11

Praphon Angtrakool

Food and Drug Administration

Terminal SterilizationTerminal Sterilization

vs. vs.

Aseptic ProcessingAseptic Processing

22

Sterile Drug Products Produced Sterile Drug Products Produced by Aseptic Processingby Aseptic Processing

It is a wellIt is a well--accepted principle that sterile drugs should be accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal manufactured using aseptic processing only when terminal sterilization is not feasiblesterilization is not feasible..

However, some final packaging may afford some unique and However, some final packaging may afford some unique and substantial advantage (e.g., some dualsubstantial advantage (e.g., some dual--chamber syringes) that chamber syringes) that would not be possible if terminal sterilization were employed. would not be possible if terminal sterilization were employed. In such cases, a manufacturer can explore the option of In such cases, a manufacturer can explore the option of adding adjunct processing steps to increase the level of adding adjunct processing steps to increase the level of sterility assurance.sterility assurance.

From ; Guidance for Industry Sterile Drug Products Produced by Aseptic Processing; US FDA (2004)

33

Product requirementsFDA has stated, where possible, that the use of terminal sterilization should be used in the manufacture of sterile product Where this is not feasible without detriment to the product, an alternative means of achieving the end objective must be demonstrated

Consequently, the first step in establishing the processing conditions, and therefore the design of the manufacturing facility, is to determine whether terminal sterilization will berequired.

In some cases an additional method e.g. heat treatment, can be added to aseptic processing to better assure product safety

From : ISPE Guide, Volume 3 Sterile Manufacturing Facilities, First Edition. 1999

44

PDA Technical Report #36 : Current Practices PDA Technical Report #36 : Current Practices in the Validation of Aseptic Processing in the Validation of Aseptic Processing -- 20012001

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

55

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

66

Recalls Recalls Lack of Sterility AssuranceLack of Sterility Assurance

0

10

20

30

40

50

60

'88 '90 '92 '94 '96 '98 '00 '02

Lack of Sterility Assurance is the #1 reason for drug recalls in last 5 yearsNearly all drugs recalled due to Lack of Sterility Assurance in last 20 years were produced via aseptic processing

Number of

Recalls

Fiscal Year

77

Global SceneGlobal SceneEuropean 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

““AdjunctAdjunct”” ProcessingProcessingFoFo >> 8 minutes, 8 minutes, andandPNSU PNSU >> 1 in 101 in 1066

Terminal Sterilization Terminal Sterilization FoFo >> 15 minutes15 minutes

88

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

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

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

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

99

QuestionsQuestions

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?

1010

Decision treeDecision tree

for selection of the sterilisation methodsfor selection of the sterilisation methods

European MedicEuropean Medicineines Agencys Agency

1111

Those products intended to be sterile should be terminally Those products intended to be sterile should be terminally sterilised in their final container as clearly stated in the Eursterilised in their final container as clearly stated in the European opean Pharmacopoeia, and in the CPMP Notes for Guidance.Pharmacopoeia, and in the CPMP Notes for Guidance.Where it is not possible to carry out terminal sterilisation by Where it is not possible to carry out terminal sterilisation by heat heat due to formulation instability, a decision should be taken to due to formulation instability, a decision should be taken to utilise an alternative method of terminal sterilisation, filtratutilise an alternative method of terminal sterilisation, filtration ion and/or aseptic processing.and/or aseptic processing.It is recognised that new terminal sterilisation process other tIt is recognised that new terminal sterilisation process other than han those described in the pharmacopoeia may be developed to those described in the pharmacopoeia may be developed to provide sterility assurance levels equivalent to present officiaprovide sterility assurance levels equivalent to present official l methods, and such processes when properly validated may offer methods, and such processes when properly validated may offer alternative approaches.alternative approaches.

