SIST-TP CEN/TR 17612:2021

SLOVENSKI STANDARD
SIST-TP CEN/TR 17612:2021
01-marec-2021
Alge in izdelki iz alg - Specifikacije za uporabo v farmacevtski industriji
Algae and algae products - Specifications for pharmaceutical sector applications
Spezifikationen für Anwendungen im Nicht-Lebensmittel-/Futtermittelsektor
Algues et produits d’algues - Spécifications pour les applications dans le secteur
pharmaceutique
Ta slovenski standard je istoveten z: CEN/TR 17612:2021
ICS:
11.120.01 Farmacija na splošno Pharmaceutics in general
SIST-TP CEN/TR 17612:2021 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.

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SIST-TP CEN/TR 17612:2021


CEN/TR 17612
TECHNICAL REPORT

RAPPORT TECHNIQUE

January 2021
TECHNISCHER BERICHT
ICS 13.020.55
English Version

Algae and algae products - Specifications for
pharmaceutical sector applications
Algues et produits d'algues - Spécifications pour les Spezifikationen für Anwendungen im Nicht-
applications dans le secteur pharmaceutique Lebensmittel-/Futtermittelsektor


This Technical Report was approved by CEN on 4 January 2021. It has been drawn up by the Technical Committee CEN/TC 454.

CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway,
Poland, Portugal, Republic of North Macedonia, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and
United Kingdom.





EUROPEAN COMMITTEE FOR STANDARDIZATION
COMITÉ EUROPÉEN DE NORMALISATION

EUROPÄISCHES KOMITEE FÜR NORMUNG

CEN-CENELEC Management Centre: Rue de la Science 23, B-1040 Brussels
© 2021 CEN All rights of exploitation in any form and by any means reserved Ref. No. CEN/TR 17612:2021 E
worldwide for CEN national Members.

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Contents Page
European foreword . 4
Introduction . 5
1 Scope . 6
2 Normative references . 6
3 Terms and definitions . 6
4 Product characteristics . 8
4.1 Product purity . 8
4.1.1 General . 8
4.1.2 Purity of microalgae and cyanobacteria . 9
4.1.3 Purity of macroalgae . 9
4.1.4 Purity of algae derivatives or extracts . 10
4.1.5 Methods of analysis . 11
4.2 Contamination . 12
4.2.1 General . 12
4.2.2 Physical, biological and chemical contaminants . 12
4.2.3 Microbiological quality of algae and algae biomass . 12
4.2.4 Contaminants in algae and algal pharmaceutical ingredients . 13
4.3 Other product characteristics . 16
4.3.1 Identification . 16
4.3.2 Particle size . 16
4.3.3 Foreign matter . 16
4.3.4 Total ash, insoluble ash . 17
4.3.5 Extractable matter . 17
4.3.6 Swelling index . 17
4.3.7 Bitterness value . 17
4.3.8 Loss on drying . 17
4.3.9 Water (for herbal drugs with high essential oil content) . 17
4.3.10 Assay . 18
5 Storage . 18
6 Labelling . 18
7 Product information documents . 19
7.1 General . 19
7.2 Material Safety Data Sheet . 19
7.3 Other relevant product information . 19
7.3.1 Origin . 19
7.3.2 Strain origin . 19
7.3.3 Product origin . 19
7.4 Protected species . 19
7.5 Algae extracts . 20
8 Sustainable development . 20
8.1 General . 20
8.2 United Nations sustainable development goals . 20
8.3 Sustainable development of macroalgae production . 20
8.4 Sustainable development of microalgae production . 21
9 Traceability . 21
9.1 General . 21
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9.2 Chain of Custody . 22
10 Algae in EP and USP General monographs. 22
Annex A (informative) Regulatory framework . 23
Annex B (informative) Raw Material Specifications examples . 24
Annex C (informative) Technical Data Sheets (TDS) examples. 27
Annex D (informative) Origin of algae products . 30
Annex E (informative) Algae extracts . 33
Annex F (informative) Purity identification methods and gap analysis algae . 36
Bibliography . 38

