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Sterile Overview
Index
1- Definitions
2- Sterile Basic GMP
3- Sterilization Methods/ Sterile Process
4- Qualifications/ Media fill
Definitions
Sterile product: A dosage form free from living microorganisms and
pyrogen.
Endotoxin :An endotoxin is a lipopolysaccharide (LPS) found in the
cell wall of gram-negative bacteria. It is a typical pyrogen.
Bio-burden: referring to the number of microorganisms on a surface or
within a liquid
CFU : colony forming unit
Aseptic: Is the practice to reduce or eliminate contaminants (such as
bacteria , viruses, fungi, and parasites)
Terminally sterilized product :Terminal sterilization is defined as the
“process where product is sterilized after being filled in its container.
Pharmaceutical products classifications
Two main classes
1- Sterile products
2- Non- Sterile products
• Examples of sterile dosage forms
Ampoules
• Examples of sterile dosage forms
Vials
- Glass
- Rubber Stopper
- Flip off
• Examples of sterile dosage forms
Eye drops
• Examples of sterile dosage forms
Large volume parenteral
Part 1
Sterile Basic GMP
What is GMP ?
Aspect of Quality Assurance that ensures that
medicinal products are consistent.
produced and controlled to the quality standards
appropriate to their use and as required by the
product specification.
(World Health Organization)
Overview of main GMP
components
1. Facilities
2. Environment
3. Personnel
4. Sanitation & Hygiene
5. Equipment
6. Materials
7. Production & Quality Processes
8. Packaging & Labeling Control
9. Handling & Distribution
10. Laboratory Control
11. Records & Reports
12. Returned Drug Products.
1. Facilities
• Minimum risk for contamination of products and materials.
• Pollution Level.
• Noise Level.
The layout and design should aim to:
• Permit effective cleaning.
• Avoid cross-contamination, build-up of dirt and dust.
• Separate material and personnel flow.
• Clear and logical process flow.
Production Areas
• Rest rooms separate from manufacturing and quality
control areas.
• Maintenance workshops separated from production –
if not possible – tools in reserved areas.
• Interior surfaces (walls, floors, ceilings) – smooth,
free from cracks and open joints.
• Drains of adequate size, and equipped to prevent back-
flow.
• access restricted
-Smooth wall and floor Surface
-No sharp edges
Storage Areas
• Sufficient capacity.
• Separate and segregated areas.(hold/released and
reject)
• Facility to clean incoming materials.
• Use of air curtains.
• Appropriate temperature and relative humidity`.
• Good storage conditions: clean, dry and appropriate
lights.
• access restricted
Weighing Booth
Weighing areas
• different path flow for materials and personnel.
• one material to be weighed under weighing booth to
prevent any cross contamination.
• In case of weighing photosensitive materials, sodium
lamp should be used and weighed material is kept in
opaque/black bags.
2. Environment
Temp
.
RH
Pressure
2. Environment
Cleanroom:
A room in which the concentration of air particles is controlled,
and which is constructed and used in a manner to minimize the
introduction, generation, and retention of particles inside the room
and in which other relevant parameters, e.g. temperature,
humidity, and pressure, are controlled as necessary.
Device for monitoring
1- RH
2-Temperature
3-deffrential pressure
2. Environment
Heating Ventilation Air Conditioning system and Air Handling Unit
HVAC system and AHU
2. Environment
Airlock type Definition
Cascade airlock Higher pressure on one side of airlock and lower
pressure on the other
Sink airlock Lower pressure inside the airlock and higher pressure
on both outer sides
Bubble airlock Higher pressure inside the airlock and lower pressure
on both outer sides
2. Environment
Pressure Difference and Airflow Pattern
• A pressure difference of (Min. = 12.5 Pa) is often used to achieve
containment
• between two adjacent zones of two different cleanliness grades
• Diff. pressure between 2 classes = 15-20 Pa
Diff. pressure within the same class = 5-10 Pa
2. Environment
2. Environment
Condition Definition
As built condition where the installation is complete with all
services connected and functioning but with no
production equipment, materials, or personnel
present.
At rest condition where the installation is complete with
equipment installed and operation in a manner agree
upon by the customer and supplier, but with no
personnel present.
In operation condition where the installation is functioning in the
specified manner, with the specified number of
personnel and working in the manner agreed upon.
2. Environment
Points to consider for Aseptic Processing
PDA – Jan 2015
Environmental Monitoring
• Grade A and B or Product contact surface contamination should be investigated and
the impact on any production batches should be assessed prior to batch release.
(N.B: For Grade A, any micro-organism present would require action).
3. Personnel
• Regular washing and bathing/daily shower.
• Teeth brushing/ good oral hygiene is important.
• Ear wax/ nose to be cleaned regularly before entering cleanroom.
• Face, hands and fingernails must be clean at all times.
