1. Advisory Committee for Pharmaceutical Science Sterilization Options 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.” “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 “[Otherwise,] adjunct processing steps (e.g., heat exposure conditions which provide (e.g., heat exposure conditions which provide some F O ) to increase the level of sterility some F O ) to increase the level of sterility confidence should be considered.” 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 10 6 -- the probability that a unit is non-sterile is one in a million  F O - Sterilization Process Equivalent Time  The equivalent number of minutes at 121.1°C delivered to a unit by a sterilization process.  F O = 8 minutes -- the cycle delivered a microbial lethality equivalent to 8 minutes at 121.1°C

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 F O > 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 85% 2% No 67.4% Yes 32.6% 30% (mean) If Yes, then percentage of products affected n = 43

6. Probability of a Non-Sterile Unit (PNSU) Terminal Sterilization  Designed and qualified for a PNSU > 1 in 10 6  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 Unit Aseptic (Estimated*) vs. Terminal 10 2 10 3 10 4 10 5 10 6 10 7 Probability of a Non-Sterile Unit (1 in …) Percentage of Firms (n=40) * Aseptic processing PNSU estimates from PDA TR#36, 2001

8. Recalls Lack of Sterility Assurance  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 Number of Recalls Fiscal Year

9. Global Scene European Agency for the Evaluation of Medicinal Products (EMEA) From: Decision Trees for the Selection of Sterilization Methods (10/1999) Aseptic Processing “Adjunct” Processing  Fo > 8 minutes, and  PNSU > 1 in 10 6 Terminal Sterilization Fo > 15 minutes Fo > 15 minutes

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.” “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.” “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 terminal sterilization be used when feasible? Should adjunct processing be considered in order to increase confidence in aseptically processed products? Should adjunct processing be considered in order to increase confidence in aseptically processed products?