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An Overview of Guidelines and Regulationsfor ProbioticsVirender K.Batish
Molecular Biology UnitD i Mi bi l Di i iairy Microbiology Division,NDRI, Karnal (Haryana) 132 001, INDIA
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Probiotics the magic bugs Boom in probiotic based functional / health foods
Catchy slogans billion a day keeps Dr. away Probiotics as alternative therapy
Exaggerated health claims without scientific evidence
Optimism versus skepticism,
products
Consumer confidence and acceptability ?
Urgent need for guidelines / regulations for probiotic
management at global level
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World Scenario of Regulatory approaches on Probiotics Probioticstandards/regulationsdifferamongdifferent
countr es
NoharmonizationofstandardsamongEUcountriesandUSA/Canada
Asfoods/functionalfoods/NovelFood/ Naturalremedy
(Denmark/
Sweden/
Finland)
sna ura ea pro uc ana a
AsDieteticfood(Italy)
Dietar su lement USA
Biotherapeutic/Pharmaceuticals(Canada,China,EastEuropeancountries/France/Germany/Belgium/Austria/
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Current Status of National/ International Regulatory Agencies Standardsf r E l ti d S f t f Pr bi ti i r i l r d tor Evaluation and Safety of Probiotics in commercial products FA0/WH0(www.fao.org)(www.fao.org) Worldwide
Developedguidelinesforevaluationofprobiotics IDF(www.filidf.org) Worldwide
Jointactionteamonestablishingmethodstodeterminefunctional/safetyattributesofpro ot cs n oo n new t
EFECA(www.effca.com) Europe
Developedguidelinesforuseofprobioticsinfoods o exs an ar s or ermen e m s
(www.codexalimentarius.net) Worldwide
Minimum number of characterizing and additional level of microbes in yoghurt / acidophilus
milk / kefir / kumiss and others
NYA (www.aboutyoghurt.com)
US
Minimum level of viable cultures
FDA www.fda.or US Minimum level of viable cultures
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FAO/WHO Standards/ guidelines on Probiotics
Nutritional properties of Probiotics in foods(Argentina, 1-4th Oct., 2001)
Workinggroup guidelines,criteria/methodologyforevaluation
ofProbiotic
IdentifyanddefinedataforsubstantiatingHealth
Claims
MinimumrequirementsforProbiotic status
Scope Probioticsasfoodsonly
ExcludedGMOs/Biotherapeuticagents
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Definitions of ProbioticsfNo universal legal definition
Probiotics as live micro -organisms which when
administered in adequate amounts confer a health benefit
on the host
(FAO/WHO, 2001)
Probiotics are microbial cell preparations or components ofmicrobial cells that have a beneficial effect on the health &
wellbeing of the host.
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.,
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FAO/ WHO- Guidelines for the assessment of Probioticsf f DefinitionofProbiotics
Identificationat
Genus,
species
and
strain
level
(Phenotypic
andgeneticTests)
ProbioticFunction strainspecific
Invitro
tests
for
evaluation
of
probiotics
(Human)PhaseI/PhaseII/PhaseIII
NoadverseeffectsrelatedtoProbioticadministrationto
occur
Theoutcomeofhumanstudies(evenwithnegativeresults)
o epu s e napeerrev ewe ourna s
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Selection of probiotic strains for human use
Specificity of the action of probiotic
bacteria not the source that is moreimportant
Viability at the target site and effectiveness
Refinement of in vitro tests to predict theability of probiotics to function in human
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Classification and identification
The probiotic functions highly strain specific
Identification as per international code of nomenclature at
strain level
Potential molecular tools for probiotic identification DNA-
FISH, probes as a complement to phenotypic tests
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Defining and measuring the health benefits ofpro iotics
Dose and duration of probiotic use critical formeasuring their efficacy to confer health
benefits on the host
Minimum daily amount required to confer the
purported health benefits is to be defined explicitly
ase on n v ro an n v vo stu es on ce nes ananimal models as well as humans clinical trials
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Testing methods for establishing health benefits conferred
y p o o cs
thehealth
benefits
prior
toinvivotrials
Batter oftestssuchasacidandbiletolerance
antimicrobialproductionandadherence abilityto
beconducted
depending
on
the
purported
health
benefits
Invivotesting RDBPChumantrialsbyenrolling
adequatenumber
of
subjects
to
achieve
statistical
significance
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Safety considerations specific tests for assessingbi i frobiotic safety Antibiotic resistance patterns
Undesirable metabolic activities (D-lactate, bile saltdeconjugation)
Epidemiological surveillance of
adverse incidents in consumers(post market)
Toxin production
Lack of infectivity in immuno-
com romised animal models
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FAO/ WHO recommended In vitro tests for Probiotics
Resistanceto
gastric
acidity
esa res s ance o on za on
Adherence
to
mucus
/
human
epithelial
cells Antimicrobialactivityagainstpathogens
Abilitytoreducepathogenadhesiontosurfaces
Bilesalt
hydrolase
activity
(As
aProbiotic
Marker)
Resistancetos ermicides va inala licationofProbiotics
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Pr bi ti r d t ifi ti Q litrobiotic product specifications QualityAssurance and Regulatory Issues
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e ulator issues
Regulations differ among countries
Status of probiotics as a component of food not
established on International basis
Disease reduction claims to be permitted for specificprobiotics if demonstrated successfully
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Appropriate labeling
Identity of microbial strains to be stated on the label
Indicate viable concentration of each probiotic
bacteria in food products
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Manufacturing and handling proceduresg g pStock cultures be maintained under appropriate
conditions to ensure that the given culture maintains
e ene c a proper es
ec pur y, v a y an pro o c ac v y roug
out processing, handling and storage of the food
end of shelf life (follow QA)
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Post mar et surveillanceAll the stake holders to develo some form
of system to monitor the health outcome oflong term probiotic administration
Potential side effects and long term
-
for surveillance of probiotic products
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Regulating Pre- and Pro-biotics:a US FDA Perspective
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Objectivesbjectives
biotherapeutic. Review the regulatory definition of drug, biologic,
dietary supplement and GRAS.
