joint dossiers from microbes - efsa.europa.eu · joint dossiers on enzymes from microbial sources...

Joint dossiers on enzymesfrom microbial sources

EFSA FIP Unit – food enzyme team

16 March 2020

Legal basis of joint dossiers

Regulation EU N. 562/2012 amending Commission Regulation (EU) N.234/2011

Food enzymes may be grouped, provided that:

Same catalytic activity

Substantially the same manufacturing process

Produced by the same source material microorganism from the same species (excl. GM)

QPS status, or

Already evaluated by France or Denmark

Edible parts of plants or animal (excl. GM)

2

16 joint dossiers on enzymes obtained from microorganisms

10 production microorganisms (species)

? numbers of production strain

27 producers/interested parties

could all of them potentially be an individual applicant?

Potentially up to 99 food enzymes (2-12 per dossier)

16 different declared enzyme activities

17 intended uses

Not every enzyme in the same dossier can be relevant for all intended uses

Joint dossiers overview

3

Challenges/data gaps found in submitted joint dossiers

4

Production strain => starting point for the assessment

Data on identification, characterization and details on depositionnumber not provided.

Specific chemical composition of each food enzyme =>necessary for the calculation of TOS, comparability of thecommercial and tox batches

Not provided for all enzymes under assessment in the samedossier

Enzyme activity measured with different methods andexpressed in different units

Enzyme activity analysed in tox studies different from theactivities claimed in the commercial batches

5

Assessment must be specific for declared activities and intended uses

Some dossiers pool different declared activities and uses, data on only one activity provided

Exact amino acid sequence is necessary for the allergenicity assessment

Specific amino acid sequence not reported

•-

•-

•-

•-

•-

•-

Challenges/data gaps found in submitted joint dossiers

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Example: 2015-00038-42 / Pectinase, poly-galacturonase, pectin-esterase, pectin lyase and arabanase from Aspergillus niger.

Producer

PECTINASE POLY-GALACTURONASE PECTIN-ESTERASE PECTIN-LYASE ARABANASE

Hydrolysis of pectin Random hydrolysis of (1→4)-α-D-galactosiduronic linkages in pectate and other galacturonans

Hydrolysis of methyl groups on methylated galacturonic acid chain

Cleavage of (1→4)-α-D-galacturonan methyl ester

Endo-hydrolysis of (1→5)-α-arabinofuranosidiclinkages in (1→5)-arabinans

A x

B x

C x x x x

D x x x x x

E x x x

F x x x x x

G x

H x

I x x x

J x

Enzyme activity

A B C D E F G H I J

Pectinase 972 720,266 590 13 6,000,000 61,633 17,900 307,125

Unit PE/g AVJP/g ASV-U/ml GPS/g µ/ml µ/ml Not provided

U/g

Poly-galacturonase

2,986 3,316 153 98 8,373

Unit µ/ml PGU/g endoPG/ml PGNU/mg TOS PG/g

Pectin-esterase

5,545 4,167 0,09 2,670 2,690

Unit PEU/g PE-U/ml PEU/mg TOS PE/g Not provided

Pectin-lyase 400 77,333 224 950

Unit PEL/g PL-U/ml PECTU/mg TOS PL/g

Arabanase 10 131 232

Unit endo-Arab-U/ml ARA/g Not provided

Example of the variety of data provided

7

Splitting dossiers

8

A single production

strain?

A single manufacturing

process?

blended catalytic

activities?

Enzymeswith different activities obtained from the same

microbe species

Enzymeswith the same catalytic

activities

Keep the dossier as it is

yes

nono yes

yes no

Split the dossier by food enzyme

Split the dossier by

manufacturing process

Split the dossier by production

strain

Proposed way forward

9

Joint Dossier (from AMFEP)Joint Dossier (from AMFEP)

Data package 1 (from A)

(EFSA-Q-2020-xx1)

Data package 1 (from A)

(EFSA-Q-2020-xx1)EFSA Opinion 1EFSA Opinion 1

Data package 2 (from B)

(EFSA-Q-2020-xx2)

Data package 2 (from B)


Data package 3 (from C)

(EFSA-Q-2020-xx3)

Data package 3 (from C)


AM

FEP

EC mandateEC mandate

remains remains

Data package n (from Z)

(EFSA-Q-2020-xxn)

Data package n (from Z)

(EFSA-Q-2020-xxn)

EFSA-Q-2015-xxx

To be closed?

EFSA-Q-2015-xxx

To be closed?