Decision tree for selection of Decision tree for selection of the sterilisation methods the sterilisation methods (1)(1)

1212

When moving down the decision tree it is clear that these methodWhen moving down the decision tree it is clear that these methods s generally show decreasing level of sterility assurance, and it igenerally show decreasing level of sterility assurance, and it is s therefore essential for product quality and safety to ensure thatherefore essential for product quality and safety to ensure that the t the highest level of sterility assurance is achieved in conjunction highest level of sterility assurance is achieved in conjunction with with the lowest level of prethe lowest level of pre--sterilisation bioburden appropriate.sterilisation bioburden appropriate.

These decision tree are intended to assist in the selection of tThese decision tree are intended to assist in the selection of the he optimal sterilisation method taking into account the various optimal sterilisation method taking into account the various complicating factors. (A similar approach should be considered icomplicating factors. (A similar approach should be considered in n the selection of sterilisation methods for intermediates to be the selection of sterilisation methods for intermediates to be incorporated into the finished product using aseptic processing)incorporated into the finished product using aseptic processing)

Decision tree for selection of Decision tree for selection of the sterilisation methods the sterilisation methods (2)(2)

1313

The use of an inappropriate heatThe use of an inappropriate heat--labile packaging material cannot labile packaging material cannot in itself be the sole reason for adoption of aseptic processing.in itself be the sole reason for adoption of aseptic processing.

Rather manufacturers should choose the best sterilisation methodRather manufacturers should choose the best sterilisation methodachievable for a given formulation and select the packaging achievable for a given formulation and select the packaging material accordingly.material accordingly.

However, it may be that the choice of a packaging material for aHowever, it may be that the choice of a packaging material for agiven product has to take into account factors other than the given product has to take into account factors other than the method of sterilisation.method of sterilisation. In such cases these other factors need to In such cases these other factors need to be clearly documented, explained and scientifically justified inbe clearly documented, explained and scientifically justified inthe MA dossier.the MA dossier.

Decision tree for selection of Decision tree for selection of the sterilisation methods the sterilisation methods (3)(3)

1414

Conventionally, it has been accepted that other factors such as Conventionally, it has been accepted that other factors such as the the type of container, route of administration and patient benefit htype of container, route of administration and patient benefit have ave contributed to the choice of a particular container type, which contributed to the choice of a particular container type, which will will not withstand terminal heat sterilisation (e.g. certain ophthalmnot withstand terminal heat sterilisation (e.g. certain ophthalmic ic products) and such products are therefore manufactured by products) and such products are therefore manufactured by validated aseptic processing.validated aseptic processing.In such cases manufacturers have a duty to continue the search In such cases manufacturers have a duty to continue the search for acceptable alternative containers which would allow the movefor acceptable alternative containers which would allow the moveto the preferred terminal sterilisation in an acceptable timefrato the preferred terminal sterilisation in an acceptable timeframe.me.Commercial considerations should not be used as justification foCommercial considerations should not be used as justification for r not using terminal sterilisation with the highest possible levelnot using terminal sterilisation with the highest possible level of of sterility assurancesterility assurance

Decision tree for selection of Decision tree for selection of the sterilisation methods the sterilisation methods (4)(4)

1515

Decision tree for the sterilisation Decision tree for the sterilisation choices for aqueous productschoices for aqueous products

Can the product be sterilised by moist

heat at 121 oC for 15 minutes ?

Use pre-sterilised individual components

and aseptic compounding and filling

Can the product be sterilised by moist heat

at Fo ≥ 8 minutes achieving SAL of ≤10 -6

Can the formulation be filtered

through a microbial retentive filter

Use autoclaving at

121 oC for 15

minutes

Use moist heat with Fo ≥ 8 minutes

Use a combination of aseptic

filtration and aseptic processing

YES

YES

YESNO

NO

NO

1616

Decision tree for sterilisation choices for nonDecision tree for sterilisation choices for non--aqueous aqueous liquid, semiliquid, semi--solid or dry powder productssolid or dry powder products

Use sterilisation with an absorbed minimum dose of ≥ 25 KGy ?

