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Microbiological Consulting 1

Risk Assessment and Setting

Microbial Limits Specificationsfor Non-Sterile Pharmaceutical

and Over-The-Counter DrugProducts

A3P MeetingA3P Meeting

Montreal, CanadaMontreal, Canada

November 22, 2005November 22, 2005Tony Cundell, Ph. DTony Cundell, Ph. D

Consulting MicrobiologistConsulting Microbiologist

Scarsdale, New York, USAScarsdale, New York, USA


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Risk Assessment and Setting

Microbial Limits Specifications

Presentation Overview:Presentation Overview:

!! Risk Assessment for Microbial ContaminationRisk Assessment for Microbial Contamination

of Nonof Non--Sterile Pharmaceutical ProductsSterile Pharmaceutical Products

!! Setting Microbial Limits SpecificationsSetting Microbial Limits Specifications

!! Establishing Objectionable MicroorganismsEstablishing Objectionable Microorganisms

Requirements for Different Dosage FormsRequirements for Different Dosage Forms!! Implementing Reduced Testing ProgramsImplementing Reduced Testing Programs


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Risk Assessment for Microbial

Contamination

!! Is there a hierarchy for risk of microbialIs there a hierarchy for risk of microbial

contaminations based on dosage form, route ofcontaminations based on dosage form, route of

administration, formulation, manufacturingadministration, formulation, manufacturing

processes, product packaging, storageprocesses, product packaging, storageconditions, and drug recipient health status?conditions, and drug recipient health status?


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Risk Assessment

The descending order of risk for microbialThe descending order of risk for microbial

infection of the drug product recipient based oninfection of the drug product recipient based on

route of administration is:route of administration is:

!! Parenteral andParenteral and intrathecalintrathecal products (sterileproducts (sterileproducts)products)

!! Ophthalmic products (sterile products)Ophthalmic products (sterile products)

!! Inhalation solutions (sterile products)Inhalation solutions (sterile products)

!! Aerosol inhalantsAerosol inhalants

!! Nasal spraysNasal sprays!! OticsOtics

!!

Vaginal suppositories, ointments, and creamsVaginal suppositories, ointments, and creams

!! Transdermal patchesTransdermal patches



Risk Assessment

The descending order of risk for microbialThe descending order of risk for microbial

infection (continued):infection (continued):

!! Topical lotions, ointments and creamsTopical lotions, ointments and creams

!! Rectal suppositories, ointments, and creamsRectal suppositories, ointments, and creams

!! Oral liquids (aqueous)Oral liquids (aqueous)

!! Oral liquids (nonOral liquids (non--aqueous)aqueous)

!! LiquidLiquid--filled capsulesfilled capsules

!! Oral tablets and powderOral tablets and powder--filled capsulesfilled capsules



Factors Influencing Potential for

Microbial Infection

!! PathogenicityPathogenicity of the organismof the organism

!! Invasiveness of the organismInvasiveness of the organism

!! Virulence of the organismVirulence of the organism

!! InoculumInoculum sizesize

!! Route of introduction into the bodyRoute of introduction into the body

!! Frequency of administrationFrequency of administration

!! Host resistanceHost resistance



Risk Assessment

Other major considerations in terms ofOther major considerations in terms of

susceptibility of a nonsusceptibility of a non--sterile pharmaceuticalsterile pharmaceutical

product to microbial contamination includes:product to microbial contamination includes:!! Whether the active ingredient has inherentWhether the active ingredient has inherent

antimicrobial activityantimicrobial activity

!! Whether the formulation supports microbialWhether the formulation supports microbial

growthgrowth

!!

The water activity of the productThe water activity of the product!! The manufacturing processThe manufacturing process

!! Whether it is a multiple or singleWhether it is a multiple or single--use productuse product



The Water Activity, Use Profile, Potential for Microbial Growth,

Invasiveness of the Route of Administration and Potential for Recipient

Infection of the Major Pharmaceutical Dosage Forms

HighHighHighMultiple0.99Inhalation

solutions

LowHighModerate to

high

Form-fill-seal

(single use)

Liquids and

creams (0.97)

ointments(0.55)

Ophthalmic

products

LowVery highModerate to

high

Pre-filled

syringe (single

use)Vials

(multiple use)

0.99Parenteral

Products

Potential for

patient

infection

Invasiveness

of the route of

administratio

n

Potential to

support

microbial

growth

Single or

multiple use

Water

Activity (Aw)