EFSA Opinion nEFSA Opinion n

Union listUnion list

Individual data package, individual timeline

Lack of submission of data package from D is acceptable

send to [[email protected]]

Proposal way forward

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Advantages:

Simplicity: Each data package will have its own opinion, as usual for “regular” dossiers; no issues with confidentiality

Flexibility: Non-responsive manufacturers will not condition the opinions of responsive manufacturers

Joint Dossier (from AMFEP)Joint Dossier (from AMFEP)

Data package 1 (from ABC)

(EFSA-Q-2020-xx1)

Data package 1 (from ABC)


Data package 2 (from BCD)

(EFSA-Q-2020-xx2)

Data package 2 (from BCD)


Data package 3 (from DEF)

(EFSA-Q-2020-xx3)

Data package 3 (from DEF)


AM

FEP

EC mandateEC mandate

remains remains

Data package n (from ZZZ)

(EFSA-Q-2020-xxn)

Data package n (from ZZZ)

(EFSA-Q-2020-xxn)

EFSA-Q-2015-xxx

To be closed

EFSA-Q-2015-xxx

To be closed

EFSA Opinion nEFSA Opinion n

Union listUnion list

- Unlikely?

- To be treated as a regular dossier

Could a dossier remain joint?

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Enzymes from the same production strain obtained by the same

manufacturing process and with the same declared activities

Enzymes from the same production strain obtained by the same

manufacturing process and with the same declared activities

Cases in which the dossier could remain joint

- Clarity on the role of each interested party

- To be treated as a regular dossier

Only one of the interested parties is the applicant

Only one of the interested parties is the applicant

How it works

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Each enzyme applicant will send a full data package to EFSA

A QN will be allocated to each

Existing QN may be closed

Each applicant will indicate a contact point to EFSA

For each dossier, EFSA will deal with the contact point individually

Additional information requests

Teleconferences, extension of deadlines

AMFEP will arrange with contact points to be notified as the official applicant

EFSA will issue a separate opinion for each QN

Opinions will be published as soon as adopted, even separately in time

Opinions will include an explanation about which concrete substance is under assessment among the joint dossier

Joint dossiers on food enzymes from animal sources


16 March 2020

Enzyme activities and source tissues

2

EFSA-Q-2015-00131 Triacylglycerol lipase

Source material Species Enzyme activities

Pre-gastric tissues: “gullet”

• the oro-pharyngeal tissues (De Caro et al., 1995)

• Esophagus(Ramsey, 1961, 1962)

• cattle• goat• sheep

• pregastric lipase

• pregastric esterase ?

EFSA-Q-2015-00237 Rennet

Source material Composition ranges of batches(from 9 producers)

Abomasum of:• cattle• buffalo• goat• sheep

• Enzyme activity: 79–2,543 IMCU/mL• Protein: 0.2–6.2%• Ash: 7–19%• TOS: 0.48–7.2%• Activity/mg TOS: 3.0–54.8 IMCU/mg TOS

• different types of rennet and its physical state (liquid, powder or paste) (EFSA, 2014)

• the ratio between chymosin and pepsin activity

3

Source tissue: some dossiers include food enzymes from differenttissues/species of animals

Have all food enzymes the same catalytic activity?

Chemical composition, including TOS, significantly vary among foodenzymes from different producers

Methods to ensure the absence of infectivity vary among producers

Details are lacking on the concrete manufacturing process of eachproducer

Challenges


4

Enough technical details?

Food enzymeobtained from animal

tissue


no

yesA single applicant?

no

Split the dossier by

manufacturer

Enrich the dossier with

data

yes

SOURCE MATERIAL

NEED OF TOXICOLOGICAL DATA?

ALLERGENICITY

DIETARY EXPOSURE

CHEMICAL COMPOSITION

Information to be provided per manufacturer/food enzyme

5

Are interested parties equal to applicants?

Specific tissues/organs used as a source of the food enzyme

Documented evidence of human consumption

Quantity of consumption in the EU or elsewhere

Documented compliance with meat inspection requirements and inaccordance with good hygienic practice

Data on the absence of infectious gents in the source tissue andmethods to ensure the absence of any risk of infectivity

Detailed description of the manufacturing process and list ofspecific raw materials

Characteristics of the enzyme(s) (e.g. identification, amino acidsequence, molecular weight, pH and temperature optimum – literatureor experimental data)

Chemical composition of the food enzyme, impurities and by-products from the source tissue/manufacturing process


6

Batch-to-batch variation (e.g. SDS-PAGE)

Intended/unintended reaction products of the food enzyme withfood constituents or from the degradation of the food enzyme

Allergenicity assessment – a comprehensive literature search forpossible adverse reactions, allergy after consumption of source material,published in the last 10 years

Intended uses of the food enzyme aligned with the ‘EC workingdocument describing the food processes in which food enzymes areintended to be used’

Specify the intended uses per applicant

Flowcharts for each intended food process and indication atwhich step(s) the food enzyme is added and yield factor

Use levels to be expressed as mg TOS/kg raw material

will be discussed together with the joint dossiers from plants

Waiving of toxicological studies

7

Joint dossiers on food enzymes

from plant sources


16 March 2020

Interested parties and enzyme activities

2

2015-00559 Activity

Interested parties

(applicant: AMFEP)

Papain sensu stricto Chymopapain Glycyl endopeptidase Caricain Value

Preference for an amino acid bearing a hydrophobic side chain at the P2 position.

