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Microbiome product development: Crossing the technical CMC and regulatory science

Speaker:

Marielle Fournier, Senior Director, Drugs, Devices & Combination Products,Voisin Consulting Life Sciences, Switzerland

3

MICROBIOME: Crossing the technical CMC and regulatory science

MAY 15, 2018

Marielle FournierSenior Director, Drugs, Devices and Combination products @ VCLS

[email protected]

mailto:[email protected]

4Housekeeping Notes

DURATION QUESTIONS

[email protected]

http://www.voisinconsulting.com/


5

Agenda• EU regulatory framework for Microbiome

products

• Main challenges of Microbiome drug

product development

• Summary points and Take Home

Messages

• Q&A

6

1 EU regulatory framework for Microbiome products

2 Main challenges of Microbiome Drug Product Development

3 Summary points and Take Home Messages

L

Agenda

7

The collection of microbes that inhabit an environment, creating a “mini ecosystem”.

100 thousand billion

bacteria

> 3 million genes

2-5 pounds of bacteria

(30% caloric intake)

Introduction

Gastro-Intestinal upsets & GI-

related complications

Brain health

Cardiovascular system

Immune system

Diabetes

Obesity

8

Development challenges

Regulatory:

product positioning, legal

route/classification

Quality/CMC technical:

characterization, reproducibility,

alignment to cGMP

9

Regulatory development challenges: Legal basis

• Product classification: What actually is the product / new development?

• Applicable product positioning in key global markets

Regulatory pathway has impact on cost & time to market and life cycle

o Dietary supplement

o Foods with categorized Health claims

o Medical Food

o Drug / Biological product / Live

Biotherapeutic Products (LBP)

o Food supplement

o Functional foods/Foods with Health claims

o FSMP

o Biological product / Medicinal product

10

Approaches to regulatory development solutions

• Upfront clarification of Target Product Profile (TPP)

o Target efficacy/indication statement

o Clarified mechanism of action

o Galenical and route of administration

• Choice of optimal regulatory path

o Identify the optimum EU regulatory path

o Identify pros and cons of different available pathways

o Consider associated development timelines and development cost

o Consider competitive differentiation versus other products

o Weigh and match pros & cons of different routes against corporate exit strategy

o Examine the rigors of required developmental efforts (CMC, nonclinical, clinical)

11



3 Summary points and Take Home Messages

L

Agenda

Chemistry Manufacture and Controls (CMC)

12

Turning Therapeutic Potential into a Medicinal product

• The research and development of potential microbiome drug candidates may

be originated via various scientific ‘angles of attack’.

o modulation of the microbiome in some way

o altering its genetic constitution

o focus on metabolic and functional pathways

• The objective is to then move this from R&D and into first in human trials

13

The Nature of the Challenge

1. Identification of a potential disease

‘target’ through analysis of the

microbiome (biological constitution,

function etc.)

2. Identify a promising and potential

active substance that may be

already in use.

Convert the drug candidate into a

medical product.

DEVELOPMENT STAGERESEARCH STAGE

1

2

3

14

Microbiome medicinal product: Example of drug design and development formats

Potential Active Substance / target Drug product Class

1 Microbiome organism/s

e.g. bacteria

Microbial Biologic

2 Molecular biology of above ? Enhanced microbial Biopharmaceutical

3 Metabolic pathway/functionality Chemical/Biologic Pharmaceutical/

biopharmaceutical

4 Modulation of microbiota Probiotic Biologic

5 Modulation of

micro environment

Prebiotic Natural (or synthetic)

15

Realization of CMC

Standard life-cycle of a medicinal product prior to launch

Pre-clinical Phase I Phase II Phase III Registration Launch

CMC proceeded and optimized

CMC aspects are Chemistry, Manufacture, Control

CTA, IMPD updates

CTA, IMPD

Manufacturing Scale

Small Scale Pilot Scale

MANUFACTURING

Fully Validated In-

process and

Release Tests

Valid Safety TestingValidated Safety,

Identity, Purity,

Impurities

ANALYSIS

Safety

Efficacy

Quality

Quality

16

Establishing a Target Product Profile (TPP)

Outline of some elements of a Target Product

Profile (example)

Indication

Active substance e.g. microbial, fungal, viral, probiotic,

prebiotic origin etc.