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European foreword
This document (CEN/TR 17612:2021) has been prepared by Technical Committee CEN/TC 454 “Algae
and algae products”, the secretariat of which is held by NEN.
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. CEN shall not be held responsible for identifying any or all such patent rights.
The European committee for Standardization (CEN) was requested by the European Commission (EC) to
draft European standards or European standardization deliverables to support the implementation of
Article 3 or Directive 2009/28/EC for algae and algae products or intermediates. The request presented
as Mandate M/547, also contributes to the Communication on “Innovating for Sustainable Growth: A Bio
economy for Europe”.
The former working group CEN Technical Board Working Group 218 “Algae” was created in 2016 to
develop a work programme as part of the Mandate. The technical committee CEN/TC 454 “Algae and
algae products” was established to carry out the work program the secretariat of which is held by NEN.
CEN/TC 454 set up a number of topic specific working Groups listed below to develop standards for algae
and algae products.
This document has been prepared by Working Group 5 “Specifications for the pharmaceutical
applications sector” with the support of UNI as the secretariat, in close collaboration with the other
CEN/TC 454 working groups:
CEN/TC 454/WG 1 “Terminology”;
CEN/TC 454/WG 2 “Identification”;
CEN/TC 454/WG 3 “Productivity”;
CEN/TC 454/WG 4 “Specifications for food/feed sectors applications”;
CEN/TC 454/WG 6 “Product test methods”.
Algae-based products and intermediates, in this TR referred to as ‘products’, are defined as whole
biomass, extracts or derivatives from algae, including a.o. algae oil and algal meal.
This document will allow the stakeholders to have access to a clear point of reference on the use of algae
in pharmaceutics.
Pharmacy had standards which date back to ancient Egypt; through the first pharmacopoeias which were
the Arab one, the Totum continens (Elhavi) of ar-Razi, and that of the Salerno medical school.
Then national Pharmacopoieas developed in Europe in the Eighteenth Century.
Today pharmacetical industry has the European Pharmacopoiea (EP) [3], with legal status according
medicinal regulatory framework (Annex A), being harmonized with American (USP) [4] and Japanese (JP)
[5] through ICH [6].



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Introduction
The interest in algae and algae-based products or intermediates as a renewable and sustainable source
of carbohydrates, proteins, lipids and pigments has increased significantly in Europe.
The purpose of this document prepared by WG 5 is to provide an overview on how quality indicating
parameters for algae and algae-based products and intermediates relevant for pharmaceutical
applications can be handled and to identify the need for any future standard developments for
pharmaceutical applications. Algae are highly available and used in many countries as fertiliser,
biostimulant, animal feed, medicine, cosmetic and food ingredients, and have different compounds
depending on species.
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1 Scope
This document gives an overview of recommendations on product specifications, and other relevant
information, for algae and algae products for pharmaceutical applications.
This document does not apply to food and feed applications.
This document does not provide instructions on handling of technical requirements in existing
legislations.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
EN 16751, Bio-based products - Sustainability criteria
EN 16760, Bio-based products - Life Cycle Assessment
EN 16848, Bio-based products - Requirements for Business to Business communication of characteristics
using a Data Sheet
EN 16935, Bio-based products - Requirements for Business-to-Consumer communication and claims
EN 17399, Algae and algae products - Terms and definitions
1
EN 17477 , Algae and algae products - Identification of the biomass of microalgae, macroalgae,
cyanobacteria and Labyrithulomycetes - Detection and identification with morphological and/or molecular
methods
3 Terms and definitions
For the purposes of this document, the terms and definitions given in EN 17399 and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https://www.iso.org/obp
— IEC Electropedia: available at http://www.electropedia.org/
3.1
algae and algae products
functional group of organisms consisting of microalgae, macroalgae, cyanobacteria, labyrinthulomycetes
and products derived thereof
3.2
Raw Material Specification
RMS
several pages technical dossier about the product, usually prepared by manufacturer, directed to provide
all product approval information to the customer and usually attached to commercial contract

