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Prep QP > Formulation And Processing > Flashcards

Formulation And Processing Flashcards

1
Q

What are the adv of tablet as a formulation?

A 
Pt acceptability - painless admin
Dose uniformity
Established tech - cheap + large scale
Portable + discreet
Stable + robust formulation - transport
Target release at specifict section of GIT
Easily identifiable
Suitable for a wide range of API
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2
Q

What are the dis adv of tablet as a formulation?

A 
Swallow reflex required
Subject to first pass - F < 1.0
Food effect
Erratic release profile
Poor organoleptic qualities
Patient need to sit up straight
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3
Q

List and describe the main stages of tablet manufacturing.

A 
API and excipients: approval
Weigh + check
Seive + add solvent to make granulation solution
Dry blend - fill sachets or capsules
Granulate with granulation fluid
Dry granules 
Mill/seive granules
mix with lubricants
Compress
Coat (optional)
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4
Q

What are the main constituents of a tablet? (With examples)

A

Diluent (bulking agent): Lactose + sucrose + mannitol
Binder: PVP, HPMC, Starch paste
Disintegrants: Microcrystallise Cellulose, sodium starch gycollate, crosspovidone
Glidants: Silicone dioxide
Lubricants: Mg Sterates, fatty acids, alcholol
Colourants: Quniolines (Yellow 10 + 11)
Sweeteners: Aspartame + fructose

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5
Q

What is the BP/USP limit of enteric coated tablets?

A

USP: Intact for >30 mins 37 deg in a disintegration apparatus pH 1.2 simulated gastric fluid
BP: Intact for >2hrs 37 deg 0.1M HCL disintegration apparatus; disintegrate <1hr BP mixed phospate buffer at pH6.8

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6
Q

How do you formulate SL tablets?

A

Drug mixed in solution with granules made using mannitol as the diluent - compress without coating
Melt Tech: freeze dry drug solution - wafer

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7
Q

How do you formulate soluble tablets?

A

Direct compress/dry granulation
Needs soluble API and excipients
Organic acid + alkaline salt: API stable in slight alkaline solution
i.e. citric aicd + sodium bicarbonate

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8
Q

Direct compression - adv/dis + requirement?

A

Need poweder flow into die - consistant flow properties
Adv: Easy + cheap + min powder loss + no water/heat invovled
Dis Adv: uniformity of content + separation + segregation

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9
Q

Dry granulation - ad/dis + requirement?

A

Adv: No need binder + misture/heat sensitive + continuous + less equipment/space+ improve flow
Dis Adv: Dust + specialist equipment

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10
Q

List QC testing of tablets.

A 
Hardness
Thickness
Fraibility
Wt uniformity
Appearance
Assay
Content unifromity
Disintegration
Dissolution
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11
Q

Discuss validation implication of tableting stages.

A

Dry powder mix: content uniformity + particle size distribution
Granulating solution: microbiological hold time + viscosity + mixing time/speed
Milled granules: Moisture content + bulk density + content uniformity
Lubricated granules: content + bulk density
Film coating solution: solid content + micro + residual solvents

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12
Q

Describe the action of high shear mixing.

A

Granulaor blade “chops” the wet mass
Both blades are independently controlled
Homogeneity achieved during dry mix

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13
Q

What are the wet granulation end point control?

A

Time
Mechanical monitor: torque, rotation, speed
Electrical monitors: current, power
Other: sound, conductance, reflectance

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14
Q

What are the key controls in dry mixing/blending?

A

Mixing speed
Loading
Time
Temperature

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15
Q

What are the key controls in wet granulation?

A

Water quality
Water volume + flow rate
Speed
Time

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16
Q

What are the problems caused by over granulation?

A

Increased granule size
Hard agglomerates
Difficulties in Fluid bed drying - poor +uneven drying
Milling large agglomerates - release moisture in the blend
Large particles - weight control in compression

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17
Q

Describe fluid bed drying process.

A

Granules placed in drying bowl with fine mesh base
Heated air - pulled through and fluidise agglomerates
Filter bag prevent granule escaping
At pre-set interval: drying stopped and shake bag filter to release stuck product
End point: exhaust temperature + product differential temp on the granule + NIR - PAT

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18
Q

Describe the stages of tablet compression.

A

Filling - force or open feed
Weight control - raise lower punch - scrape off blade
Consolidation - rearrangement then consolidation
Ejection - lower punch raise further to level with die

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19
Q

What are the main components of a rotary tablet press?

A

Punch + dies: shape / wt control - tight control (log etc)
Granule feed provision: open / force - paddles
Wt control: wt control cam - overfill + remove - granule recriculation
Compression force: Consolidation - upper/lower roller
Decompression + tab ejection

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20
Q

What are the adv of multilayer tablets?

A

Aestetics - diff colour used
Unique/multiple release profile with each layer
Physical separation of incompatible drugs

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21
Q

What are the dis Adv of multilayer tablets?

