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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
What are five stages of sugar coating?
``` Sealing Sub-coating Smoothing Colour coating Polishing ```
26
What are the common components of a film coating solution?
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
What are the key coating pan control parameters?
``` Drying air: vol / temp / RH Atomising air: Press / vol Spray rate Pan speed Gun to bed distance ```
28
What are the common coating faults?
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
Characterisation of API should include:
``` ID Assay/purity Particle size Particle shape Polymorphism Final solven crystallisation ```
30
What are the principal IPCs of solid dosage form maufacturing process?
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
IPC at blending:
Blend analysis only needed for validation batches
32
IPC at graulation
detection of granulation end point Target moisture content Particle size distribution
33
IPC at compression:
Start up: sample from each punch station | Visual check: marking
34
Describe a typical IPC sampling schedule of tablet manufacturing
Weight: 20 tablets every 20 minutes
35
What are the main stages in capsule filling?
``` Orientation: Separation: Filling Rejoining Closing ```
36
List common used solvent in liquid formulation with examples
Aqueous: water based - purified water Non-Aq: alcohol - Ethanol Non-Aq: Glycols - propylene glycol, glycerol - inc viscosity
37
What are the ways in which aq solubility in a liquid formation can be enhanced?
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
Why is microbiological preservation necessary in liquid formulation?
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
What are the GMP issues with oral liquid manufacturing?
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
Describe the main stages of suspension/solution manufacturing.
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
Describe the validation considerations in suspension/solution manfuacturing.
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
What are the considerations of a CIP system?
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
How would you validate Bulk mixing in liquid manfuacturing?
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
Summary of EU GMP Annex 9: Liquid, creams and ointment
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
Tell me about your product Eyedrops
``` 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
Benfits of UD over multidose
no preservative | patient has less SE
47
Common Preservative: Adv+ Dis
BAK Adv: Disadv:
48
What are the major routes of parenteral administration routes?
``` Subcutaneous Intramuscular Intravenous Intraspinal (Intrathecal + intracesternal + peridural) Intra-arterial Opthalmic (Intravitreal + intracemeal+ subconjunctival + retrobulbar) Intra-articular Intramammary Intraperitoneal Intradermal Intra-cardiac ```
49
Describe terminal sterilisation manufacturing process
``` Weight (Dispense) Mix Filter Fill/close - Container (wash and sterilise) Sterilise Inspect Label and pack ```
50
What are the critical control points of a terminal sterilisation process?
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
What are the controls in place to maintain a clean environment in sterile manufacturing
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
Describe DOP testing
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
What are the differences in US and EU cleanroom standards?
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
What are the Annex 1 particle and micro limits?
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
What are the EU GMP grade requirement for TS and aseptic manufacturing?
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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