Pharmaceutics Lecture On Sterlization Techniques

Front 1

what is aseptic

Back 1

free of pathogenic microorganisms

Front 2

what is sterile

Back 2

complete absense of life and ability to reproduce

Front 3

what is aseptic processing

Back 3

Product components,
containers, closures and the product are
sterilized separately and then assembled in an
aseptic environment.

Front 4

what is terminal sterilization

Back 4

The individual product
components (container, closure and product) are assembled and sealed in a controlled environment and then sterilized

Front 5

aseptic vs terminal sterilization

Back 5

aseptic is assembled separately then sterilized
terminal is assembled together and then sterilized

Front 6

SAL (Sterility Assurance Level)

Back 6

This is a statistical probability of survival of
microorganisms from the sterilization process

Front 7

what are SAL levels based on...

Back 7

controls in place for
each process (i.e. moist heat TS vs aseptic
processing)

Front 8

Moist heat terminal sterilization has a SAL of 10^6, while aseptic are 10^3

Back 8

true

Front 9

F0 Term

Back 9

F0 is the equivalent
sterilizing time (minutes)
of exposure to saturated
steam at 121.1oC

Front 10

Fo is an accumulated
(total) value above

Back 10

100oC

Front 11

What is Fo used for?

Back 11

Used as a term describing sterilizing effectiveness

Front 12

what is a thermal resistance D value

Back 12

the time in
minutes required for a one
log or 90% reduction of the
microbial population under
specified lethal conditions. (FDA)

Front 13

what is a thermal resistance Z value

Back 13

is temperature
change required to change
the D value by a factor of 10

Front 14

Terminal Sterilization and Aseptic
Processing Methods of Drug Products

Back 14

 Moist Heat (Autoclave)-Preferred method
 Sterile Filtration
 Combination (Aseptic processing with
moist heat-bioburden based)
 Dry Heat
 Irradiation (γ or e-beam)
Gas sterilization

Front 15

Terminal Sterilization of Drug Products by Moist Heat

Back 15

see lecture slide #12

Front 16

terminal sterilization by moist heat: advantages

Back 16

Simple process
 Provides for a higher level of sterility assurance
 Less dependant on “sterility” of each
component (formulation, stopper, glass, etc) of the product (more things to monitor and go wrong

Front 17

terminal sterilization by moist heat: disadvantages

Back 17

Harsh condition to product (stability)
 Must have water in the product (not powder, lyophile or oleageneous) to be effective

Front 18

Biological Indicators (BI’s)- definition

Back 18

Characterized preparation of a specific
microorganism that provides a defined
and stable resistance to a specific
sterilization process.

Front 19

BI's can be used to:

Back 19

 Qualify the sterilization equipment
 Development of sterilization
process for a drug product
 Development of sterilization
process for packaging components

Front 20

Typical BI’s for drug product challenge

Back 20

Geobacillus stearothermophilus
(D=1.5-3 min)
 Clostridium sporogenes (D= 0.7-1.2
min)
 B. subtilis var. 5230 (D= 0.2 -0.6 min)

Front 21

sterility testing

Back 21

 Test a portion of the drug product batch
 Statistical probability
 Destructive test
 Must be performed in a sterile environment
(isolator)
 Test results are slow (14 day minimum)
 Need to wait for microbes to grow
 Different incubation conditions
(temperature and media) required
 Testing can be technique dependant

Front 22

Sterilization of Drug Products by Sterilizing Filtration

Back 22

see slide #19 and #20

Front 23

sterilizing filtration: advantages

Back 23

Can be applied to a broader spectrum of
products
 Accepted standard (with appropriate validation)
for “sterilizing” heat labile products
 Removes all material below the target porosity
(viable and non-viable particulates)

Front 24

sterilizing filtration: disadvantage

Back 24

Membranes can rupture and loose “integrity”
causing filter failure and lost product
 Does not provide the same SAL as terminal sterilization

Front 25

The Biggest Culprit to Microbial Contamination

Back 25

people

Front 26

Room Classifications in Aseptic Processing

Back 26

Hospitals and small
manufacturing use laminar flow
hoods applying High Efficiency
Particulate Air (HEPA) filters
 Aseptic manufacturing suites
(clean rooms) use same filter
approach
 Rooms are pressurized to move
air out from “aseptic core”
 Grade A, B, C, D for EU
 Class 100, 10,000, 100,000 for USA

Front 27

RABS and Isolators

Back 27

RABS – Restricted
Access Barrier
Systems
 RABS – composed
of rigid wall
enclosures
 Isolators – Fully
enclosed, sealed
and pressurized
units
 Both usually have
glove port access

