HSLF-FS 2018:7

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Gemensamma författningssamlingen

avseende hälso- och sjukvård,

socialtjänst, läkemedel, folkhälsa m.m.

ISSN 2002-1054, Artikelnummer 88518007HSLF

Utgivare: Chefsjurist Pär Ödman, Socialstyrelsen

Läkemedelsverkets föreskrifter

om ikraftträdande av reviderad monografi för

fermentationsprodukter i Europafarmakopén och om

supplement 9.4 till Europafarmakopén;

beslutade den 15 mars 2018.

Läkemedelsverket föreskriver följande på förslag av Svenska farmakopé-

kommittén och med stöd av 9 kap. 11 § läkemedelsförordningen (2015:458).

1 §

Monografin för fermentationsprodukter i nionde utgåvan av Europa-

farmakopén (European Pharmacopoeia Ed. 9.0) ska ersättas med monografin

enligt bilaga 1 till dessa föreskrifter.

2 §

Supplement 9.4 till den nionde utgåvan av Europafarmakopén (Europe-

an Pharmacopoeia Ed. 9.0) ska gälla som föreskrifter i Sverige och komplet-

tera den nionde utgåvan av Europafarmakopén och dess supplement 9.1, 9.2

och 9.3 samt den reviderade monografin för fermentationsprodukter i frågor

som rör läkemedelslagen (2015:315).

3 §

De svenska namn på monografierna som anges i bilaga 2 ska användas

i all den produktinformation för berörda läkemedel som krävs enligt gällande

regler. De ändringar av svenska namn som anges i bilaga 2 ska vara genom-

förda i sådan produktinformation senast den 1 april 2023.

Dessa föreskrifter träder i kraft den 1 april 2018.

Läkemedelsverket

JOAKIM BRANDBERG

Kenneth Nordback

HSLF-FS

2018:7

Utkom från trycket

den 23 mars 2018

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Bilaga 1

PA/PH/SG (17) 63 PUB

NOTE ON THE MONOGRAPH

Due to the public health risk associated with histamine contamination (see for example:

Public Health Risks of Histamine and other Biogenic Amines from Fish and Fishery

Products, Meeting report, 23-27 July 2012 FAO headquarters, Rome Italy), further

requirements related to the quality of raw materials were added to the Raw materials

section of the monograph.

The present monograph was adopted by the European Pharmacopoeia Commission by

correspondence on 12 January 2018. The date on which the states party to the Convention

on the Elaboration of a European Pharmacopoeia shall implement, within their territories,

the revised version of the monograph has been set to 1 April 2018.

04/2018:1468

PRODUCTS OF FERMENTATION

Producta ab fermentatione

This monograph applies to indirect gene products obtained by fermentation. It is not

applicable to :

– monographs in the Pharmacopoeia concerning vaccines for human or veterinary use ;

– products derived from continuous cell lines of human or animal origin;

– direct gene products that result from the transcription and translation from nucleic

acid to protein, whether or not subject to post-translational modification ;

– products obtained by semi-synthesis from a product of fermentation and those obtained

by biocatalytic transformation ;

– whole broth concentrates or raw fermentation products.

This monograph provides general requirements for the development and manufacture

of products of fermentation. These requirements are not necessarily comprehensive in a

given case and requirements complementary or additional to those prescribed in this

monograph may be imposed in an individual monograph or by the competent authority.

DEFINITION

For the purposes of this monograph, products of fermentation are active or inactive

pharmaceutical substances produced by controlled fermentation as indirect gene

products. They are primary or secondary metabolites of micro-organisms such

as bacteria, yeasts, fungi and micro-algae, whether or not modified by traditional

procedures or recombinant DNA (rDNA) technology. Such metabolites include

vitamins, amino acids, antibiotics, alkaloids and polysaccharides.

They may be obtained by batch or continuous fermentation processes followed by

procedures such as extraction, concentration, purification and isolation.

PRODUCTION

Production is based on a process that has been validated and shown to be suitable. The

extent of validation depends on the critical nature of the respective process step.

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CHARACTERISATION OF THE PRODUCER MICRO-ORGANISM

The history of the micro-organism used for production is documented. The

micro-organism is adequately characterised. This may include determination of

the phenotype of the micro-organism, macroscopic and microscopic methods

and biochemical tests and, if appropriate, determination of the genotype of the

micro-organism and molecular genetic tests.

PROCESSES USING A SEED-LOT SYSTEM

The master cell bank is a homogeneous suspension or lyophilisate of the original cells

distributed into individual containers for storage. The viability and productivity of

the cells under the selected storage conditions and their suitability for initiating a

satisfactory production process after storage must be demonstrated.

Propagation of the master cell bank may take place through a seed-lot system that uses a

working cell bank.

The working cell bank is a homogeneous suspension or lyophilisate of the cell material

derived from the master cell bank, distributed in equal volumes into individual

containers for storage (for example, in liquid nitrogen).

Production may take place by batch or continuous culture and may be terminated under

defined conditions.

All containers in a cell bank are stored under identical conditions. Once removed from

storage, the individual ampoules, vials or culture straws are not returned to the cell bank.

PROCESSES USING STAGED GROWTH IN CULTURES

The contents of a container of the working cell bank are used, if necessary after

resuspension, to prepare an inoculum in a suitable medium. After a suitable period of

growth, the cultures are used to initiate the fermentation process, if necessary following

preculture in a prefermentor. The conditions to be used at each stage of the process are

defined and must be met with each production run.