Mode of action

Route of administration

Source / starting material

Initial market demand /projected market demand

Bench/pilot scale process

Starting point analytical methods: identity, purity,

quantity, biological activity/potency

Stability

Start with the end in mind

17

Assembly of CMC ‘building blocks’ (abridged)

Target Product Profile

Quality Target Product Profile

Critical Quality

Attributes

Process and

Analytical Derivation

Control

Strategy

General Sequence of Proceeding from the TPP

Process Product

Materials

Control parameters

18

Basic Process Design Considerations

‘Hypothetical Product’ Notes/Production Format

Subclass of microbiota: bacterium or an enhanced strain Microbial production

May involve strain selection or genetic manipulation of the

bacterium

DSP would include need to consider if

live/dead/lyophilized product

Probiotic The starting material may be identified from an existing

source to have therapeutic potential

This may involve employing some of the existing process.

DSP – as above

Prebiotic Probable partial use of existing process / or supply as

starting material (if quality criteria can be met)

Genetic Modification Complex: Strict attenuation and release criteria would be

needed

Other pharmaceutical compound or biopharmaceutical

recombinant

19

Process Design Considerations

• It is therefore clear that a number of process variants/variations could exist.

• In each situation critical process parameters will need to be identified controlled and the quality of materials & starting materials entering the process will need to be of an acceptable quality and specification for human medicinal purposes:

• Product and Process related impurities will need to be controlled to within acceptable limits.

• Although a process or partial process (e.g. probiotic, prebiotic) may exist; this will have to be pulled into full alignment to cGMP for the purpose of clinical manufacture.

• Transition of R&D into cGMP manufacture:

• Consideration: in house quality step up (e.g. from ISO etc.?) vs cGMP outsource partner

20

From Development to First in Human

FIH STUDYDEVELOPMENT

Operational CMC: cGMP

Microbiome drug product

Manufacture and Analytics Transfer

Manufacture of first GMP batches

Regulatory CMC:

Dossier Assembly (CMC =

Preparation of a First Module 3)

Consideration of EMA Scientific

Advice

Microbiome drug product

candidate

Proof of Concept Studies

Development Data at Lab

Scale and Lab/Pilot Procedure

Publications

Intellectual Property

CMC & Quality Alignment

Technology

Transfer

21

Excerpt of ‘Shopping list’ for moving from development into cGMP

• Proof of principle will have been demonstrated as a requisite

• Define bench or, more appropriately, pilot scale process

• Ascertain which materials need to be upgraded in terms of Quality for in

human application

• Perform sufficient characterization / apply analytical methods

• Non-clinical Toxicology; needs to be representative to cGMP process

• cGMP clinical manufacture: in house capability vs contract manufacture?

• Develop a technology transfer package…

• Once cGMP manufacture is performed; the preceding development and

cGMP data package needs to be collated and assembled as part of the IMPD

(EU) or IND (US).

• The phase 1 clinical trial can now be effected.

22

Meeting CMC Regulatory Expectation

• Whilst there is certain regulatory guidance we can draw upon for microbiome orientated products, this is still a developing field

• The regulatory route can therefore be still somewhat case by case and very much relies on the product positioning.

• “Quick Start” CMC development guidelines include:

o Guidance for Industry: Early clinical trials with live biotherapeutic products: chemistry manufacturing and control information (FDA)

o ICH Q8 (R2) Pharmaceutical development

o ICHQ11, on development and manufacture of drug substances (chemical entities and biotechnological / biological entities)

o Guideline on the requirements for quality documentation concerning biological investigational medical products in clinical trials (EMA)

23



3 Summary Points and Take Home Messages

L

Agenda

24

Summary & Take Home Message

• A well defined TPP will drive optimal product positioning, and can also help

articulate the competitive landscape. A consideration of these aspects can

inform the different development regulatory strategies to deploy.