A

Copmlicated wt control - carry over of granlues
Delamination between layer over time (temp + RH)
Slower production rate

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22
Q

What are the factors affecting tablet weight contol?

A

Poor flow: powder size, moisture content, EM condition
Machine: fill cam, feed frame set up
Erratic wt: uniform discharge from feed hopper? Flooding of feed frame? Check tooling clean? Check wt control features

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23
Q

What are the issues affecting tablet strength?

A

Low breaking strength could have been over compressed
laminates: low moisture, over-comperssion, over-blending, excessive lubricant
strength compromised during ejection: “rub mark”? Check tooling

24
Q

What are the factors affecting disintegration?

A

Compression force
Lubricant mix times
Lubricant quantity
Particle size distribution of granulation

25
Q

What are five stages of sugar coating?

A 
Sealing
Sub-coating
Smoothing
Colour coating
Polishing
26
Q

What are the common components of a film coating solution?

A

Polymer: PVP, PEGs, Cellulose materials (HPMC, HPC, MC)
Plasticiser: PEGs, glycerine, triethyl citrate, glycerol, mineral and veg oils
Colour: Iron oxide, titanium oxide, natural dyes
Solvent: water, ethanol, methanol, acetone
Wetting agents
Flavours
Source of microbial growth

27
Q

What are the key coating pan control parameters?

A 
Drying air: vol / temp / RH
Atomising air: Press / vol
Spray rate
Pan speed 
Gun to bed distance
28
Q

What are the common coating faults?

A

Colour variation/mottling: to little coating + inadequate tab mix + poor opacity of solution + too few spray guns + too many tabs
Roughness / “orange peel”: poor atomised solution (viscosity) hi drying temp + too high spray rate
Bridging: tablet surface + solution applied too quick + air in solution + low viscosity
Blistering/cracking/splitting/peeling: core expansion + lack of relaxation after compression + poor solution
Picking: film broken - adherence to another tablet
Sticking: stuck together
Twinning
Edge chipping / splitting: soft tab + sharp tab edge + warn tab punches + high pan speed + low spray rate
Core erosion: soft core + senstitive to moisture

29
Q

Characterisation of API should include:

A 
ID
Assay/purity
Particle size
Particle shape
Polymorphism
Final solven crystallisation
30
Q

What are the principal IPCs of solid dosage form maufacturing process?

A

Granules + powders: visual + size analysis + bulk density + loss of drying
Weight variation: filling + compression
Physical dimension: thickness, capsule length
Friability checks
Hardness
Disintegration/dissolution test
Visual on product

31
Q

IPC at blending:

A

Blend analysis only needed for validation batches

32
Q

IPC at graulation

A

detection of granulation end point
Target moisture content
Particle size distribution

33
Q

IPC at compression:

A

Start up: sample from each punch station

Visual check: marking

34
Q

Describe a typical IPC sampling schedule of tablet manufacturing

A

Weight: 20 tablets every 20 minutes

35
Q

What are the main stages in capsule filling?

A 
Orientation: 
Separation:
Filling   
Rejoining
Closing
36
Q

List common used solvent in liquid formulation with examples

A

Aqueous: water based - purified water
Non-Aq: alcohol - Ethanol
Non-Aq: Glycols - propylene glycol, glycerol - inc viscosity

37
Q

What are the ways in which aq solubility in a liquid formation can be enhanced?

A

pH adjustment: weak acids and bases
Co-solvent sys: alter polarity of the solvent by adding a miscible co-solvent
Surfactant solubilisation: via micellar system HBL value >15 i.e. polysorbates, poloxamers and lecithins
cyclodextrin solubilisation:
Complexation: i.e. polyvinylo pyrrolidone with iodine

38
Q

Why is microbiological preservation necessary in liquid formulation?

A

Deal with in use contamination
Product properties can hide microbial growth
Suspended particles/emulsion droplets can adsorp/absorb large quantities of preservation from aq phase
Excipients can neutralise preservatives
Formulation break down could be the first sign of spoilage

39
Q

What are the GMP issues with oral liquid manufacturing?

A

Order: ingredients added to mixing vessels
Mixing: Vessel dead legs + mixing power and time + cont mixing to prevent separation
Homogeneity: maintain at filling for suspension/emulsion
Cleaning: viscosity difference + no emulsifying agents + paritlces and oils + syrups + deposition

40
Q

Describe the main stages of suspension/solution manufacturing.

A

Dispensing: Mix up of ingredients + ventilation (downflow booth + no recirculation)
Mixing/solubilisation: closed sys preferred + Solid via man lid + open process (EU7 filter + 6-12 ACR + positive pressure)
Holding/transfer
Optional filtration: for solution - filter management
Filling: most open stage - protect by filtered air
Labelling/Packaging
Cleaning: Wash bays,

41
Q

Describe the validation considerations in suspension/solution manfuacturing.