Dosage Form

The Water Activity Use Profile Potential for Microbial Growth


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The Water Activity, Use Profile, Potential for Microbial Growth,

Invasiveness of the Route of Administration and Potential for Recipient

Infection of the Major Pharmaceutical Dosage Forms

LowLowLowLowLowLowSingleSingle0.30.3Tablets andTablets and

CapsulesCapsules

LowLowLowLowLowLowSingleSingle0.30.3LiquidLiquid--filledfilled

CapsuleCapsule

Low toLow to

ModerateModerate

LowLowModerate toModerate to

HighHigh

MultipleMultiple0.900.90Oral LiquidsOral Liquids

Low toLow to

ModerateModerate

Low toLow to

ModerateModerate

Moderate toModerate to

HighHigh

MultipleMultiple0.97(lotion) to0.97(lotion) to

0.6 (0intment)0.6 (0intment)

TopicalsTopicals

Low toLow to

ModerateModerate

ModerateModerateLowLowSingleSingle0.300.30VaginalVaginal

SuppositoriesSuppositories

ModerateModerateModerateModerateHighHighMultipleMultiple0.990.99Nasal SprayNasal Spray

LowLowHighHighLowLowMultipleMultiple0.250.25AerosolAerosol

InhalantInhalant

Potential for

patient

infection

Invasiveness

of the route of

administratio

n

Potential to

support

microbial

growth

Single or

multiple use

Water

Activity (Aw)

Dosage Form


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Microbial Standard Setting

!! The U.S.The U.S. PharmacopeialPharmacopeial Convention Inc. is anConvention Inc. is an

independent standards organization,independent standards organization,

empowered by the U.S. Federal Food, Drug,empowered by the U.S. Federal Food, Drug,and Cosmetic Act as the official drug standardand Cosmetic Act as the official drug standard--

setting organization for drug products.setting organization for drug products.

!! The USPThe USP--NF contains legally recognizedNF contains legally recognizedstandards of identity, strength, quality, purity,standards of identity, strength, quality, purity,

packaging and labeling for more than 3,500packaging and labeling for more than 3,500

drugs.drugs.!! Individual drugs may have a USP/NFIndividual drugs may have a USP/NF

monograph which may or may not containmonograph which may or may not contain

Microbial Limits requirements.Microbial Limits requirements.


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Microbial Standard Setting

!! The referee microbial testing methods forThe referee microbial testing methods for

pharmaceutical ingredients are defined in USPpharmaceutical ingredients are defined in USP

Chapter Chapter Microbial L imit TestsM icrobial L imit Tests. The. Themicrobial enumeration tests are the Totalmicrobial enumeration tests are the Total

Aerobic Microbial Count (TAMC) and theAerobic Microbial Count (TAMC) and the

Total Combined Yeast and Mold CountTotal Combined Yeast and Mold Count

(TCYMC).(TCYMC).

!!

Also pharmaceutical products are screenedAlso pharmaceutical products are screenedusing the USP Absence of Specifiedusing the USP Absence of Specified

Microorganisms test appropriate for the dosageMicroorganisms test appropriate for the dosage

form.form.


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Microbial Standard Setting!! The draft USP Informational Chapter The draft USP Informational Chapter

Microbiological Quality of NonM icrobiological Quality of Non--sterilesterile

Pharmaceutical ProductsPharmaceutical Productsinin PharmacopeialPharmacopeial

Forum 29 (5) 1733Forum 29 (5) 1733--1735 September1735 September--OctoberOctober2003 and at Stage 5b in the international2003 and at Stage 5b in the international

harmonization process, at the time of thisharmonization process, at the time of this

presentation, contains the acceptance criteriapresentation, contains the acceptance criteriafor the microbial quality of nonfor the microbial quality of non--sterile dosagesterile dosage

forms and pharmaceuticalforms and pharmaceutical excipientsexcipients..