• In this section, we have provided a fleeting look at some of the CMC ‘building

blocks’ and sub elements that can be assembled for the moving a microbiome

product from R&D and into first into human studies.

• This in no way provides any form of CMC regulatory ‘blueprint’ but serves to

provide important considerations which should be made for deriving a solid

technical and regulatory strategy for those initiating microbiome medical

products

Questions & Answers

Voisin Consulting Life Sciences

linkedin.com/company/voisin-consultingwww.voisinconsulting.com

http://www.linkedin.com/company/voisin-consulting

http://www.voisinconsulting.com/

Evaluating the different steps to successful health claims’ authorisation

Speaker:

Patrick Coppens, Managing Director, Europe & MEA - EAS Strategies, Belgium

© EAS Strategies 2018

Evaluating the different steps to

successful health claims’ authorisation

Special focus on probiotics

Types of Nutrition and Health Claims

REDUCTION OF

DISEASE RISK

CLAIM

Any health claim that

states, suggests or

implies that the

consumption of a food

category, a food or one

of its constituents

significantly reduces a

risk factor in the

development of a

human disease

‘Food x helps lower

blood cholesterol

‘Substance y helps

reduce blood pressure’

NUTRITION

CLAIM

Any claim which states,

suggests or implies that

a food has particular

beneficial nutrition

properties due to the

energy, nutrients or

other substances it

contains or does not

contain

‘Source of calcium’

‘High in vitamin C’

‘Naturally high in fibre’

CHILDREN

DEVELOPMENT

& HEALTH

?????

(Health claims solely referring to the

development and health of children (+ scientific

substantiation only valid for children) or used on products intended ex-clusively for children)

(Standing Committee

guidance, December

2007)

HEALTH

CLAIM

Any claim that states,

suggests or implies that

a relationship exists

between a food

category, a food or one

of its constituents and

health

‘Calcium helps in the development of strong

teeth and bones’

‘Food x helps maintain

healthy teeth & bones’

Health ClaimsNutrition

Claims

List of approved

Nutrition Claims

(Annex 1)

Art 14

Authorisation procedure:

Art 14-17

Reduction of

disease risk

claims

Claims referring to

children’s

development and

health

Art 13.1

‘Community list’

to be established

(basic positive list)

by 2010

Based on

generally

accepted scientific

data

Art 13.5

Authorisation

procedure:

Art 18

Based on ‘new

scientific evidence’

and/or proprietary

data

PROHIBITED CLAIMS (Art 12)

NUTRIENT PROFILES (Art 4)

Procedures

Art 13.4

Changes:

EFSA assessment

Scrutiny

procedure

Submission


Commission

By 31 January 2008National Lists

Article 13 list establishment

Standing

Committee

Community List 25 May 2012

By July 2010 ?


EFSA investigates:

– If characterisation of the food or food component is sufficient• The substance for which the claim is made must be the same as that for which the evidence is

provided

• Control authorities must be able to determine that the substance for which the claim is made is

the same as that for which the claim is authorised

– If the claimed effect is beneficial to health• In terms of the validity of end-point used

• In terms of the size of the effect

• In terms of benefit for specific EU population groups

• For RDRC the effect must relate to a risk factor

– If there is a cause-effect relationship between consumption of the food or

food component and the claimed effect• With particular focus on whether the evidence has been obtained in the same population

group the claim is intended for

• With particular focus on the intake required to obtain the claimed effect

The EFSA methodology

EFSA Guidelines: https://www.efsa.europa.eu/en/applications/nutrition/regulationsandguidance


• Insufficient characterisation

• Unspecific health benefits

– E.g. gut health, immune function

• Medicinal claims

– E.g. antibiotic diarrhea

• Inappropriate outcome

measures

• Inappropriate target

population

• Flaws in study design

Claims for probiotics failed for a number of reasons

• Changes in immune markers– e.g. numbers of various lymphoid subpopulations in

the circulation, proliferative responses of lymphocytes,

phagocytic activity of phagocytes, lytic activity of

natural killer cells and cytolytic T cells, production of

cellular mediators, serum and secretory

immunoglobulin levels, delayed-type hypersensitivity

responses;

