Solid Oral Dosage Forms 7 Flashcards
What are samples taken for?
Test on raw materials- identity, assay, contamination/adulteration
In process tests- mix quality, validation of equipment or process
Sampling solid raw materials
Best method is to take from moving stream
Possible to sample limited number of containers if supplied from approved reliable audited source
If more than 1 take samples from either √N + 1 or
10 + (N/10) containers
Take number of samples, test identity of each one then combine for assay
Sampling thief
Simple tube with chamber in end, opened by twisting
Get sample of material that flows best
Depends upon operator, need training in technique
Sample size reduction- representative sample
Scoop 7% Mix and quarter 4% Chute splitter 2% Spinning Riffler 0.5% Smaller samples use sampling thief
Spinning riffler parts
Mass flow hopper
Vibrating chute
Rotating carousel
Sample containers
Sampling for verification
Looking for homogeneity
Take samples from various positions in drum/mixer
Sampling theory for inspection
Medicines manufactured in millions of units
100% sampling possible
Test on samples are destructive
Based on probability theory
Quality assessment: inspection plans
Conformity and non-conformity
Attributes- visual: large samples, robust, not affected by distribution shape
Variables- dimension: smaller samples, affected by distribution shape, takes more time, gives process average
Finished product: inspection by sampling
Problem, if fault levels low, how to estimate quality of lot from sample
Producer’s risk- chance of rejecting acceptable batch
Consumer’s risk- chance of approving rejectable batch
Inspection by sampling: BS6001
Acceptable quality levels: maximum percent defective that can be considered satisfactory as process average
Acceptable outgoing quality level: maximum average outgoing quality for given acceptance plan
Inspection plan: visual quality
Major faults- stop process or product working correctly
Minor faults- cosmetic in nature
Major faults accept 0.015%
Minor faults accept 0.4%
Inspection plans: criteria
Measurements are subjective, not a precise value
Can only compare data if method is strictly controlled- lighting, time, viewing conditions
Operators must be trained in inspection
Validation and qualification
Validation: act of proving in accordance with GMP that any procedure, process, equipment, material, activity or system leads to the expected results
Qualification: act of proving that any equipment works correctly and actually leads to expected results, sometimes widened to incorporate concept of validation
Validation
Set objectives and acceptance criteria Write protocol Organise team Assess results Final report, including information for future production e.g. specifications and limits
Agitator mixer
Ribbon blender
Main mechanism- convection
Good for mixer poorly flowing materials, less likely to cause segregation
Problem- elimination of dead spots
Cleaning
Equipment and area
Cross contamination- active ingredients, inactive materials
Microbiological- non-sterile products, sterile product
Cleaning validation active ingredients
Potency Precision of assay Properties of all materials Process, detergents Determination of contamination
Cleaning and contamination
Equipment logs- products, people, tasks
Area logs- product, people, tasks
Environmental monitoring- bio-burden, indicator before problem occurs
Factory design
Control of people and product flow
Use gravity to transfer bulk materials
Restrict access to clean manufacturing areas
Minimise contamination of non-clean areas with active materials
Supply services, electricity, water, compressed air, vacuum, outside of clean area, supply through walls directly to machines
Dry products factory
All services to clean area accessed from technical area
Through the floor feeding from supply to manufacturing to delivery
IBC docking station
Powders delivered from sealed containers through floor to tabletting/capsule filling machine on floor below
Environmental monitoring- physical
Pressure
Non-viable particle count
Air flow velocity
Air change rate
Environmental monitoring-microbiological
Active air sampling- known volume drawn through filter
Settle plates- 90mm diameter, for 4 hours
Contact plate- 55mm diameter
Glove print, 5 fingers
Printed packaging
Fixed information- pre-printed, labels, cartons, leaflets
Variable information- lot number, expiry date
Most frequent cause of product recall- product in wrongly labelled package
Complaints and product recalls
Designated person for each
Written up to date procedures
Actions- identify problem, lots involved, every step documented, notify authorities, records of supply, system to alert supply chain, system for returning, investigation and destruction
MHRA
Manufacturer needs to show- right facilities and equipment with properly trained and qualified people
Medicines inspectors- ensure compliance with GMP, carry out inspections of factories and make constructive audits
Harmonisation
Pharmaceutical Inspection Co-operation Scheme- mutual acceptance of inspections, exchange of reports, training of GMP inspectors promoting international harmonisation
EU/FDA mutual recognition agreement
International Standards Organisation 9000
Applies to companies that manufacture and sell
Certification by approved independent bodies
Advantages- partnerships in quality e.g. on time delivery, customer confidence, less testing
Post registration changes
Formulation and manufacturing process is that used for batches on which product was approved
Problems in changing this to improve process
Initiatives in quality systems
Process Analytical Technology- significant improvements in instrument technology, miniaturisation and portability. Enables measurement of key properties in real time during manufacture
Quality by Design- applies techniques used in other industries to better understand how processes work and the variables to design a system that will always produce the correct product
USA FDA: quality by design
Define desired product performance upfront; identify product CQAs
Design formulation and process to meet product CQAs
Understand impact of material attributes and process parameters on product CQAs
Identify and control sources of variability in material and process
Continually monitor and update process to assure consistent quality
Process capability
A statistical measure of inherent process variability for a given characteristic
Process capability index = upper limit - lower limit/ 6 standard deviation
Robust process if CpK significantly >1
EMA FDA cooperation
Pilot program for parallel assessment of quality by design applications to ensure consistent implementation of ICH Q8, 9 and 10 guidelines and share regulatory decisions on new concepts
Share knowledge and further collaboration
Better defined interaction
Variations during manufacture
Materials- different suppliers or within lot variations
Machines- different equipment, different adjustments, poor maintenance
Methods- inexact, inadequate procedures
People- training, team work, motivation
Package functions
Contain
Protect- damage, contamination, tampering
Identify- batch number, manufacturer
Provide information- usage, warnings, storage
Self inspection
Check implementation and compliance with GMP
Trained people and external experts
records- observations, corrective measures, actions
Packaging security
Secure storage Security for issue Security in transfer Counting and reconciliation Line clearance checks Code readers- on-line, bar codes
