sterilization process

1. PRODUCTION LINE
SCALING UP , PROCESSING ,
BATCH RECORD DESIGN
Sterile Dosage Forms
Alaa Mohamed deabes

2. parenteral Ophthalmic
Sterile Dosage Forms

3. Sterile Pyrogen free
 Sterile products are
dosage forms of
therapeutic agents
that are free of viable
microorganism.
 Sterility is absolute
term.
 Pyrogens are substances
that produce a fever. The
most common pyrogens
are endotoxins, produced
by G-ve bacteria .
 Thermostable
Sterile Dosage Forms

4. Pyrogen
 Removed by oxidizing to easily eliminated gases or to
non volatile solid easily separated by fractional
distillation .
Several distillation
are done , purified
sterile , pyrogen free
Pyrogen test
In vivo ( rabbit )
In vitro
Limulus amebocyte
lysate LAL

5. Distilled
water Purified
water
Type of water

6. Solvent and vehicle for injections
Water for injection WFI
Sterile water for injection SWFI
Bacteriostatic water for injection
Nonaquous vehicle

7. Water for injection WFI
Purified by distillation or
reverse osmosis

8. Water for injection WFI
 It is not sterile
 No added substance.
 For manufacture of injectable products which are to
be sterilized after preparation.
 Used withen 24 hr after its collection.
 Collected in sterile and pyrogen free container glass
or glass lined.

9. Sterile water for injection SWFI
 Sterile
 Pyrogen free
 No bacteriostatic or other added substance
 Contain greater amount of solid than WFI Why
Diluent for
already sterilized
and packaged
injectable
medication
Used
IV
Not
used

10. Sterile water for injection SWFI
 sterilised within 12 hours of collection and
distributed in sterile containers
 It should be packaged only in single dose containers
of not larger than 1-litre size

11. Bacteriostatic water for injection
 Sterile water for injection contain antimicrobial agents .
 containing 0.9% (9 mg/mL) of benzyl alcohol added as
a bacteriostatic preservative . Package is not more than
30 ml of water .
 can be used in diluting drugs that can subsequently be
administered by intravenous, intramuscular, or
subcutaneous injection.
Why

12. Nonaqueous vehicle
 Substance liable to hydrolysis
 Substance insoluble in water
 Must be non toxic , non irritating
 without pharmaceutical activity
 Viscosity & pH must be suitable
 Misciblity with body fluid
Glycerin , PEG , Fixed vegetable oil ,
Alcohol

13. Sterilization
• Saturated steam under
pressure
• Dry heatclassical
• Filteration
• Ionizing radiation
( gamma , electron
radiation )
• Gas ( ethylene oxide,
formaldyde)
others

14. Microbial destruction
D value
Z value
F0
Time required to reduce the bioburden
by 90%
D =
U
Log N0 - logNu
Exposure time
Original bioburden Remaining populaton
Diff in temp requried to change D value
by 90%
Z =
T2 –T1
Log D1 –log D2
F0 = D121 ( logN0 – logNu )
Autoclave
Z value based on B.stearothermophilius

15. Steam
sterilization
( autoclaving)
1) Mechanism
2) for what
3) Not for
what
4) Air most
removed
115.5 for 30 min
121.5 for 20 min
126.5 for 15 min
temp Time
Most
common
121 ±2 °C

16. Temperature distribution Heat penetration
 On empty & loaded
chamber
 Coldest spot during
empty ch to provide the
slowest heating
location
 15 – 20 thermocouples
 Any deviation more
±2.5 °C ….. Undesirable
 Depend on the thickness
of the container
 Coldest point in the
product load
 Container similar to
formula and put B.S
 Biological is paced with
thermocouples ( location)
 F0 is determinded
Validation of Steam sterilization
( autoclaving)IQ
OQ

18. Dry heat
sterilization
1) Mechanism
2) for what
3) Not for
what
160 for 180 min
170 for 60 min De
pyrogenation

19. Dry heat sterilization valdiation
 Designed as overkill that deliver heat in excess than
that required to inactivate 1000 EU of E.Coli
endotoxin ( challenge)
 USP recommends a 3-log reduction in endotoxin
using lamulus amebocyte lysate reagent with a
senseitivity greater than 0.15 EUml
 All pervious tests in addition to pyrogen test

20. Filtration
1) Mechanism
2) For what
3) Disadvantages
Pore size 0.22
micrometer
Double filter
layer or second
filtration
Don’t use more
than 24 hr * *
 Membrane filters : cellulose esters ,
plastic ..
 Asbestos-containing filters should
not be used. Or fiber shedding
 followed by an aseptic transfer of
the sterilized solution to the final
containers
 All filters, tubes, and equipment
used "downstream" must be sterile
( autoclave)
 Filter integrity test
 filters should not interact with the
product

21. Radiation
1) Mechanism
2) For what
3) Disadvantages
 Laws and regulations for
protection against radiation must
be respected.
 Radiation doses should be
monitored with specific
dosimeters

22. Aseptic sterilizationTerminal sterilization
 Drug product & container
& closure are first
sterilized separately.
 Each aseptic process can
introduce error .
 Only used when terminal
sterilization is not
feasible.
 Product in its final
container is sterilized as
whole.
 Can be manufactured
under clean rather than
aseptic .
 most common ??
Sterile Dosage Forms

25. Air classification system
 B at rest = A at operation
 C at rest = B at operation
 D at rest = C at operation
 A for high risk operation
 B surround area A
 C & D for less critical stages

29.  For ISO 7, particles smaller than 0.5 microns (≥0.1
µm, ≥0.2 µm, ≥0.3 µm) are not taken into
consideration. The concentration of particles of ≥0.5
µm and above should be below 352,000, for particles
of 1 micron and above 83,200 or lower and for
particles of 5 microns and above 2,930 or lower.

