Pilot plant scale up techniques - BP702TT - Industrial Pharmacy II

 Pilot plant scale up techniques

INDUSTRIAL PHARMACY ll

BP702TT

B.PHARMA SEMESTER 7

jsmasipharmacy.blogspot.com

Contents : 

1. .INTRODUCTION
2.  GENERAL CONSIDERATION
3.  PILOT PLANT DESIGN FOR TABLETS
4. PILOT PLANT SCALE-UP TECHNIQUES FOR CAPSULES
5.  SCALE-UP LIQUID ORALS
6. SCALE-UP and POST APPROVAL CHANGES (SUPAC)
7. INTRODUCTION TO PLATFORM TECHNOLOGY

1. INTRODUCTION

pilot plant: "Define as part of pharmaceutical industry where a lab scale formula is transformed into a viable product by development of reliable prectical method of manufacture."

Scale up: The art of designing of prototype using the data obtain from pilot plant model.

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.

Pilot plant scale-up techniques involve reproducible manufacture of an experimental formulation on high-speed production equipment, in a cost-effective manner. 

It is a part of the pharmaceutical industry.

1.1 Pilot Plant Scale-up must include:

1. A close examination of the formula to determine its ability to withstand large scale and process modification.

2. A review of a range of relevant processing equipment to determine which would be most compatible with the formulation as well as the most economical, simple and reliable in producing the product.

1.2 During pilot plant scale-up ensure the:

1. Determination of the availability of raw materials 

2. Determination of the physical space required and the layout of related functions 

3. Evaluation, validation and finalizing of production and process controls.

4. Issuing of adequate records and reports to support  GMPs 

5. Development and validation of meaningful product reprocessing procedures.

6. Identification of all critical, features of a scale up process, so that it can be adequately monitored to provide assurance that the process is under control 

7. Production rate and future market requirements.

2. General considerations

2.1. Reporting Responsibilities:

•  R and D group with separate staffing.
•  The formulator who developed the product can take into the production and provide support even after transition into production has been completed.

2.2. Personal Requirements:

•  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.

2.3. Space Requirements:

•  Administration and information process: Adequate office and desk space should be provided for both scientists and technicians. The space should be adjacent to the working area.
•  Physical testing area: This area should provide permanent bench top space for routinely used physical testing equipment.
• Standard pilot-plant equipment floor space: Discrete pilot plant space, where the equipments are needed for manufacturing all types of dosage forms, is located.

                (a) Intermediate sized and full-scale production equipment is essential in evaluating the                                 effects of scale-up of research formulations and processes.

                (b) Equipments used should be made portable. So that after use it can be stored in the small                           store room.

                (c) Space for cleaning of the equipment should also be provided.

•  Storage area:

                (a) It should have two areas divided as approved and unapproved area for active ingredients                         as well as excipients.

                (b) Different areas should be provided for the storage of the in-process materials, finished                              bulk products from the pilot-plant and materials from the experimental scale-up batches                          made in the  production. Storage area for the packing material should also be provided.

2.4. Review of the Formula:

•  A thorough review of each aspect of formulation is important.
•  The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory and 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 to be predicted, or recognized.

2.5. Raw Materials:

• One purpose/responsibility of the pilot plant is the approval and validation of the active ingredients and excipients raw materials.
•  Raw materials used in the small-scale production cannot necessarily be the representative for the large-scale production.

2.6. Equipments:

•  The most economical and the simplest and efficient equipments, which are capable of producing product within the proposed specifications, are used. 

• The size of the equipments should be such that the experimental trial’s run should be relevant to the production sized batches.
•  If equipment is too small, the process developed will not scale up; whereas if equipment is too big, then there is wastage of the expensive active ingredients.

2.7. Production Rates: 

• The immediate as well as the future market trends/requirements are considered while determining the production rates.

2.8. 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 temperature and drying time.

2.9. Master Manufacturing Procedures:

•  The weight sheet should clearly identify the chemicals required in a batch. To prevent confusion the names and identifying numbers 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, etc. should be mentioned in the batch record directions.

2.10. 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 as raw material.

2.a. GMP CONSIDERATIONS

1. Equipment qualification.

2. Process validation.

3. Regularly schedule preventative maintenance.

4. Regularly process review and revalidation.

5. Relevant written standard operating procedures.

6. The use of competent technically qualified personnel.

7. Adequate provision for training of personnel.

8. A well-defined technology transfer system.

9. Validated cleaning procedures.

10. An orderly arrangement of equipment so as to ease material flow and prevent crosscontamination.

3. PILOT PLANT DESIGN FOR TABLETS

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.

