Solid Oral Dosage Forms 7 Flashcards by Siobhan Nickels

What are samples taken for?

Test on raw materials- identity, assay, contamination/adulteration
In process tests- mix quality, validation of equipment or process

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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

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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

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Sample size reduction- representative sample

Scoop 7%
Mix and quarter 4%
Chute splitter 2%
Spinning Riffler 0.5%
Smaller samples use sampling thief

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Spinning riffler parts

Mass flow hopper
Vibrating chute
Rotating carousel
Sample containers

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Sampling for verification

Looking for homogeneity

Take samples from various positions in drum/mixer

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Sampling theory for inspection

Medicines manufactured in millions of units
100% sampling possible
Test on samples are destructive
Based on probability theory

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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

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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

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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

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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%

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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

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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

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Validation

Set objectives and acceptance criteria
Write protocol
Organise team
Assess results
Final report, including information for future production e.g. specifications and limits

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Agitator mixer

Ribbon blender
Main mechanism- convection
Good for mixer poorly flowing materials, less likely to cause segregation
Problem- elimination of dead spots

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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 ```