30. HEPA Filters
 High-efficiency particulate air (HEPA) filters
 Can remove at least 99.97 % of dust , pollen , mold ,
bacteria and any airporn particle 0.3 microgram

31. HEPA Filters
 Air cleanliness is achieved by passing the air through
HEPA filters. The more often the air passes through
the HEPA filters, the fewer particles are left in the
room air.
 Number of air change with hour =
Volume of air filtered by one hour /volume of the room
ISO class Average number of air changes per hour
ISO 5 240–360 air changes per hour (unidirectional
airflow)
ISO 6 90–180 air changes per hour
ISO 7 30–60 air changes per hour
ISO 8 10–25 air changes per hour
Conventional building 2–4 air changes per hour

32. ISO 5 (A) (100)
 use unidirectional airflow
 (not just below a LAFW hood)
 ISO 5 zone | 240–360 air changes per hour
Entry
Air
lock

33. must be taken into consideration
 the size of the room,
 the number of people in the room,
 the equipment in the room,
 the processes involved,
 the heat gain, etc

34. Laminar flow hold

36. Production line

37. Closed
container
Other
ointment
Suspension

38. ideal Cost

39. AB BC
Eye drops
Aseptic

42. Flow chart of sterile dosage form
IPC
Raw material
AI + additive +pack
Engineering
chart
Sizing and
sieving
Ball mill
Sieving machine
Det of particle
size
Drying Tray dryer
Det of moisture
content
Weighing Electric balance
Douple chek
Wt
WFI Line

43. Flow chart of sterile dosage formsolution
Dissolving
Det of sol ,temp,
Water quality ,pH
Mixing &
Dilution
Propeller
Trubine mixer
( viscous)
Propeller
Trubine mixer
(viscous)
Det of sol ,temp
SP gravity , volwt
PH adjustment pH meterpH determination
Filling &
sealing
sterlization
Sterile
filteration
Aseptic filling
F drying
Aseptic sealing
Filling
machine
autoclave
Sterility ,
Leakage ,
Gross Wt ,
VolWt of*
Container
suitablity
Terminal

44. Flow chart of sterile dosage form
Emulsion
suspension
gel
Dissolving & filteration
Meta filter
Turbine mixer
( viscous)
Det of sol ,temp,
Water quality ,pH
1 ry emulsion
1 ry suspension
Conc gel
Collid mill
High speed
agitator
Sterlization for oil
,powder, aq
Mixing & dilution
PH adjustment
Make up to volume
Turpine mixer
pH meter
Filling, Capping ,
Sealing
Rh , Vis,
Creaming rate
Rh , Vis, Sed rate
Rh , Vis , gel
stregnth
pH
determination
Dryness
Gross Wt
Leakage
Sterlity test
Filling machine

45. Flow chart of sterile dosage formOintment
Dissolving &
sterilization
Oily base melting &
sterlization
Meta filter
Turbine mixer
( viscous)
Det of sol ,temp,
Water quality
,pH
DJ-SH melting
tank
Aseptic mixing &
homogenization
DJ-SH melting
tank with
agitator
Aseptic tube filing &
sealing & labelling
Filling machine
Gross Wt-
leakage
Temp –mix time
Homogeneity
Oil glob size
Wt –clarity –
temp

46. Flow chart of sterile dosage form
Packaging
Labelling , cartoning
Package
machine
Recon of label ,
carton data,
good packaging
Inspection of
pamphlet &
leakage test
Intermediate
store
Quality control
Final store
Content uniformty
Volwt check
Viscosity –
rheology Clarity
Sed rate – cream
rate
Gel stregnth
Consistency
Spreading
Gritty sensation
Strility test

47.  https://www.sciencedirect.com/topics/chemistry/py
rogen
 http://www.authorstream.com/Presentation/tausif1
991-1795419-design-layout-operational-facilities-
sterile-products/
 https://www.slideshare.net/shettyuc/cgmps-for-
sterile-products
 https://www.sciencedirect.com/topics/engineering/
terminal-sterilization
 https://www.sciencedirect.com/topics/agricultural-
and-biological-sciences/aseptic-processing
Reference

48.  https://www.google.com/search?q=air+classificatio
n+system&source=lnms&tbm=isch&sa=X&ved=0ah
UKEwjq0p2QysXhAhUFxhoKHRy_CaYQ_AUIDigB
&biw=1366&bih=604#imgrc=ij9hpgPzJYLM6M:
 http://www.hefilter.com/Industry-News/Common-
Types-of-HEPA-Filter.shtml
 https://www.mecart-cleanrooms.com/learning-
center/cleanroom-classifications-iso-8-iso-7-iso-6-
iso-5/
 https://www.slideshare.net/yuvas2010/377218gmpt
rainingsterilefacility
Reference