Advisory Committee for Pharmaceutical Science

1
Advisory Committee for Pharmaceutical Science

• Sterilization Options
• Kristen D. Evans
• Investigative Engineer, USFDA
• October 22, 2002

10/22/02 OPS Advisory Committee - Aseptic
Processing
2
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.

3
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 121.1C
  delivered to a unit by a sterilization process.
• FO 8 minutes -- the cycle delivered a microbial
  lethality equivalent to 8 minutes at 121.1C

4
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.

5
At your site, is aseptic processing used for
products that could be terminally sterilized?
Source PDA Technical Report 36 Current
Practices in the Validation of
Aseptic Processing - 2001
6
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

7
Probability of a Non-Sterile UnitAseptic
(Estimated) vs. Terminal
Percentage of Firms (n40)
102 103 104 105 106
107 Probability of a Non-Sterile Unit
(1 in )
Aseptic processing PNSU estimates from PDA
TR36, 2001
8
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

9
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)

10
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)
11
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?