aspetics Flashcards
What does GMP cover in manufacturing process?
- quality management
- personnel
- sanitation
- building, facilities, equipment
- documentation
Why is documentation essential to GMP?
- prevents errors associated with verbal communication
- helps tracing of manufacturing history of pharmaceuticals
- ensures reproducibility in all aspects of manufacturing
document specificity order (4)
- quality manual (least specific)
- company policies
- SOPs
- specifications, validation documents, batch records, logbooks
What are quality manuals?
a guide to introduce GMP for medicinal products and devices
What are company policies?
describe in general terms how specific aspects of GMP will be implemented
eg. how staff will receive training to do their jobs properly
What are SOPs?
a series of step by step instructions to help carry out complex routine operations
What are SOPs often based on?
specifications/requirements from the Pharmacopoeia and company policy
What is the focus of SOPs?
on the repetition of a process with no deviations
What do SOPs allow for?
- consistency
- allows for errors to be tracked and identified
- can be used as a reference by employees
Who writes SOPs?
QC personnel
What are SOPs based on?
Pharmacopeia requirements and company policy
What are specifications?
exact requirements for raw materials, packaging materials and final products
What are validation documents?
documentation that provides a high degree of assurance that a planned process will perform consistently
What are batch records?
records specifically what happens for each batch
who made it, when, which equipment
What are logbooks?
forms used to record operations
cleaning, servicing etc.
4 stages of qualifications
- design qualification DQ
- installation qualification IQ
- operation qualification OQ
- performance qualification PQ
What does DQ demonstrate?
that the proposed design will satisfy all the requirements are suitable
eg. facility design
What is IQ?
ensuring equipment is installed, operated per manufacturer’s specifications and documentation is in place for continued use
What is OQ?
demonstrates that equipment/process works properly
establishes worst case scenarios
What is PQ?
demonstrates that process/equipment works properly over time
should maintain data to show performance over time
What is validation?
the process of getting evidence that your procedure maintains compliance at all stages
4 types of validation
- prospective
- concurrent
- retrospective
- revalidation
What is prospective in validation?
establishes documented evidence of what a system does based on a plan
What is concurrent in validation?
establishes documented evidence of what a system does based on a system that is implemented
What is retrospective in validation?
establishes documented evidence of what a system does based on previously acquired data
What is revalidation in validation?
process which occurs after a change in the process takes place which could have an impact on efficacy or safety
(when something goes wrong)
2 types of sterilisation?
terminally sterilised
aseptically manufactured
What is terminal sterilisation?
product is manufactured and packaged then subjected to a sterilisation process
What is aseptic preparation?
separate components of a drug subjected to sterilisation prior to packaging
Which sterilisation could introduce a contaminant easier?
aseptic preparation
Which sterilisation minimizes bioburden?
terminal sterilisation
What sterilisation if preferred?
terminal sterilisation
Why is terminal sterilisation preferred?
- actually kills microorganisms
- reliable sterility assurance level can be calculated
When is aseptic preparation used?
not all drugs can be terminally sterilised
- API may require sterilisation by a different method to containers
- API may require reconstruction before use due to stability issues
3 methods used to assess risk of microbial contamination
- hazard analysis critical control points (HACCP)
- failure mode and effects analysis (FMEA)
- fault tree analysis (FTA)
Where is hazard analysis critical control points used?
food industry
becoming more common in pharmaceutical manufacturing
7 principles of HACCP
- perform hazard analysis and ID preventative measures for each stage
- determine critical control points (CCP)
- establish target levels and critical limits
- establish a monitoring system of CCPs
- establish what corrective action occurs when something goes wrong
- establish a verification system to make sure its working properly
- establish a record keeping system
When is each principle of HACCP addressed first?
during initial design and IQ
When are HACCP principles checked and monitored?
during OQ and PQ
4 grades for facility design of sterile products (WHO/EU standards)
A, B, C, D
When are grades C and D used?
clean areas for carrying out less critical stages in the manufacture of sterile poducts
When is grade B used?
aseptic preparation and filling
background environment for grade A zones
When is grade A used?
local zone for high risk operations
eg. filling zone, stopper bowls, open ampoules and vials, masking aseptic connections
ISO standards compared to WHO/EU standards
ISO 1-8
A/B = ISO 5
C = ISO 7
D = ISO 8
What is a cleanroom?
a contained space where airborne particulates are controlled and environmental conditions controlled as needed
basic requirements for a cleanroom
- floors, walls, ceilings: coated with chemically resistant materials
- exposed surfaces: smooth and sealed to minimize accumulation of dirt
- equipment, fixtures: can be on movable surfaces to facilitate cleaning
other considerations for a clean room?
- air locks: buffer zone prevention of contamination entry of all air substances/personnel into a clean room must occur via air-lock systems
- interlocking system: ensures doors are never open at the same time, mechanical (high risk area) or alarm (low risk area)
- separate entries/exits: for personnel, raw materials and products (pass thru hatch)
When are the considerations for a clean room addressed?
during the DQ and IQ phases of setting up a facility
How to reduce the risk of people contaminating a clean room?
- ensure staff are properly trained
- provide specialised equipment
- minimize personnel in the clean room at one time
What to wear at ISO level 8?
beard cover
hair cover
lab coat
What to wear at ISO level 7?
beard cover
hair cover
lab coat
What to wear at ISO level 6?
beard cover face mask booties coverall gloves hair cover
What to wear at ISO level 5?
beard cover face mask booties coverall gloves hair cover hood
What to wear at ISO level 4?
beard cover face mask booties coverall gloves hair cover hood
What filters do clean rooms use for airflow?
HEPA or ULPA
How efficient are HEPA filters?
remove 99.9% or particles > 0.3 micrometers
How efficient are ULPA filters?
remove 99.999% of particles > 0.1 micrometers
2 airflow principles in HEPA/ULPA filters?
laminar
turbulent
What is laminar air flow?
unidirectional flow, constant velocity
influenced by wall curtains, machinery
What is turbulent air flow?
random directions
non specific velocities
3 types of airlocks?
cascade
bubble
sink
How do airlocks work?
use pressure differences between spaces to stop particles moving between areas
usually 10-15 Pa between areas
Where are samples taken for monitoring of clean rooms?
- physical (pressure, particles, temp, RH)
- microbiological
- personnel (gloves, nails)
- surfaces (swabs, contact plates)
How often is monitoring done in each classification?
grade A - once per shift grade B - daily grade C - weekly grade D - monthly UDAF B - once per shift UDAF C - weekly UDAF D - monthly
How long are settle plates exposed for?
4 hrs
if less than 4hrs, limits applied
if process > 4hrs, change plates at 4hrs
microbial limits in air samples for each grade A-D
A - <1 CFU/m squared (should be 0)
B - 10
C - 100
D - 200
When are particulate levels monitored?
- in use - normal operations with personnel present
part of routine environmental monitoring - at rest - all equipment, control systems in place but not running, no staff present
not part of routine environmental monitoring
How are particles measured in particulate monitoring?
by a light scattering instrument
What happens if limits are broken?
need to establish how and where problem has come from
Why is aseptic preparation relevant to clinical pharmacy?
because not all drugs can be ready made
eg. TPN bags, chemotherapy and radiopharmaceuticals, extemporaneous preparations
