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Revision Flashcards

1
Q

Why is powder/particles used?

A

Due to the greater surface area as smaller particles have larger surface area

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2
Q

WHat are the concerns around using powder?

A

Powders can stick which reduces the surface area so we granulate and keep a passage of air to increase interaction between liquid and solid

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3
Q

What is a crystalline structure?

A

Where atoms are well distributed periodically e.g. salt, sugar,lactose

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4
Q

What is a amorphous structure?

A

Atoms are randomly distributed and liquid can penetrate easily e.g. maltodexterine

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5
Q

What is a solid bridge and how is it formed?

A

A liquid binder at high temperature is added to material which will become solid after room temp creating a solid bridge

Adding liquid to crystalline or amphorus it will dissolve part of the material and when concentration is high then it will solidfy with time to produce a solid bridge

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6
Q

What is viscocity and what does it represent?

A

It is the internal resistance to flow

Represents the bonding between molecules in liquid when bonding is strong viscocity is strong but flowability is limited e.g. honey

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7
Q

WHat molecule has the second highest surface tension?

A

Water

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8
Q

When does surface tension occur?

A

When cohesion between molecules of liquid is strong but between liquid and air is weak

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9
Q

When do electrostatic forces occur?

A

Through friction caused by particle collisions and rubbing against equipment surfaces

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10
Q

What units consist in Primary Manufacturing?

A

Reactor, centrifuge, crystalliser and dryer

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11
Q

What units consist in secondary manufacturing?

A

Blending, granulation, drying and tabletting

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12
Q

Types of lactose?

A

Crystal, amorphous, aggregate

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13
Q

WHat does milling produce?

A

Particles of less purity due to stress acting on particle

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14
Q

What type of lactose does spray drying produce?

A

Amorphous

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15
Q

What type of lactose does a rotating drum produce?

A

Aggregate

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16
Q

Wet Granulation process?

A

Powder+liquid -> Wtting(liquid bridge) -> agglomeration(solid bridge)

Particles interlock to push liquid to the surface and allow particles to stick

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17
Q

Dry Granulation process?

A

under high pressure particles come close together to make them stick

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18
Q

What is porosity?

A

ratio of volume occupied by air divided by total volume of granules

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19
Q

What is segregation?

A

Where all tablets have different amounts of API

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20
Q

describe the interaction between hydrophobic powder and water and how to overcome issues?

A

Difficult interaction as droplet wont penetrate and bounce.

Use spray drying to overcome this and produce a amorphous which is easy to penetrate

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21
Q

What is plastic deformation?

A

Changes to shape when stress is applied bringing particles close increasing contact area and adhesion forces

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22
Q

WHat is a brittle fracture?

A

High adhesion forces, when force is applied to break structure

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23
Q

What is the NIR range?

A

780-2500mm

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24
Q

What is the optical range?

A

380-780mm

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25
Q

Direct tabletting Process

A

Dosing -> Blending -> Tabletting

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26
Q

Continuous via dry granulation process?

A

Dosing -> belnding -> granulation -> milling -> blending -> tabletting

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27
Q

Continuous via wet granulation process?

A

Dosing -> blending -> Wet granulation -> drying -> milling -> blending -> tabletting

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28
Q

Future end to end process?

A

Synthesis -> crystallisation -> purification -> blending -> wet/dry granulation -> drying -> milling -> blending -> tabletting

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29
Q

What are the benefits of continuous manufacturing?

A
  • Speed up introduction of new drugs
  • smaller production facilities
  • fewer people needed during operation
  • reduction in energy consumption and waste
  • monitoring drug quality
  • easy scale up
  • high efficiency
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30
Q

When is it diffucult to do dry granulation?

A

When powder is cohesive dry granulation is diffcult and if material is brittle

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31
Q

What is unbound moisture?

A

Surface moisture

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32
Q

What is bound moisture?

A

Liquid may become bound in solids by retention in small capillaries, by solution in cells or by chemical absorption

hot air heats granules(heat transfer) and liquid is passed to air (mass transfer)

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33
Q

what is a mill?

A

A rotating arm to hit granules and break them and reduce granule size

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34
Q

Why does segregation occur?

A

Due to:
- size distribution
- shape
- density

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35
Q

What is convective mixing

A

macromovement

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36
Q

What is diffusive mixing

A

Micromixing

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37
Q

how are granules tabletted?

A

placed in a die and are compressed

particles plastically deform to be in contact easier
fragmentation makes them mechanically interlock

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38
Q

High Shear mixer?

A

A bed of powder where binder iis added and agitated using impellers

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39
Q

Fluidized bed?

A

hot air enters from bottom

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40
Q

twin screw granulation?

A

two screws rotating to mix powder and binder, quick process

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41
Q

roller compactor?

A

two rollers to push stress on material and compact powder to produce a ribbon

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42
Q

WHat are the granulation research goals?

A
  • Better system control
  • Better product quality
  • Better process understanding
  • understand microscopic interactions
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43
Q

What type of NIR do high shear mixer, twin screw and roller compactor use?

A

Mixer -> optical, monitors change in size with time
Twin screw-> optical, measures velocity and size
Roller compactor -> thermal camera

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44
Q

Industrial needs of drug development?

A

Flowability, density, compressability, productivity

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45
Q

Clinical needs of drug development?

A

Dosage and efficiency

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46
Q

Paitent needs of drug development?

A

taste colour, compliance feeling

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47
Q

Challenges of drug development?

A
  • Poor compactability (alter excipent amount or moisture content)
  • Poor flowability (Solve via granulation)
  • Non Uniform (due to segregation caused by particle size)
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48
Q

Advantages of roller compaction?

A
  • No liquid binder so suitable for heat sensitive materials
  • Economical
  • No drying so environmentally friendly
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49
Q

Disadvantages of roller compactor?

A
  • low strength
  • Must be compressible
  • Produces fines
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50
Q

What is a critical quality attribute?

A

Physical, chemical, biological or microbiological property e.g. particle size distribution or moisture content

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51
Q

What is a critical process parameter?

A

Process parameter whose variability impacts CQA and should be monitored

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52
Q

What is a critical material attribute

A

characterstic of input material to ensure quality

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53
Q

How does a feed system work?

A

powder is red into roller compactor and there is an agitator and multiple screws

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54
Q

what is a screw feeder?

A

powder is forced between rollers so good for materials with poor flowability

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55
Q

What is a gravity feeder?

A

depends on flowability if cohesive then amount of powder entering will be inconsistent affecting quality

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56
Q

what is a deaeration system?

A

Consists of sintered metal filter or mesh screen and removes air from powder bed as air will resist compaction and prevent particles getting close to each other

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57
Q

how do rollers work?