• Changes in markers of inflammation– (including markers of chronic, subclinical

inflammation), such as interleukins or C-reactive

protein;

• Changes in short-chain fatty acid production

in the gut– e.g. butyrate;

• Changes in the structure of the intestinal

epithelium

• Changes in the composition of the gut

microbiota

Evidence of a beneficial physiological effect or clinical outcome is required


• Relief of gastrointestinal discomfort– e.g. bloating, abdominal pain/cramps, straining, borborygmi (rumbling) or sensation of

incomplete evacuation

– Measured by validated subjective global symptom questionnaires

– Irritable bowel syndrome patients are an acceptable target population

– Sustained effect on global assessment of symptoms is required

• Reduction of excessive intestinal gas accumulation– measured by hydrogen breath test or intestinal gas volume imaging techniques (e.g.

functional magnetic resonance imaging).

• Increased frequency of bowel movements, transit time, fecal bulk or

decreased stool consistency– Assessed by physician or by validated questionnaires for self-reported outcomes

– Subjects with functional constipation are an acceptable target population

– Plausible biological mechanism/mechanism of action is critical

• Improved digestion or absorption of nutrients– e.g. lactose

– Only if absorption is a limiting factor for the maintenance of an adequate status

Acceptable outcomes for claims for probiotics


• Defence against pathogens

– Differential diagnosis and/or with microbiological data/validated questionnaires

– Accepted outcomes:• Clinical outcomes related to infections

Incidence, severity and/or duration of symptoms, e.g. diarrhea, rhinitis, pharyngitis, sinusitis, otitis

media and common cold, pneumonia, bronchitis and bronchiolitis, allergic manifestations, urinary

tract infection

• Increase in the number of responders to vaccination

– Not sufficient:• changes in relevant immunological markers

• in vitro inhibition of the bacterial adhesion to uro-epithelial cells

– subjects without an infection at baseline, including subjects at high risk for infection

are acceptable target groups

• Reduction of infection risk

– Presence of certain bacteria is established risk factor

– Not established risk factors• IgA

• in vitro inhibition of the bacterial adhesion to uro-epithelial cell

Acceptable outcomes for claims for probiotics


• Communication on probiotics is quite explicit on most websites

• Communication on the strength of the product (number of bacteria/multistrain)

• Using approved claims for other nutrients

• Shifting to non-health claim communication

• Using testimonials of satisfaction without mentioning health benefits

• Cross-referring to other sites or publication

• Food for Special Medical Purposes?

• Communicating to health care professionals

BUT CASE C-19/15:

How have companies coped?


• Probiotics International Ltd

– Bio-Kult Candea contains seven strains of probiotic bacteria along with added garlic and

grapefruit seed extract. -> The term “probiotic” is a health claim

• Clasado Ltd t/a Bimuno

– TRAVELAID supports your tummy while abroad / Bimuno has the most potent bifidogenic

(Bifidobacteria promoting) effect of any available prebiotic / Your body's natural defence

against 'foreign tummy bugs' are the good bacteria in your gut -> non-authorised health

claims

• Yakult Ltd

– Yakult's unique bacteria are scientifically proven to reach the gut alive -> The body of

evidence submitted indicated that significant numbers of viable LcS organisms survived

transit to the gut after consumption of fermented milk products, such as the Yakult product.

-> Not a nutrition or health claim and substantiated

– The references to sport, regular exercise and keeping a balanced life, both in the voice-

over and the animation, together with the claim about LcS reaching the gut alive and the

closing statement, "Yakult. A bottle for you every day", formed a general impression that

there was a health advantage to drinking Yakult. -> Implied health claim

Control and enforcement: examples from the ASA


Change the 2007 guidelines

• Non-legal document

Change the health claims Regulation

• Requires Council and Parliament

Voluntary Consumer Information

• Art 34.4 of FIC is a possibility in theory

Generic descriptor

• Application is on hold. Only covers Italy

EC put claims for probiotics on hold

• Similar to the decision on botanicals

Convince national authorities

• Is already the case in some Member States

Options on how to break the deadlock

Generic entry via article 13.4

• Requires and EFSA assessment

Application for authorisation

• Using the accepted outcome parameters

Change in micro-flora as beneficial

• Lack of support from scientific community

REFIT of the Claims Regulation

• Not immediately planned

Work at Codex Alimentarius

• Initiated by the sector

Explore other legal frameworks

• Medical device, medicinal product


The EU health claims Regulation has created a problem

The term ”probiotic” is a health claim but not sufficiently precise to be assessed

