Transcript Sterilization Options Advisory Committee for Pharmaceutical Science Kristen D. Evans

Advisory Committee for
Pharmaceutical Science
Sterilization Options
Kristen D. Evans
Investigative Engineer, USFDA
October 22, 2002
10/22/02 OPS Advisory Committee - Aseptic Processing
Sterile Drug Products Produced
by Aseptic Processing
Draft Concept Paper, Section III. Scope (lines 52-58)
“It is a well-accepted principle that sterile drugs
should be manufactured by aseptic processing
only when terminal sterilization is not feasible.”
“[Otherwise,] adjunct processing steps
(e.g., heat exposure conditions which provide
some FO ) to increase the level of sterility
confidence should be considered.”
Terms

PNSU - Probability of a Non-Sterile Unit
 The probability of a unit (product container) being
non-sterile after the application of a lethal agent.
 PNSU of 1 in 106 -- the probability that a unit is
non-sterile is one in a million

FO - Sterilization Process Equivalent Time
 The equivalent number of minutes at 121.1°C
delivered to a unit by a sterilization process.
 FO = 8 minutes -- the cycle delivered a microbial
lethality equivalent to 8 minutes at 121.1°C
PDA Technical Report #36:
Current Practices in the Validation of
Aseptic Processing - 2001
At your site, is aseptic processing
used for products that could be
terminally sterilized?
For this response, “could be terminally
sterilized” means capable of withstanding a
steam sterilization cycle with FO > 8 minutes.
At your site, is aseptic processing used for
products that could be terminally sterilized?
No
67.4%
85%
Yes
32.6%
30% (mean)
2%
n = 43
If Yes, then percentage of
products affected
Source: PDA Technical Report #36: Current Practices in the
Validation of Aseptic Processing - 2001
Probability of a
Non-Sterile Unit (PNSU)
Terminal Sterilization


Designed and qualified for a PNSU > 1 in 106
Generally only one critical system to control
Aseptic Processing

Impossible to scientifically determine a PNSU
Many critical systems involved

“Contamination Rate” assessed with media fills

Probability of a Non-Sterile Unit
Aseptic (Estimated*) vs. Terminal
100
90
80
Percentage
70
of
60
Firms
50
(n=40)
40
30
20
10
0
Aseptic
Processing
(estimate*)
Terminal
Sterilization
102
103
104
105
106
107
Probability of a Non-Sterile Unit
(1 in …)
* Aseptic processing PNSU
estimates from PDA
TR#36, 2001
Recalls
Lack of Sterility Assurance
Number
of
Recalls
Fiscal Year
 Lack of Sterility Assurance is the #1 reason for drug recalls
in last 5 years
 Nearly all drugs recalled due to Lack of Sterility Assurance
in last 20 years were produced via aseptic processing
Global Scene
European Agency for the Evaluation
of Medicinal Products (EMEA)
Terminal Sterilization
Fo > 15 minutes
“Adjunct” Processing
 Fo > 8 minutes, and
 PNSU > 1 in 106
Aseptic Processing
From: Decision Trees for the Selection of Sterilization Methods (10/1999)
Global Scene
European Agency for the Evaluation of
Medicinal Products (EMEA)
“Where a choice is made not to utilise a method
of terminal sterilization, … proper scientific
explanation and justification should be
provided in the dossier.”
“Heat lability of a packaging material should
not in itself be considered as adequate
justification for not utilising terminal
sterilisation, for otherwise heat stable
products.”
From: EMEA Note for Guidance on Development Pharmaceutics (July, 1998)
Questions for
Advisory Committee
Should terminal sterilization be used
when feasible?
Should adjunct processing be considered
in order to increase confidence in
aseptically processed products?