A

Equipment qualification: material of construction, product compatibility, mixer + pump speed and efficiencies + EM controls
Filtration: additive/adsorptive - preservatives/active + on all ingredients
Cleaning: swap sample vs rinse sample + valves and fitting designs

42
Q

What are the considerations of a CIP system?

A

Design considerations for sys to be cleaned: deadlegs + area/distance + dirt traps
Validation of computer system: IQ + OQ + PQ (GAMP5)
Control of water quality
Control of water pressure
Control of water temperature
Control of detergent: addtional/removal
Blind spot
Holding times: dirty vessels before cleaning + clean vessel before use
Microbiological cleanliness

43
Q

How would you validate Bulk mixing in liquid manfuacturing?

A

Multiple sample from various location:at least 3 (top, bottom and middle)
Analyse key ingredients - establish homogeneity (API, preservatives etc)
Sample size: approximate a single dose
Mixing time: up to proposed mixing time - demixing unlikely
Batch size: three runs @ Max, min and intemediate sizes for each mixer
Acceptance criteria: Statistical evaluation - mean+/- 3SD meets release spec
Holding/transfer: demo no adverse effect i.e. settling + splitting
Filling: Sample during filling + fill volume

44
Q

Summary of EU GMP Annex 9: Liquid, creams and ointment

A

Closed system preffered
Filtered air if open vessel/process (EU F7 or F8)
Easy to clean + min dead leg (< three D)
Use high quality steel i.e. 316L + avoid glass
Micro limit: 100cfu/mL at the most
Pipe transfer system - beware of mix up
No cardboard/fibre shedding materials in area of product or container exposed
Validate mixing and filling
Specified and validate hold time

45
Q

Tell me about your product Eyedrops

A 
Active:
Other ingrediates and use:
Main serious side effects: 
Indication: 
Treatment resistance: 
Mech of Action: 
Posology: 
Dose: 
Max:
Route of admin:
Do for Bimatoprost eyedrops, and Ganfor eyedrops and Botox
46
Q

Benfits of UD over multidose

A

no preservative

patient has less SE

47
Q

Common Preservative: Adv+ Dis

A

BAK
Adv:
Disadv:

48
Q

What are the major routes of parenteral administration routes?

A 
Subcutaneous
Intramuscular
Intravenous
Intraspinal (Intrathecal + intracesternal + peridural)
Intra-arterial
Opthalmic (Intravitreal +  intracemeal+ subconjunctival + retrobulbar)
Intra-articular
Intramammary
Intraperitoneal
Intradermal
Intra-cardiac
49
Q

Describe terminal sterilisation manufacturing process

A 
Weight (Dispense)
Mix 
Filter
Fill/close - Container (wash and sterilise)
Sterilise
Inspect
Label and pack
50
Q

What are the critical control points of a terminal sterilisation process?

A

Raw materials: bioburden (micro&endotoxin) + heat penetration
Filling environment: microbiological contamination
People: operator as a source of contamination
Sterilisation: heat penetration + conditions + product damage
Pack integrity: leak testing + distribution and use

51
Q

What are the controls in place to maintain a clean environment in sterile manufacturing

A

Remove potential sources of contamination: drains + contamianted RM + humans
Continous supply of clean air
Sterilise materials entering: autoclave (solutions + filling pumps + filters); oven (glassware); filtration (solutions); disinfection;
Changing room
Clothing
Operator training + validation
Area for prepration: filter assembly + component washing + maschine parts assembly
Positive pressure cascade
Cleaning + disinfectants

52
Q

Describe DOP testing

A

Ondina EL aerosol injected at a concentration of 50-100microgram per litre upstream of filter
Scan filter face and seals via isokinetic probe - aerosol photometer
Leak = >0.01% of the upsteram challenge

53
Q

What are the differences in US and EU cleanroom standards?

A

FDA: require active air sampling - settle plate optional ; EU: active air, settle and contact
US do not monitor 5 micron particles
US do not specify EM requirement for TS
US do not have equivalent Grade D

54
Q

What are the Annex 1 particle and micro limits?

A

Particles:
Grade A: 3520 / 20 (Manned and unmanned)
Grade B: Unmanned (3520 / 29) Manned (352000 / 2900)
Grade C: Unmanned (352000 / 2900) Manned (3520000 / 29000)
Grade D: Unmanned (3520000 / 29000)
Micro: (Air / SettlePlates / Contact platesP)
Grade A: <1 (also glove)
Grade B: 10 / 5 / 5 (Also Glove)
Grade C:100 / 50 / 25
Grade D: 200 / 100 / 50

55
Q

What are the EU GMP grade requirement for TS and aseptic manufacturing?

A

TS / Asp
Grade A: Filling of product when unusally at risk / Aseptic preparation and filling
Grade B: Not applicable / Background filling room
Grade C: Preparation of solutions whne unusally at risk + filling / Preparation of solutions to be filtered
Grade D: Prepration of solution and compoenents for subsequent filling / Handling of components after washing

Prep QP (12 decks)

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