The scientific criteria applied by EFSA are demanding

No single health claim for a probiotioc bacteria is authorised yet

Companies cope with the situation

Not al Member States enforce in the same way

Legal communication about probiotics is possible

A solution for the probiotic health claims issue is awaited

Better scientific evidence required

A change of scientific principles is unlikely

Conclusions


Thank you for your attention!

[email protected]

Managing Director Europe & MEAEAS Strategies Brussels


An update on the new Novel Food Regulation and authorisation process

Speaker:

Dr. Hannah Lester, Scientific Director, Pen & Tec Consulting

AN UPDATE ON THE NOVEL FOOD REGULATION AND AUTHORISATION PROCESS

DR HANNAH LESTER

PEN & TEC CONSULTING GROUP

FOOD & FEED REGULATORY AFFAIRS

VITAFOODS, 15TH MAY 2018

43

TODAY’S TALK

▪ What is a novel food?

▪ What are the main changes?

▪ How does the new procedure work?

▪ Potential pitfalls

▪ Tips for preparing a Novel Food dossier

44© Pen & Tec Consulting Group

WHAT IS A NOVEL FOOD?

▪ A food not consumed to a significant degree in the EU before 15 May 1997

✓Newly developed, innovative food

✓ Food produced using new technologies and production processes

✓ Food traditionally eaten outside of the EU

▪ Novel Foods must be:

✓ Safe for consumers

✓ Properly labelled, to not mislead consumers

✓ If novel food is intended to replace another food, it must not differ in a way that the consumption of the Novel Food would be nutritionally disadvantageous for the consumer.


WHAT IS NOT A NOVEL FOOD?

The new Novel Food regulation does not apply in the following cases:

✓ Food additives

✓ Flavourings for use in foods

✓ Food enzymes

✓ Extraction solvents

✓GMOs for food and feed

✓Covered by their own specific regulations


NEW NOVEL FOOD REGULATION Regulation (EU) 2015/2283

▪ Entered into force 1st January 2018

▪ Centralised procedure

▪ More categories

▪ Speeding up approval time

Repealed on 1st January 2018

47

Regulation (EC) No

258/97

12 recitals & 15

Articles

Regulation (EU)

2015/2283

42 recitals & 36

Articles

vs.

© Pen & Tec Consulting Group

WHAT IS NEW?Routes to market

Novel foods can be introduced via two routes:

1. Food or ingredient not consumed before May 1997

▪ Innovative new ingredients/foods

▪ Innovative processes/manufacturing methods

2. Traditional food from a third country

▪ Foods from primary production

▪ Minimum 25 year history of safe use


WHAT IS NEW?New categories

▪ Scope of the NF regulation expanded & provides clarity

▪ Number of NF categories increased from 4 to 10 to include:

✓ Food from animal clones

✓Whole animals

✓ Food from cell culture or tissue culture

✓ Food consisting of engineered nanomaterials


Novel food category Example

Category (i): Foods with a new or intentionally modified molecular structure

Synthetic lycopeneSynthetic lacitol

Category (ii): Food consisting of, isolated from or produced from microorganisms, fungi or algae

Clostridium butyricum (CBM 588)Oil rich in DHA (docosahexaenoic acid) from the micro-algae Schizochytrium sp.

Category (iii): Food consisting of, isolated from or produced from material of mineral origin

Clinoptolite

Category (iv): food consisting of, isolated from or produced from plant material

Noni juice, chia seeds

Nangai nuts, coriander seed oil

Category (v): Food consisting of, isolated from or produced from animal material

Insects, meal worms, hyaluronic acid from rooster comb

Category (vi): Food from cell culture or tissue cultures Lab grown meat (if not GMO!)

