UNIT OPERATION / PRODUCTION PROCESS


Introduction

PILOT PLANT / KILO LABS

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.

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 complex food processing plant from laboratory data alone with any degree of success.

PURPOSE OF PILOT PLANT STUDIES

  • 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 marketing testing or furnishing samples to potential customers, shelf-lives, and storage stability studies.
  • Determining possible salable by products or waste stream requiring treatment before discharge.
  • 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.

Considerations in pilot plant development

  • Kind and size – depends on goals; evaluating product and process; producing samples of product for evaluation; market testing or furnishing to potential customers.
  • Location – liaison between research and development and pilot plant staff is essential.
  • Labor requirements and costs – engineering staff, skilled operations and maintenance staff. The pilot plant may be used for training personnel for a full-scale plant.

Objectives of Pilot Production

  • To produce physically and chemically stable therapeutic dosage forms.
  • To identify the critical features of the production process.
  • To provide master manufacturing formula.
  • To review the processing equipment, production and process control, guidelines and validation procedures.

Pilot plant studies include the close examination of the formula to determine:

  • The ability to withstand batch scale.
  • For process modification.
  • Compatibility of the equipment with the formulation.
  • Availability of raw materials meeting the specifications required to produce the product.
  • Market requirement
  • Physical space required and the layout of the related functions.

Thus, during the scale up efforts in the pilot plant:

  • Production and process controls are evaluated, validated and finalized.
  • Product reprocessing are developed and validated.
  • Appropriate records and reports are issued to support cGMP.

All critical features of a process must be identified so that as the process so that as the process is scaled up, it can adequately monitored to provide assurance that the process is under control and that the product produced at each level of the scale up maintains the specified attributes originally intended.


Pilot Plant Design

A pilot plant design should support the following:

  • Formulation and process development.
  • Clinical supply manufacture.
  • Technology evaluation, scale up and transfer.

Attributes playing a key role in achieving the above considerations:

  • cGMP compliance
  • A flexible highly trained staff.
  • Equipment to support multiple dosage form development.
  • Equipment at multiple scales based on similar operating principles to those in production.

The pilot plant design should be according to cGMP norms. The layout should be according to the need for flexibility (portable equipment installed, use of multipurpose rooms), restricted access, personnel flow and material flow. The facility and equipment (e.g. cell therapy aseptic isolator, pass boxes) should be able to capture critical process information. Cell therapy aseptic isolators, pass boxes, and other equipment that will aid the continuity of the process flow must also be according to cGMP standards. These will be helpful to attain sterility without disturbing the containment of the facility. Intermediate sized and full scale production equipment should be available in order to evaluate the effects of scale up of research formulations. Adequate space required to carry out each function smoothly (e.g., cleaning of pilot plant equipment). The final design should result in a facility that support the key strategic objectives and should have low maintenance and operating costs.

Although the pilot plant design must simulate the manufacturing environment in which the new product will ultimately be produced, there are many differences in operation because of the specific objectives of the two types of facilities e.g. the pilot plant facilities product development activities, whereas the manufacturing plant routinely fabricates products for the market place.

Pilot Plant Operation

Operational Aspects of Pilot Plant

  1. Validation

A validation master plan should have the design specification, installation, operational, and performance qualification of all major utility systems, process equipment, and computer control systems. A fully validated pilot plant should ensure compliance with cGMP and should meet current FDA standards.

  1. Training

All staff should have the proper training on the compliance with quality standards such as cGMP, safety and environmental responsibilities, compliance with SOPs, and technical skills and knowledge.

  1. Engineering Support

This operational support is required for design, construction, commissioning, validation of the pilot plant facility, coordination, scheduling and direction of ongoing operations.

  1. Calibration

Calibration of critical instruments and equipment is required for compliance with cGMP. It is also utilized in maintaining the integrity of data generated during the development process.

  1. Material Control

More flexible and efficient computer based system required for material control in pilot plant.

  1. Inventory

Inventory should be maintained in a Computer Based Inventory-Ordering-Dispensing System.

  1. Orders

All orders must be placed through the computer system. For placement of the order, First In First Out (FIFO) criteria is allowed.

  1. Labeling

Labels should comply with GMP-GLP requirements. Computer system must be used for labeling.

  1. Process and Manufacturing Activities

This operational protocol includes formulation and process development studies, clinical supply manufacture, technology evaluation, scale up and transfer.

  1. Quality Assurance (QA) and Quality Control (QC)

The following are the activities of the QA team:

  • Auditing pilot plant.
  • Auditing and approval of component suppliers.
  • Reviewing, approving, and maintain 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 standard operating procedures (SOPs).
  • Review and approval of validation and engineering documentation.