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forms

S.S. aureusaureus; P.; P. aeruginosaaeruginosa

BileBile--tolerant Gramtolerant Gram--negativenegativebacteriabacteria

1010100100Topical and nasalTopical and nasal

productsproducts

S.S. aureusaureus; P.; P. aeruginosaaeruginosa

BileBile--tolerant Gramtolerant Gram--negativenegative

bacteriabacteria

1010100100InhalantsInhalants

S.S. aureusaureus; P.; P. aeruginosaaeruginosa1010100100Transdermal patchesTransdermal patches

(per patch)(per patch)

S.S. aureusaureus; P.; P. aeruginosaaeruginosa; C.; C.

albicansalbicans

101010001000Vaginal productsVaginal products

--101010001000Rectal productsRectal products

E. col iE. coli101010001000Oral LiquidsOral Liquids

E. coli ; Salmonell aE. col i; Salmonel lasppspp..

(Containing unprocessed animal,(Containing unprocessed animal,

plant or mineral ingredients)plant or mineral ingredients)

10010010001000Tablets and capsulesTablets and capsules

Absence of SpecifiedAbsence of Specified

Microorganism Requirement (1Microorganism Requirement (1

g or mL)g or mL)

TCYMCTCYMC

cfu/gcfu/g or mLor mL

TAMCTAMC

cfu/gcfu/g or mLor mL

Dosage FormDosage Form


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Objectionable Organisms

!! It is aIt is a cGMPcGMP requirement to excluderequirement to exclude

objectionable microorganisms from nonobjectionable microorganisms from non--sterilesterile

pharmaceutical products. The pertinentpharmaceutical products. The pertinent

sections are 21 CFR 211.113 Control ofsections are 21 CFR 211.113 Control ofmicrobiological contamination (a) Appropriatemicrobiological contamination (a) Appropriate

written procedures designed to preventwritten procedures designed to prevent

objectionable microorganisms in drug productsobjectionable microorganisms in drug productsnot required to be sterile shall be establishednot required to be sterile shall be established

and followed.and followed.


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!! 21 CFR 211.165 Testing and release for21 CFR 211.165 Testing and release for

distribution (b) There shall be appropriatedistribution (b) There shall be appropriatelaboratory testing, as necessary, of each batchlaboratory testing, as necessary, of each batch

of drug product required to be free ofof drug product required to be free of

objectionable microorganisms that may causeobjectionable microorganisms that may causeinfection when given by the route ofinfection when given by the route of

administration of the drug product and/oradministration of the drug product and/or

cause physicochemical deterioration to thecause physicochemical deterioration to theproduct. The objectionable microorganismsproduct. The objectionable microorganisms

will vary by dosage form.will vary by dosage form.


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!! How should a firm establish the objectionableHow should a firm establish the objectionable

organisms for each drug products?organisms for each drug products?

!! These are limited to organisms that can beThese are limited to organisms that can be

isolated using the compendial methods, causeisolated using the compendial methods, cause

infection in the recipients of the drug productinfection in the recipients of the drug product

when given by the route of administration ofwhen given by the route of administration of

the dosage form or deteriorate the product bythe dosage form or deteriorate the product by

proliferating within the product.proliferating within the product.

!! Also the medical status of the target patientAlso the medical status of the target patient

population may be considered.population may be considered.


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!! The objectionable microorganisms will vary byThe objectionable microorganisms will vary by

dosage form. For example, objectionabledosage form. For example, objectionable

organisms for a topical drug product may beorganisms for a topical drug product may be

the pathogensthe pathogens P.P. aeruginosaaeruginosa, S., S. aureusaureus,, andand S.S.pyogenespyogenes. I n addition, P.. I n addition, P. fluorescensfluorescens, B., B. cepaciacepacia

and S.and S. marcescensmarcescensthat may overcome thethat may overcome the

preservative system may also be consideredpreservative system may also be consideredobjectionable.objectionable.


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Objectionable Organism Policies!! Companies should develop scientificallyCompanies should develop scientifically--

justified guidelines listing objectionablejustified guidelines listing objectionable

microorganisms for each pharmaceuticalmicroorganisms for each pharmaceutical

dosage formdosage form

!!

For example, if the TAMC exceeds the alert orFor example, if the TAMC exceeds the alert oraction level then representative colonies wouldaction level then representative colonies would

be identified and if an objectionable organismsbe identified and if an objectionable organisms

is found then the lot would be rejectedis found then the lot would be rejected!! This approach would result in consistentThis approach would result in consistent

decision making and shorten the releasedecision making and shorten the release

decision makingdecision making


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Patient Populations

!! Should separate Microbial Limit specificationsShould separate Microbial Limit specifications

should be developed for drug productsshould be developed for drug products

administrated toadministrated to immunoimmuno--compromisedcompromised

individuals?individuals?


