Inhalation products Flashcards
What are the microbial Limits for an inhalation product?
200cfu/mL microbial, 20cfu/mL Yeasts and Moulds
Do you know what the difference is between metered dose and delivered dose?
The difference between what was actually measured by the valve and what was delivered to the patient.
A pharmacist has complained that the dose on the pack is incorrect (should be metered, has delivered) and returns it. Do you uphold it as a complaint / what do you tell the pharmacist?
At this point he hadn’t explained it was a UK pharmacist and so it should be 400/12, also kept confusing me by talking about pMDIs and turbohalers intermittently. I dithered here as I wasn’t sure whether it was correct for market or not but didn’t explain that clearly. Got into labelling requirements being different in different markets.
If the MDI box said 120 doses and the label on the inhaler said 60 doses What would your concerns be?
So this is definitely a labelling error of some kind - either the inhaler contains 60 doses and the box suggests 120 or the inhaler contains 120 doses and the primary says 60.
MDI incorrect dose on label. Why could it be a patient risk, what is this product to treat?
it was a corticosteroid and long acting beta agonist used in the maintenance of Asthma and COPD so it wouldn’t be that someone was there with their rescue medication in the middle of an attack and run out when they didn’t think that they would so it was not immediately life threatening. However, if a patient did not have the full number of doses that they expected they may run out when they are not expecting to and it is possible that they would not be able to get a new prescription immediately (e.g. on holiday / away)What level of recall would it be and why? So if it is that we have said 120 doses and there are only 60 this would be class 2, probably to pharmacy level. If it was that we had labelled 60 and given 120 then this would be class 3 probably to wholesaler as it is labelled incorrectly although there is no harm to patients who got extra doses than expected. Who would you call at the DMRC? Phone number on website or yellow card reporting or email.
Inhalers - Mode of Action:
Enter lungs as aerosol (fine dispersions of solids/liquid droplets in a gas (air))
Drug must be aerosolised so it can be inhaled by patient and delivered to lung
Particle size NB: 2-3um optimum, 5um max. Any factor that might impact particle size/distribution must be monitored to ensure bioavailability is not affected by any changes.
Should provide consistent, efficient dosing
Inhalers - Product and Formulation Design Considerations
API: particle size, micronisation, solubility characteristics
Surfactants: aid suspension of API, aid valve lubrication
Propellants: aid aerosolization (pMDI)
Agglomeration: bulking agent/carrier can reduce risk, may be caused by moisture (DPI)
Need to avoid creaming (API settling on top) and sedimentation (API settling on bottom)
Valve: Components (metal, plastic, elastomer), cleaning, design, passivation of metal cpts
Canister: Coating
Drug and Diluent: Interactions, mixing and segregation, particle size, potential for moisture
Inhalation CPPs
Homogenisation speed/time
Mix speed/time
Pressure (pMDI)
Temperatures
Inhalation CQAs
Particle size analysis (size & dist): CI/Anderson (PS Dist)
Assay
Dose Uniformity
Inhalation Container Closure System (Inhalers/Nasal Sprays)
Dose administered depends on design, reproducibility and performance characteristics of the container closure system
Pump selection NB: Consider viscosity, density, surface tension etc.
Information in M3 needed on:
Container, closure, assembled pump and pump parts manufacturers
Unique identifiers for container, closure, assembled pump and pump parts
Engineering drawings with precise measurements of the above
Composition and quality of materials of the above
Control extraction methods & data for elastomeric and plastic components
Toxicological evaluation of extractables extractable profiles
Acceptance criteria (performance & dimensional), test methods, sampling
For products in semi-permeable containers need more detailed info on SECONDARY packaging components as need to protect entry of external contaminants from environment into drug product.
Dry powder inhaler testing
Testing (IPC):
Valve function: 100%
Leak testing: 100%
Weight Control - checkweigh
Crimp Control – diameter/height
Moisture (API/propellant/DPI)
Canister Marking
Testing (Release):
Fill weight/no. doses
Moisture Content
Identification
Drug Content (Assay)
Valve Delivery
Dose Delivered
Respirable Dose (Anderson/CI)
Impurities/Degradants
Particle Size (Malvern/Microscopy)
Leakage
Micro
Foreign Particulates
Dry powder inhaler types
Vapour Inhalers
Nebulizers (deliver drug combination)
Aerosol Inhalers
pMDI
DPI
Typical drugs given by inhalation
B2 adrenoceptor agonists: Salbutamol
Corticosteroids
Pressurised Metered Dose Inhalers (pMDI)
Micronised API powder suspended in propellant (Ventolin)
‘Blow’ effect from device generates the aerosol
Optimum particle size 5um
Water bath bubble test after filling (check for leaks)
Formulation: Aerosol filling consists of solution, suspension or emulsion of API under pressure with suitable propellants.
Typical propellant = butane, HFAs. Used to be CFCs but being replaced over time as v. bad for environment.
Surfactants used in formulation
Formulation must be non toxic
Device design critical
Design of mouthpiece/valve NB spacer may be used to aid with increasing travel time more time for particles to reduce in size before being inhaled
Valves NB – this meters the dose to the patient
Regulatory requirements more extensive than for DPIs wrt to propellant toxicity, leakage, spray patterns, leaching, pressure testing and reproducibility of valve operation.
Product left upside down for set period after filling to allow valve to ‘seat’
Annex 10: Manufacture of pMDI
Minimise micro and particulate contamination
Two common manufacturing and filling methods
Two shot system (pressure filling): API & propellant added to container separately.
One shot system (cold filling): API & propellant added to container at same time.
Closed system
Filling environment specified as Grade D
Propellants to be filtered to 0.2 micron
Emphasis on quality and cleanliness of valves, cans etc
Emphasis on check weighing (100% recommended)
Leak testing required. Water bath method generally not used, usually store cans then 100% check weigh.