A

Powder is sealed on sides of rolls by cheek plates on either size and rolls apply compressive force to the powder compressing the material to form densified compact (ribbon)

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58
Q

Describe the three roller orientations?

A

Horizontal -> High material loss in nip region, incorporation of side sealing system reduces material by pass

Vertical -> direct bypass is minimised because material is not governed by gravity

Incline -> reduces material bypass by 15%

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59
Q

Desribe different roll designs?

A

Smooth, corrugated are commonly used surfaces. Smooth minimises sticking
Fluted and corrugated are suitable for increasing density of light materials

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60
Q

Main phases of powder densification?

A

Particle rearrangement, deformation, particle bonding, elastic recovery after pressure release

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61
Q

Describe the slip region?

A

slipping of particles, roll surface moves faster than powder.
Weak compaction forces
particle rearrangement is prevalent and deaeration should occur

the entry to the slip region is governed by friction between wall and particle which drives particles to NIP

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62
Q

Describe NIP region?

A

MAx stress formation of the ribbon
particles move at the same speed as roller
particle deformation os prevelant

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63
Q

Describe the Release region?

A

decrease in roll pressure as roll gap increases
ribbon cracks at high eleasticty

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64
Q

Ribbon tensile strength

A

min tensile strength required for fracture initation within a ribbon

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65
Q

describe relationship between solid fraction and tensile strength?

A

positive correlation
ribbons of adequate solid fraction produce better flowing granules

low fraction: high fines, poor flow and good compactability

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66
Q

what is the most crucial quantatity in roller compaction?

A

Nip angle or pressure graident at slip and nip region

Nip angle can be determined from where the slip and nip pressure gradients cross

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67
Q

What happens when you increase roll pressure?

A

increases ribbon density, granule mean particle size and granule flowability

Increasing pressure increases ribbon strength
increasing pressure decreases porosity
fines decrease with pressure

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68
Q

Roll gap is the point where…?

A

max compaction occurs which dictates ribbon thickness

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69
Q

roll speed characterstics?

A
  • inversely related to residence time for particle compaction which affects ribbon density
  • roll speed needs to be adjusted to screw speed and flow of powder
    if speed is too high segregation can occur
  • roll speed is material dependent
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70
Q

Formulation challenges using roller compactor?

A
  • Compactability of primary particles
  • uniformity
  • plastic deformation
  • fractures
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71
Q

relationship between hardness and other CQAs roller compaction?

A

lower hardness, higher ribbon strength and more fines

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72
Q

when does drying occur?

A

When the vapour pressure of the solvent at the surface is greater than the vapour pressure of the solvent in the gas surronding the solid

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73
Q

4 types of drying equipment?

A
  • Vaccum
  • conical
  • double cone
  • agitated filter
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74
Q

Describe two types of liquid feed drying?

A

Drum drying - A thin film of liquid is spread over the surface of the drum and heat transfer via conduction is present and dried material is scraped off. However there is limited opportunity for heat transfer

Spray Drying - Liquid feed is atomised into small droplets by spraying into a tower. Hot air dries the droplets and rapid drying is used for heat sensitive materials

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75
Q

Describe two types of particultate feed drying?

A

Rotatory tray - Liquid added at the top onto rotating stack of trays and is used with heat sensitive material but takes a long time

Flash Drying - Wet particles are dispersed into a hot air stream with high agitation. Rapid drying occurs due to high air temperatures and fine particles are carried out by air flow but only removes surface moisture

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76
Q

Describe Fluid Bed Drying?

A

Fluidisation of feed materials. There is a rapid upward flow if air through the bed of moist particles which lifts the wet solids and suspends them(fluidised state). The vapourised liquid is carried away by drying gas. there is excellent heat and mass transfer

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77
Q

What is fluidisation?

A

when a fluid is passed through a bed of particles a point is reached when the upward drag force is equal to the weight

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78
Q

What is voidage?

A

Amount of air space compared to particle space

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79
Q

What are the drawbacks of using fluidisation correlations?

A
  • Scatter in results
  • Error is greater for non spherical particles
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80
Q

What is the typical value of min fluidisation velocity and what does it increase with?

A

0.5-1 m/s
increases with granule size and density

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81
Q

what is particle densisty

A

real granule density

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82
Q

what is absolute true density?

A

literature value

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83
Q

when do bubbles appear?

A

Beyond fluidisation velocity

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84
Q

desribe condiur and gill plates?

A

create swirling air flows which stops particles from settling, increases pressure drop and inhibits local defluidisation.

They are more effective than plain mesh

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85
Q

Geldarts classification of powders?

A

Group A: smooth, when fluidised have a region of non bubbling followed by bubbling as Umf increases

Group B: Bubbling from start, sand like

Group C: Fine, cohesive powders, incapable of fluidisation, clump due to size

Group D: Large Particles

Particles size and density have the main effect

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86
Q

When does slugging occur?

A

When bubbles are greater than 1/3 of diameter. Slugging causes large pressure fluctuations

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87
Q

WHat happens when velocities are too low in drying?

A

Bed can defluidise and revert back to packed bed, reduction in heat transfer and uniform mixing is lost

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88
Q

WHat happens when velocity is too high in drying?

A

Reaches terminal velocity and particles are blown out

Smaller particles have lower fluidisation elutration velocity

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89
Q

What design measures can be implemented to reduce elutration and entrainment?

A
  • Increase dryer diameter to reduce air velocity
  • freeboard above bed to allow disentraintment
  • bag filter to collect fines
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90
Q

what is equilbrium moisture content?
what does it depend on and typical value?

A

Point where drying stops and depends on RH and temp with a typical value of 1-2%

Solids can regain moisture as T falls and RH increases

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91
Q

Describe the 3 drying stages?

A

Induction period: Where the solids are preheated and vapour transport is limiting

Constant rate period: All heat input is used for evaporation and unbound moisture is removed

Falling rate: Bound moisture is removed and moisture transport from interior becomes limiting

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92
Q

desribe 3 heat transfer mechanisms?

A

Conduction: Heat transfer across stationary medium in which there is a temperature gradient

Convection: Heat transfer occuring between surface and moving fluid

Radiation: Surfaces emit energy

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93
Q

What type of heat transfer is dominant in fluid bed drying?

A

convection

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94
Q

Why do multiple drying periods occur?

A
  • Moisture transport: Multiple mechamisms
    heat transfer to evaporate moisture: driving force is gas to solid
  • vapour transport in gas
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95
Q

What is the effect of rapid heat and mass transfer in drying?

A
  • small HTU
  • Large NTU
    exhaust air saturated
    high energy efficiency
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96
Q

how to scale up fluid bed dryer what needs to be considered?