• Hand washing and drying
• Don’t smoke in cleanroom – don’t smoke for 30 min. before entering.
• If you are ill, inform your supervisor. You may not be able to enter
manufacturing area until you are better.
Personnel
• High standards of hygiene and cleanliness
• Periodic health checks
• No shedding of particles
• No introduction of microbiological hazards
• No outdoor clothing
• Changing and washing procedure
• No watches, jewellery and cosmetics
Personnel
DO VS Never DO
Wash your hands Brush your hands
DO VS Never DO
Keys, coins, cigarette, matches, Never eat, drink, chew gums
Watches, jewelry should be kept inside cleanroom.
in your locker. Do Not store food in your locker.
Behavior inside cleanroom
Moving fast =
Turbulence = Vortex = Moving slowly
Particulate dispersion = Contamination
Behavior inside cleanroom
Do not be a barrier against air flow movement towards items.
Behavior inside cleanroom
Behavior inside cleanroom
Handle the item so as not to intersect
air flow over it
Behavior inside cleanroom
Upon dropping a tool,
it should not be used
again, unless
cleaned/disinfected
Item Design and Arrangement
inside cleanroom
Solid top - workstation Perforated top - workstation
Part 2
-Sterilization Methods
-Sterile Process
Sterilization
• Sterilization describes a process that destroys or
eliminates all forms of microbial life and is carried
out in health-care facilities by physical or chemical
methods. ..
• Sterilization Methods :-
• 1- Moist Heat Sterilization
• 2- Dry Heat Sterilization
• 3- Filtration (0.22 µm sterilizing grade filter)
• 4-ethylene oxide
• 5-Radiation
Sterilization (Moist Heat)
Conditions:-
1- Sterilization Temperature is 121.1 c for exposure time of 20 minutes
(commonly used approach)
2- Time, temperature and pressure should be used to monitor the
process
Machines:-
1- Tools Autoclave
2-Terminal sterilization Autoclave
3- SIP Tanks
Sterilization (Dry heat)
Conditions:-
1-Belt speed within sterilizing zone.
2-Temperature – Minimum and maximum temperatures.
3- Heat penetration of material
4-Heat distribution/uniformity
Machines:-
1- Tunnel (Ampoule / vials de pyorgenation)
2-Oveans
Sterilization (Filtration )
• Passing the Non-Sterile product through
0.22 µm sterilizing grade filter, to remove
any microorganism out of the product
Basics of Sterile Manufacturing
Key process components & Process description
Sterile drug production by “Aseptic Processing”
Part 3
- Qualification
- Media fill
Qualification is defined as an action of providing that
equipment or systems are properly installed, work correctly,
and actually lead to the expected results.
Equipment(Autoclave – tunnel – tanks…)
Media fill tests
Cleanroom
Calibration is a comparison between a know measurement
(the standard) and the measurement using your instrument.
Media Fill
• A media fill is the performance of an aseptic
manufacturing procedure using a sterile
microbiological growth medium, in place of the drug
solution, to test whether the aseptic procedures are
adequate to prevent contamination during actual drug
production.
• Media fill testing is just one part of a necessary overall
quality assurance program (HVAC qualification, cleaning
procedure, sanitization, personnel training, …)
Media Fill
• It is usual to include the “worst case”
conditions that can occur in production
runs
Which kind of interventions have to be
considered ?
Media Fill
Key element: interventions –both routine and
non-routine-
The interventions should simulate what occurs in a production run;
media fill records should document all interventions performed and the
number of units removed.
Routine interventions: aseptic line set-up in which sterilised parts are
removed from protective materials and installed is a potential danger; it
is common to identify the first containers filled as they may be more
indicative of potential problem with aseptic assembly.
Other routine interventions: stoppers bowl feeding, remove fallen vials,
remove jam stoppers, operators breaks, gloves change, environmental
monitoring.
Non routine interventions (occur randomly): glass breakage,
change / reset of filling needles, interventions on weight adjustments,
sensor failure, rail adjustments
Media Fill
The root cause of a failure (contamination), or at least the
most probable one, must be identified
It is important to be able to isolate and identify (to species
level) the microorganisms
An appropriate corrective action / preventive action plan
must be implemented
The impact of the failure on product lots already released (if
any) must be evaluated
After the corrective actions have been implemented, a new
media fill study is performed to confirm their efficacy
References
• WHO GMP guidelines – Technical Report series
n. 937
• EU GMP guidelines, Part I annex 1 & 15
• ICH Q7A or EU GMP Part II chapter 13
• FDA Guidance for Industry: sterile drug products
produced by aseptic processing cGMP
• PIC/S Recommendations PI 007-5
• USP <797> ‘media fill testing’ / <71> ‘growth
promotion test’
• EP 2.6.1 ‘sterility’
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