1
Under preparation. Stage at the time of publication: prEN 17477.
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Note 1 to entry: Examples of RMS for some algae categories are attached as Annex B.
3.3
Technical Data Sheet
TDS
one (few) page technical document showing the technical (biochemical) parameters adopted to
characterize the product and therefore being the paradigm of the Certificate of Analysis (CoA)
Note 1 to entry: TDS includes ranges of different parameters used to define the product characteristics or
applicable regulatory limits.
Note 2 to entry: Models of TDS for some algae categories are attached as Annex C.
3.4
Certificate of Analysis
CoA
one (few) page document issued from laborator(ies) and reporting test results for a specific lot, usually
in front of TDS parameters, including references to test method
3.5
Material Safety Data Sheet
MSDS or SDS
document issued with the aim of providing information about product compliance in respect of human
health and safety at the workplace and protection of the environment
3.6
sustainable development
development that meets the environmental, social and economic needs of the present without
compromising the ability of future generations to meet their own needs
[SOURCE ISO Guide 82:2019, 3.2]
3.7
algae as herbal raw material
whole, fragmented or cut algae, in an unprocessed state, usually in dried form but sometimes fresh,
precisely defined by the botanical scientific name according to the binomial system (genus, species,
strain, (variety) and author)
3.8
extracts
concentrated preparations of liquid, solid or intermediate consistency, usually obtained from dried algae
matter
Note 1 to entry: For some preparations, the matter to be extracted undergo a preliminary treatment, for example,
inactivation of enzymes, grinding or defatting.
3.9
algal drug preparations
products obtained by subjecting herbal drugs to treatments such as extraction, distillation, expression,
fractionation, purification, concentration or fermentation, including comminuted or powdered herbal
drugs, tinctures, extracts, essential oils, expressed juices and processed exudates
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3.10
active principles of algal origin
substances having proven clinical activity
3.11
pesticides
any substances or mixture of substances intended for preventing, destroying or controlling any pest,
unwanted species of plants or animals causing harm during or otherwise interfering with the production,
processing, storage and transport or marketing of vegetable drugs
Note 1 to entry: Pesticides include substances intended for use as growth-regulators, defoliants or desiccants and
any substance applied to crops either before or after harvest to protect the commodity from deterioration during
storage and transport.
4 Product characteristics
4.1 Product purity
4.1.1 General
The product characteristics specified from 4.2 to 4.6 should comply with the relevant Pharmacopeia (e.g.
European Pharmacopea (EP) [3], US Pharmacopea (USP) [4] and Japanese Pharmacopea (JP) [5]),
depending on the product final destination Country. This condition is applicable to algae and algae
products extracts.
In case the product characteristics are referred to algae and algae products raw materials, the compliance
applies after processing (extraction, refining).
The product purity is defined by the percentage of specific component in the total amount of product or,
in case of whole algae biomass, by species/strain amount as percentage of the total dry weight of the
product. Any other substances should be specified in the technical data sheet.
The purity percentage is specified by mass fraction (kg/kg). When this is not possible according to the
3 3
state in which the product is presented, it can be expressed by volume fraction (m /m ) or cell fraction
(cell counts/all cell counts) or their corresponding concentrations if more appropriate.
The presence of GMO material in algae and algae products is to be considered as impurity (ref to EU Reg
on GMO).
The presence of not organic material in organic algae and algae products is to be considered as impurity
(ref to EU Reg on organic production).
NOTE 1 Purity is referred to contractual limits. Purity is generally not directly related to contamination since the
latter is often of small extent and does not affect the amount of required substance.
NOTE 2 Purity is related to species identification and test methods. For methods on the identification of species
1
refer to EN 17477 .
When a product is not pure, this impurity can be detected by different types of detection methods listed
in Table 1.
Macroscopical/microscopical characterization includes features, which distinguish the algae material
from potential non-specified substances. Identification tests need to be specifically validated for algae
and are usually a combination of methods depending on the algae species. Identification tests include
macroscopical characters, microscopical characters, chromatographic procedures and physicochemical
analysis. Automated tools might help like cell counters or cell flow cytometers.
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The development of tests based on nucleic acids characteristics (microsatellites, NGS, barcoding, RAPD,
AFLP, etc.) to be sequenced from product samples would provide simple and fast tools for the
identification of multiple targeted species and would help to indicate the presence of other nucleic acids
than those of the algal material. In general, there is a lack of algae databases for the identification of
foreign matter.
Currently these tests are not yet standardized and available for routine testing. Therefore, quality
assurance methods aimed at reduction / prevention of risk of impurity like good farming practices (GFP),
good manufacturing practices (GMP), traceability and Chain of Custody systems are essential to monitor
the level of purity for algae and algae products.
An overview of the currently available methods for qualitative and quantitative determination of algae
purity is shown in Table 1. The reliability of these different methods depends on the complexity of the
species and impurities and are not necessarily sufficient for each case.
The following substances affecting the purity of a product can be addressed:
— Physical foreign matter (i.e. (micro) plastic fragments, wires from fishing nets and ropes, feathers
from birds, shells);
— Other algae (including toxin-producing cyanobacteria), bacteria or organic materials (i.e. grass,
proteins or oils from other species);
— Algae from other location then stated (i.e. from Asia instead of Europe). Most promising test to detect
the presence of algae from other regions then stated, is the use of stable isotopes. However, first
databases with the characterization of isotopes from different regions need to be established.
Macroscopic examination is suitable for determining the presence of particles of foreign matter in whole
or cut (macro)algae. Foreign matter are all materials which are not part of the (macro)algae biomass.
Additional aids (like UV-light, sieving, centrifugation) might be helpful to find the foreign matter.
The algae harvesting and farming company should provide the purity on a CoA for each batch of algae.
4.1.2 Purity of microalgae and cyanobacteria
Microscopy is a suitable tool for microalgae, cyanobacteria and all powdered materials. Reduction of
particle size or powdering materials can hide the presence of non-specified substances and make it more
difficult to detect. Also diluted samples cannot be qualified and need a quantification step.
The determination of purity in fresh sample can be possible using inverted microscopy (Utermöhl
technique according to EN 15204) to determine the microalgae and cyanobacteria biovolume. This
European Standard describes the necessary methods for measuring cell dimensions and for the
calculation of cell or counting unit volumes to estimate the biovolume (wet weight biomass) in
phytoplankton samples. This method has been successfully used by French spirulina producers to
monitor the quality and purity of their biomass.
Where available, methods based on nucleic acid analysis of specific species, fingerprinting or
metabarcoding (using 1 or 2 markers) may provide information on purity of any algae powder.
Currently these methods are not yet available for routine tests.
4.1.3 Purity of macroalgae
By their very nature, macroalgae growing in the wild may be found to grow interspersed with other
species. Therefore, it is not always practical to obtain a harvest of macroalgae that is 100 % pure.
Macroscopic examination is suitable for determining the presence of foreign matter in whole or cut
macroalgae. This applies also to algae cultivated in tanks.
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Visual inspection is suitable for freshly harvested algae as the intact cells can be recognized as a whole.
When the holdfast is removed, or when epiphytic organisms are present on the surface visual inspection
may not be sufficient to identify the species after harvesting. For ground algae, cells are disrupted and
algae type can no longer be recognized nor be quantified.
Microscopy is indispensable for all powdered materials. Reduction of particle size or powdering
materials can hide the presence of non-specified substances and make it more difficult to detect. Also
diluted samples cannot be qualified and need a quantification step.
The most reliable way to monitor the purity of macroalgae is for companies to assess the freshly
harvested raw material by visual, macroscopic means. Purity should be expressed as the percentage of
the target macroalgae of interest over the total weight of the harvested biomass. In case the growth of
other algae/bacteria on the macroalgae is noticed, some follow-up test may be needed (microscopical for
instance) in order to check for potential impurities from hazardous organisms to verify if the product is
safe for the purpose of the product.
It is noted that macroalgae harvested from the wild may contain up to 10 % of other species that grow
alongside and co-occur with the main species that is harvested; of course, if the composition of such
products is fit for use, it can still be considered a single ingredient product, defined by its 90 %
component, because the presence of other macroalgae is not regulated by specific limits provided all the
macroalgae is safe for intended use.
4.1.4 Purity of algae derivatives or extracts
Pure algae extract can include a range of compounds present in the algae and/or it may refer to a pure
fraction containing one ore more compounds. Purified extracts with single components or a small
number of components can be responsible for the product efficacy. In complex mixtures of natural origin
(extracts) the efficacy may be related to synergistic effects of several components of the raw material and
not to a single molecule.
