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Patient Populations

!! In a few cases, the target population of a drugIn a few cases, the target population of a drug

product is clearly known to beproduct is clearly known to be immunologicallyimmunologicallycompromised. However, in the majority ofcompromised. However, in the majority of

cases medications can be taken by patientscases medications can be taken by patients

ranging in age from newborns to the elderlyranging in age from newborns to the elderlyand from those in excellent health to those inand from those in excellent health to those in

poor health and seriously compromised. Givenpoor health and seriously compromised. Given

this situation, the author believes that a singlethis situation, the author believes that a singlespecification for each drug dosage form isspecification for each drug dosage form is

preferable to multiple specifications.preferable to multiple specifications.


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Patient Populations

!! For example, what should be the MicrobialFor example, what should be the Microbial

Limits requirements of anLimits requirements of an immunoimmuno--

suppressant drug used for organ transplant?suppressant drug used for organ transplant?

!! The USPThe USP--recommended requirements for anrecommended requirements for anoral tablet are TAMC NMT 1000oral tablet are TAMC NMT 1000 cfu/gcfu/g;;

TCYMC NMT 100TCYMC NMT 100 cfu/gcfu/g; absence of E. coli in; absence of E. coli in

10 g. Are these counts too high?10 g. Are these counts too high?

!! What should be the designated objectionableWhat should be the designated objectionable

microorganisms?microorganisms?


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Organ Transplant Microbial

Infections

!! ConventionalConventional NoscomialNoscomial Infection, 0Infection, 0 --1 months:1 months:

Wound infections, catheterWound infections, catheter--related infectionrelated infection

and pneumonia.and pneumonia. CandidaCandidasppspp..

!! Opportunistic Infections, 1Opportunistic Infections, 1 --6 months: As6 months: Asabove plusabove plus NocardiaNocardia,, ListeriaListeriaand tuberculosis.and tuberculosis.

AspergillusAspergillusandand CryptococcusCryptococcus

!! CommunityCommunity--Acquired or Persistent Infections,Acquired or Persistent Infections,

>6 months:>6 months: ListeriaListeriaand tuberculosis.and tuberculosis.

CryptococcusCryptococcussppspp..


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Organ Transplant Microbial

Infections

!! In general, the presenter believes thatIn general, the presenter believes that

transplant patients will be more likely to obtaintransplant patients will be more likely to obtain

infections through invasive procedures, theirinfections through invasive procedures, their

food , and the general environment than fromfood , and the general environment than frompharmaceutical drug products.pharmaceutical drug products.


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General Risk Assessment

!! Clearly,Clearly, injectableinjectable products because of theirproducts because of their

invasiveness must be sterile while tablets andinvasiveness must be sterile while tablets andcapsules, in the absence of food bornecapsules, in the absence of food borne

pathogens, may contain a moderate bioburdenpathogens, may contain a moderate bioburden

without impacting the recipient of the drugwithout impacting the recipient of the drugproduct. Contamination, with high numbers ofproduct. Contamination, with high numbers of

microorganisms, will impact nasal sprays,microorganisms, will impact nasal sprays,

vaginal products, topical products, and oralvaginal products, topical products, and oralliquids more than aerosol inhalants, tablets andliquids more than aerosol inhalants, tablets and

capsules because their high water activity willcapsules because their high water activity will

support microbial growth.support microbial growth.


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Product Recalls

!! What does the product recall history tell usWhat does the product recall history tell us

about the risk of microbial contamination?about the risk of microbial contamination?

!! A good summary may be found annually inA good summary may be found annually in

March issue ofMarch issue ofThe Gold SheetThe Gold Sheet

!! The number of recalls for nonThe number of recalls for non--sterilesterilepharmaceutical products for microbialpharmaceutical products for microbial

contamination has been stable at an average ofcontamination has been stable at an average of

6 recalls annually for the past 10 years.6 recalls annually for the past 10 years.!! What products are recalled and whichWhat products are recalled and which

microorganisms are implicated?microorganisms are implicated?

