Sterile Dosage Forms

PRODUCTION LINE
SCALING UP , PROCESSING
, BATCH RECORD
DESIGN
 Sterile Dosage Forms

parenteral Ophthalmic
 Sterile Dosage Forms

Sterile Pyrogen free

Sterile products are Pyrogens are substances

dosage forms of that produce a fever.

therapeutic agents The most common
that are free of viable pyrogens are endotoxins,
microorganism. produced by G-ve
bacteria .
Sterility is absolute
Thermostable
term.
 Pyrogen

Removed by oxidizing to easily eliminated gases or to

non volatile solid easily separated by fractional
distillation .
Pyrogen test

Several distillation
In vivo ( rabbit )
are done , purified
sterile , pyrogen free
In vitro
Limulus amebocyte
lysate LAL
 Type of water

Distilled
water Purified
water
 Solvent and vehicle for injections

Water for injection WFI

Sterile water for injection SWFI

Bacteriostatic water for injection

Nonaquous vehicle
 Water for injection WFI

Purified by distillation or
reverse osmosis
 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.
 Sterile water for injection SWFI

Sterile
Pyrogen free
No bacteriostatic or other added substance
Contain greater amount of solid than WFI
Why

Not
Used
Diluent for used
already sterilized IV
and packaged
injectable
medication
 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
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 .
Why
can be used in diluting drugs that can subsequently be
administered by intravenous, intramuscular, or
subcutaneous injection.
 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
 Sterilization

• Saturated steam under

pressure
classical • Dry heat

• Filteration
• Ionizing radiation
( gamma , electron
others radiation )
• Gas ( ethylene oxide,
formaldyde)
 Microbial destruction
Time required to reduce the bioburden
D value by 90%
U Exposure time
D =
Original bioburden Log N0 - logNu Remaining populaton

Diff in temp requried to change D value

Z value
by 90%
T2 –T1
Z
= Log D1 –log D2
Autoclave

F0 F0 = D121 ( logN0 – logNu )

Z value based on B.stearothermophilius
Steam 115.5 for 30 min
sterilization 121.5 for 20 min
temp Time
( autoclavi 126.5 for 15 min
ng)
1) Mechanism 121 ±2 °C
2) for what
3)Not for
what
4)Air most
removed

Most
common
 Validation of Steam sterilization
IQ
( autoclaving)
OQ

Temperature distribution Heat penetration

On empty & Depend on the

loaded chamber thickness of the
Coldest spot during container
Coldest point in the
empty ch to provide the
product load
slowest heating
Container similar to
location
formula and put
15 – 20 thermocouples
B.S
Any deviation more Biological is paced with
±2.5 °C ….. Undesirable thermocouples ( location)
F0 is determinded
 160 for 180 min
Dry heat 170 for 60 min De
sterilization pyrogenation

1) Mechanism
2) for what
3)Not for
what
 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 EU\ml
All pervious tests in addition to pyrogen test
 Membrane filters : cellulose esters
Filtration , plastic ..
1) Mechanism
 Asbestos-containing filters
should not be used. Or fiber
2) For what shedding
3)Disadvantages  followed by an aseptic transfer
Pore size 0.22 of the sterilized solution to the
micrometer final containers
All filters, tubes, and equipment
Double filter used "downstream" must be sterile
layer or second ( autoclave)
filtration Filter integrity test
Don’t use more  filters should not interact with
than 24 hr * * the product
  Laws and regulations for
Radiation protection against radiation must
be respected.
1) Mechanism Radiation doses should be
2) For what monitored with specific
dosimeters
3) Disadvantages
 Sterile Dosage Forms

Terminal sterilization Aseptic sterilization

Product in its final Drug product &

container is sterilized as container & closure are
whole. first sterilized separately.
Can be manufactured Each aseptic process
under clean rather than can introduce error .
aseptic . Only used when terminal
 most common ??
sterilization is not
feasible.
 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
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.
 HEPA Filters
 High-efficiency particulate air (HEPA) filters
Can remove at least 99.97 % of dust , pollen ,
mold , bacteria and any airborn particle 0.3
microgram
 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

 ISO 5 (A) (100)

use unidirectional airflow Entry

(not just below a LAFW hood)

ISO 5 zone | 240–360 air changes per hour Air
lock
 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
Laminar flow hold
Production line
 Closed
container
Other
ointment
Suspension
ideal Cost
A\B B\C

Eye drops
Aseptic
 Flow chart of sterile dosage form

Raw material Engineering

IPC AI + additive +pack chart

Det of particle Ball mill

Sizing and
size sieving
Sieving machine

Det of moisture Drying Tray dryer

content
Douple chek
Wt Weighing Electric balance

WFI Line
 solution Flow chart of sterile dosage form
Propeller
Det of sol ,temp,
Dissolving Trubine mixer
Water quality ,pH
(viscous)
Det of sol ,temp Mixing & Propeller
SP gravity , vol\wt Dilution Trubine mixer
( viscous)
pH determination PH adjustment pH meter

Sterility , Sterile Terminal

Leakage , filteration
Filling
Gross Wt , Filling & machine
Vol\Wt of* Aseptic filling sealing
Container
suitablity F drying autoclave
sterlization
Aseptic sealing
 Emulsion
suspension
gel Flow chart of sterile dosage form
Meta filter
Det of sol ,temp, Dissolving & filteration Turbine mixer
Water quality ,pH
Sterlization for oil
( viscous)
Sterlity test ,powder, aq
Rh , Vis,
1 ry emulsion
Creaming rate Collid mill
Rh , Vis, Sed rate 1 ry suspension
Rh , Vis , gel Conc gel High speed
stregnth agitator
Mixing & dilution Turpine mixer
pH
PH adjustment pH meter
determination
Dryness Make up to volume
Gross Wt Filling machine
Filling,
Leakage Capping ,
Sealing
Ointment Flow chart of sterile
dosage form
Det of sol ,temp, Meta filter
Dissolving & Turbine mixer
Water quality
sterilization ( viscous)
,pH
Wt –clarity – Oily base melting & DJ-SH melting
temp sterlization tank

Temp –mix time DJ-SH melting

Aseptic mixing &
Homogeneity tank with
Oil glob size homogenization agitator

Gross Wt- Aseptic tube filing &

Filling machine
leakage sealing & labelling
Recon of label ,
carton data,
Flow chart of sterile
good packaging dosage form
Inspection of
Packaging Package
pamphlet & Labelling , cartoning
leakage test
machine

Content uniformty
Vol\wt check Intermediate
Viscosity – store
rheology Clarity
Sed rate – cream
rate Quality control
Gel stregnth
Consistency
Spreading
Gritty sensation Final store
Strility test
 Reference
https://www.sciencedirect.com/topics/chemistry/py

rogen
http://www.authorstream.com/Presentation/tausif1
991-1795419-design-layout-operational-facilities- s
terile-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

https://www.google.com/search?q=air+classificatio
n+system&source=lnms&tbm=isch&sa=X&ved=0a
h UKEwjq0p2QysXhAhUFxhoKHRy_CaYQ_AUIDi
gB &biw=1366&bih=604#imgrc=ij9hpgPzJYLM6M
:
http://www.hefilter.com/Industry-News/Common-
Types-of-HEPA-Filter.shtml
https://www.mecart-cleanrooms.com/learning- c
enter/cleanroom-classifications-iso-8-iso-7-iso-6-
iso-5/
https://www.slideshare.net/yuvas2010/377218gmpt

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