The following are the activities of the QC team:

  • Release testing of finished products.
  • Physical, chemical, and microbiological testing of finished clinical products, components and raw materials.
  • Testing for validation and revalidation programs.

General Considerations

Separate provisions for API excipients further segregated into approved and unapproved areas according to GMP. Storage area for in process materials, finished bulk products, retained samples, experimental production batches, packaging materials (segregated into approved and unapproved areas). Controlled environment space is allocated for storage of stability samples.

Process Evaluation:

Preparation of Master Manufacturing Procedure

The procedure/s include/s the following:

  • The chemical weight sheet. It should clearly identify the chemicals required in a batch and present the quantities and the order in which they will be used.
  • The sampling directions
  • In-process and finished product specifications
  • Manufacturing directions should be in a language understandable by the operator termed as SOPs.
  • Batch Record Directions should include specifications for addition rates, mixing times, mixing speeds, heating and cooling rates, and temperature.

Product stability and uniformity

  • The primary objective of the pilot plant is the physical as well as the chemical stability of the products.
  • Each pilot batch representing the final formulation and manufacturing procedure should be studied for stability.
  • Stability studies should be carried out in finished packages.

GMP Considerations

  • Equipment qualification
  • Process validation
  • Regularly schedule preventive maintenance
  • Regularly written standard operating procedures
  • The use of competent technically qualified personnel
  • Adequate provision for training of 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.

Transfer of Analytical Methods to Quality Assurance

Analytical methods developed in research must be transferred to QA department. Transfer includes:

  1. Review the process to make sure that proper analytical instrument is available.
  2. Personnel should be trained to perform all the specific test.
  3. Reliability of the test should be checked.
  4. Assay procedure should be reviewed before transfer.

Scale Up Techniques

Scale-Up Techniques

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

S C A L E  U P  S T E P S

 

Pilot Plant Design for Tablets

  • The primary responsibility of the pilot plant is to ensure that the newly formulated tablets developed by the 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 the shipment of supplies.
  • Extraneous and microbiological contamination must be guarded against by incorporating the following features in the pilot plant design:
    • Fluorescent lighting fixtures should be the ceiling flush type.
    • The various operating areas should have floor drains to simplify cleaning.
    • The area should be air-conditioned and humidity controlled.
    • High-density concrete floors should be installed.
    • The walls in the processing and packaging areas should be enamel cement finish on concrete.
    • Equipment in the pharmaceutical pilot plant should be similar like those used by the production division.
  1. Material handling system
    1. 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.
    2. If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination.
    3. Any material handling system must deliver the accurate amount of the ingredient to the destination.
    4. The type of system selected also depends on the characteristics of the materials.
    5. More sophisticated methods of handling materials such as vacuum loading systems, metering pumps, and screw feed system.
  2. Dry Blending
    1. Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution.
    2. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency.
    3. For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible.

The equipment used for blending are:

  • V-blender
  • Double cone blender
  • Ribbon blender
  • Bin blender
  • Orbiting screw blender and/or vertical and horizontal high intensity mixers.

Scale Up Considerations

  • Time of blending
  • Blender of loading
  • Size of blender
  1. Granulation

The most common reasons given to justify granulating are:

  1. To impart good flow properties to the material,
  2. To increase the apparent density to the powders,
  3. To change the particle size distribution,
  4. To attain the uniform dispersion of the active ingredient.

Traditionally, wet granulation has been carried out using,

  • Sigma blade mixer,
  • Heavy-duty planetary mixer.

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

The use of multifunctional “processors” that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment.

Fluid Bed Granulations

  1. Process Inlet Air Temperature
  2. Atomization Air Pressure
  3. Air Volume
  4. Liquid Spray Rate
  5. Nozzle Position and Number of Spray Heads
  6. Product and Exhaust Air Temperature
  7. Filter Porosity
  8. Cleaning Frequency
  9. Bowl Capacity

  1. Binders
    1. Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling.
    2. In some instances, the binding agent imparts viscosity to the granulating solution, hence, transfer of fluid becomes difficult.
    3. This problem can overcome by adding some or all binding agents in the dry powder prior to granulation.
      1. Some granulation, when prepared in production sized equipment, take on a dough-like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.
      2. This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all.
  2. Drying
    1. The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either stem or electricity.

    1. 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.
    2. 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.
    3. Drying times at specified temperatures and airflow rates must be established for each product, and for reach particular oven load.
    4. Fluidized bed dryers are an attractive alternative to circulating hot air ovens.