Prod ct Recalls


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Product Recalls

!! The emphasis on waterborne gramThe emphasis on waterborne gram--

negative bacteria of the speciesnegative bacteria of the species

BurkholderiaBurkholderia(Pseudomonas)(Pseudomonas)cepaciacepacia(9(9recalls),recalls), PseudomonasPseudomonasputidaputida(3 recalls),(3 recalls),PseudomonasPseudomonasaeruginosaaeruginosa(3 recalls),(3 recalls),PseudomonasPseudomonassppspp. (2 recalls). (2 recalls) RalstoniaRalstonia(Pseudomonas)(Pseudomonas)pickettiipickettii(1 recall) is(1 recall) isnotable (40% 0f all recalls) and reflectsnotable (40% 0f all recalls) and reflects

the concern for bacteria capable forthe concern for bacteria capable for

growth in liquid oral dosage formsgrowth in liquid oral dosage forms

overwhelming the preservative system.overwhelming the preservative system.

P d t R ll


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Product Recalls

!! Analysis of the underlying probable causeAnalysis of the underlying probable cause

by the presenter suggest that they are 1)by the presenter suggest that they are 1)

microbial contamination of water formicrobial contamination of water for

pharmaceutical purposes, 2) the use ofpharmaceutical purposes, 2) the use of

pharmaceutical ingredients with higherpharmaceutical ingredients with higher

microbial counts, 3) failures of preservativemicrobial counts, 3) failures of preservative

systems to protect liquid products, 4)systems to protect liquid products, 4)

microbial contamination during themicrobial contamination during the

manufacturing process, and 5) impropermanufacturing process, and 5) improper

storage of the products during their shelfstorage of the products during their shelf

life.life.

Factors Influencing the Potential


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g

for Microbial Contamination

!! Product formulationProduct formulation

!! Pharmaceutical ingredientsPharmaceutical ingredients

!! Preservative systemsPreservative systems

!! Manufacturing processesManufacturing processes

!! Equipment cleaningEquipment cleaning!! Environmental controlsEnvironmental controls

!! PackagingPackaging -- multiple versus single usemultiple versus single use

!! Water activityWater activity

!! Potential for misuse by customerPotential for misuse by customer


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Manufacturing Processes and

Microbial Contamination

!! Manufacturing steps with a potential toManufacturing steps with a potential to

increase the product bioburden of aincrease the product bioburden of a

compressed tablet include equipment cleaning,compressed tablet include equipment cleaning,

milling, wet granulation, static air drying, andmilling, wet granulation, static air drying, andfilm coating.film coating.

!! Steps will a potential to decrease the bioburdenSteps will a potential to decrease the bioburden

include fluid bed drying and compression.include fluid bed drying and compression.


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Microbial Limit Specifications

!! Is it necessary to include Microbial LimitIs it necessary to include Microbial Limit

specifications in the regulatory filings for allspecifications in the regulatory filings for all

nonnon--sterile pharmaceutical dosage forms?sterile pharmaceutical dosage forms?

Mi bi l Li it S ifi ti


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Guidance for setting Microbial LimitsGuidance for setting Microbial Limits

specifications for nonspecifications for non--sterile drug productssterile drug products

may be found in:may be found in:

!! The ICH Harmonized TripartiteThe ICH Harmonized Tripartite

GuidelineGuideline Specif ications: Test ProceduresSpecif ications: Test Proceduresand Acceptance Criter ia for New Drugand Acceptance Criter ia for New Drug

Substances and New Drug Products:Substances and New Drug Products:

Chemical Substances Q6AChemical Substances Q6A Step 4 OctoberStep 4 October6 19996 1999-- Decision Tree #8: MicrobiologicalDecision Tree #8: Microbiological

Attributes of NonAttributes of Non--Sterile Drug ProductsSterile Drug Products


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!! Draft Guidance for IndustryDraft Guidance for IndustryDrug ProductDrug Product

Chemistry, Manufacturing, and ControlsChemistry, Manufacturing, and Controls

(CMC) Information January 2003 references(CMC) Information January 2003 references

Decision Trees # 6 and #8 in ICH Q6aDecision Trees # 6 and #8 in ICH Q6aSpecification for the rationale for notSpecification for the rationale for not

performing microbial limits testing for nonperforming microbial limits testing for non--

sterile drug substances andsterile drug substances and excipientsexcipients, and, andnonnon--sterile drug productssterile drug products



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!! The draft FDA guidance document states it isThe draft FDA guidance document states it is

advisable to perform microbial limit testingadvisable to perform microbial limit testing

of a nonof a non--sterile product unless its componentssterile product unless its componentsare tested before manufacture and theare tested before manufacture and the

manufacturing process is known, throughmanufacturing process is known, through

validation studies, not to carry a significantvalidation studies, not to carry a significantrisk of microbial contamination orrisk of microbial contamination or

proliferation. A proposal to excludeproliferation. A proposal to exclude

microbial limit testing from the specificationmicrobial limit testing from the specification

should be scientifically justified.should be scientifically justified.