3.1. Material Handling:

In the laboratory, materials are simply scooped or poured by hand, but in intermediate or large-scale operations, handling of these 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 are vacuum loading systems, metering pumps, screw feed system.

3.2. 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. The equipments 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, etc.

Scale-up Considerations;

• Powders to be used for encapsulation or to be granulated prior to tableting must be well blended to ensure good drug distribution.
• Inadequate blending could result in drug content uniformity variation, especially when the tablet or capsule is small and the drug concentration is relatively low.
•  Ingredients should be lumps free, otherwise it could cause flow problems.

3.3. Granulations:

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, etc. 

Traditionally, wet granulation has been carried out using, sigma blade mixer, heavy-duty planetary mixer:

•  to improve the flow properties.
•  to increase the apparent density of the powder.
• to change the particle size distribution so that the binding properties on compaction can be improved.

3.4. Drying:

 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.

Fluidized Bed Dryer:

• Optimum loads - rate of airflow.

• Inlet air temperature.

• Humidity.

• Data used for small scale batches (1-5 kg) cannot be extrapolate processing

conditions for intermediated scale (100 kg) or large batches.

Fluidized Bed Dryer

3.5. Reduction in Particle Size:

 

 Compression factors may be affected by the particle size distribution, flow ability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, tablet colour uniformity.

Equipments:

•  Oscillating granulator
•  A hammer mill.
•  Screening device.

Too large particle size causes:   Weight variation ,Mottling

Too fine particle size causes:Weight variation.,Capping, Both oversized and undersized granulation can adversely affect tablet content uniformity , Lubricants and Giants are added at final blend.

3.6. Blending:

Equipments:

• Planetary type mixer

• Twin shell mixture

• Cone type

Over loading in blender:

• Retards the free flow of granules

• Reduces the efficiency

• Causes content un-uniformity

If the load is to small:

• Powder blend slides rather than roll in blender.

• It causes improper mixing.

3.7. Slugging:

 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 and finely recycled through the slugging operation.

3.8. Compression:

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

Compression characteristics can be evaluated by press speed equal to normal production

speed.

Then detect the problems such as,

• Sticking to punch surface

• Tablet hardness

• Capping

• Weight variation

Granules must be delivered at adequate rate.

3.9. Tablet 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:

• 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:

• Batch size.
• Drying/fluidizing air volumes.
• Spray nozzle dynamics.
• Spray evaporation rate.

Equipments:

• Conventional coating pan.
• Perforated pans of fluidized-bed coating column.

Types:

• Sugar coating.
• Film coating.

(i) Tablet must be sufficiently hard to withstand the tumbling to which they are

subjected while coating.

(ii) Operation conditions to be established for pan or column operation are optimum

tablet load, operating tablet, bed temperature, drying air flow rate, temperature,

solution application rate.

4.PILOT PLANT SCALE-UP TECHNIQUES FOR CAPSULES

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.

Different Steps in capsule production:

1. Mixing of ingredients

2. Granulation and lubrication

3. Making of capsules

4. Filling of capsules

5. Uniformity testing

6. Packing and labeling

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 and compressibility required to promote good flow properties and result in the formation of compact of the right size and sufficient cohesive ness to be filled into capsule shells.

4.1 Manufacturing of Hard Gelatin Capsules

4.1.1 Shell Composition:

•  Gelatin: It is prepared by the hydrolysis of collagen. 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.

• Combination of pork skin and bone gelatin is 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. Colorants not only play a role in identifying the product, but also play a role in improving patient compliance. For example, white - analgesia, lavender - hallucinogenic effects, orange or yellow - stimulants and antidepressants.

• 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.

4.1.2 Shell Manufacturing:

• 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 50oC 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.

• Drying: The racks of gelatin coated pins are then passed into a series of four drying ovens. Drying is mainly done by dehumidification. A temperature elevation to 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.

• 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.

• 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.

• Sizes and Shapes: For human use, empty gelatin capsules are manufactured in eightsizes, ranging from 000 to 5. 
• The largest size normally acceptable to patient is a No. 0. Three larger sizes are available for veterinary use: 10, 11, and 12 having capacities of about 30, 15, and 7.5 gm, respectively. The standard shape of capsules is traditional, symmetrical bullet shape. Some manufactures have employed distinctive shapes. For example, Lilly’s pulvule tapers to a bluntly pointed end, Smith Kline Beacham’s spansule capsules  taper at both the cap and body ends.