CHANGE CONTROL

If the production process is altered in a way that causes a significant change in the

impurity profile of the product, the critical steps associated with this change in impurity

profile are revalidated.

If a significant change has taken place in the micro-organism used for production that

causes a significant change in the impurity profile of the product, the critical steps of

the production process associated with this change, particularly the procedure for

purification and isolation, are revalidated.

Revalidation includes demonstration that new impurities present in the product as

a result of the change are adequately controlled by the test procedures. If necessary,

additional or alternative tests must be introduced with appropriate limits. If the change

in the process or in the micro-organism results in an increase in the level of an impurity

already present, the acceptability of such an increase is addressed.

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PA/PH/SG (17) 63 PUB

When a master cell bank is replaced, the critical steps of the production process must be

revalidated to the extent necessary to demonstrate that no adverse change has occurred

in the quality and safety of the product. Particular attention must be given to possible

changes in the impurity profile of the product if a modified or new micro-organism

is introduced into the process.

RAW MATERIALS

The raw materials employed in the fermentation and/or down-stream processing are of

suitable quality for the intended purpose. They are tested to ensure that they comply

with written specifications. Special attention must be paid to the levels of free histidine

in fish peptones as the presence of free histidine may lead to histamine formation in

certain conditions.

Levels of bioburden in media or in the inlet air for aeration are reduced to an adequately

low level to ensure that if microbial contamination occurs, it does not adversely affect

the quality, purity and safety of the product. Addition of components such as nutrients,

precursors, and substrates during fermentation takes place aseptically.

IN-PROCESS CONTROLS

In-process controls are in place to ensure the consistency of the conditions during

fermentation and down-stream processing and of the quality of the isolated product.

Particular attention must be paid to ensure that any microbial contamination that

adversely affects the quality, purity and safety of the product is detected by the controls

applied.

Production conditions may be monitored, as appropriate, by suitable procedures for

example to control and check:

– temperature,

– pH,

– rate of aeration,

– rate of agitation,

– pressure,

and to monitor the concentration of the required product.

DOWN-STREAM PROCESSING

At the end of fermentation, the producer micro-organism is inactivated or removed.

Further processing is designed to reduce residues originating from the culture medium

to an acceptable level and to ensure that the desired product is recovered with consistent

quality.

Various purification processes may be used, for example, charcoal treatment,

ultrafiltration and solvent extraction. It must be demonstrated that the process or

processes chosen reduce to a minimum or remove:

– residues from the producer micro-organism, culture media, substrates and precursors,

– unwanted transformation products of substrates and precursors.

If necessary, suitable tests are performed either as in-process controls or on the isolated

product of fermentation.

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IDENTIFICATION, TESTS AND ASSAY

The requirements with which the product must comply throughout its period of

validity, as well as specific test methods, are stated in the individual monographs.

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Bilaga 2

Namn på monografier i supplement 9.4 till Europafarmkopén

Nya monografier

Ändrade engelska namn

Ändrade svenska namn

Engelskt namn

Svenskt namn

Bupleurum root

Harört, rot

Green tea

Grönt te, blad

Guarana

Guarana, frö

Houttuynia herb

Ödleblad, ört

Mate leaf

Mate, blad

Moutan bark

Buskpion, bark

Platycodon root

Praktklocka, rot

Szechwan lovage rhizome

Sichuanloka, jordstam

Formic acid

Myrsyra

Gammadex

Gammadex

Raltegravir potassium

Raltegravirkalium

Soya phospholipids for injection

Sojafosfolipider för injektion

Sucrose, liquid

Sackaros, flytande

Tigecycline

Tigecyklin

Choline ([¹¹C]methyl) injection

Kolin([¹¹C]metyl)injektionsvätska

Nytt engelskt namn

Tidigare engelskt

namn

Svenskt namn

Metoclopramide

hydrochloride

monohydrate

Metoclopramide

hydrochloride

Metoklopramid-

hydrokloridmono-

hydrat

Svenskt namn

Tidigare svenskt

namn

Engelskt namn

Järn(III)kloridhexa-

hydrat

Ferrikloridhexahydrat

Ferric chloride hexa-

hydrate

Järn(II)fumarat

Ferrofumarat

Ferrous fumarate

Järn(II)sulfat, torkat

Ferrosulfat, torkat

Ferrous sulphate, dried

Järn(II)glukonat

Ferroglukonat

Ferrous gluconate

Järn(II)sulfathepta-

hydrat

Ferrosulfatheptahydrat

Ferrous sulphate

heptahydrate

Koagulationsfaktor IX

(rDNA), human, kon-

centrerad lösning

Koagulationsfaktor IX

human, rekombinant,

koncentrerad lösning

Human coagulation

factor IX rDNA con-

centrated solution

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Koagulationsfaktor IX

(rDNA), human, pulver

till injektionsvätska

Koagulationsfaktor IX

human, rekombinant,

pulver till injektions-

vätska

Human coagulation

factor IX (rDNA) pow-

der for solution for

injection

Koagulationsfaktor

VIIa (rDNA), human,

koncentrerad lösning

Koagulationsfaktor

VIIa, human rekombi-

nant, koncentrerad

lösning

Human coagulation

factor VIIa rDNA

concentrated solution

Elanders Sverige AB, 2018

HSLF-FS kan laddas ner via Läkemedelsverket.

Webb: www.lakemedelsverket.se

Författningen kan beställas via:

Norstedts Juridik

106 47 Stockholm

Telefon: 08-598 191 90 Fax: 08-598 191 91

E-post: kundservice@nj.se

Internet: www.nj.se/offentligapublikationer