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!! The guidance document specifically states thatThe guidance document specifically states that

Periodic Quality Indicator Tests (PQIT)Periodic Quality Indicator Tests (PQIT)

designated and justified in a regulatory filingdesignated and justified in a regulatory filing

can include microbiological testing of solid oralcan include microbiological testing of solid oral

dosage forms.dosage forms.

!! This can be the basis of a reduced testingThis can be the basis of a reduced testing

programprogram



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!! Applications may propose a Sunset TestApplications may propose a Sunset Test

Protocol with a commitment to drop aProtocol with a commitment to drop a

specification such as Microbial Limitsspecification such as Microbial Limits

after an agreed number of productionafter an agreed number of production

batches, e.g. 10 to 20 lots, are tested andbatches, e.g. 10 to 20 lots, are tested and

meet the test criteria.meet the test criteria.

!! Also, a proposal to drop a test, based onAlso, a proposal to drop a test, based on

historical data, may be submitted posthistorical data, may be submitted post--approval in a prior approvalapproval in a prior approval

supplement.supplement.

Mi bi l Li i S ifi i


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!! The proposal should include: 1) the reasonThe proposal should include: 1) the reason

why the sunset provision is proposed, 2) thewhy the sunset provision is proposed, 2) thenumber of consecutive batches that will benumber of consecutive batches that will be

tested, 3) the criteria for dropping the test,tested, 3) the criteria for dropping the test,

and 4) the postand 4) the post--approval reportingapproval reportingmechanism for notifying CDER of the testmechanism for notifying CDER of the test

results when the criteria have been met.results when the criteria have been met.

Opportunities


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Opportunities

!! When justified by formulation,When justified by formulation,

manufacturing processes and testingmanufacturing processes and testing

histories, lothistories, lot--byby--lot Microbial Limit testinglot Microbial Limit testingof liquidof liquid-- and powderand powder--filled capsules,filled capsules,

compressed tablets, rectal suppositories,compressed tablets, rectal suppositories,

topical ointments, aerosol inhalants and liptopical ointments, aerosol inhalants and lipbalms may be replaced by periodic testingbalms may be replaced by periodic testing

or the elimination of all testing.or the elimination of all testing.

!! The microbial resistance of other dosageThe microbial resistance of other dosage

forms may be increased by decreasing theforms may be increased by decreasing the

water activity of the formulations.water activity of the formulations.

Water Activity to Prevent


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y


!! EniglEnigl && SorrellsSorrells (1997)(1997) Water Activity andWater Activity and

SelfSelf--Preserving FormulasPreserving Formulas, I n: Preservative, I n: Preservative--

F ree and SelfF ree and Self--Preserving Cosmetics andPreserving Cosmetics and

Drugs: Principles and Practice, J.J.Drugs: Principles and Practice, J.J. KabaraKabara& D.S.& D.S. OrthOrth, 1997 , 1997 There is no technicalThere is no technical

reason why selfreason why self--preserving formulations,preserving formulations,

i.e. using low water activity, cannot be usedi.e. using low water activity, cannot be usedfor cosmetics, OTC drugs &for cosmetics, OTC drugs &

pharmaceuticalspharmaceuticals

W t A ti it t P t


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Water Activity to Prevent


USP draft chapter USP draft chapter MicrobiologicalMicrobiological

Attr ibutes of NonAttr ibutes of Non--ster i le Pharmaceuticalster i le PharmaceuticalProductsProducts

The microbial quality of non The microbial quality of non--aqueous or dryaqueous or drydosage forms that do not support microbialdosage forms that do not support microbial

growth because of low water activity willgrowth because of low water activity will

primarily be a function of thoseprimarily be a function of thosemicroorganisms introduced throughmicroorganisms introduced through

ingredients or during processing.ingredients or during processing.

