant

Equipments :

Equipments Mixer Homogenizer Filtration assembly Bottling assembly

Filtration assembly :

Filtration assembly

Slide 145:


Semisolid dosage forms:

Semisolid dosage forms In general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase .

Semisolid dosage forms:

The physical properties of the dosage form depend upon various factors, including the size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology . These factors combine to determine the release characteristics of the drug, as well as other characteristics, such as viscosity . Semisolid dosage forms

Critical manufacturing parameters:

Critical manufacturing parameters For a true solution, the order in which solutes are added to the solvent is usually unimportant. The same cannot be said for dispersed formulations, however, because dispersed matter can distribute differently depending on to which phase a particulate substance is added. In a typical manufacturing process, the critical points are generally the initial separation of a one-phase system into two phases and the point at which the active ingredient is added.

Critical manufacturing parameters:

Because the solubility of each added ingredient is important for determining whether a mixture is visually a single homogeneous phase, such data, possibly supported by optical microscopy, should usually be available for review. This is particularly important for solutes added to the formulation at a concentration near or exceeding that of their solubility at any temperature to which the product may be exposed. Critical manufacturing parameters

Critical manufacturing parameters:

Variations in the manufacturing procedure that occur after either of these events are likely to be critical to the characteristics of the finished product. This is especially true of any process intended to increase the degree of dispersion through reducing droplet or particle size (e.g., homogenization). Aging of the finished bulk formulation prior to packaging is critical and should be specifically addressed in process validation studies. Critical manufacturing parameters

General stability consideration:

General stability consideration The effect that SUPAC (Scale up and post-approval changes) may have on the stability of the drug product should be evaluated. For general guidance on conducting stability studies, see the FDA (Food and Drug Administration) Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics.

General stability consideration:

For SUPAC submissions, the following points should also be considered: In most cases, except those involving scale-up, stability data from pilot scale batches will be acceptable to support the proposed change . 2. Where stability data show a trend towards potency loss or increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative prechange batch be submitted for comparison. General stability consideration

General stability consideration:

It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. General stability consideration

General stability consideration:

3. A commitment should be included to conduct long-term stability studies through the expiration dating period, according to the approved protocol, on either the first or first three (see section III-VI for details) production batches, and to report the results in subsequent annual reports. General stability consideration

The Role of In Vitro Release Testing:

The Role of In Vitro Release Testing The key parameter for any drug product is its efficacy as demonstrated in controlled clinical trials. The time and expense associated with such trials make them unsuitable as routine quality control methods. Therefore, in vitro surrogate tests are often used to assure that product quality and performance are maintained over time and in the presence of change.

The Role of In Vitro Release Testing:

A variety of physical and chemical tests commonly performed on semisolid products and their components (e.g., solubility, particle size and crystalline form of the active component, viscosity, and homogeneity of the product) have historically provided reasonable evidence of consistent performance. More recently, in vitro release testing has shown promise as a means to comprehensively assure consistent delivery of the active component(s) from semisolid products. The Role of In Vitro Release Testing

The Role of In Vitro Release Testing:

An in vitro release rate can reflect the combined effect of several physical and chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. In most cases, in vitro release rate is a useful test to assess product sameness between prechange and postchange products. The Role of In Vitro Release Testing

The Role of In Vitro Release Testing:

However, there may be instances where it is not suitable for this purpose. In such cases, other physical and chemical tests to be used as measures of sameness should be proposed and discussed with the Agency. With any test, the metrics and statistical approaches to documentation of “sameness” in quality attributes should be considered The Role of In Vitro Release Testing

The Role of In Vitro Release Testing:

The evidence available at this time for the in vitro-in vivo correlation of release tests for semisolid dosage forms is not as convincing as that for in vitro dissolution as a surrogate for in vivo bioavailability of solid oral dosage forms. Therefore, the Center’s current position concerning in vitro release testing is as follows: The Role of In Vitro Release Testing

The Role of In Vitro Release Testing:

In vitro release testing is a useful test to assess product “sameness” under certain scale-up and post approval changes for semisolid products. 2. The development and validation of an in vitro release test are not required for approval of an NDA, ANDA or AADA nor is the in vitro release test required as a routine batch-to-batch quality control test. The Role of In Vitro Release Testing

The Role of In Vitro Release Testing:

3. In vitro release testing, alone, is not a surrogate test for in vivo bioavailability or bioequivalence. 4. The in vitro release rate should not be used for comparing different formulations across manufacturers . The Role of In Vitro Release Testing

Slide 162:

Mixing equipment Motors (used to drive mixing system and must be sized to handle the product at its most viscous stage) Mixing speed Component homogenization Heating and cooling process Addition of active ingredients Product transfer Working temperature range (critical to the quality of the final product)

Slide 163:

Shear during handling and transfer from manufacturing to holding tank to filling lines Transfer pumps While choosing size and type of pump : Product viscosity Pumping rate Product compatibility with the pump surface Pumping pressure required should be considered

Suppositories :


Introduction : :

Introduction : Suppositories are MEDICATED solid dosage forms of various shapes and sizes meant for insertion into body cavities like rectum, vagina, urethra, ear, nose etc .

