PILOT PLANT SCALE UP TECHNIQUES - PowerPoint PPT Presentation

Loading...

PPT – PILOT PLANT SCALE UP TECHNIQUES PowerPoint presentation | free to download - id: 3cf76b-YmYwZ



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

PILOT PLANT SCALE UP TECHNIQUES

Description:

PILOT PLANT SCALE UP TECHNIQUES Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy BELGAUM-590010 ... – PowerPoint PPT presentation

Number of Views:746
Avg rating:3.0/5.0
Slides: 106
Provided by: apiNingC83
Learn more at: http://api.ning.com
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: PILOT PLANT SCALE UP TECHNIQUES


1
PILOT PLANT SCALE UP TECHNIQUES
  • Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
  • Department of Pharmaceutics
  • KLE University College of Pharmacy
  • BELGAUM-590010, Karnataka, India
  • Cell No 00919742431000
  • E-mail nanjwadebk_at_gmail.com

2
CONTENTS
  • Introduction
  • Objectives of the Pilot Plant
  • Importance of the Pilot Plant
  • Pilot plant design for tablets
  • Pilot plant scale-up techniques for capsules
  • Pilot plant scale-up techniques for Parenterals
  • References

3
Introduction
  • 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.

4
Objectives of Pilot Plant
  • Find mistakes on small scale and make profit on
    large scale.
  • To produce physically and chemically stable
    therapeutic dosage forms.
  • Review of the processing equipment.
  • Guidelines for productions and process control.
  • Evaluation and validation.
  • To identify the critical features of the process.
  • To provide master manufacturing formula.

5
Importance of Pilot Plant
  • Examination of formulae.
  • Review of range of relevant processing
    equipments.
  • The specification of the raw materials.
  • Production rates.
  • The physical space required.
  • Appropriate records and reports to support GMP.

6
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.

7
Pilot Plant design for Tablets
  • 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 to that used by production
    division- manufacture of tablets.

8
Pilot Plant design for Tablets
9
Pilot Plant design for Tablets
10
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.
  • The type of system selected also depends on the
    characteristics of the materials.
  • More sophisticated methods of handling materials
    such as vacuum loading systems, metering pumps,
    screw feed system.

11
Material handling system
Vacuum loading machine
12
Dry Blending
  • Powders to be used for encapsulation or to be
    granulated must be well blended to ensure good
    drug distribution.
  • Inadequate blending at this stage could result in
    discrete portion of the batch being either high
    or low in potency.
  • Steps should also be taken to ensure that all the
    ingredients are free of lumps and agglomerates.
  • For these reasons, screening and/or milling of
    the ingredients usually makes the process more
    reliable and reproducible.

13
Dry Blending
  • 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.

14
Dry Blending
V cone blender
Double cone blender
15
Dry Blending
Ribbon blender
16
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.

17
Granulation
Sigma blade mixer
Planetary mixer
18
Granulation
  • Wet granulation can also be prepared using tumble
    blenders equipped with high-speed chopper blades.

19
Granulation
  • More recently, 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.

20
Granulation
  • Binders
  • Used in tablet formulations to make powders more
    compressible and to produce tablets that are more
    resistant to breakage during handling.
  • In some instances 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.

21
Granulation
  • 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.
  • 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.

22
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.

23
Drying
  • 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.

24
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.

25
Reduction of Particle size
Oscillating type granulator
Hammer mill
26
Reduction of Particle size
  • 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, are usually added to the dried
    granulation during the sizing operation.
  • This is done because some of these additives,
    especially magnesium stearate, tend to
    agglomerate when added in large quantities to the
    granulation in a blender.

27
Blending
  • Type of blending equipment often differs from
    that using in laboratory.
  • In any blending operation, both segregation and
    mixing occur simultaneously are a function of
    particle size, shape, hardness, and density, and
    of the dynamics of the mixing action.
  • Particle abrasion is more likely to occur when
    high-shear mixers with spiral screws or blades
    are used.
  • 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.

28
Reduction of Particle size
  • Equipments used for mixing
  • Sigma blade mixer.
  • Planetary mixer.
  • Twin shell blender.
  • High shear mixer

29
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.

30
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.

31
Dry Compaction
32
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 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.

33
Compression
  • When evaluating the compression characteristics
    of a particular formulation, prolonged trial runs
    at press speeds equal to that to be used in
    normal production should be tried.
  • 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.
  • 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.