A

scale up by keeping air velocity constant to maintain fluidiation.

evaporation rate and throughput increase with air flow and area but not with bed depth and drying time is proportional to bed depth

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97
Q

describe 3 macro- scale modelling techniques?

A
  1. Heat and mass balance - gives overall perfomance
  2. scoping design (charts)- used for constant drying rate with exhaust at adibatic saturation
  3. Scaling(integral method) - gives basic falling rate affects
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98
Q

Desrcribe micro scale modeeling?

A

particle tracking , which is rearely needed

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99
Q

What are the limitations of modelling in drying?

A

A theoretical model is a representation of real phenomena and model may be mechanistic or data driven

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100
Q

what velocity favours shorter drying time e.g. high/low?

A

high velocity shorter drying time and good fluidisation

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101
Q

what temperature favours shorter drying time e.g. high/low?

A

high temperatures, which also leads to greater energy input, lower RH

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102
Q

Describe fluid bed granulation?

A

granulation and agglomeration or layering
spray rate needs to balance evaporation rate
if too dry particles wont adhere and of too wet tan bed defluidises

air flowrate must keep particles fludised

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103
Q

What is a hard capsule shell made from?

A

Gelatin
Hydroxy propyl methyl cellulose (HPMC)
Starch

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104
Q

Soft shell is made from?

A

oily liquid fill

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105
Q

What is the process to produce capsules?

A

compress powder into a plug and eject.

sift and blend each ingreident one at a time

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106
Q

Differences between tablets and hard capsules?

A

Capsules can hold pellets and minitablets
there is quick development of capsules and reduced usage
capsules are not amendable to PAR
Capsules are not directly weighed and have issues with moisture uptake

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107
Q

Advantages and disadvantages of gelatin capsules?

A
  • Cheap and readily available
  • contains 12-16% moisture so not good for moisture sensitive materials
  • hydrpscopic so will crack at low humidity
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108
Q

Advantages and disadvantages of HPMC capsules?

A
  • More expensive
  • More brittle -> can split easily
  • low moisutre 6-7%
  • free from animal concerns
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109
Q

CQA standards for capsules?

A

Assay - 90-110 USP
Content uniformity - RSD 6-7%
Dissolution: Q=85% at 30mins
Disintegration: <15mins in 37 degrees of water

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110
Q

rank tablets, plugs, ribbons, powders and capsules in terms of highest solid fraction

A

tablets -> ribbons -> capsules -> plugs -> powders

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111
Q

Describe the texture analyser experiment

A

Plugs formed at different densities via force control and are inserted into capsules
dissolution testing is carried out to examine effects of the force

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112
Q

How is solid fraction calculated?

A

solid fraction = enevelope denisty/ true density

true density -> known density
envelope density -> density of material after compression

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113
Q

what are formulation challenges in capsule production?

A
  • ingriendent compatability and stability
  • powder blending and homgenity
  • powder flow and lubrication
  • powder compressability and plug formation
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114
Q

What formualtion considerations need to be considered in capsule production?

A
  • API:Particle size
  • Filler: material properties
  • Disintegrant: Reduces dissolution variability and range
  • Glidant: improves flow and weight variation
    Lubricant: Impacts dissolution and plug strength
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115
Q

Process differences between plugs and tablets?

A
  • compression forces generally under 200N and tablets up to 50kn
  • high height to diameter ratios but tablets <1
  • Breaking strength =1N tablets>100N
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116
Q

Capsule process challenges

A
  • ability to measure out accurate precise volumes of powder
  • ability to quantively transfer such dry solids to solid capsule shells is a dertmining factor in weight variation and uniformity
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117
Q

Capsule process challenges

A
  • ability to measure out accurate precise volumes of powder
  • ability to quantively transfer such dry solids to solid capsule shells is a dertmining factor in weight variation and uniformity
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118
Q

Describe a dosator and examples?

A

pin goes down, sleeve moves in to bed to collect powder and pin tamps it to produce plug and lifts out and drops into shell.
piston height and powder bed height impact the weight

compression distance and force impact density hence dissolution

e.g. IMA north american, MG american, Romaco

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119
Q

Describe dosing discs?

A

Disc rotates and powder gets pushed into each hole at the 6th holr it gets pushed into a capsule

disc thickness and powder bed height impact weight

e.g. Bosch, Index, Bohanan

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120
Q

What is design space?

A

tells you where it is most suitable to operate

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121
Q

formulation requirements for dosator and dosic dics?

A
  • flowability
  • lubricity
  • compactability
  • piston heighr
  • powder bed height
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122
Q

How is flow measured for powder properties in capsules?

A

carr index
higher carr index then better the flow
typically 15-25%

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123
Q

describe two blenders used in mixing and which is better?

A

drum and ribbon blender.

in ribbon blender powder gets stuck to corners which is not desired

124
Q

What is dissolution a function of in capsules ?

A
  • dissolution rate of shell
  • rate of penetration of disso medium
  • rate of de aggregation of powder mass
  • Nature of drug particles
125
Q

How long does it take for shell to dissolve

A

4 mins
cross linking can reduce gelatin shell solubuility in water

126
Q

Why is micronisation used?

A

to improve dissolution of porrly soluble drugs but has adverse affects on flow and mixing

poorly soluble drugs we increase size to increase surface area to increase dissolution

127
Q

Common fillers?

A

lactose monohydrate, spray dried lactose, anhydrous lactose, starch, partially pregelatinsed starch, dicalcium phosphate and MCC

128
Q

Glidants?

A

conc<1%
typically 0.25-0.35%
used to make powders flow

129
Q

Lubricants?

A

0.5-1%
hydrophobic so avoid over lubrication since dissolution can be affected and plugs can soften
avoid overmixing
more lubricant dissolution is worse

130
Q

disintegrants?

A

promote dissolution by enhancing liquid penetration and dispersion
4-8%
effectiveness may improve with increasing compression force

131
Q

surfactants?

A

can enhance dissolution rate by increasing wetability of powder mass

132
Q

what do tablets disintegrate into?

A

agglomerates and disperse into primary particles

133
Q

what is dispersion?

A

process of breaking down an agglomerate.

Mechanical stress can be applied through collisions and exposure to shear, agglomerates break down into primary particles when applied stress exceeds a fracture strength that scales the interparticle forces and hold the particle together

134
Q

What is tensile strength

A

when particles collide with each other or a boundary

135
Q

what does agglomerate strength depend on

A

structure and strength of primary particle bonds

136
Q

dispersion of an agglomerate in a liquid involves which processes?

A

wetting, inhibition of fluid and dispersion of aggglomerate

137
Q

what do kinetics of dispersion depend on

A

stresses applied to agglomerate by flow field

high viscosity -> increased drag on particles -> lower reynolds -> less particle collision -> poor dispersion

138
Q

fragmentation induced by shear is more important in?