Classification Of Suppositories ::

Classification Of Suppositories : Rectal suppositories Vaginal suppositories ( PESSARIES ) Urethral suppositories ( BOUGIES ) Nasal suppositories Ear suppositories

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Classification Of Suppositories Via Position Of Action :

Classification Of Suppositories Via Position Of Action

Therapy for rectal route ::

Therapy for rectal route : SUPPOSITORY WILL BE MELTED AND RELEASED LOCAL EFFECT : In case of pain, itching and hemorrhoid. Locally active drugs include astringents, antiseptics, local anesthetics, vasoconstrictors, anti-inflammatory, soothing and protective agents and some laxatives. SYSTEMIC EFFECT : Anti-asthmatics, anti rheumatics, anti-pyretic and analgesics


VAGINAL SUPPOSITORY They are also called as PESSARIES. SHAPE : globular, oviform or cone-shaped. Used occasionally. Intended for local effects like contraceptives, antiseptics in feminine hygiene.


URETHRAL SUPPOSITORY Also called as BOUGIES . SHAPE – slender, pencil-shaped. Intended for anti-bacterial or as a local anesthetic preparative for urethral examination. Occasionally used.


RECTAL SUPPOSITORY Intended for local action to relieve constipation, irritation, itching and inflammatory associated to hemorrhoids.


ADVANTAGES EASILY ADMINSTERED to children, old persons, to unconscious or sometimes to mentally unstable persons who cannot swallow the drug. Convenient mode of administration for drugs which irritate the GIT, causing vomiting and destroyed in acidic ph of stomach and enzymes of GIT. FASTER ONSET OF ACTION as compared to oral administration because absorption of drug through rectal mucosa directly reaches blood.




WHY THERE IS NEED FOR MEDICAMENTS AS SUPPOSITORIES ?? TO EXERT DIRECT ACTION ON RECTUM : they are usually used to relieve pain and irritation and usually used as local anesthetics EXAMPLES : ASTRINGENTS : bismuth subgallate . ANTI-INFLAMMATORY : hydrocortisone and its acetate.


WHY THERE IS NEED FOR MEDICAMENTS AS SUPPOSITORIES ?? TO PROVIDE SYSTEMIC EFFECT : EXAMPLES INCLUDE :- 1. AMINOPHYLLINE – for relaxing involuntary muscles, gives relief to asthamatics and chronic bronchitics . 2. MORPHINE – powerful analgesic. 3. ERGOTAMINE TARTRATE ( IN TREATMENT OF MIGRAINE ) – acts as analgesic.


WHY THERE IS NEED FOR MEDICAMENTS AS SUPPOSITORIES ?? TO PROMOTE EVACUATION OF BOWELS laxative drugs like glycerol and bisacodyl exert effect by irritating the rectum.


DISADVANTAGES Drugs which are irritant to mucous membrane (rectum) cannot be formulated as suppository. Demands stringent storage conditions. Problematic in large scale production of suppositries and achievement of suitable shelf life. Leaking problem of the material through cavities causes embarrassment to the patient.


DISADVANTAGES Development of procitis (inflammation of anus and lining of rectum) in some cases.


DISADVANTAGES Slow and incomplete absorption of drug.


SUPPOSITORY BASES Suppository base play important role in release of the medication and therefore in availability of drug. CLASSIFICATION


IDEAL PROPERTIES OF SUPPOSITORY BASES It should melt at body temperature or dissolve or disperse in body fluids. It should release any medicament easily. It should keep its shape when being handled. It should be non-toxic and non-irritant to the mucous membrane. It should be stable on storage and also stable if heated above its M.P.


IDEAL PROPERTIES OF SUPPOSITORY BASES It should be easily molded and should not adhere to the mold. It should possess good wetting and emulsifying properties. It should be able to incorporate a high percentage of water. It should be chemically and physically stable.


184 METHODS OF PREPARATION Suppositories can be extemporaneously prepared by one of three methods . Hand Rolling It is the oldest and simplest meth od of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. It has the advantage of avoiding the necessity of heating the cocoa butter. A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar.

Follow; 1. Hand Rolling :

185 Follow; 1. Hand Rolling The mass is formed into a ball in the palm of the hands , then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.