34
Compression
  • 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 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.
  • So that optimum feed for every granulation can
    be obtained.

35
Compression
  • 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
    a single event as the heads of the punches pass
    over the lower and under the upper pressure
    rollers.
  • This cause the punches to the penetrate the die
    to a preset depth, compacting the granulation to
    the thickness of the gap set between the punches.
  • The rapidity and die wall time in between this
    press event occurs is determined by the speed at
    which the press is rotating and by the size of
    compression rollers.
  • Larger the compressions roller, the more
    gradually compression force is applied and
    released.
  • Slowing down the press speed or using larger
    compression rollers can often reduce capping in a
    formulation.

36
Compression
  • The final event is ejection of compressed tablets
    from die cavity.
  • 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.

37
Compression
DIFFERENT PUNCHES DIES
38
Compression
MULTI ROTARY MACHINE
HIGH SPEED ROTARY MACHINE
39
Compression
DOUBLE ROTARY MACHINE
UPPER PUNCH AND LOWER PUNCH
40
Compression
SINGLE ROTARY MACHINE
41
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.

42
Compression
  • 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 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.

43
(No Transcript)
44
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

45
Pilot Plant scale-up techniques for Capsule
  • The manufacturing process for capsulated products
    often same to that tablets.
  • 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.

46
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.

47
Manufacture of Hard Gelatin Capsules
  • 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.

48
Manufacture of Hard Gelatin Capsules
  • 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.

49
Manufacture of Hard Gelatin Capsules
  • Shell manufacture

50
Manufacture of Hard Gelatin Capsules
  • 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 500C 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.

51
Manufacture of Hard Gelatin Capsules
  • 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.

52
Manufacture of Hard Gelatin Capsules
  • 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.

53
Manufacture of Hard Gelatin Capsules
  • 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.

54
Manufacture of Hard Gelatin Capsules
  • Sizes and shapes
  • For human use, empty gelatin capsules are
    manufactured in eight sizes, ranging from 000 to
    5.
  • Capsule capacities in table

55
Manufacture of Hard Gelatin Capsules
  • 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. Lillys pulvule tapers to a
    bluntly pointed end.
  • Smith Kline Beachams spansule capsules
    taper at
  • both the cap and body ends.

56
Manufacture of Hard Gelatin Capsules
  • 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.

57
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.

58
ZANASI AUTOMATIC CAPSULE FILLING MACHINE
HOFLIGER KARG AUTOMATIC CAPSULE FILLING MACHINE
59
Filling of hard gelatin capsules
  • 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.

60
OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE
FILLING MACHINE
61
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.

62
Manufacture of Soft Gelatin Capsules
  • 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 liquid can be between 2.5 and 7.5.
  • Emulsion can not be filled because water will be
    released that will affect the shell.

63
Manufacture of Soft Gelatin Capsules
  • 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 350c or less.
  • The sealing temperature of gelatin films is
    37-400C.

64
Manufacture of Soft Gelatin Capsules
  • 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.

65
Manufacture of Soft Gelatin Capsules
  • 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.

66
Manufacture of Soft Gelatin Capsules
67
Manufacture of Soft Gelatin Capsules
  • 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.

68
Manufacture of Soft Gelatin Capsules
  • Bubble method
  • The Globex Mark II capsulator produces truly
    seamless, one-piece soft gelatin capsules by a
    bubble method.

69
Manufacture of Soft Gelatin Capsules
  • 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.

70
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.

71
Soft/Liquid-filled hard gelatin capsules
  • 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.

72
AUTO MATIC CAPSULE ARRANGEMNT
CAPSULE POLISHING MACHINE
73
Scale-up for Parenterals
74
Injectables
  • The majority of the parenteral solutions are
    solutions requiring a variety of tankage, piping
    and ancillary euipment for liquid mixing,
    filteration, transfer and related activities.
  • The majority of the equipments are composed of
    300 series austenitic stainless steel, with
    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.

75
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 material is
    performed in a dedicated sampling area and a
    central weighing suite, respectively.
  • The route for final products is separated from
    the incoming goods storage of final products is
    done in designated areas in the warehouse while
    they are awaiting shipment.
  • Several clothing and cleaning procedures in the
    controlled transport zone and production area
    ensure full quality compliance.
  • In addition, a technical area is located in
    between the production zone and the area for
    formulation development.
  • Here, the water for injection equipment is
    located, as well as the technical installation of
    the lyophilizer.