Tray Dryer

Parameters to be considered for scale up are:

  1. Air flow
  2. Air temperature
  3. Depth of the granulation on the trays
  4. Monitoring of the drying process by the use of moisture and temperature probes.
  5. Drying times at specified temperature and air flow rates for each product.
  6. Reduction of Particle Size
    1. 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.
    2. First step in this process is to determine the particle size distribution of granulation using a series of stacked sieves of decreasing mesh openings.
    3. Particle size reduction of the dried granulation 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.
    4. As part of the scale-up of a milling or sieving operation, the lubricants and glidants, which in the laboratory are usually added directly to the final blend.

  1. Blending
    1. In any blending operation, both segregation and mixing occur simultaneously are the function particle size, shape, hardness, and density, and of the dynamics of the mixing action.
    2. Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used.
    3. 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.

                     In scale up of blending, following these parameters should be considered:

  • Blender loads
  • Blender size
  • Mixing speeds
  • Bulk density of the raw materials
  • Characteristics of the material

COMPRESSION

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

During compression, the tablet press performs the following function:

  1. Filling of empty die cavity with granulation.
  2. Precompression of granulation.
  3. Compression of granules

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

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

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

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.

    1. Granulation feed rate.
    2. Delivery system should not change the particle size distribution.
    3. System should not cause segregation of coarse and fine particles, nor it should induce static charges.

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. The smaller the tablet, the more difficult it is to get a uniform fill in a high press speeds. For high-speed machines, induced die feed systems is necessary. These are available with a variety of feed paddles and with variable speed capabilities. After the die cavities are filled, the excess is removed by the feed frame to the center of the die table. Compression of the granulation usually occurs as the heads of the punches pass over the lower and under the upper pressure rollers. This cause the punches to penetrate the die to a present depth, compacting the granulation to the thickness of the gap set between the punches. The rapidity and dwell time in between this press is determined by the speed at which the press is rotating and by the size of compression rollers. The larger the compression roller, the more gradually the compression is force is applied and released. Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation. During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking. 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. 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. 

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. 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. Some tablet core materials are naturally hydrophobic, and in these cases, film coating with an aqueous system may require special formulation of the tablet core and/or the coating solution.

A film coating solution may have been found to work well with a particular tablet in small laboratory coating pan but may be totally unacceptable on a production scale.

Pilot Plant Designs for Parenterals

Injectables

  • The majority of the parenteral solutions requiring a variety of tankage, piping and ancillary equipment for liquid mixing, filtration, transfer and related activities.
  • The majority of the equipment are compose of stainless steel, tantalum or glass lined vessels employed for preparation of formulations sensitive to iron and other metal ions.
  • The vessels can be equipped with external jackets for heating and/or cooling and various types of agitators, depending upon the mixing requirements of the individual formulation.

Working area of a parenteral pilot plant

  • Incoming goods are stored in special areas for Quarantine, Released and Rejected status.
  • A cold room is available for storage of temperature-sensitive products. Entrance into the warehouse and production areas is restricted to authorized personnel.
  • Sampling and weighing of the raw materials is performed in a dedicated sampling area and a central weighing suite.
  • The route for the final products are separated from the incoming goods; storage of final products is done in designated areas in the warehouse.
  • Several clothing and cleaning procedures in the controlled transport zone and production area ensure full quality compliance.
  • A technical area is located in between the production zone and the area for formulation development.

Facility Design

This should provide control to microbial, pyrogen and particles during the production.

Warehousing

All samples should be aseptically taken, which mandates unidirectional airflow and full operator gowning.

Preparation Area:

The material utilized for the production of the sterile products will move towards the preparation area through a series of progressively cleaner environment.

 

Compounding Area:

The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled environments in which class 100 unidirectional flow hoods are utilized to provide greater environmental control during material addition.

These areas are designed to minimize the microbial, pyrogen, and particulare contamination to the formulation prior to sterilization.

Compounding Isolators

Aseptic filling rooms

The filling of the formulation is performed in a Class 100 environment.

  • Capping and Crimp sealing areas

The air supply in the capping line should be Class 100.

  • Corridors

They serve to interconnect the various rooms. Fill rooms, air locks, and gowning rooms are assessed from the corridor

  • Aseptic Storage Rooms

Laminar Flow Storage Cabinet

  • Airlocks and pass-throughs

Airlocks serve as a transistion point between one environment to another. They are fitted with the ultraviolet lights, spray systems, or other devices that may be effectively for decontamination of materials.

Biopass™ Pass Through

Formulation aspects

  • Solvent

The most widely used solvent for parenteral production is water for injection. WFI is prepared by distillation or reverse osmosis. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving.

  • Solubilizers

They are used to enhance and maintain aqueous solubility of poorly water-soluble drugs.

