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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
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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
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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
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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
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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
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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Microbiological Consulting 9
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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Objectionable Organisms
!! 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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Objectionable Organisms
!! 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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Objectionable Organisms
!! 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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Microbial Limit Specifications
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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Microbial Limit Specifications
!! 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
Mi bi l Li it S ifi ti
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Microbial Limit Specifications
!! 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.
Microbial Limit Specifications
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Microbial Limit Specifications
!! 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
Mi bi l Li it S ifi ti
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Microbial Limit Specifications
!! 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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Microbial Limit Specifications
!! 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
Microbial Contamination
!! 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
Microbial Contamination
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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Water Activity of Dosage Forms
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
Water Activity of Dosage Forms
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Water Activity of Dosage Forms
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