Can the formulation be filtered through a microbial retentive filter

Can the product be sterilised by dry heat at 160 oC for 120 minutes

Can the product be sterilised by dry heat with an alternative combination of time and temperature to the standard cycle achieving SAL of ≤10 -6 ?

Can the product be sterilised by method different from dry heat e.g. ionising radiation with an

absorbed minimum dose of ≥ 25 KGy ?

Use pre-sterilised individual components and aseptic compounding and filling

Use sterilisation at 160 oC for 120 minutes

Use filtration and aseptic processing

Use dry heat with alternative combination of time and temperature to the standard

cycle achieving SAL of ≤10 -6

Can the product be sterilised by using a validated lower irradiation dose (ref. ISO 11137)

Use sterilisation by validated irradiation dose.

NOYES

YES

YES

YES

YES

NO

NO

NO

NO

1717

Process Validation :Process Validation :Moist Heat Sterilization for PharmaceuticalsMoist Heat Sterilization for Pharmaceuticals

Health CanadaHealth CanadaHealth Product and Food BranchHealth Product and Food Branch

1818

The Health Products and Food Branch Inspectorate (HPFBI) of The Health Products and Food Branch Inspectorate (HPFBI) of Health Canada recognizes that terminal moist heat sterilization,Health Canada recognizes that terminal moist heat sterilization,when practical, is presently considered the method of choice to when practical, is presently considered the method of choice to ensure sterility.ensure sterility.For the purpose of ensuring sterility, all aqueousFor the purpose of ensuring sterility, all aqueous--based sterile based sterile products are subject to terminal moist heat sterilization, with products are subject to terminal moist heat sterilization, with the the following exceptions :following exceptions :

Instances where terminal moist heat sterilization is not Instances where terminal moist heat sterilization is not practical, e.g., product practical, e.g., product degradation. Suchdegradation. Such instances are fully instances are fully evaluated and documented.evaluated and documented.And for aseptic processes that exclude human intervention And for aseptic processes that exclude human intervention e.g., robotics, forme.g., robotics, form--fillfill--seal and barrier system, may be seal and barrier system, may be employed in lieu of terminal moist heat sterilization providing employed in lieu of terminal moist heat sterilization providing that validation data demonstrated equivalence.that validation data demonstrated equivalence.

1. Introduction 1. Introduction (1)(1)

1919

9. Sterilisation cycle development 9. Sterilisation cycle development (1)(1)

Two basic approaches are employed to develop sterilization Two basic approaches are employed to develop sterilization

cycles for moist heat processes :cycles for moist heat processes :

OverkillOverkill

Probability of Survival.Probability of Survival.

The "F" and "D" terms used below to describe theseThe "F" and "D" terms used below to describe these methods methods

are defined in Section 10.are defined in Section 10.

2020

9.1 The Overkill method9.1 The Overkill method

The Overkill method is used when the product can withstand The Overkill method is used when the product can withstand

excessive heat treatment such as an Fo excessive heat treatment such as an Fo ≥≥ 12 without adverse effects12 without adverse effects.

Bioburden and resistance data are not required to determine the Bioburden and resistance data are not required to determine the

required "Fo" values.required "Fo" values.

Cycle parameters are adjusted to assure that the coldest point wCycle parameters are adjusted to assure that the coldest point withinithin

the load receives an "Fo" that will provide at least a 12the load receives an "Fo" that will provide at least a 12--log log

reduction of microorganisms having a "Dreduction of microorganisms having a "D121121" value of at least one " value of at least one

minute (i.e.: Fo minute (i.e.: Fo ≥≥ 12)12)

9. Sterilisation cycle development 9. Sterilisation cycle development (2)(2)

2121

9.2 The Probability of Survival9.2 The Probability of Survival

The Probability of Survival approach is used primarily for heat The Probability of Survival approach is used primarily for heat

labile products. In this approach, the process for the terminal labile products. In this approach, the process for the terminal

sterilization of a sealed container is validated to achieve the sterilization of a sealed container is validated to achieve the

destruction of predestruction of pre--sterilization bioburden to a level of 10sterilization bioburden to a level of 1000, with , with

a minimum safety factor of an additional sixa minimum safety factor of an additional six--log reduction log reduction

(1x10(1x10--66). The probability that any one unit is contaminated is ). The probability that any one unit is contaminated is

therefore no more than one in a million; this is considered to therefore no more than one in a million; this is considered to

be an acceptable level of sterility assurance.be an acceptable level of sterility assurance.