Discuss the regulatory difference between a dietary
.
Focus on the regulation of probiotics as biologics.
Discuss re ulator considerations in the
development of probiotics for clinical indications.
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Non-regulatory Termson regulatory TermsProbiotic
Prebiotic
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Live BiotherapeuticCBER/OVRR Working Definition Live microorganisms with an intended therapeutic effect in
humans. May include bacteria or yeast
May be used in disease prevention or treatment
Intended local or regional action
Includes robiotics for clinical use
Biotherapeutic Agent
Microorganisms having therapeutic effects in humans.
,
general beneficial effects on the health of animals or
humans.
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How are probiotics andprebiotics regulated in the US?
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Intended use determines how ab l dubstance is regulated?
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Regulatory Definitionsy fDrug article intended for use in the diagnosis,cure,
m ga on, rea men , or preven on o sease
(Food, Drug & Cosmetic Act of 1938).
Biological product a virus, (i.e., bacteria,fungi, etc.) etc.
applicable to the prevention, treatment, or cure of a disease orcon on o uman e ngs
(Public HealthService Act of 1944, 42 USC 262).
Dietary supplement - a product taken by mouth that contains a
dietary ingredient intended tosupplement the diet
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(DSHEA of 1994,amendment to the Food, Drug & Cosmetic Act).
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GRASRAGenerall Reco nized As Safe
21 CFR 170.3 and 170.30
A food ingredient classification that
distinguishes a substance from a food
about safety for its intended use.
Pertains to the use of a food substance,
rather than the substance itself.
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Dietary Supplement v/s Biological Productpp / gA robiotic ma be marketed and re ulated as a
dietary supplement and/or a biological product.
It all depends on how it is intended to be used.
Biological products require premarket review
and approval by FDA. Dietary supplements do not.
The safety, purity and potency, as well as efficacy,
of a biological product must be demonstrated forapproval. Dietary supplements need not demonstrate
an of these to be marketed.
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FDAs Center for Food Safety andDA s Center for Food Safety andApplied Nutrition (CFSAN) regulatesp ( ) gprobiotics and prebiotics marketed asdietary supplements or foodietary supplements or foodingredients.
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When is a probiotic a drug/biologicalproduct?
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A probiotic used for diagnosis, cure, mitigate,
treat, or prevent disease is a drug and
a o og ca pro uc .
FDAs Center for Biologics Evaluation and Research (CBER)
regulates probiotic products when used for clinical indications
CBERs Office of Vaccines Research and Review hasregulatory jurisdiction over most probiotic products for clinical use.
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Currently, CBER/OVRR views probiotics for clinical useas live biotherapeutics
CBER/OVRR has vast experience in regulating products
Focus and experience to date has been
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Regulating the Safety of Probiotics TheEuropean approachuropean approach
Probiotics for human foods not governed under specific EU regulatory
.
Novel Food regulation EU 258/97 relevant in some specific cases.
Probiotics as feed additives regulated by Council Directive
70/254/EEC & in accordance with the uidelines of SCAN
Transmissible antibiotic resistance markers?
Production of harmful metabolites?
EU uidelines do not differentiate between s ecies & strains with lon
history of safe use.
Concern regarding over-regulation of Probiotics for human food use.
Concept of Qualified Perception of Safety (QRS)
allow strains with established safety status to enter the marketwithout any testing requirement.
EFSA Central role in the regulation of both human & animal
probiotics.
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Japanese perspectivep p p Japan a key player in probiotic based functional foods accounting
for more than half of global proboitoc foods market.
Japan the only nation that has legally defined functional/healthfoods.
n ro uc on o sys em o regu a e oo s or spec c ea
use.
Unique features of FOSHU
Specific health claims approved prior to use.
Approval based on documented scientific evidences.
.