Solubilizing agents used in sterile products include:

  1. Co-solvents : glycerine, ethanol, sorbitol, etc.
  2. Surface active agents : polysorbate 80, polysorbate 20, lecithin.
  3. Complexing agents : cyclodextrin, etc.

They act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical, conductance capabilities of the solvent and thus, increasing the solubility.

  • Antimicrobial preservative agents
  • Buffers

They are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum/optimal solubility of the drug in the solution.

  • Antioxidants

Antioxidants function by reacting preferentially with molecular oxygen and minimizing or terminating the free radical.

Pilot Design for Liquid Orals

  • The physical form of a drug product that is pourable displays Newtonian or pseudoplastic flow behavior and conform to its container at room temperature.
  • Liquid dosage form may be dispersed systems or solutions.
  • In dispersed system there are two or more phases, where one phase is distributed in another.

Steps of Liquid Manufacturing Process

  1. Planning of material requirements
  2. Liquid preparation
  3. Filling and Packing
  4. Quality Assurance

Critical Aspects of Liquid Manufacturing

  • Physical Plant
    • Heating, Ventilation and Air Conditioning (HVAC) System


      • The effect of long processing times at sub optimal temperatures should be considered in terms of consequences on the physical or chemical stability of ingredients as well as product.
  1. Suspension

Parameters to be considered are

  1. Addition and dispersion of suspending agents ( Lab scale  - sprinkling method and production scale – vibrating feed system)
  2. Hydration/wetting of suspending agent
  3. Time and temperature required for hydration of suspending agent
  4. Mixing speeds (High speed leads to air entrapment)
  5. Selection of the equipment according to the batch size.
  6. Versator (to avoid air entrapment)
  7. Mesh size (Must be capable of removing the unwanted foreign particulates but should not filter out any of the active ingredients. Such a sieve can only be selected based on production batch size trials).
  1. Emulsion

Parameters to be considered are:

  1. Temperature
  2. Mixing equipment
  3. Homogenizing equipment
  4. In process or final product filters
  5. Screens, pumps and filling equipment
  6. Phase volumes
  7. Phase viscosities
  8. Phase densities
  1. Solution

  1. Tank size
  2. Impeller type
  3. Impeller diameter
  4. Rotational speed of the impeller
  5. Number of impellers
  6. Number of baffles
  7. Mixing capability of impeller
  8. Clearance between impeller blades and wall of the mixing  tank
  9. Height of the filled volume in the tank
  10. Filtration equipment (should not remove active or adjuvant ingredients)
  11. Transfer system
  12. Passivation of stainless steel (pre reacting the stainless steel with acetic acid or nitric acid solution to remove the surface alkalinity of the SS.)

Formulation aspects of oral liquids

Suspension

Purpose

Agent

Facilitating the connection between API and vehicle

-Wetting agents

Salt formation ingredients

Protecting the API

-Buffering systems, polymers, antioxidants

Maintaning the suspension appearance

-Colorings, suspending agent, flocculating agent

Masking the unpleasant taste/smell

-Sweeteners, flavorings

Emulsion

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

Sweeteners, flavorings

Solutions

Purpose

Agent

Protecting the API

Buffers, antioxidants, preservatives

Maintaining the appearance

Colorings, stabilizers, co-solvents, antimicrobial preservatives

Taste/smell masking

Sweeteners, flavorings

Pilot Plant Design for Semisolid Products

The following parameters are to be considered during the scale up of semisolid products:

  1. Mixing equipment (should effectively move semisolid mass from outside walls to the center and from bottom to top of the kettle).
  2. Motors (used to drive mixing system and must be sized to handle the product at its most viscous stage.)
  3. Mixing speed
  4. Component homogenization
  5. Heating and cooling process
  6. Addition of active ingredients
  7. Product transfer
  8. Working temperature range (critical to the quality of the final product)
  9. Shear during handling and transfer from manufacturing to holding tank to filling lines.
  10. Transfer pumps (must be able to move viscous material without applying excessive shear and without incorporating air)
  11. The size and the type of pump
  • Product viscosity
  • Pumping rate
  • Product compactibility with the pump surface
  • Pumping pressure required.

Pilot Plant Design for Biotechnology-Derived Products

The following parameters are to be considered for scale up of biotechnological products

Bioreactor operation

Mixing efficiency are given by the following parameters:

  1. Impeller rate
  2. Aeration rate
  3. Hydrostatic pressure
  4. Agitation rate
  5. Mixing time

         

TideCell® Bioreactor                                                   StirCradle™

Filtration Operation

Key process parameters for filtration scale up are

  1. Transmembrane pressure
  2. Volume
  3. Operating time
  4. Temperature
  5. Flux rate
  6. Protein concentration
  7. Solution viscosity
  8. Retention flow rate
  9. Permeate flux