A

liquid phase dispersion acheived by shear

139
Q

Dissolution of solid bridges or primary particles lead too..

A

reduction in contact area between particles leading to reduction in adhesion forces

140
Q

generation of internal mechanical stress

A

if agglomerate particles absorb fluid they expand

if it is rigid it can generate an internal mechanical stress that can faciltate fracture of agglomerate

141
Q

modification of van der waals

A

immersing particles in a liquid reduces van der waals relative to its value in a gas

dispersant can aid the creation of a net replulsive electrostatic force between particles which faciltates and maintains dispersion

142
Q

modification of van der waals

A

immersing particles in a liquid reduces van der waals relative to its value in a gas

dispersant can aid the creation of a net replulsive electrostatic force between particles which faciltates and maintains dispersion

143
Q

creation and modification of cappilary forces

A

as liquid penetrates and displaces the gas it forms a cappilary bridge around the particle contacts which adds strength.

Liquid saturation increases so number of cappilary bonds increase and yield strength increases however reduction in tensile strength as strength of bonds will also decrease

144
Q

wetting

A

dry particles must be able to imbide the fluid
wetting solid surfaces can be assessed using contact angle, which is where vapour liquid interface meets surface

poor wetted solids have a high contact angle, dispersion kinetics and are controlled by the rate of enfulgment into the fluid.

145
Q

spherical agglomerates can be spontaneously engulfed at what interface?

A

air fluid interface when the constact angle is less than max

146
Q

what is the contact angle equal to in neutrally buoyant agglomerates?

A

it is zero

147
Q

what is dependent on thetha max?

A

spontaneous liquid inhibition into pores of agglomerates

148
Q

how can the rate of agglomerate enflugment and liquid inhibition through pores be altered?

A

by the use of dispersant

149
Q

what are the two modes of agglomerate breakage and describe them?

A

cohesive failure
- occurs in agglomerates in which fluid infiltration does not change packing structure of agglomerate and tensile strength applied by shear field is transmitted to both regions
Adhesive failure
- occurs in agglomerates in which fluid infiltration changes packing structure
- if primary particle packing is changes the interparticle forces at the boundary are dusmissed
- tensile strength is transmitted only in filtrated region and agglomerate can break due to weak wet region

150
Q

what is single particle dissolution

A

rate at which powder dissolves is sum of rates at which each particle dissolves and can be calculated for stagnant and non zero velocity conditions

assumptions
- spherical particles
- dissolution is mass transfer controlled

151
Q

factors affecting dissolution

A
  • Properties of API: solubility, wettability, particle size, surface area
    formulation characterstics: excipents, hardness, manufacturing process
    dissolution method: appratus, medium and sampling
152
Q

what are the 4 types of dissoluttion appratus

A
  • rotating basket
  • padd;e
  • reciprocating cylinder
  • flow through cell
153
Q

how does a rotating basket work describe its characterstics?

advantages and disadvantages?

A

made of glass with a semi hemispherical bottom and a cylindrical basket attatched at low part of the stirrer.
used for capsules and tablets

full ph change
easily automated
basket can get clogged
hydrodynamic deadzone under the basket
degasifcation of medium
mesh can get corroded

154
Q

what is a paddle basket and the advantages and disadvantages?

A

same as basket
paddle is formed from blade and a shaflt is used for stirring, sinkers may be used for dosage forms

easy to use
ph change is possible
easily automated
sinkers are needed
hydrodynamics are complex

155
Q

what is a recipracting cylinder and the advantages and disadvantages?

A

set of cylindrical flat bottom glass and insert fittingd snd screens at top and bottom, Motor and drive assemmbly used to reciprocated the cylinders vertically and is used for tablets and beads

easy to change Ph
hydrodynamics can be directly influenced by dip rate
different ph profiles can be developed
small volume
limited experience

156
Q

what is a recipracting cylinder and the advantages and disadvantages?

A

set of cylindrical flat bottom glass and insert fittingd snd screens at top and bottom, Motor and drive assemmbly used to reciprocated the cylinders vertically and is used for tablets and beads

easy to change Ph
hydrodynamics can be directly influenced by dip rate
different ph profiles can be developed
small volume
limited experience

157
Q

what is a flow through cell and the advantages and disadvantages?

A

for dissolution medium
forces medium through cell
laminar flow
used for low solubility drugs

sink condtions are maintained
can operate in closed and open systems
can develop different ph profiles
deaeration neccassary

158
Q

what is a flow through cell and the advantages and disadvantages?

A

for dissolution medium
forces medium through cell
laminar flow
used for low solubility drugs

sink condtions are maintained
can operate in closed and open systems
can develop different ph profiles
deaeration neccassary

159
Q

immediate relase?

A

release drug immediately or as quick as possible after administration

160
Q

modified release?

A

deliver drug with a delay after adminstration

161
Q

delayed release?

A

systems which are formulated to release the active at a time other than immedatly after

162
Q

extended release

A

allows for drug to be released over a prolonged period can be acheived using sustained or controlled dosage forms

163
Q

sustained release

A

drug release over a sustained period

164
Q

controlled release

A

to lead to predictability constant drug concentrations

165
Q

what should the dissolution media meet?

A

should meet sink conditions and be biologically relevant for the site dissolution in vivo

sink conditions ensure the ammount of drug dissolved in the mdeia does not open affect dissolutionn

166
Q

describe offline analystics in dissolution?

A

sample aquilots are withdrawn from dissolution vessel and filtered conc of API is measured

common techniques
- UV spectroscopy
- HPLC

167
Q

describe rela time analytics for dissolution?

A

more frequent data points and gives more accurate dissolution profile.

common techniques
- UV fibre optic dip probes
- imaging: NMR, raman
- particle size analysis
- turbidity probes
- conductivity probes
- refractometry

168
Q

choice of appratus

A

conformanace to dimensions and tolerance of dissolution appratus

crtical parameters
rotating basket and paddle: volume and temp of dissolution media and rotation speed
recipracoating cylinder: Dip rate
Flow through cell: flow rate of media

169
Q

immediate release testing (performance verification test)

A

Q is the amount of dissolved active expressed as % of labelled content of dosage unit

S1 -> 6 units -> <Q+5%
S2 -> 6 units -> (S1+S2) for 12 units >Q and not unit less that Q-15%

170
Q

extended release performance verication test

A

L corresponds to amount dissolved at each dosing interval

6 units -> no value lies outside range
L2 -> 6 units -> average 12 (l1+l2) lies within range

look at notes

171
Q

delayed release performance verifcation test

A

stage 1
A1 -> 6 units -> no individual value exceeds 10% dissolved
A2-> 6 units -> 12 units (A1+A2) no more than 10% dissolved
no individual unit >25%

stage 2
B1 unit not less than Q+5%
B2 - (B1+B2)>Q
no unit less than 15%

172
Q

What is crystalisation?