2. Compression Molding:

186 2. Compression Molding Compression molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold using suppository making machines . The suppository base and the other ingredients are combined by thorough mixing . The friction of the process causing the base to soften into a past-like consistency.

Slide 187:

187 On a small scale, a mortar and pestle may be used (preheated mortar facilitate softening of the base). On large scale, mechanically operated kneading mixers and a warmed mixing vessel may be applied. In the compression machine, the suppository mass is placed into a cylinder which is then closed. Pressure is applied from one end to release the mass from the other end into the suppository mold or die.

Slide 188:

188 When the die is filled with the mass, a movable end plate at the back of the die is removed and when additional pressure is applied to the mass in the cylinder, the formed suppositories are ejected. The end plate is returned, and the process is repeated until all of the suppository mass has been used.

Slide 189:

189 The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.

3. Fusion Molding:

190 3. Fusion Molding Fusion Molding involves: 1- Melting the suppository base 2- Dispersing or dissolving the drug in the melted base. 3- The mixture is removed from the heat and poured into a suppository mold. 4- Allowing the melt to congeal 5- Removing the formed suppositories from the mold . The fusion method can be used with all types of suppositories and must be used with most of them.

Suppository molds:

191 Suppository molds Small scale molds are capable of producing 6 or 12 suppositories in a single operation. Industrial molds produce hundreds of suppositories from a single molding.

Lubrication of the mold:

192 Lubrication of the mold Depending on the formulation, suppository molds may require lubrication before the melt is poured to facilitate the clean and easy removal of the molded suppository. Lubrication is seldom necessary when the suppository base is contracting sufficiently on cooling. Lubrication is usually necessary when glycerinated gelatin suppositories are prepared.

Testing of suppositories:

193 Testing of suppositories Finished suppositories are routinely inspected for: Appearance. Content uniformity Melting range test Drug release test Fragility test Disintegration test

Breaking test (Hardness):

194 Breaking test (Hardness) To measure the fragility or brittleness of suppository Double wall chamber in which the test suppository is placed. Water at 37ºC is pumped through the double wall. The suppository supports a disc to which rod is attached. The other end of the rod consist of another disc to which weights are applied.

Follow; Hardness:

195 Follow; Hardness The test was conducted by placing the suppository to support the axis of 600 g weight. At one minute intervals 200 gm weights are added. The weight at which the suppository collapses is the breaking point When the breaking point reached in the first 20 sec, the added weight was not calculated When the breaking point reached in the second 20 sec, half the added weight was calculated When the breaking point reached in the third 20 sec, all the added weight was calculated

Melting range test:

196 Melting range test Macro-melting range is a measure of the time it takes for the entire suppository to melt when immersed in a constant-temperature (37ºC) water bath. USP tablet disintegration apparatus is used

In-vitro drug release:

197 In-vitro drug release In-vitro drug release pattern is measured by using the same melting rang apparatus. Aliquots of the release medium were taken at different time intervals within the melting period. The drug content in the aliquots was determined. The drug release pattern was plotted (time versus-drug release curve)

Factors influencing absorption:

198 Factors influencing absorption Physiologic factors Physicochemical factors of the drug and the base: 1- Lipid-water solubility of the drug 2- Particle size of the drug 3- degree of drug ionization 4- Nature of the base

1- lipid-water solubility:

199 1- lipid-water solubility The lipid water partition coefficient of the drug is an important consideration in the selection of the suppository base and in anticipating drug release from that base. A lipophilic drug that is distributed in a fatty suppository base in low concentration has less of a tendency to escape to the surrounding aqueous fluids than a hydrophilic drug in its saturation concentrations.

Slide 200:

200 Water-soluble bases dissolve in rectal fluids and release both water-soluble and oil-soluble drugs. The more drug in the base, the more dug will be available for potential absorption A drug with a high partition coefficient is likely to be absorbed more readily from a water soluble bases.

2- Degree of ionization:

201 2- Degree of ionization Absorption through rectal mucosa proceeds in accordance with pH-partition theory. At the slightly alkaline pH of rectal mucosa, weakly basic drugs will exist in their lipid– soluble unionized form and readily absorbed.

3- Particle size:

202 3- Particle size For drugs present in the suppository in the un-dissolved form, the size will influence the amount released and dissolved for absorption. The smaller the size, the more readily the dissolution of the particle and the greater the chance for rapid absorption.

4- Nature of the base:

203 4- Nature of the base If the base interacts with the drug inhibiting its release, drug absorption will be impaired or even prevented. If the base is irritating to the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, negating the prospect of thorough drug release and absorption.