Category (vii): Food resulting from new production processes fruit preparations pasteurised using a high-pressure treatment process.

Category (viii): Food consisting of engineered nano-material Nano-encapsulation, nano-emulsification

Category (ix): Sources of vitamin, minerals and other substances. Organic silicon, (6S)-Methyltetrahydrofolic acid, Glucosamine salt as a source of folate

Category (x): Food used exclusively in food supplements. Betaine 50

WHAT IS NEW?Centralised authorisation procedure:Novel food

▪ NF dossier submit directly to EC instead of individual MS

▪ EFSA will perform safety evaluation when necessary

▪ Timelines are clearly defined

▪ Aim to reduce approval process from 3.5 to 1.5 years

✓However, likely to be 2-3 years

✓Request for supplementary information

✓Other regulatory hurdles

Reduced time to market?

▪ Current average = 3.5 years

▪ Reduced to 1.5 years?

▪ SIns? Other delays?

2-3 years?51© Pen & Tec Consulting Group

WHAT IS NEW?Centralised authorisation procedure:Traditional food

▪ Notification submitted to EC

▪ EFSA/MS consideration

▪ If no safety concerns OK to market

▪ If safety concerns EFSA will evaluate

▪ 8-14 month approval process

▪ Only applicable for certain categories:

▪ Plants/animals or their parts

▪ Micro-organisms, fungi or algae

▪ Cell or tissue culture derived from the above

▪ History of safe use for ≥ 25 years in a 3rd country

▪ Past: chia seeds, noni fruit juice, baobab dried fruit pulp …

▪ Future: Insects? Certain algae? Plants?

52

WHAT IS NEW?Data protection

▪ NF authorisations no longer holder-specific

▪ All previously approved NFs “generic”

▪ Listed in Union List

▪ FBO complies with specification can market without proving substantial equivalence

However…

▪ 5-year data protection

✓ Proprietary data

✓No guarantee that EC will accept

▪ NF with narrow specification can maintain competetive advantage

✓ e.g. Bacterial strains with specific name and deposit number or extracts with defined composition

▪ Not applicable to traditional foods


WHAT IS NEW?Union list of novel foods Regulation (EU) 2017/2470

▪ List of all novel foods authorized or notified under Reg. (EC) Nº 258/97

▪ Only novel foods complying with the list can be marketed

▪ Entry of a novel food in the list will include its specifications & where appropriate:

▪ The conditions of use

▪ Additional specific labelling requirements

▪ Post-market monitoring requirements

▪ Substantial equivalence procedure will disappear

Easier to enter the market? Piggyback on successful applications?


WHAT IS NEW?Determination of NF status

▪ Responsibility of FBO to determine NF status

▪ However, new consultation process outlined in Regulation (EU) 2018/456

▪ FBOs can send a “consultation request” to a MS

✓ Should be the MS where they wish to market food initially

✓ If multiple MS, FBO must choose one

▪ Consultation request includes

✓Cover letter (Annex I)

✓ Technical dossier (Annex II)

✓ Supporting documentation

✓Can request confidentiality of proprietary information


NEW REGULATION SUMMARY

▪ Major changes

✓ 10 NF categories

✓ Supporting innovation

✓Centralised procedure

✓Quicker authorisation process

✓Union list

✓Clear identification of approved NFs

✓No substantial equivalence

▪ Easier to bring new and innovative foods to EU market


THE STORY SO FAR…. (old regulation)

Withdrawn13%

Approved50%

Rejected3%

Ongoing34%

Not novel0%

228 SUBMITTED DOSSIERS SINCE 1997

▪ 10% approved without objections

▪ 70% evaluated by EFSA

▪ 15% withdrawn

▪ 5% rejected

▪ 0.4% not novel


THE STORY CONTINUED…. (new regulation)

▪ 14 NF dossiers “under consideration”

▪ 4 dossiers “in progress”

58

Type of food?

Significant consumption in EU before May 1997?

