PH3114 Unit 2

quality assurance and manufacturing

contaminants in iv fluids

particles

air

microbes and their associated endotoxins

intrinsic sources of contamination

present to prior use

includes infusion fluids/additives, punctures/cracks in delivery containers, vacuum seal of bottles, infusion delivery sets, set ports, disinfectants and catheter dressings

extrinsic sources of contaminants

introduced in use

includes container changes, air vents, delivery set changes, bolus or concurrent injections/infusions, catheter insertion/manipulation, connectors, drug interaction (precipitation)

use of particulates

to target specific organs = controlled uptake of drug

slowed/controlled release of drug

detection in TQM

inspection and quality control

reactive and inefficient

quality assurance

concentrates on improved product, service and process design to stop non conforming products or services being produced or delivered in the first place

total quality management

sophisticated application of tools and techniques supported by more emphasis on people, process management, training development and greater focus on waste elimination

pure food and drug act of 1906

prohibited interstate commerce of misbranded and adulterated food and drugs

allowed seizure and criminal penalties

enforced by division of chemistry

1938 food, drug and cosmetic act

extended control to cosmetics and therapeutic devices

required new drugs to be demonstrated as safe before marketing

provided standards and safe tolerances

authorised factory insepections

1962 kefauver harris amendments

drug manufacturers required to prove drug effectiveness and safety to FDA before marketing

advertisements must show risk benefit

adverse effects must be reported to FDA

GLP

good laboratory practice regulations put into place in 1978 to assure a study validity

establish standard of practice that results from non clinical laboratory study are reported to FDA and that they are valid and accurately reflect the study

environmental protection agency

issued glp in 1983 to cover required health and safety testing of agricultural and industrial chemicals under FIFRA4 and TSCA5

OECD

economic cooperation and development to harmonise international trade

regulatory study def

when the regulatory authority to whom the data will be submitted to, requires that study to be conducted in compliance with the principles of GLP

FDA and aseptic processing

the suitability, efficacy and limitations of disinfecting agents and procedures should be assesses.

the effectiveness of these disinfectants and procedures should be measured by their ability to ensure that potential contaminants are adequately removed from surfaces

qualification of disinfectant

suspension test, carrier test, surface test

management def

the persons who have power and responsibility to direct resources and to ensure that the study conduct is in compliance with GLP regulations

study director def

serves as single point of study control and is responsible for overall study conduct

principle investigator def

individual who is appropriately trained, qualified and experienced to supervise delegated phases of study

QA personnel def

inspect site to ensure that the study is performed according to GLP. they check SOPs, master schedule, study plan and final report

written procedures def

provide instruction to user and are reviewed and approved by management and QA.

a periodic schedule of review and revision is established.

facilitate a quality audit that takes place after the study is complete

essential elements of SOP

purpose, responsibility of personnel, reference to other related documents, materials, equipment, procedure, approval

final study report

includes statement of objectives, description of all methods employed, all experimental data and results generated in conduct of the study, descriptions of all calculations, all conclusions drawn

raw data

any laboratory worksheets, memoranda, notes or exact copies thereof, that are results of original observations and activities

non clinical lab study

necessary for reconstruction and evaluation

contemporaneous documentation

data are recorded at the time the observation is made

original documentation

the first recording of the data, assumed to be the most accurate and reliable recording of the data

logbooks

written records that shall be maintained of all inspection, maintenance, testing, calibrating and/or standardization operations

archive

all study materials should be stored for 10 years after completion

reagent and solution regulations

label must indicate identity, titer, concentration, storage requirements and expiration date

corrective and preventative action

log and track all issues, assigning personnel to complete that, allocating resources for the completion, following each action to completion

responsibility of lab manager

GLP compliance

• document control system

• change control system

• metrology program

• quality assurance unit

equipment qualification def

documents that evidence instruments are fit for purpose and kept in state of maintenance and calibration

design qualification

performed by manufacturer

design of user requirement specification for intended application

defines the functional and operational specification of the instrument

installation qualification

covers installation of instrument up to and including initial turn on

operational qualification

follows installation qualification

repeated following relocation of instrument, maintenance of instrument and periodically at defined intervals

performance qualification

undertaken regularly during routine use

provides evidence that performance remains consistent and within required limits over time

initial performance qualification

holistic performance test to verify correct functioning and performance of entire system

analyses test mix on test column under defined operating conditions

allows performance to be compared to other instruments and throughout life

linearity of detector response

important for accuracy of results

determined by producing calibration curve of detector response against standard solution concentration