A

refers to the phase transformation of a compound from a fluid or an amphorus solid to a crystalline solid state

173
Q

What is crystaliisation employed as?

A

A separation and purification technique in order to obtain pure crystals of a substance from an impure mixture or from solvent.

can also be used fir concentration, particulate product formation and analysis

174
Q

what industries is crystallisation used and %?

A
  • 80% of pharmaceuticals
  • 60% of fine chemicals
  • 30% food products
175
Q

Examples of crystallisation application?

A
  • Absorbic acid (Vitamin C)
  • Caprolactam (used in polymer industry)
  • Sucrose (from sugar cane or beet)
176
Q

examples of food in crystalline form?

A

Salts, vitamins, organic acids, polyols and lipids

177
Q

examples of food in amorphous soilds?

A

polysacharides, proteins, fibres and cocoa

178
Q

examples of food in crystal and amorphous form?

A

refined sugars and thermoplastics

179
Q

what is semi crystalline and example?

A

region where some crystal and some amorphous, complex structures like starch

180
Q

What is a crystal?

A

A solid in which its building units are packed in regularly ordered, repeated patterns extending 3D. Crystalline solids can exist in several subphases such as polymorphs, solvates, hydrates and cocrystals

181
Q

how can the molecular organisation of amorphous and crystalline materials be assessed?

A

Using polarised light, no brighrtness it is amorphous and if it appears bright it is crystal

182
Q

Alternative approach to assess the molecular organisation of crystalline materials

A

X ray diffraction

183
Q

What is a phase diagram?

A

Displays all the possible thermodynamic states of a system the proportion and the composition of each coexisting phase

184
Q

WHat are thermodynamic states described by?

A

A set of independently fixed variables such as pressure, temperature and mass fraction of components

185
Q

WHat is the eutectic point in a phase diagram?

A

two pure crystalline components and a solution of eutectic composition Xb are all in equilbrium

186
Q

What is the liquidus line?

A

gives all possible compositions of liquids in equilbrium with a solid (above line system is liquid)

187
Q

WHat is solidus line

A

below line solid phases are present at all compositions in equilbrium

188
Q

what are the 5 types of binary phase diagrams?

A
  • Eutectic systems: where only solid phases are pure components
  • Mixed solid phase:
  • solid azeotrope
  • eutectic and solid solution behaviour
  • Miscible systems without melting temperature minimum
189
Q

Examples of phase diagrams for fat binary mixtures?

A

Miscible - everything mixed
Eutectic - random mixed
molecular compound forming - creating a new compound

190
Q

WHat is the liquidus line equal to when looking at melting or solution for components A and B

A

Melting: SOlubility curve of A in B
SOlution: Solubility curve of A in the solvent

191
Q

How can solubility curves be established?

A

Through microscopy
starting with a saturated solution and increasing temperature as you cross solubility line image disappears

192
Q

Phase diagram (lever rule) -> what can it calculate?

A

it is used to calculate yield of crystalisation
fraction of saturated solid below liquidus line
fraction of crystalline material

193
Q

What is glass transition temperature?

A

exist in crystal and amorphous corresponds to transition from rubbery state to glassy

Phase diagrams become state diagrams when glass transition temperature is incldued

194
Q

describe different crystallisation pathers through state diagrams?

  • From solution
  • From Amorphous
A

From solution
1. Spontaneous below crystalisation line
2. grow from seeds between solubility line and crrystaline line
- increase T abd decrease C

From Amorphous solids
- spontaneous above glass transition line
- decrease conc and increase T

look at slide 30

195
Q

desrcibe crystallisation from amorphous solids?

A

A rubbery to solid transition that may occur spontaneously upon hesting above glass transition temperature.

196
Q

what is primary nucleation

A

occurs spontaneously when driving force is large enough

197
Q

What is secondary nucleation

A

takes place in the precense of larger crystals

198
Q

Gribs free energy

A

needs to be minimised
ctritical gibbs free energy needs to be passed to create clusters
r* critical radius of nucleation

199
Q

what happens to gibbs free energy when the driving force is increased

A

delta G will be higher so more favourable to trigger crystalisation

200
Q

If lower delta G is favoured for nucleation what is the ideal driving force and interfacial free energy?

A

low interfacial free energy and high driving force

201
Q

What is a homogenous reaction?

A

when there is no impurities

At high driving force homogenous nucleation is dominant

202
Q

What is a heterogeneous reaction?

A

When foreign particles exist which affect free energy and attatchment rate therefore affect nucleation

at low driving force heterogenous nucleation is dominant

203
Q

desrcibe three regions in a constant pressure phase diagram to form crystals

A

region 1: Metastable region (between equilbium solubility and SNT)
seeds present: they will grow
seeds absent: no crystalisation

Region 2: secondary nucleation region (between SNT and PNT)
seeds present: nucleation will occur
Seeds absent: No nucleation will occur

Region 3: Primary nucleation region (Below PNT)
nucleation occurs with or without seeds both homo and hetreo

204
Q

crystal growth on surface

A

the ability of a crystal tp capture and intergrate growth units into a crystal lattice depends on the strength and number of interactions that can form between the surface and the growth unit

205
Q

smooth or layer growth on crystal surface

A

growth units attatch to kinks in the steps which propgate along the crystal and form growth layers

206
Q

rough growth on crystal surface

A

growth units attatch anywhere to the surface and the energy for the formation of a step is low inducing creation of surface with many kink and step sites
diffusion is the limiting step since every unit reaching the surface will find a growth site

207
Q

what are the benefits of direct compression compared to granulation?

A

reduced complexity, typically reduced costs, reduced stress on API

208
Q

how can segregation occur (3 ways)

A

from elutriation and fluidisation, sifting and trajectory

209
Q

What are the benefits of coninuous direct compression

A
  • reduces the inherent risk of scale up
  • reduction in material handling
  • reduction in process steps
  • more streamlined manufacturing platform
  • enhanced product quality assurance
  • robust scalability and demand driven supply
210
Q

describe the process of contunuous direct compression?

A
  • continous flow of formulation ingridents using loss in weight feeders
  • passed through a comill to deagglomerate and improve distribution of products
  • continuous mixing to produced a homogenous blend
  • compression
  • coating
211
Q

what are the process sewlection paramters in CDC

A
  • Bulk density
  • Dose
  • API flowability
  • API sticking propensity
212
Q

Describe feeder fundamentals

A

hopper, agitator and conveying screw

as the screw rotates a volume is swept out based on the screw geometry (free volume of screw bitch Vs)

213
Q

Describe gravimentric and volumetric feeding?