Manufacturing process used

before May 1997?

OK to marketNovel food

Registration

RegistrationNovel food

PROCEDURE – NOVEL OR NOT NOVEL…. THAT IS THE QUESTION!▪ Responsibility of FBO to determine NF status

If borderline or unclear submit consultation request to MS

Exempted from NF Reg:

✓ GMOs

✓ Food additives

✓ Food enzymes

✓ Extraction solvents

Ingredient/food

Yes No

Yes No

✓ Check Union List✓ History of safe use in other

countries?


NF EXAMPLE – MEAL WORM LARVAE

Questions to ask:▪ Is the food/ingredient a food additive, enzyme, solvent or GMO? = No

▪ Is the food/ingredient listed in the NF Union list? = No

✓Does it comply with the conditions of use?

✓ Is the authorisation protected?

▪ Has the food been consumed in EU to a significant degree

before 15th May 1997? = No

✓ Is it a conventional food?

✓Conventional ingredients?

✓Conventional manufacturing process?

✓Comparable to foods consumed before 1997?

✓ Significant consumption?


Questions to ask:

▪ Was the food only used in food supplements? = No

✓ If yes, will be a NF is used for another purpose other than a food supplement

▪ Does the food fit within one of the 10 NF categories? =Yes

✓ food consisting of, isolated from or produced from animals or their parts…

✓ Has the animal been bred by traditional breeding practices?

✓ Does the animal/parts have a history of safe use?

✓ Is the food/product derived from insects?

✓ Is the processing of the source material coventional?

✓ Is the food isolated & purified?

Outcome = meal worm larvae require NF registration

NF EXAMPLE - MEAL WORM LARVAE


IF NOVEL… WHAT NEXT?

▪ If novel a pre-market authorisation is required

▪ Generate data to support NF application

✓ Extensive safety data/toxicological studies to support safety of NF

▪ Requirements referred to in Article 10 are laid out in Regulation (EU) 2017/2469

▪ EFSA Guidance for NF applications published February 2018

✓ Appendix A = comprehensive checklist

✓ Appendix B = examples of summary data tables


IF TRADITIONAL FOOD… WHAT NEXT?▪ Notification must provide enough evidence to support safety

▪ History of safe use (minimum 25 years)

▪ Requirements concerning traditional foods from third countries laid down in Regulation (EU) 2017/2468

▪ EFSA Guidance available

✓ Part 1: Administrative data

✓ Specifications, Regulatory status outside EU

✓ Part 2: Characterization, technical & scientific data

✓ Identity, manufacturing process, compositional data, stability, specification

✓Data to support use in third country

✓ Proposed use in EU

✓ Part 3: Annexes

✓CoAs

✓ Full copies of studies

Important:

• How is NF produced,

prepared & consumed

in 3rd country?

• History of use in

different countries is

not additive!63© Pen & Tec Consulting Group

POTENTIAL PITFALLS

The main issues EFSA identify when assessing NF dossiers include:

▪ Other EFSA guidance is not considered (e.g. Guidance on genotoxicity, default values, use of EFSA Food consumption database, etc.)

▪ No information on identification/source of data or the search strategy

▪ Incomplete dossiers, missing study reports

▪ Omitting pertinent data available in the literature, particularly if the data are not favourable to the NF or uncertainties are not considered, discussed or addressed

▪ No justification for omissions

✓ EFSA encourages applicants to provide logical, scientific arguments for not conducting certain studies

✓Deviations/omissions from guidelines must be fully justified


TIPS FOR A SUCCESSFUL DOSSIER

▪ Follow the key novel food guidance documents:

✓ Guidance for novel foods: EFSA Journal 2016;14(11):4594

✓ Administrative guidance: EFSA supporting publication 2018:EN-1381

✓ Guidance for traditional foods from third countries: EFSA Journal2016;14(11):4590

▪ Don’t forget to consult other EFSA guidance documents:

✓ Genotoxicity testing strategies: EFSA Journal 2011;9(9):2379

✓ Use of the EU Food Consumption database (exposure assessment): EFSAJournal 2011;9(3):2097

✓ Assessment of bacterial susceptibility to antimicrobials (AMR): EFSA Journal2012;10(6):2740

✓ GMO guidance: EFSA Journal 2011;9(6):2193

✓ Guidance for food additives: EFSA Journal 2012;10(7):2760

✓ Assessment of botanicals: EFSA Journal 2009;7(9):1249

✓ Etc.