Contract manufacturing :

Contract manufacturing

Definition of contract manufacturing:

Definition of contract manufacturing Production of goods by one firm, under the label or brand of another firm. Contract manufacturers provide such service to several (even competing) firms based on their own or the customers' designs, formulas, and/or specifications. Also called private label manufacturing.

Contract manufacturing:

Contract manufacturing Contract manufacturing is a process that established a working agreement between two companies. As part of the agreement, one company will custom produce parts or other materials on behalf of their client. In most cases, the manufacturer will also handle the ordering and shipment processes for the client. As a result, the client does not have to maintain manufacturing facilities, purchase raw materials, or hire labour in order to produce the finished goods.

Contract manufacturing.:

Contract manufacturing. The basic working model used by contract manufacturers translates well into many different industries. Since the process is essentially outsourcing production to a partner who will privately brand the end product, there are a number of different business ventures that can make use of a contract manufacturing arrangement. There are a number of examples of pharmaceutical contract manufacturing currently functioning today, as well as similar arrangements in food manufacturing, the creation of computer components and other forms of electronic contract manufacturing.

Contract manufacturing:

Contract manufacturing Even industries like personal care and hygiene products, automotive parts, and medical supplies are often created under the terms of a contract manufacture agreement. In order to secure contract manufacturing jobs, the contract manufacturer usually initiates discussions with the potential client. The task is to convince the prospective customer that the manufacturer can use their facilities to produce quality goods that will meet or exceed the expectations of the customer.

Contract manufacturing:

Contract manufacturing At the same time, the manufacturer will demonstrate how the overall unit cost of production to the customer will be less than any current production strategies in use, thus increasing the amount of profit that will be earned from each unit sold There are several advantages to a contract manufacturing arrangement. For the manufacturer, there is the guarantee of steady work. Having contracts in place that commit to certain levels of production for one, two and even five year periods makes it much easier to forecast the future financial stability of the company.

Contract manufacturing:

For the client, there is no need to purchase or rent production facilities, buy equipment, purchase raw materials, or hire and train employees to produce the goods. There are also no headaches from dealing with employees who fail to report to work, equipment that breaks down, or any of the other minor details that any manufacturing company must face daily. Contract manufacturing

Contract manufacturing:

Contract manufacturing All the client has to do is generate sales, forward orders to the manufacturer, and keep accurate records of all income and expenses associated with the business venture. The general concept of contract manufacturing is not limited to the production of goods. Services such as telecommunications, Internet access, and cellular services can also be supplied by a central vendor and private branded for other customers who wish to sell those services. Doing so allows the customer to establish a buy rate from the vendor, then resell the services at a profit to their own client base

Scopes of contract manufacturing:

Scopes of contract manufacturing The scope of the Contract Manufacturing Procurement business scenario outlined in this documentation only concerns the customer side (OED - The Office of Enterprise Development ). This business scenario does not cover how an ERP ( Enterprise Relationship Management ) system on the supplier's side (that is, the contract manufacturer's side) receives messages sent by the customer, and how it deals with the additional information (for example, components) submitted with these messages.

Scopes of contract manufacturing:

Mappings are only provided for A2A communication (between the OED's ERP system and SAP * SNC * ) from IDoc to XML and vice versa. This business scenario does not cover the tracking of the manufacturing process (production phases) that takes place at the contract manufacturer's site - it does not take into account the current production phase at the contract manufacturer' site. Consequently, the OED planner cannot predict the supply situation of finished goods. * SAP- Supply Network Planning * SNC- Supply Network Collaboration Scopes of contract manufacturing

Limits of contract manufacturing:

The Contract Manufacturing Procurement business scenario has the following limitations: Once a schedule line in the ERP purchase order is changed, the date and quantity data originally requested are lost. Even if the information is stored in SAP SNC, it is not possible to send this information to the CM. The Contract Manufacturing Procurement business scenario is based on functions introduced in SAP ERP 6.0. For lower releases, you need to develop a customer modification. Limits of contract manufacturing

Limits of contract manufacturing:

No data import control functions are provided for messages sent from the CM to SAP SNC. The bill of material (BOM) is not available in SAP SNC. New purchase order items cannot be created in SAP SNC. Product substitution is not supported. Scheduling agreements for the subcontracted material are not allowed. Limits of contract manufacturing

Limits of contract manufacturing:

A supplier should be able to update the component consumption in SAP SNC until a good receipt has been posted in the customer ERP back-end system. The subcontracting scenario of the Rosetta Network Order Management Program as described in the PIPs * 7B5 (Notify of Manufacturing Work Order), 7B6 (Notify of Manufacturing Work Order Reply), and 7B1 (Work In Process Notification) is not included in the scope of SAP SCM * . * PIP- Partner Interface Process * SCM- Supply Chain Management Limits of contract manufacturing

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