A

loss in weight feeders use data from load cell to monitor the mass of material. When the feeder is operating in gravimetric mode the rate of weight loss os controlled by manipulating the screw speed.

when the data from the load cell is unreliable unintentional disturbances can occur such as knocks/bumps and variability in powder flow and intentional disturbances such as refilling the feeder hopper.

in this case the ffeder should operate in volumetric modebased on the expected feed factor

214
Q

By using a simple moving average filter to compare data from external balance and feeder what considerations need to be accounted for?

A

feeder noise: screw agitator motion, material movement
Balance noise: material impact and heap motion

215
Q

what are the three typical CDC powder mixing equipments

A

GEA: inclined linear blender with internal paddles
Gericke: Horizontal linear blender with internal paddles and weir
GEA CMT mixer

216
Q

describe the three powder mixing mechanisms

A

Convective mixing
- macroscopic transport of parts of the mixture which reduces the scale of segregation
- occurs when blades or paddles move through materials

Diffusive mixing
- Induced by random motion of individual particles and is required fro microscopic mixing and to reduce intensity of segregation

Shear mixing
- required for cohesive particles
- occurs when a layer of material flows over another layer resulting in mixing at the interface

217
Q

WHat happens in a continuous powder mixer?

A

At steady state there will be a consistent quantity of powder in the mixer which will dpened on operating conditions and material properties

particles will be conveyed axially and experience back mixing, shearing and radial transport

218
Q

what two tests can be completed to measure residence time distributions

A

Spike test
- A known quantity of powder added to the inlet and concentration is measured of the component leaving

Step change test
- increaase feeder set point for once component and do a step increease/decrease, then measure conc at outlet

219
Q

Residence time distribution concepts for continupus direct compression

A

RTD in downstream equipment filters out feeder fluctutations and perturbations, can preduct the mean downstream conc if RTD is known.

A high frequency variability in the inlet conc due to the feeders is smoothed out after the blender due to the axial mixing. RTD in the blender can be used to understand the level of acceptance variability from feeders

can be visualised using a funnel plot where tablet concs are plotted as a function of magnitude and duration of a conc pertubation from the feeder.

220
Q

key process parameters in a horizontal linear mixer

A
  • impeller speed
  • throughput
  • blade configuration
221
Q

key process parameters in a horizontal mixer

A
  • impeller speed
  • throughput
  • blade configuation
  • weir angle
222
Q

key process parameters in CMT

A

impeller speed
mass hold up
throughput

223
Q

desribe tabletting processes and key requirements?

A

force is applied to compact powder.

filling -> lower punch is lowered to create space to fill powder
metering -> powder is leveled off to get a controlled volume
precompression -> top punch is lowered to apply force
compression -> intented force is applied to compact
ejection

HAs to be strong enough to withhold packaging and transport but weak enough to diintergrate.

224
Q

what are the mechanical properties of a powder

A

compressiability, tabletability, compactability

we can get elasric, plastic or brittle tablets formed

225
Q

what tablet defects can occur

A

pre capping/lamination -> splits and cracks on the side due to excessive compression and ejection forces, air entrapment, poor compactability

capping -> separation of tablet face

Picking -> removal of material from the tablet face and poor lubrication on punches

226
Q

types of mixture formed due to differeneces in tensile strength in binary mixtures

A
  • 5050 mixutre
  • deviations from ideal behaviour
  • perculation behaviour
  • hogh/low tensile strength
227
Q

In process measurements of tablets

A

tablet tester - dimensions, weight, breaking force
at line spectroscopy - identity, assay, content uniformity
soft sensor - assay, content uniformity

228
Q

What is PAT?

A

PAT is a system for designing, analysisng and controlling manufacturing through timely measurements of crtical quality and performance attributes of raw and in process materials and processes with the goal of ensuring final product quality

229
Q

Wha is a common CDC in line measurement?

A

blend uniformity using spectroscopic techniques

230
Q

what are the challenges of inline measurement of powder streams?

A
  • fouling of measurement probe
  • diffcult to define sample size
  • ensuring location of probe does not influence the process and collects a representative sample
231
Q

what are the challenges of inline measurement of powder streams?

A
  • fouling of measurement probe
  • diffcult to define sample size
  • ensuring location of probe does not influence the process and collects a representative sample
232
Q

list a. few common areas of regulatory scrutiny for CDC

A

batch definition/scale
process description
material attributed
material traceability
state of control
automated control
RTRT
models
process validation

233
Q

describe batch definition

A

quantatity of material required to be prodiced will be a project descion

batch size must be defined prior to the initation of each production run

batch definition should be based on the production period time operating at define mass flow

need to account for material that is diverted to quarantine during run

234
Q

describe batch definition

A

quantatity of material required to be prodiced will be a project descion

batch size must be defined prior to the initation of each production run

batch definition should be based on the production period time operating at define mass flow

need to account for material that is diverted to quarantine during run

235
Q

what is state of control

A

A condition in which a set of controls consistently provide assurance of continued process performance and product quality

crticial for continuous operation as there could be transient disturbances

236
Q

increased need for process control strategy elements to:

A

Maintain the process in a state of control
detect temporary process diturbances
segregate resultant non conforming material from the system

237
Q

control strategy implementation in CDC?

A

Level 3 -> conventional approach, establised IPC control limits based on established ranges for CMAs and CPPS. system monitors CPPs and activates diversion to quarantune if outside limits. product release based on end quality testing

level 2 -> real time quality assurance, system monitors CQAs and activates quarantine if product quality is out of range. product release based o end product testing

Level 1 -> active process control, same as level 2 but also uses active process control to automatically adjust the process to maintain quality in range. Combination of end product testing and RTRT for product release

238
Q

Why do we use film coating?

A

Appearance and Image
- masks unpleasant taste of drugs and eases swallowing
- masks discoloration and improves surface asthetics

Performance and stability
- delayed or modified drug release
- provide stability to oxygen, moisture and light

Robustness safety and efficiency
- eliminate dust hazard
- tablet flow

239
Q

what is the formulation of a film coat and what is each ingreident used for?

A
  • Polymer used for strength and elasticity
  • Plasticiser -> used to reduce film brittlness
  • color
  • solvent
  • wetting agents
240
Q

what is the mechanism and transformation of film coating?

A

Atomisation -> wetting and spreading -> water evaporation and packing -> polymer deformation -> coelscence into mechanically coherent dry film -> continuous polymer film -> water diffusion

241
Q

What are the common defects in film coating?