TIPS FOR A SUCCESSFUL DOSSIERPart 1

Administrative

Part 2

Technical

Part 3

Annexes

Cover letter Section I Description Abbreviations used

List of confidential parts Section II Production CoAs

List of proprietary data Section III Compositional data Laboratory accreditations

Section IV Specifications Study reports (unpublished)

Section V History of use Published scientific data

Section VI Proposed use Pertinent publications

Section VII ADME

Section VIII Nutritional

Section IX Toxicological

Section V Allergenicity

References

66


Compositional data:

▪ Should be discussed in detail to facilitate assessment

▪ At least 5 batches, representative of final product

▪ Qualitative & quantitative characterization of main constituents

▪ Proximate analyses (complex mixtures) – mass balance

▪ If several production processes are proposed, provide data for each process

▪ Physicochemical properties (e.g. appearance, melting & boiling point), solubility, particle size, purity

▪ Stability

Characterization of micro-organisms

▪ WGS

▪ Absence of AMR, toxins, virulence factors

▪ For plant-based products no need for WGS as long as plant is fully described

Manufacturing process

▪ Describe in detail

✓ Include operational limits

✓ Provide information on substances of concern (e.g. lead used as catalyser)

✓ Define key parameters

▪ Confidential but will help facilitate safety assessment & determine need for toxicological/kinetic studies



Intake assessment

▪ Describe all assumptions made & methodology used

▪ Highest consumption level = 2 x mean NOT accepted

▪ Consider all sources: dietary & non-dietary

▪ Discuss intake of undesirable substances & consider in exposure assessment

✓No use level? Create a scenario using historical data or similar products

✓ Take the source of the NF into account – amount is key!

✓ 1 g of NF produced from 100 g of berries ≠ 1 g produced from 10 kg of berries

✓ 100 g of berries is a normal consumption pattern (hence, no risk) but 10 kg isn’t!

▪ EFSA Comprehensive Food Consumption Database & Food Additive Intake Model


TIPS FOR A SUCCESSFUL DOSSIERHistory of source

▪ Should be described in detail

▪ 90-day rat study may not be necessary if:

✓ Source & production process safe

✓ Intended use level low

Kinetics

▪ If NF is well characterised may not be necessary to conduct studies

✓ Is the substance absorbed?

✓How is it metabolised & excreted?

✓Does it accumulate?



Toxicity

▪ Carefully analyse all available data

✓Nature of NF

✓Use levels

✓ Production process

▪ With good scientific arguments, toxicity tests can be avoided

▪ If toxicity studies are required, make sure test item is representative of final product

Allergenicity

▪ Does the NF contain protein?

✓No = no allergenicity risk

✓ Yes – allergenic potential

Note – absence of reported allergenicity does not prove absence of allergenic potential!


GETTING IT WRONG….

▪ Results from a month-long EU-wide investigation found 428 non-authorisednovel foods being sold online!

▪ 25 Member states & Norway & Switzerland took part

▪ Inspectors are now on the lookout!!

▪ Check legal status

▪ Get advice

▪ Penalties – differ between MS, but can be hefty:

✓ Latvia = 700 EUR; Austria = 50,000 EUR

✓ Spain, minor infringement up to 5,000 EUR; major infringement 20,000 EUR


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Barcelona, Spain

Pen & Tec Consulting, S.L.U.

Pl. Ausias March 1

4th Floor, D01

08195 Sant Cugat del Valles

Barcelona, Spain

+34 936 758 015

Reading, UK

Pen & Tec Consulting Ltd.

Davidson House

Forbury Square

Reading, RG1 3EU

United Kingdom

+44 118 900 0708

[email protected]

Please email me if you have any questions:

[email protected]

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