The document discusses the key elements required for terminal sterilization qualification including: 1) Description of the sterilization process, parameters like temperature and time, and loading patterns. 2) Studies demonstrating heat distribution and efficacy like biological indicators. 3) Specifications for controlling the process and ensuring sterility of the product and packaging. 4) Procedures for monitoring the sterilization environment and packaging integrity.

1. Terminal Sterilization Qualification
Process & Highlights
(Tutorial-7-1 B)
Sterile Operations for Parenteral Preparations
Roohi B. Obaid
14 Jul 2018 at Karachi

2. Discussion
• Science & good
science
Sharing
• Current
Knowledge &
Experience
Navigation
• Towards mutual
goal & Future
directions
Knowledge Sharing Exercise
To Learn through Debate, Discussion & Experience of others
Acknowledgement: Documents of US-FDA & PDA consulted

3. Lets see what are the Fundamental Information for
Moist Heat Terminal Sterilization Process

4. Process Product
Container Closure System

5. Sterilization Process
Process used to sterilize the drug
product in its final container
closure system
Other sterilization process for
components
Efficacy of these processes

6. Autoclave
Process & performance
specifications
Cycle type (e.g. saturated steam,
water immersion, water spray)
Cycle parameters (e.g.
temperature, pressure, time, F0)

7. Loading pattern
Methods & Controls to monitor
production cycle
Thermocouples, pilot bottles,
Biological Indicators (no.,
location, acceptance & rejection)
Autoclave

8. Routine & unscheduled
requalification
Frequency should be clear
Autoclave

9. Reprocessing
Additional thermal processing or
reprocessing
Subject to stability

10. Thermal Qualification
Cycle

11. Heat
Distribution & Penetration
Studies
Demonstrate uniformity,
reproducibility & conformance to
specifications of sterilization
Min. 3 consecutive successful
cycle results

12. Thermocouples
No of monitors and locations
Diagram is preferable
Calibrated

13. Effect of load on
thermal input
Minimum and maximum load to
demonstrate the effect ..
Additional study for different fill
volumes

14. Effect of load on
thermal input
E.g.
High low temperatures (range),
average temperature during the
dwell period, min & max F0
values …

15. Microbiological Efficacy
Cycle

16. Lethality
Viability
Demonstrate efficacy of production cycle
for all parts of drug product that are claimed to be sterile

17. Remember Lethality
Viability
Specific method to carry out specific study
Product and process specific & may vary
from manufacturer to manufacturer

18. Lethality
Viability
Identification & characterization of bio-burden organisms
Method & Results … Amount & Type of information
E.g. more information may be needed for bio-burden based
autoclave process than for over kill process … Type & resistance
of bio-burden organisms may be necessary … particularly
organisms associated with the product solution and container
closure … identify most heat resistant bio-burden organism

19. Lethality
Viability
Specifications for Bio-burden
Alert & Action Levels for Bio-burden
Program for routinely monitoring bio-burden to ensure that
validated and established limits are not exceeded
Frequency of analysis and method used in bio-burden screening
should be clear

20. Lethality
Viability
Identification, Resistance & Stability of Biological Indicators
Qualification of Biological Indicator
is Important

21. Lethality
Viability
Biological Indicator Resistance & Relative Bio-burden
Product solution, surface of containers or
closure or interface are areas of interest
The determination of resistance of spores on the
carriers relative to that of directly inoculated product
will be helpful

22. Lethality
Viability
Microbiological Challenge Studies
Demonstrate the Efficacy of Minimum Cycle
to Provide SAL
Most difficult to sterilize load with Biological Indicator at
Microbiological Master Site or in Master Product

23. Microbiological Monitoring
Environment

24. Scientifically sound & appropriate

25. Scientifically sound & appropriate
Specifications

26. Scientifically sound & appropriate
Specifications
Standards

27. Scientifically sound & appropriate
Specifications
Standards
Sampling plan

28. Scientifically sound & appropriate
Specifications
Test procedures
Standards
Sampling plan

29. Scientifically sound & appropriate
Specifications
Test procedures
Standards
Sampling plan
to ensure that components, DP
containers, closures, in-process
materials and DP

30. Scientifically sound & appropriate
Specifications
Test procedures
Standards
Sampling plan
Conforms to appropriate quality standards
to ensure that components, DP
containers, closures, in-process
materials and DP

31. Container/Closure Package
Integrity

32. Microbial Integrity of Drug Packaging Components
Experimental design simulates the stresses of the Sterilization
Process, Handling and Storage of the drug and their effect on the
Container Closure System
Physical, Chemical & Microbiological Challenge Studies may be
necessary

33. Microbial Integrity of Drug Packaging Components
Integrity Following the Maximum Exposure
Demonstrate Container Closure Integrity on product units that have
been exposed to the maximum sterilization cycles
If a product is exposed to more than one process, then exposure to
the maximum cycle of all processes should be incorporated into the
study design

34. Microbial Integrity of Drug Packaging Components
Multiple Barriers
Each barrier that separates area of drug product claimed to be
sterile need to be separately evaluated and validated

35. Microbial Integrity of Drug Packaging Components
Test Sensitivity
Sensitivity of method used to determine the container closure
integrity be specific.

36. Microbial Integrity of Drug Packaging Components
Integrity over the Product Shelf Life
Integrity of the container closure system throughout the shelf life is
mandatory

37. Bacterial
Endotoxin Test
& Method
Sterility Testing
Method &
Release Criteria
Evidence of
Formal Written
Procedures
Walk with mechanics of regulators mind