MHLW new regulatory system Foods with health claims (FHC) and
foods with nutrient functions (FNFC) in 2001.
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Japanese perspective New Subsystems of FOSHU
Standardized FOSHU
Qualified FOSHU
Disease risk reduction claims for FOSHU.
336 probiotic based products approved by FOSHU.
FOSHU a role medal for other countries.
Application for grant of FOSHU Label submitted to local regional
authorities/MHW (1 year processing time) with following inputs : Scientific evidence for health claim.
Recommended dose of the functional food/ingredient.
Safety of the ingredient.
Physical & chemical characteristics. Relevant test methods.
Compositional analysis.
Scientific paper that substantiate health claims.
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Canadian perspective
In Canada, probiotics regulated by natural health product
Directorate (NHPD) which became a law in 2004
Covers therapeutic claims, risk reduction and structure /function claims
Under item 8 (schedule 1) the term probiotic is defined as
monoculture or mixed culture of live micro-organisms that
benefit the microbiota indigenous to humans Provision of dead microbes or other microbes not labeled as
probiotics
Direct fed microbes for animal nutrition covered under the
jurisdiction of Canadian feed inspection agency (CFIA)
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Contd.
presented by NHPDs clearly defined criteria New NHPD uidelines allow for ualified
claims based on the weight of evidence
provided The design of clinical trials to assess
probiotics follow the ICH and GCP guidelines
use or p armaceut ca pro ucts
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Indian Scenario Regulatory standards and guidelines of probiotics no
formulated as yet.
India a potential market for Probiotic foods
Entr of s urious roducts with false claims.
Non-availability of proven and well characterized Indian
Probiotic cultures.
Indian gut due to short transit time.
Need for development of indigenous probiotic strains for
.
Holistic approach for formulating guidelines and regulations for
evaluating the efficacy of Indian probiotics in hormony with
.
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Indian Scenario Currently foods regulation by PFA and drugs by FDA in India.
Initiatives being taken by DBT/ICMR/MFPI to formulate
guidelines on Probiotics.
Food safet and standards Act assed in arliament 2006 to
regulate foods, dietary supplement & nutraceuticals.
Creation of Food Safety and Standards Authority (FSSA, 2005)
draftin rules and re ulations in the food sector
Liberal regulationS permitting claims if not misleading
Stringent regulations for Food supplements/biotherapeutics for
.
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Risk concerns associated with Probiotics R l iegulations
Regulation of Probiotics as Foods
Food/dietary supplement
Pharmaceutical a biological products No stringent requirements when used as food/dietary supplements
.
Legal requirements when intended for use in infants/children in Europe.
In U.S., no pre-market review & approval by FDA. FDA approval needed when
marketed as biologicals specifically for treatment/prevention of target disease. IN Australia Probiotics as complementary medicine for specific health
benefits require pre-market review by Therapeutics goods Administration.
Japan General probiotics products have FOSHU status for specified health
Probiotics GRAS status safety concerns in particular population (septis,bacteriocin, endocarditis).
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Current status of Marketing of Probiotics Marketing of Probiotic products concurrent with science based
substantiation of product efficacy.
Enforced regulation on Probiotic quality & efficacy - non existent
worldwide.
Recall of Probiotic products in USA due to non allowable disease
claims.
Mislabeled products wrt genes, species, cell count or unsubstantiated
structure function statements invariably found in the market in
.
Consumer disillusionment & loss of confidence declining market.
Regulating approaches differ among different countries & hence no
.
Regulations & guidelines yet to be formulated in developing countriesincluding India.
Holitic a roach on uidelines and re ulations needed for each
country for judicious & effective use of Probiotics.
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Contd.
Identificationof universalprobioticmarkersfor massscreeningofmicrobial
culturesfromdifferentecologicalniches
Nosolid
documentation
that
strains
performing
well
in
physiological
tests
perform anybetterinhumanevaluationsthanthoseperformingpoorly inthese
Establishing standardoperating procedures forlimitednumberoffunctional
assays isprematureconsideringthecurrentstatusofresearch
Noclarityon theeffectivedosesofprobiotics.Mayvaryfromstraintostrain
andthe food andthehost(age,sexandtargetspecific)healthyand
immunocompromised
Needfor
multicentric
approach
for
human
clinical
trials
for
validating
the
specifichealthclaimsof probiotic strains forhighlevelofconfidenceand
statistical significance
Formulating uniform StandardOperating Procedures(SOPs)andanalytical
assays forassessingthequality,safetyandefficacyofprobiotics
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ConclusiononclusionRegulatory standards and guidelines at National/International levelare extremely important for assessing the efficacy and safety of
However, there is need for harmonization of these
regulations and guidelines on probiotics at the global level
to ensure the quality and safety of probiotic foods fortheir effective utilization in different countries
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A Quote on Probiotic regulations guidelinesg g
We need someone like Bono to sit down with politicians &
tell them that probiotics are integral to health, to the budget
& for the future of the country
Prof. G. Reid 2007
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