A

Due to process equipment, tablet cose and coating formulation
logo infilling
colour variation
sticking
edge wear
breakage
cracking
erosion
peeling
scruffing

242
Q

what are the main considerations for tablet core/excipients in film coating?

A

tablet tensile strength
stability
moisture and temperature sensitivity

243
Q

What are the 3 elements of film coating

A

spraying, drying and mixing

244
Q

describe the drum drying process in film coating?

A

consists of; air duct, perfrated pan, spray dryer and tablet bed

operates in laminar flow

avoid turbulent eddies as they impact droplet flight path which contributes to spray drying of film coat

245
Q

describe the mixing process in film coating (types and parameters)?

A

Types: slipping, slumpingm rolling, cascading and centrifuging
Parameters: pan size, baffle design, pan load, pan speed, tablet size and tablet shape

246
Q

what are the spray gun considerations in film coating

A

spray loaction:2/3 bed length
gun to bed distance: 15-25cm
gun to gun distance: 15-20cm

247
Q

spray set up considerations in film coating

A

gun to gun distance impact
- spray overlap causing overwetting
- spray separate causing color variation

atomising pressure impact
- atomising pressure: 1-2.5 bar
- spray width pressure: atomising 0 to 1 bar

248
Q

what is the basis of film coat model?

A

thermodynamic conditions such as temp and RH provided in film coating process which impact film coat formation and product quality

249
Q

film coating process cycle

A

load -> warm -> Spray (30% RH and 20-70oC) -> Dry (10% RH) -> cool (RH<60% 35oC)

250
Q

modellling application in film coating

A

the purpose is to predict steady state inlet temp and help to get stabilty on transition from warm to spray

251
Q

what are the limitations of adiabatic film coating

A

max spray rate compatible with film coat formation
ever increasing sensitivity variation in spray rate and exhaust temperature
impact of control system capability

252
Q

process imposed boundary deviation

A

can distinguish response at 25%RH and 40-45oC

can distinguish two types of operation dependent on temperature

exhaust T>45oC
- suitable for moisture sensitive products
- limits choice of exipients
exhaust T<40oC
-suitable for products with core instability
- requires dehumidification
- need for increased core strength

253
Q

Why do we mix?

A

For an even distrubution of the active and to achievee a desired release of the drug

254
Q

What is mixing?

A

A unit operation that aims to treat two or more components initally in an unmixed or partially mixed state so that each unit of the components lies nearly as possible in contact with a unit of each of the other components

255
Q

What is the scale of scrutiny?

A

Is the amount of material within which the quality of mixing is important known as the weight/volume

256
Q

The number of particles contained in the scale of scrutiny depend on what?

A

Sample weight, particle size and particle density and will increase as sample weight increases and particle size and density decreases

257
Q

How do I acheive an acceptable deviation of active content in a mix?

A
  • A lower active proportion in the content a higher deviation in the content

SD= (p(1-p)/n)^0.5

258
Q

list 5 types of powder mixing equipment and the typical scale?

A

cone mixer, IBC, high shear mixer granulator, ribbon agitator, planetary mixer
100-1000L

259
Q

Describe three types of powder segregation?

A

Percolation - smaller particles fall through the voids and move to the bottom of the mass
Trajectory - Differences in kinetic energy imparted to particles during mixing
Elutriation - dust formation by very small particles by turbulent air during.mixing which sediment and form a layer on top of coarser particles

260
Q

WHat are the reasons for segregation

A

Particle size effects - larger particles have higher kinetic energy
particle density effects - dneser particles tend to move downwards
particle shape effects - round particles tend to have better flowability

261
Q

What is a CSTR

A

A system with a steady state continuous flow of feed and product streams. The feed entering the reactor immediateley assumes a final uniform composition throughout the reactor because of perfect mixing.

262
Q

residence time distributions in CSTRs

A

the moRE CSTRs the RTD becomes very narrow and acts like plug flow which has no mixing

CSTR with bypass is when a fraction of material leaves the tank early with a short res time

CSTR with a dead zone there is a fraction of material that never leaves the tank

263
Q

describe the tracer spike methodology for RTD measurement

A

A purple tracer is added at t=0 and mixes. The blend potency is proportional to the conc. Over time conc decreases. and the change in outlet overtime is measured

264
Q

what does a variant reduction ratio of high frequency signal result in?

A

dampening of a high frequency noise with a signal period smaller than the mean residence time is very effective resulting output signal with low variation

265
Q

what does a variant reduction ratio of low frequency signal result in?

A

dampening of low frequency noise with signal period equivalent to mean residence time is not effective resulting output signal with same variability

266
Q

what does a variant reduction ratio of random frequency signal result in?

A

dampening of low frequency noise with signal period equivalent to mean residence time is not effective resulting output signal with same variability

267
Q

what are the key parameters in a horizontal mixer that impact RTDs

A
  • hold up mass
    impeller rotational speed
    overall process throughput
    mixing blades configuration
268
Q

What are the key parameters in a vertical mixer that impact RTDs

A
  • mass hold up
    overall process throughput
269
Q

what can extensive mixing impacg and why

A

tensile strength, dissolution and sticking because the hydrophobic lubricant is much better distributed and can further inhibit particle adheison and wetting

270
Q

what parameters does the extent of powder lubrication effect?

A
  • decreases strength
  • increases flow
    increases density
  • decreases wetability
  • decreases powder sticking
271
Q

increasing the shear applied to a powder results in what

A

weaker tablets, slower dissolution snd lower sticking and vice versa for low shear

272
Q

process development for continuous mixing

A

minimise feeder variability at targer flow
select: impeller RPM, hold up mass and throughput

to acheive CSTR RTD and dampen feeder fluctuations and acheive Min and max extent of lubrication.

273
Q

What is quality by design?

A

A systematic approach to development that begins with predefined objectives and emphaizes product and process understanding based on sound science and quality risk management

The outcome of QbD is a well designed and understood quality product that consistently delivers the continuous performance

274
Q

What is process analytical technology (L11)

A

A system for designing, analysisng and controlling manufacturing through timely measurements of crtical performace attributes with the goal of ensuring final product quality

275
Q

what is required to gain robust reproducible processes

A

high process understanding and process control

276
Q

WHat can PAT do

A

flexible, adpatable, data rich, specific, empowers, misleads and consumers

277
Q

WHat is the PAT strategy

A

identify snf understand all critical sources of variability -> consider how to control them -> predict variability over the design space

process parameters to be monitored and control strategy apporach taken can be decided according to prior knowledge, safety, quality and scientfic understanding

278
Q

What can process analysers measure and examples

A

relative differences in materials before and during processing and provide useful info for process control

particle size and shape: laser diffraction, image analysis, FBRM
chemical composition: NIR, IR, raman, chromatography and mass spectroscopy
physical properties
crystalinity: raman and NIR

279
Q

what is spectroscopy?
describe the two types

A

the study of the interaction between electromagnetic radiation and matter the matter can be atoms ions or molecules

atomic - isolated ions where the transition of electrons between electronic energy levels in isolated atoms (optical and mass)
molecular - atoms and molecules, transition on molecules with two or more atoms e.g. NMR, IR, UV

280
Q

what does electromaghnetic radiation display?

