Advisory Committee for Advisory Committee for Pharmaceutical SciencePharmaceutical Science

Sterilization OptionsSterilization Options

Kristen D. EvansKristen D. Evans

Investigative Engineer, USFDAInvestigative Engineer, USFDA

October 22, 2002October 22, 200210/22/02 OPS Advisory Committee - Aseptic Processing

Sterile Drug Products Produced Sterile Drug Products Produced

by Aseptic Processingby Aseptic Processing Draft Concept Paper, Section III. Scope (lines 52-58)Draft Concept Paper, Section III. Scope (lines 52-58)

““It is a well-accepted principle that sterile drugs It is a well-accepted principle that sterile drugs should be manufactured by aseptic processing should be manufactured by aseptic processing only when terminal sterilization is not feasibleonly 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 Fsome FO O ) to increase the level of sterility) to increase the level of sterility

confidence should be consideredconfidence should be considered..””

TermsTerms

PNSU - Probability of a Non-Sterile UnitPNSU - Probability of a Non-Sterile Unit The probability of a unit (product container) being The probability of a unit (product container) being

non-sterile after the application of a lethal agent. non-sterile after the application of a lethal agent. PNSU of 1 in 10PNSU of 1 in 1066 -- the probability that a unit is -- the probability that a unit is

non-sterile is one in a millionnon-sterile is one in a million

FFOO - Sterilization Process Equivalent - Sterilization Process Equivalent Time Time The equivalent number of minutes at 121.1°C The equivalent number of minutes at 121.1°C

delivered to a unit by a sterilization process.delivered to a unit by a sterilization process. FFOO = 8 minutes = 8 minutes -- the cycle delivered a microbial -- the cycle delivered a microbial

lethality equivalent to 8 minutes at 121.1°Clethality equivalent to 8 minutes at 121.1°C

PDA Technical Report #36: PDA Technical Report #36: Current Practices in the Validation of Current Practices in the Validation of Aseptic Processing - 2001Aseptic Processing - 2001

At your site, is aseptic processing At your site, is aseptic processing used for products that could be used for products that could be terminally sterilized?terminally sterilized?

For this response, “could be terminally For this response, “could be terminally sterilized” means capable of withstanding a sterilized” means capable of withstanding a steam sterilization cycle with Fsteam sterilization cycle with FOO >> 8 minutes.8 minutes.

At your site, is aseptic processing used for At your site, is aseptic processing used for products that could be terminally sterilized?products that could be terminally sterilized?

Source: PDA Technical Report #36: Current Practices in the Validation of Aseptic Processing - 2001

85%

2%

No67.4% Yes

32.6% 30% (mean)

If Yes, then percentage of products affected

n = 43

Probability of aProbability of a Non-Sterile Unit (PNSU) Non-Sterile Unit (PNSU)

Terminal SterilizationTerminal Sterilization Designed and Designed and qualified qualified for a PNSU for a PNSU >> 1 in 10 1 in 1066

Generally only one critical system to controlGenerally only one critical system to control

Aseptic ProcessingAseptic Processing Impossible to scientifically determine a PNSUImpossible to scientifically determine a PNSU Many critical systems involved Many critical systems involved ““Contamination Rate” assessed with media Contamination Rate” assessed with media

fillsfills

Probability of a Non-Sterile UnitProbability of a Non-Sterile UnitAseptic (Estimated*) vs. TerminalAseptic (Estimated*) vs. Terminal

0

10

20

30

40

50

60

70

80

90

100

AsepticProcessing(estimate*)TerminalSterilization

102 103 104 105 106 107

Probability of a Non-Sterile Unit (1 in …)

Percentageof

Firms(n=40)

* Aseptic processing PNSU estimates from PDA TR#36, 2001

RecallsRecalls Lack of Sterility AssuranceLack 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

Global SceneGlobal Scene European Agency for the Evaluation European Agency for the Evaluation of Medicinal Products (EMEA)of Medicinal Products (EMEA)

From: Decision Trees for the Selection of Sterilization MethodsFrom: Decision Trees for the Selection of Sterilization Methods (10/1999) (10/1999)

Aseptic Processing

““Adjunct” ProcessingAdjunct” Processing Fo Fo >> 8 minutes, 8 minutes, andand PNSU PNSU >> 1 in 10 1 in 1066

Terminal Sterilization Terminal Sterilization

Fo Fo >> 15 minutes 15 minutes

Global SceneGlobal Scene European Agency for the Evaluation European Agency for the Evaluation of Medicinal Products (EMEA) of Medicinal Products (EMEA)

““Where a choice is made not to utilise a method Where a choice is made not to utilise a method of terminal sterilization, … proper scientific of terminal sterilization, … proper scientific explanation and justification should be explanation and justification should be provided in the dossier.provided in the dossier.””

““Heat lability of a packaging material should Heat lability of a packaging material should not in itself be considered as adequate not in itself be considered as adequate justification for not utilising terminal justification for not utilising terminal sterilisation, for otherwise heat stable sterilisation, for otherwise heat stable products.products.””

From: EMEA Note for Guidance on Development Pharmaceutics (July, 1998)

Questions for Questions for Advisory CommitteeAdvisory Committee

Should terminal sterilization be used Should terminal sterilization be used when feasible?when feasible?

Should adjunct processing be considered Should adjunct processing be considered in order to increase confidence in in order to increase confidence in aseptically processed products?aseptically processed products?