9. Sterilisation cycle development 9. Sterilisation cycle development (3)(3)

2222

a) The probability of survival is determined using a semia) The probability of survival is determined using a semi--logarithmic logarithmic microbial death curve, where a plot of the log of the number of microbial death curve, where a plot of the log of the number of survivors versus time at a fixed temperature yields a straight lsurvivors versus time at a fixed temperature yields a straight line. ine. After the line has crossed below 10After the line has crossed below 1000 (less than one survivor), the (less than one survivor), the yy--value corresponding to a given time value is expressed as the value corresponding to a given time value is expressed as the probability of survival.probability of survival.

b) The determination of the minimum "Fo" value for the Probabilib) The determination of the minimum "Fo" value for the Probability ty of Survival approach is based upon the number of of Survival approach is based upon the number of microorganisms (bioburden) found in a given product and their microorganisms (bioburden) found in a given product and their heat resistance.heat resistance.

c) Methods for conducting bioburden studies, estimating microbiac) Methods for conducting bioburden studies, estimating microbial l heat resistance and determining the minimum required "Fo" value heat resistance and determining the minimum required "Fo" value for sterilization.for sterilization.

9. Sterilisation cycle development 9. Sterilisation cycle development (4)(4)

2323

EU 2005EU 2005Steam sterilization of terminal sterilization the reference Steam sterilization of terminal sterilization the reference condition for aqueous preparations are heating at a condition for aqueous preparations are heating at a minimum of 121 minimum of 121 ooCC for 15 minutesfor 15 minutesSterility Assurance Level (SAL) 10Sterility Assurance Level (SAL) 10--66 or betteror better

USP 29USP 29Terminally sterilized Terminally sterilized products(TSPproducts(TSP) must have a ) must have a probablityprobablity of of nonsterilitynonsterility (PNS) of not more than one in (PNS) of not more than one in a million units produced. This is often stated as a PNS of a million units produced. This is often stated as a PNS of 1010--6 or the 6 or the probablityprobablity of product of product bioburdenbioburden surviving surviving the sterilization process in any single unit of product is the sterilization process in any single unit of product is less than one in one million.less than one in one million.

PharmacopoeiaPharmacopoeia

2424

ReferenceReference

Decision Trees for the Selection of Sterilization Methods (10/19Decision Trees for the Selection of Sterilization Methods (10/1999) , The European Agency 99) , The European Agency

for the Evaluation of Medicinal Products (EMEA)for the Evaluation of Medicinal Products (EMEA)

Guide Process Validation : Moist Heat Sterilization for PharmaceGuide Process Validation : Moist Heat Sterilization for Pharmaceuticals, Health Products uticals, Health Products

and Food Branch Inspectorate, Date of implementation : May 1, 20and Food Branch Inspectorate, Date of implementation : May 1, 200101

Guidance for Industry Sterile Drug Products Produced by Aseptic Guidance for Industry Sterile Drug Products Produced by Aseptic Processing, U.S. FDA, Processing, U.S. FDA,

20042004

Pharmaceutical Engineering Guides for New Renovated Facilities, Pharmaceutical Engineering Guides for New Renovated Facilities, Volume 3 Sterile Volume 3 Sterile

Manufacturing Facilities, First Edition. International Society fManufacturing Facilities, First Edition. International Society for Pharmaceutical or Pharmaceutical

Engineering, 1999Engineering, 1999