signal to noise ratio

important for sensitivity and limit of detection

determined by measuring detector response to blank injection compared to diluted standard solution

specificity def

ability to accurately measure analyte in the presence of all potential sample components

compare the response to analyte alone with response to analyte in test mixtures containing analyte and all other components

linearity def

verify that sample solution is within concentration range where analyte response is linearly proportional to concentration

test standard solutions at fiove different concentrations over a range of 50 to 150% of target analyte concentration

precision def

scatter in results obtained from multiple analyses of homogenous sample

• can be determined by repeatedly injecting into the same sample

• repeatability or intra assay precision can be determined by repeatedly analysing aliquots of same sample in same lab on same day

range

determined using data from linearity and accuracy samples

calculated from replicate analyses of spiked samples in accuracy study

limit of detection

lowest analyte concentration that produces a response that is detectable above noise

limit of quantitation

lowest level of analyte that can be accurately and precisely measured

ruggedness def

the degree of reproducibility of results obtained by the analysis of the same sample under a variety of normal test conditions

skin contamination

particles median size 20 microm

carry natural bacterial flora of the body

impervious clothing prevents dispersion of these cells

cleanroom def

special manufacturing facilities with control over the levels of contamination, both viable and non viable.

no. of particles less than 0.5 microm measured in one cubic foot of air

classification of clean rooms

as built = no equipment

with equipment but no personnel

fully operational

organism monitoring

air sampling = slit air samplers

settle plates = agar exposed to atmospheric air

contact plates = agar plates wiped on surface of units

finger dabs = glove testing

hot DOP test

filter efficiency test

detection of thermally generated particles of diocytylphthalate of average 0.3 microm

sodium flame test

filter efficiency test

detection of aerosolized sodium chloride particles of mass median size 0.6 microm

frame/seal tests

filter efficiency test

must be carried out after installation within working system

clean room validation and maintenance

1. check that design specifications have been met

2. check at specific intervals that area continues to operate within the limits required

conventional cleanroom

air supplied via air conditioning plant through ceiling diffusers

• increased air supply

• high efficiency particle air filters

• pressurised rooms

• building materials do not generate particles and are easy to clean

may be class 1,000 but more likely 10,000

unidirectional clean rooms

flow of air one direction, either vertical or horizontal, with uniform speed between 0.3 to 0.45m/s

problem when equipment and personnel convert laminar air to turbulent air flow

cleanliness directly proportional to air velocity

mixed ventilation clean rooms

conventional clean room with the critical work zones isolated within a unidirectional flow system

cheaper, unidirectional air flow systems only required in critical work areas

hepa construction

large surface area of filter paper in a frame with no leakages of unfiltered air

aluminium foil separator

mechanisms of particle removal

• diffusion (small particles)

• impaction (large particles)

• interception (medium particles)

• sieving

isolator def

free standing enclosures equipped with integral hepa filtered air supply that allows employees to manipulate products using either flexible sleeves and gloves or flexible suits that comprise part of one wall of the isolator

cleanroom rules

• minimise number of people and no personal articles

• know proper gowning technique

• cannot return to air lock and come back without regowning

• know disinfection techniques

• clean up immediately

• use intercom for external communications

particle size analysis

particle characterisation, particle counting and xamination of particle size distributions

important particle size analysis factors

• knowledge of sample materials properties

• sampling

• expected results and data presentation

• knowledge of particle size analysis techniques

• handling of sample material and its carrier vehicle

visual inspection

most important method

improve observation conditions (black and white backgrounds, good lighting, angled lighting, fibre optic lighting)

if particles can be seen with the naked eye then other techniques will give false results

optical/light microscopy

cheap and rapid

quality and calibration of microscope important

sample must be representative

problems include contamination and operator error

electrical sensing zone

measurement of change in electrical resistance across a glass aperature orifice when the sample particles are drawn through the orifice

resistance change proportional to size of particle

light blockage

measure of obscured white light or laser projected beam

bp recommended method for QC assessment of particulates in injectable products

counts particles 1 microm or greater

laser light scattering methods

rapid and accessible

scattering and diffraction methods

sample prepped in liquid or air, media where particle is insoluble

problems with sedimentation rate

photon correlation spectroscopy

side scatter

small particles = rapid and weak scatter at wide angles

large particles = slow and strong scatter

brownian motion so dependence on viscosity and temp so particle shape effects are minimised

diffraction

large particles = scatter light at narrow angles

small particles = scatter light at wide angles

background noise and sample prep important

rapid method of analysis