Water Activity and Microbial


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Limits Testing

FriedelFriedel and Cundell (1998)and Cundell (1998)

Since the water activity requirements for Since the water activity requirements fordifferent gramdifferent gram--reactive bacteria,reactive bacteria,

bacterial spores, yeast & molds are wellbacterial spores, yeast & molds are well

described in the literature, thedescribed in the literature, the

appropriate microbial testing programappropriate microbial testing program

for products of differing water activitiesfor products of differing water activitiescan established.can established.

Wh is A Important for


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Why is Aw Important for

Microbial Growth?

!! Microorganisms need availableMicroorganisms need available

water within a product to proliferate.water within a product to proliferate.

!! Water activity and not water content isWater activity and not water content is

a better measure of the free water, ina better measure of the free water, in

contrast to bound water, that microbialcontrast to bound water, that microbial

cells require for metabolic activity andcells require for metabolic activity andosmotic regulation.osmotic regulation.

Effects of Reduced Aw on


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w

Microbial Growth!! Longer lag phase, slower growth rate, andLonger lag phase, slower growth rate, and

lower numbers of organisms in thelower numbers of organisms in the

stationary phasestationary phase

!! Reduced microbial toxin productionReduced microbial toxin production

!! Below a specified ABelow a specified Aww for an organism,for an organism,microbial growth will not occur andmicrobial growth will not occur and

vegetative microorganism will dievegetative microorganism will die--offoff

!! However, the resistance of microorganismsHowever, the resistance of microorganisms

to heat increases with decreasing Ato heat increases with decreasing Aww

Microbial Growth Limits and


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Water Activity

AwAw

0.910.91

0.880.88

0.860.86

0.800.800.700.70

0.600.60

Microbial Growth LimitMicrobial Growth Limit

Bacterial pathogens with the exceptionBacterial pathogens with the exception

ofofS.S. aureusaureus

Yeast (Practical Limit)Yeast (Practical Limit)S.S. aureusaureus

Production ofProduction ofMycotoxinsMycotoxinsMolds (Practical Limit)Molds (Practical Limit)

Absolute limit for all microbial growthAbsolute limit for all microbial growth

Role of Water Activity in Drug


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Formulation

!! Formulations can be developed to lower waterFormulations can be developed to lower water

activity to make products especially inhalants,activity to make products especially inhalants,nasal sprays, topical products and oral liquidsnasal sprays, topical products and oral liquids

less susceptible to microbial contamination andless susceptible to microbial contamination and

to optimize preservative systems.to optimize preservative systems.

Water Activity of Dosage Forms


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High RiskHigh Risk

!!

Aw >0.95:Aw >0.95: Nasal sprays, inhalant solutions,Nasal sprays, inhalant solutions,rectal creams, liquid antacids, and eye drops.rectal creams, liquid antacids, and eye drops.

!! Aw >0.90: Oral liquids, and topical lotionsAw >0.90: Oral liquids, and topical lotions

!! Aw >0.85: Cough syrups, oral canker soreAw >0.85: Cough syrups, oral canker sore

gels, and oral analgesic suspensionsgels, and oral analgesic suspensions



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Low RiskLow Risk!! Aw >0.55: Ophthalmic ointments, andAw >0.55: Ophthalmic ointments, and

topical ointmentstopical ointments

!! Aw > 0.45:Aw > 0.45: LiquidLiquid--filled capsulesfilled capsules

!! Aw >0.40:Aw >0.40: LiquidLiquid--centered cough dropscentered cough drops

!! Aw >0.30:Aw >0.30: Lip balm, powderLip balm, powder--filledfilled

capsules, compressed tablets, vaginalcapsules, compressed tablets, vaginal

suppositories, rectal suppositories, andsuppositories, rectal suppositories, and

multiple vitamin tabletsmultiple vitamin tablets

!! Aw < 0. 20 Metered dose aerosol andAw < 0. 20 Metered dose aerosol and

powder inhalantspowder inhalants


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Conclusions!! The risk of microbial contamination variesThe risk of microbial contamination varies

widely amongst nonwidely amongst non--sterile pharmaceuticalsterile pharmaceuticaldosage forms.dosage forms.

!!

With low risk dosage forms the eliminationWith low risk dosage forms the eliminationroutine microbial limit testing may be justifiedroutine microbial limit testing may be justified

!! A knowledge of the risk can be used to reduceA knowledge of the risk can be used to reduce

the incidence of microbial contaminationthe incidence of microbial contamination

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