A

properties of both particles and waves

281
Q

what is a photon

A

A particle component where the energy component of a photon is proportional to the wave frequency

term photon is implied to mean small, massless particle that contains a small wave packet of EM radiation/light

282
Q

describe three spectroscopic methods

A

absorption/transmittance spectroscopy - uses a range of EM spectra in which a substance absorbs

Emission spectroscopy - uses the range of the EM spectra in which a substance radiates and emits the substance must first absorb energy

Scattering spectroscopy - it measures the amount of light that a substance scatters at a certain wavelength and incident angles. fastest process

283
Q

what are the typical components of spectroscopic instruments

A
  • source of radiation
  • wavelength slector to isolate a restricted region of the spectrum for measurement
    sample holder
    a radiation detector to greate a usable electrical signal
    a signal processor
284
Q

what are the two sources of radiation

A

continuum - emits radiation that changes in intensity only slowly as a function of wavelength widely used in absorption and fluorescence

line sources - emit a few discrete lines find wide use in atomic absorption

285
Q

what are the two types of wavelength selectors

A

filters (absorption and interference)
monochromators(Prism and grating)

286
Q

what are radiation transducers

A

most modern detectors in use convert radiant energy into electrical signal (MV units)
types: photon and thermal

287
Q

photon transducers

A

used for UV visible radiation
not applicable in infared because photons in this region lack the energy to cause photoemission of electrons

288
Q

Thermal Transducers

A

used for measurement of IR radiation
the radiation impinges on and is absorbed by a small blackbody and the temperature rise is measured
types: thermocouples

289
Q

Infared spectrometry

A

deals with the infared region of the EM that is light and works exclusively on samples with covalent bonds

the infared spectrum of a sample is recorded by passing a beam of infared light through a sample and when the frequency of the IR is the same as the vibrational frequency of a bond absorption occurs

three regions
NIR
mid IR
far IR

analysis of the position, shape and intensity of peaks in this spectrum reveal details about the molecular structure of the sample

290
Q

IR spectroscopy follows the energy conservation law….(which is?)

A

when the IR beam reaches the matter, the intensity of the incident beam Io must be equal to the sum of intensity of the reflected and transmitted beams

291
Q

desribe the two measrement modes in IR spectroscopy and equations on how they are measured?

A

Transmission
allows to measure the light through a sample. Transmittance T is defined by the light fraction crossing the entire sample
it is represented by
T=IT/Io

The absorbance
A=log(1/T)

in general the amount of absorbance or transmission of incident radiation has a linear relationship with amount of concentration of sample under measurement

292
Q

what is raman spectroscopy

A

Light scattering technique whereby a mlecule scatters the incident monochromatic light from a laser in the visible near infared range

most scattered light is at the same wavelength as the laser siurce and does not provide useful information, however a samll amount is inelastically scattered

293
Q

what is mass spectroscopy

A

an analystical technique to helpnidnetify the amount and type of chemicals present in a sample

A sample is ionised causing some of the samples molecules to break into charged fragments which are then spearated according to their mass to charge ratio and results are displayed as spectra of the relative abundance of detected ions as a function of the mass to charge ratio

294
Q

WHat is chromatography

A

important bipphysical technique that enables the separation, identification and purification of the components of a mixture for qualiative and quantative analysis

based on the principle where a solute in a solvent (mobile phase) is passed through or around an outside matrix (stationary phase) and interactions occur
between two phases

separation of compounds is based on their molecular weight and element composition

295
Q

two categories of image analysis

A

static: measures samples that typically rest on a slide moved by an automated stage

Dynamic: measures samples that flow through a cell or infront of optics which collect an image of particles with a strobe.

296
Q

Steps in image analysis process

A

Image segmentation -> image transformation and feature extraction-> immage classifcation

297
Q

light scattering

A

particles scatter light and the angle of light scatter, the frequency of the light scattering and the intensity of said scatter can be measured to determinne the size and the molecular weight of materials

298
Q

laser diffraction

A

relationship between light and surface particles
measures particle size distrbutions by measuring angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample

299
Q

multivariate analysis tools for PAT

A

pharmaceutical processes are complex multifactorial processes and one factor at a time experiemnts do not address interactions among product and process variables

using multivariate apporaches we can enable idetification and evaluation of produxt and process variables that are critical to quality

300
Q

what is chemometrics

A

multivariate chemistry discpline to design or select optimal measurement procedures and experiemnts and to provide max chemical info by analysis chemical data

301
Q

continuous improvement PAT tools

A

can contribute to justifying proposals for post approval changes.

302
Q

PAT Implementation elements

A
  1. building science (Understnading of scientific principles)
  2. process monitoring (understanding interactions between process and product is the basis for the design of the monitoring)
  3. validation of system
  4. regulatory strategies
303
Q

the validation plant of PAT system includes validation of:

A
  • software packages
  • process analysers
  • pprocess control software IT systems for the management and storage
304
Q

discuss two types of regulatory strategies in PAT implementation

A

risk based approach
- an inverse relationship between the level of process understanding and the risk of producing a poor quality product is expected

for processes that are well understood can be less restrictive in regulatory approaches

real time release
- ability to evaluate and ensure the acceptable quantity of in process based on process data

305
Q

benefits of PAT

A
  • better understanding the chemical and physical mechanisms
  • improves process robustness
  • prevents reject batches
  • reduces production cycle times
  • reduction in sampling
  • improved hygiene
  • increased automation
  • facilitates continuous processing
306
Q

PAT applications in primary manufacturing

A

identifying raw material: NIR/MIR or Raman used to idnetify raw
synthesis step: immersion transmission probes are typically used with NIR spectrometers to measure concentration during synthesis
Crystalisation: use of NIR and MIR to determine the optimum concentrations for addtion of seeding crystals
Drying: monitoring the vapor stream in the vaccum line(headspace) and direct measurement of residual solvent in powder
Milling: particle size
final API: NIR,Raman or MIR to check chemical composition

307
Q

PAT Applications: secondary manufacturing

A

Blend uniformity: critical for quality dosage form, homogenity can be monitored using NIR

Drug content uniformity
- NIR used for tablet assay and content uniformity testing

PAT (2 decks)

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