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Table 1 — Types of impurities and detection methods
Impurity Fresh materials Dry materials or powder
Qualitative Quantitative Qualitative Quantitative
Physical foreign Visual Visual Visual Visual
matter inspection inspection inspection inspection
Microscopical Microscopical Microscopical Microscopical
inspection inspection inspection inspection
Additional tools Additional tools Additional tools Additional tools
Other algae, Visual Visual Visual Visual
bacteria and inspection inspection inspection inspection
organic materials
Microscopical Microscopical Microscopical Microscopical
inspection inspection inspection inspection
Nucleic acid –- Nucleic acid –-
analysis analysis
Chemical –- Chemical –-
a a
fingerprinting fingerprinting
Regional identity Isotopic analysis Isotopic Isotopic analysis Isotopic
b b
analysis analysis
a
chemical fingerprinting includes different techniques, for example: IR spectra, NMR, TLC, Mass Spectrometry,
fatty acid profile.
b
   methods to be developed.
4.1.5 Methods of analysis
The inventory of available methods and recommendation for prioritizing future method development on
purity of algae and algae products are listed in Tables F.1 and F.2.
Specific gaps to use these methods are lack of respectively [7]:
— sampling strategies for visual inspection and microscopy;
— quantification method for microscopy;
— databases, algae selective primers and protocols for nucleic acid identification; and
— databases for molecular and chemical fingerprinting and isotope analysis (see Annex F).
In addition to the gap per analysis methodology, methods are lacking for the quantification of the found
foreign matter. Furthermore, protocols describing what to do with the product if the presence of a foreign
matter is detected, are lacking.
It is recommended to further develop and standardize t
...