• 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.

4.1.3  Filling of Hard Gelatin Capsules:

Equipments used in capsule filling operations involve one often of two types of filling

systems:

1. Zanasi or Martelli encapsulator: Forms slugs in a dosatar which is a hollow tube with a plunger to eject capsule plug.
2. Hofliger-Karg machine: Forms compacts in a die plate using tamping pins to form a compact.

• In both these systems, the scale-up process involves bulk density, powder flow,

compressibility and lubricant distribution. Overly lubricated granules are responsible

for delaying capsule disintegration and dissolution.

• Osaka Model R-180 Semi-Automatic Capsule Filling Machine.

4.2 Manufacturing of Soft Gelatin Capsules

• 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.
• Upto 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%.

Manufacture Processes:

4.2.1. Plate Process: The process involves:

• Placing the upper half of a plasticized gelatin sheet over a die plate containing

numerous die pockets,

• Application of vacuum to draw the sheet into 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.

4.2.2. Rotary Die Press:

• In this process, the die cavities are machined into 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.

4.2.3. 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 roll 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.

4.2.4. Bubble Method:

• The Globex Mark II capsulator produces truly seamless, one-piece soft gelatin

capsules by a “bubble method”. 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 consist 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.

5. SCALE-UP LIQUID ORALS

1.  The physical form of a drug product that is pourable displays Newtonian or pseudo plastic flow behaviour and conforms to its container at room temperature.
2.  Liquid dosage forms may be dispersed systems or solutions.
3.  In dispersed systems there are two or more phases, where one phase is distributed in another.
4.  A solution refers two or more substances mixed homogeneously.

Steps in Liquid Manufacturing Process:

1.  Planning of material requirements.
2.  Liquid preparation.
3. Filling and packing.
4. Quality assurance.

Formulation Aspects of Suspensions :

Formulation Aspects of Emulsions :

Formulation Aspects of Solutions :

Quality Assurance:

• Dissolution of drugs in solution

• Potency of drugs in suspension

• Temperature uniformity in emulsions

• Microbiological control

• Product uniformity

• Final volume

• Stability

6. SCALE-UP and POST APPROVAL CHANGES (SUPAC)

FDA and American association of pharmaceuticals scientist (AAPS) provided the scientific Foundation for the scale-up and post approval changes required for immediate release product called SUPAC.

It provides guidelines for post approval changes in the following:

- Components

- Compositions

- Site of manufacturing

- Process and equipment

Significance of Pilot Plant:

1. Examination of formulae.
2. Review of range of relevant processing equipments.
3. Production rate adjustment.
4. Idea about physical space required.
5. Appropriate records and reports to support GMP.
6. Identification of critical features to maintain quality.

Advantages:

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

Disadvantages:

1. The frequency of direct interaction of the formulator with the production personnel in the manufacturing area will be reduced.
2. Any problem in manufacturing will be directed towards its own pilot-plant personnels.

General Stability Consideration:

The effect that SUPAC changes may have on the stability of the drug product should be

evaluated. For general guidance on conducting stability studies, see the FDA Guideline for

Submitting Documentation for the Stability of Human Drugs and Biologics.

For SUPAC submissions, the following points should also be considered:

1.  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 more potency loss or degrading under accelerated conditions, it is recommended that historical accelerated stability data from a representative perchance batch be submitted for comparison.
3. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement.
4. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement.

7. INTRODUCTION TO PLATFORM TECHNOLOGY

Platform technologies are considered a valuable tool to improve efficiency and quality in Drug product development. The basic idea is that a platform, in combination with a riskbased approach, is the most systematic method to leverage prior knowledge for a given new molecule. Furthermore, such a platform enables a continuous improvement by adding data for every new molecule developed by this approach, increasing the robustness of the platform. The technology has distinct and differentiating competitive advantages. It can significantly improve the bioavailability of complex molecules due to its sub-micrometric size and adhesive systems for a higher time of contact to skin. It is also flexible, encapsulating a broad range of active principles and its systems can be adjusted to achieve desired

properties.

In addition, the technology is robust and versatile, with key features such as:

• Chemical stability and solubility of the active molecule.
• High drug loadings can be achieved.
• High encapsulation efficiency.
• Developed industrial process and scalability.
• Stable, simple and solvent-free technologies.
• Reformulation of drugs near patent expiration.
• Development of drugs previously thought impossible.
• New administration routes for a variety of molecules.

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