Front 28

Media Fills in Aseptic Processing

Back 28

Simulations of filling drug
product to prove the process
and area are in control of
microbial contamination.
 Microbiological “media” is
filled in place of drug product
 Actual stoppages, breaks,
repairs, etc simulating an
actual filling run
 Media filled containers are
then incubated and tested

Front 29

Sterilization of Drug Products by Combination

Back 29

Applied to products that cannot tolerate a full terminal
sterilization cycle (≥ 106 SAL)
 Drug product processed as though aseptic processing
(sterilizing filtration)
 Terminal sterilized with moist heat using a reduced cycle
temperature and/or time
 TS based on bioload in the product after aseptic processing

Front 30

State the three methods of controlling bleeding

Back 30

Direct pressure, pressure points, ***tourniquet as a last resort***

Front 31

Sterilization of Drug Products by Combination: disadvantage

Back 31

Complicated control validation necessary
 More expensive than either TS or AP alone

Front 32

Sterilization of Drug Products by Dry Heat

Back 32

Typically used for products that do not contain water (i.e.
oleaginous, dry powders, etc)
 Used for depyrogenating glassware
 Very harsh exposure conditions 150-170°C for n.l.t. 2 hr
 This method is less efficient than moist heat thus requires higher temperatures and longer exposure time

Front 33

Sterilization of Drug Products by Dry Heat: advantage

Back 33

Usually provided greater SAL than AP alone
Removes pyrogenic character

Front 34

Sterilization of Drug Products by Dry Heat: disadvantage

Back 34

Less efficient than moist heat
 Exposure time/temperature is typically too challenging for most drug products

Front 35

Pyrogens and Endotoxins

Back 35

see slide #34

Front 36

Sterilization of Drug Products
by Irradiation (γ or e-beam)

Back 36

see slide #35

Front 37

Sterilization of Drug Products
by Irradiation (γ or e-beam): advantages

Back 37

Terminal sterilization process (whole product)
 γ has good penetration for sterilization
 Does not require a “come-up” time as thermal treatment does

Front 38

Sterilization of Drug Products
by Irradiation (γ or e-beam): disadvantages

Back 38

Expensive facility and processing
 Limited penetration to sterilize
 Can be destructive to package and product
 Difficulty in attaining a high SAL (106)
 Dosing variability throughout final package

Front 39

Sterilization of Drug Products by Gas Sterilization

Back 39

 Typically uses Ethylene Oxide (EtO)
 Most often used for medical devices
 Sterilizing efficiency of ethylene oxide depends on the
concentration of the gas, the humidity, the time of
exposure, the temperature, and the nature of the load
 Packaging must allow for gas exchange (permeable)
 Degassing of final product necessary to remove toxic
residues (ethylene oxide, ethylene chlorohydrin and
ethylene glycol)
Note: VPHP (vapor phase hydrogen peroxide) is commonly
used to decontaminate isolators

Front 40

Sterilization of Drug Products by Gas Sterilization: advantages

Back 40

Can be used in hospitals and industry

Front 41

Sterilization of Drug Products by Gas Sterilization: disadvantages

Back 41

Needs degassing period after exposure
 Surface sterilization only
 Complex as compared to other methods
explosive

Front 42

Sterilization Selection Process Decision Tree

Back 42

see slide #42

Front 43

Summary of Aseptic Processing vs Terminal Sterilization

Back 43

see slide #43
*** important for test question ***

Front 44

How About Regulatory Considerations
on Sterilization

Back 44

see slide #44, 45, 46

Front 45

thermal inactivation

Back 45

Thermal inactivation of microorganisms is the first-order process: for the given conditions (temperature T, pressure…) and time t, a given fraction of microorganisms dies (i.e. the rate of killing is proportional to the concentration of microorganisms m):

Front 46

in the sterilization area ,the inactivation rate constant is replaced by

Back 46

the decimal reduction time DT - the time needed for reduction of m to 10% of the original m(0):
Dt = ln 10/kt = 2.303/kt

Front 47

see inactivation kinetics

Back 47

slide #3

Front 48

Thermal Death Time FT

Back 48

FT is the time needed to decrease the microbial population to a certain level m(t) from the initial level m(0) at the temperature T

Front 49

the thermal death time FT is (replace t by FT and separate):

Back 49

FT= DT * [log m(0) - log m(t)]

Front 50

Temperature Dependence of Inactivation I

Back 50

see slide # 5

Front 51

Temperature Dependence of Inactivation II (z-value)

Back 51

see slide #6 and...
The Z-value is the temperature change that leads to the change of the decimal killing time DT by the factor of 10

Front 52

z- value continued

Back 52

The Z-value is related to the activation energy Ea and is temperature-dependent