Similar to that of papain

Preferential cleavage: Gly, in proteins and small molecule substrates

Similar to those of papain and chymopapain

A X X X X 859 TU/mg

B X X X X 833 TU/mg

C X X X X 1,059,633 U/g

D (?) No data No data No data No data

2016-00867 Activity

Interested parties

Bromelain sensu stricto Ananain Value

Cleavage of proteins. Strong preference for Z-Arg-ArgNHMecamongst small molecule substrates

Broader specificity than fruit bromelain

E X X 2,381 GDU/g

F (?) No data No data

3

Source tissue: not always specified, edibility not obvious

How many different food enzymes? => Role of interested parties unclear

Claimed activities are those "sensu stricto" or a complex with different main activities?

Enzyme activities measured with different methods

Chemical composition/TOS vary among enzymes from different producers

Details are lacking on the concrete manufacturing process/raw materials of each producer

Challenges


4

Enough technical details?

Enzymesobtained from plant

tissue


no

yesA single applicant?

no

Split the dossier by applicant

Enrich the dossier with

data

yes

SOURCE MATERIAL

NEED OF TOXICOLOGICAL DATA?

ALLERGENICITY

DIETARY EXPOSURE

CHEMICAL COMPOSITION


5

Are interested parties equal to applicants?

Specific tissues/organs used as a source of the food enzyme

Documented evidence of human consumption

Quantity of consumption in the EU or elsewhere

Identity of the food enzyme: “strico sensu” or as the enzymatic complex with different mainactivities?

Information on pesticide residues in the source tissue and analytical data on the food enzyme

• Detailed description of the manufacturing process and list of specific raw materials

Characteristics of the enzyme(s) (e.g. identification, amino acid sequence, molecularweight, pH and temperature optimum – literature or experimental data)

Chemical composition of the food enzyme, impurities and by-products from the sourcetissue/manufacturing process


6

Batch-to-batch variation (e.g. SDS-PAGE)

Conversion between different enzyme activity units

Intended/unintended reaction products of the food enzyme with food constituents or fromthe degradation of the food enzyme

Allergenicity assessment – a comprehensive literature search for possible adverse reactions,allergy after consumption of source material, published in the last 10 years

Intended uses of the food enzyme aligned with the ‘EC working document describing the foodprocesses in which food enzymes are intended to be used’

Specify the intended uses per applicant

Flowcharts for each intended food process and indication at which step(s) the foodenzyme is added and yield factor.

Use levels to be expressed as mg TOS/kg raw material

Waiving of toxicological studies

7

(4) With regard to the toxicological properties of enzyme preparations, the SCF guidelines indicated that food

enzymes which are derived from edible parts of (non-genetically modified) plants and animals are generally

considered as posing no health problems. According to the guidelines no special documentation for safety needs to

be supplied provided that the potential consumption under normal use does not lead to an intake of any

components which is larger than can be expected from normal consumption of the source as such, and provided

that satisfactory chemical and microbiological specifications can be established.

(5) The European Food Safety Authority ("the Authority") has also indicated in its guidance on data requirements

for the evaluation of food enzyme applications that the justification for not supplying toxicological data for food

enzymes from edible parts of animals and non genetically modified plants may include a documented history on

the safety of the source of the food enzymes, the composition and the properties of the food enzyme as well as its

use in food which demonstrates no adverse effects on human health when consumed in a comparable way,

supported by any existing toxicological studies. Therefore, the enzyme application for food enzymes from such

edible sources should not be required to include toxicological data.

Commission Implementing Regulation (EU) No 562/2012

Explanation to the Article

“consumed in a comparable way”

8

Two sets of intake estimate – in a nutshell

Intake of food enzyme - TOS from processed foods Intake of plant components from foods

Concentration data TOS in raw material (e.g. barley grain ) Comparable portion of e.g. barley grain

Data source Dossier Edibility from literature, recipe, etc

Food coverage Foods produced from intended processes Foods containing or produced from barley

Assessment Method EFSA comprehensive Database (Individual food consumption data, 6 age groups)

Food selection FoodEx nomenclature / original food descriptor / food labels / recipes/ expert knowledge

Factors needed Conversion of food groups to raw material, or food ingredients to raw material

Source of factors

Open call-for-data* FAO technical conversion factor (e.g. from grain to malt) Cooking recipes (e.g. blood sausage) Ingredient list (e.g. 9% wholegrain barley in muesli) Instruction of beverage preparation (e.g. 25g of powder

in 200 ml of milk)

Dossier specific Enzyme yield factor

* to ensure transparency, consistency and equal treatment

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joint dossiers from microbes - efsa.europa.eu · joint dossiers on enzymes from microbial sources...

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