76
Lay-out of the pilot-plant
77
Facility Design
  • To provide the control of microbial, pyrogen
    and particles controls over the production
    environment are essential.
  • Warehousing
  • All samples should be aseptically taken,
    which mandates unidirectional airflow and full
    operator gowning.
  • These measures reduce the potential for
    contamination ingress into materials that are yet
    to receive any processing at any site.

78
Facility Design
  • Preparation Area
  • The materials utilized for the production of
    the sterile products move toward the preparation
    area through a series of progressively cleaner
    environments.

79
Preparation Area
First the materials are passed through class
100,000 i.e. grade D environment for
presterilization.
Transfer of materials are carried out in
air-locks to avoid cross contamination
The preparation areas are supplied with HEPA
filters. There should be more than 20 air
changes per hour
The preparation place is Class 100 area.
80
Production area
81
Production area
  • 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 particulate contamination
    to the formulation prior to sterilization.

82
Production area
  • Aseptic filling rooms
  • The filling of the formulations is performed
    in an Class 100 environment.
  • Capping and Crimp sealing areas
  • The air supply in the capping line should be
    of 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.
  • Air-locks and pass-throughs
  • Air locks serve as a transition points between
    one environment and another.
  • They are fitted with the UltraViolet lights,
    spray systems, or other devices that may be
    effectively utilized for decontamination of
    materials.

83
Formulation aspects
  • Solvent
  • The most widely used solvent used for
    parenteral production is water for injection.
  • WFI is prepared by 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 the
    aqueous solubility of poorly water-soluble drugs.

84
Formulation aspects
  • 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 cyclodextrins etc
  • They act by reducing the dielectric constant
    properties of the solvent system, thereby
    reducing the electrical, conductance capabilities
    of the solvent and thus increase the solubility.
  • Antimicrobial preservative agents

85
Formulation aspects
  • 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 or optimal solubility of
    the drug in solution.
  • Antioxidants
  • Antioxidants function by reacting prefentially
    with molecular oxygen and minimizing or
    terminating the free the free radical
    auto-oxidation reaction. Examples phenol
    (0.065-0.5), m-cresol (0.16-0.3) etc.

86
Instrumentation
  • Mixer
  • Homogenizer
  • Filteration assembly
  • Filling machinery

87
Mixer/Homogenizer
88
Filtration assembly
89
Bottling/Filling machinery
90
Sterilization and Depyrogenation
  • Steam sterilization
  • Dry-heat sterilization and depyrogenation
  • Gas and vapour sterilization
  • Radiation sterilization
  • Sterilization by filteration

91
Aseptic processing control and evaluation
  • In-process Testing
  • End-product Testing
  • Process simulations
  • Quality Assurance
  • Particulate matter
  • Pyrogen test
  • Stability test

92
Particulate matter detector
93
Liquid orals
  • The physical form of a drug product that is
    pourable displays Newtonian or pseudoplastic flow
    behaviour and conforms to its container at room
    temperature.
  • 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.

94
Steps of liquid manufacturing process
  • Planning of material requirements
  • Liquid preparation
  • Filling and Packing
  • Quality assurance

95
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.

96
Formulation aspects of oral liquids
  • Suspensions

97
Formulation aspects of oral liquids
  • Emulsions

98
Formulation aspects of oral liquids
  • Solutions

99
Layout of the pilot plant
100
Equipments
  • Mixer
  • Homogenizer
  • Filteration assembly
  • Bottling assembly

101
Filtration assembly
102
General flow chart
Raw Materials
Measured and weighed
Mixing
Distilled water
Filling
Packing
Finished products storage
Quality Assurance
103
Quality assurance
  • Dissolution of drugs in solution
  • Potency of drugs in suspension
  • Temperature uniformity in emulsions
  • Microbiological control
  • Product uniformity
  • Final volume
  • Stability

104
References
  • Lachman L. The Theory and practice of industrial
    pharmacy. 3rd Edition. Varghese publication
    house.
  • www.google.com

105
  • Thank You

Cell No 00919742431000 E-mail
nanjwadebk_at_gmail.com
About PowerShow.com