Formulation And Processing Flashcards
What are the adv of tablet as a formulation?
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
What are the dis adv of tablet as a formulation?
Swallow reflex required Subject to first pass - F < 1.0 Food effect Erratic release profile Poor organoleptic qualities Patient need to sit up straight
List and describe the main stages of tablet manufacturing.
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)
What are the main constituents of a tablet? (With examples)
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
What is the BP/USP limit of enteric coated tablets?
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
How do you formulate SL tablets?
Drug mixed in solution with granules made using mannitol as the diluent - compress without coating
Melt Tech: freeze dry drug solution - wafer
How do you formulate soluble tablets?
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
Direct compression - adv/dis + requirement?
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
Dry granulation - ad/dis + requirement?
Adv: No need binder + misture/heat sensitive + continuous + less equipment/space+ improve flow
Dis Adv: Dust + specialist equipment
List QC testing of tablets.
Hardness Thickness Fraibility Wt uniformity Appearance Assay Content unifromity Disintegration Dissolution
Discuss validation implication of tableting stages.
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
Describe the action of high shear mixing.
Granulaor blade “chops” the wet mass
Both blades are independently controlled
Homogeneity achieved during dry mix
What are the wet granulation end point control?
Time
Mechanical monitor: torque, rotation, speed
Electrical monitors: current, power
Other: sound, conductance, reflectance
What are the key controls in dry mixing/blending?
Mixing speed
Loading
Time
Temperature
What are the key controls in wet granulation?
Water quality
Water volume + flow rate
Speed
Time
What are the problems caused by over granulation?
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
Describe fluid bed drying process.
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
Describe the stages of tablet compression.
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
What are the main components of a rotary tablet press?
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
What are the adv of multilayer tablets?
Aestetics - diff colour used
Unique/multiple release profile with each layer
Physical separation of incompatible drugs
What are the dis Adv of multilayer tablets?
Copmlicated wt control - carry over of granlues
Delamination between layer over time (temp + RH)
Slower production rate
What are the factors affecting tablet weight contol?
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
What are the issues affecting tablet strength?
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
What are the factors affecting disintegration?
Compression force
Lubricant mix times
Lubricant quantity
Particle size distribution of granulation
What are five stages of sugar coating?
Sealing Sub-coating Smoothing Colour coating Polishing
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
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
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
Characterisation of API should include:
ID Assay/purity Particle size Particle shape Polymorphism Final solven crystallisation
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
IPC at blending:
Blend analysis only needed for validation batches
IPC at graulation
detection of granulation end point
Target moisture content
Particle size distribution
IPC at compression:
Start up: sample from each punch station
Visual check: marking
Describe a typical IPC sampling schedule of tablet manufacturing
Weight: 20 tablets every 20 minutes
What are the main stages in capsule filling?
Orientation: Separation: Filling Rejoining Closing
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
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
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
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
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,
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
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
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
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
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
Benfits of UD over multidose
no preservative
patient has less SE
Common Preservative: Adv+ Dis
BAK
Adv:
Disadv:
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
Describe terminal sterilisation manufacturing process
Weight (Dispense) Mix Filter Fill/close - Container (wash and sterilise) Sterilise Inspect Label and pack
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
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
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
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
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
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
