eudralex 3a

8/9/2019 Eudralex 3A

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EN

The ru les go ve rn in g m edic in a l products

in the Europ ean Un ion

V o lume 3A

uide lmes

dicinal products for human use

Q ua l i ty a n d b io technology

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A great deal of additional inform ation on the European Union is available on the Internet.

It can be accessed through the Eu ropa server http://europa.eu.int).

Cataloguing data can be found at the end of this publication.

Luxembourg: Office for Official Publications of the European Communities, 1998

ISBN 92-828-2437-3

© European Communities, 1998

Reproduction is authorised, provided the source is acknowledged.

Printed in Belgium


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The rules governing medicinal products

in the European Union

Volume 3A

Guidelines

Medicinal products for human use

Quality and biotechnology

1998 Edition

EUROPEAN COMMISSION

Directo rate Gene ral III - Industry

Pharmaceuticals and cosmetics


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THE RULES GOVERNING MEDICINAL PRODUCTS

IN THE EUROPEAN UNION

Volume 1 Pharm aceut ica l l eg is lat ion


Volume 2 Notice to applic ants


Volume 3 Gu ide l ines


Volume 4 Good ma nufac turing pract ices

Medicinal products for human and veter inary use

Volume 5 Pharm aceut ica l l eg is la tion

Veterinary medicinal products

Volume 6 Notice to app licants


Volume 7 Gu idel in es


Volume 8 Max imum residue l imits


Vo lume 9 Pha r m acov ig i l ance

Medicinal products for human use and veter inary medicinal products


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FOREWORD

Directive 75/318/EEC describes the req uire m ent s for the dem ons tratio n of the qua lity, safety

and efficacy of med icinal produc ts. The conduc t of tests and studies for such de m on str ati on

has been harmonised, both within the European Union and internat ional ly.

Volume 3 of "The Rules Governing M edicinal Products in the European Union" incorpora tes

test ing guidel ines prepared within the Euro pean Union including those which have b een

developed in the Inter nat io nal Conference on Ha rm oni sat io n (ICH) process. I t is presen ted

in three parts :

• Volume 3A - Qua lity and biotechnology

• Volume 3B - Safety and the enviro nm ent

• Volume 3C - Efficacy and inform ation on the me dicinal produc t

These guidelines serve a two-fold objective. Firstly, they are intended to provide a basis for a

pract ical harm onis at ion of the m an ne r in which the Mem ber States and the E urop ean

Agency for the Evalua t ion of Med icinal Products interpret an d apply the detai led

req uir em en ts for the dem ons tratio n of qu ality, safety and efficacy con tained in the

Com munity direct ives. Secondly, they are intende d to faci l ita te the prepa rat ion of

applicat ions for m ark et in g authorizat ion which will be recognized as val id by al l M em ber

States and the European Agency for the Evaluation of Medicinal Products.

The use of guidel ines, which are not legal ly binding, rather than a formal legal instrument,

such as a directive, has been preferred in order to maintain an element of flexibility and not

to place und ue legislative re str ai nts on scientific prog ress. It is recognized tha t in som e

cases, as a resu lt of scientific develo pm ents, an alte rna tive approach may be app ropria te.

How ever, where an applica nt chooses not to apply a guide line, tha t decision m us t be

explain ed and justified in the Expe rt Repo rts subm itted by the com pany in support of the

applicat ion.

By their very natu re, the guidel ines mu st be updated in the l ight of scientif ic and tech nic al

progress. Moreover , fur ther guidel ines are curren t ly un der discussion, thus it is in ten ded

that this volume should be updated and revised as necessary.

These Notes for Guidance, which have no legal force, have been prepared by the Committee

for Proprietary Medicinal Products of the Europ ean Agency for the Evalu at ion of Me dic ina l

Products , in consultat ion with the competent authori t ies of the Mem ber States , to assis t

applicants for a marketing authorization for a medicinal product. In case of doubt, reference

should be made to the text of the relevant EEC Directives.

Ill


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TABLE OF CONTENTS

QUALITY GUIDELINES

DEVELOPM ENT PHARMA CEUTICS AND PROC ESS VALIDATION 3

MANUFACTURE OF THE FINISHE D DOSAGE FOR M 11

LIMITATIONS TO THE USE OF ETHYLENE OXIDE IN THE MANUFACTURE OF

MED ICINAL PRODU CTS 19

THE USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL

PRODUCTS 23

CHEMISTRY OF ACTIVE SUBSTA NCES 31

REQ UIREM ENTS IN RELATION TO ACTIVE SUBSTA NCES 39

EUROPEA N DRUG MASTER FILE PROCED URE FOR ACTIVE SUBSTA NCES 47

IMPU RITIES IN NEW ACTIVE SUBSTAN CES *) 57

EXCIPIENTS IN THE DOSSIER FOR APPLICATION FOR MARKETING

AUTHO RISATION OF A MED ICINAL PRODU CT 67

PLASTIC PRIMARY PACKAGING MATER IALS 75

SPECIFICATIONS AND CONTROL TESTS ON THE FINISHE D PRODUCT 83

IMPU RITIES IN NEW MED ICINAL PRODU CTS *) 95

VALIDATION OF ANALYTICAL PRO CED URE S: METH ODOLOG Y *) 107

VALIDATION OF ANALYTICAL PROCEDURES: DEFINITIONS AND

TER MIN OLO GY *) 119

STABILITY TESTING OF NEW ACTIVE SUBSTANCES AND MEDICINAL

PRO DU CTS *) 127

STABILITY TEST ING ON ACTIVE INGR EDIEN TS AND FIN ISH ED PROD UCTS 143

STABILITY TESTIN G: REQ UIRE ME NTS FOR NEW DOSAGE FORM S *) 153

PHOTOSTABILITY TESTING OF NEW ACTIVE SUBSTANCES AND MEDICINAL

PRODUCTS*) 157

QUALITY OF PROLONGED RELEASE ORAL SOLID DOSAGE FORM S 167

RADIOPHARMACEUTICALS 175

RADIOPHARM ACEUTICALS BASED ON MONOCLON AL ANT IBOD IES 185

QUALITY OF HERBAL REM EDIES 195


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Table of contents

BIOTECHNOLOGY GUIDELINES 203

PRODUCTION AND QUALITY CONTROL OF MEDICINAL PRODUCTS DERIVED

BY RECOM BINANT DNA TECHN OLOG Y 205

QUALITY OF BIOTECHNOLOGICAL PRODUCTS: ANALYSIS OF THE

EXPRESSION CONSTRUCT IN CELLS USED FOR PRODUCTION OF RDNA

DERIVED PRO TEIN PRODUCTS*) 217

PRODUCTION AND QUALITY CONTROL OF CYTOKINE PRODUCTS DERIVED

BY BIOTECHNOLOGICAL PROCESSES '. 223

PROD UCTION AND QUALITY CONTROL OF MONOCLONA L ANT IBODIES 237

QUALITY OF BIOTECHN OLOGICAL PRO DUCTS: STABILITY TEST ING OF

BIOTECH NOLO GICAL/BIOLOG ICAL PRODUCTS*) 263

GENE THERAPY PRODUCT QUALITY ASPECTS IN THE PRODUCTION OF

VECTORS AND GENETICALLY MO DIFIED SOMATIC CELLS 275

USE OF TRANSGENIC ANIMALS IN THE MANUFACTURE OF BIOLOGICAL

MEDICINAL PRODU CTS FOR HUMAN USE 287

VIRUS VALIDATION STUDIES: THE DESIGN, CONTRIBUTION AND

INTERPRETATION OF STUDIES VALIDATING THE INACTIVATION AND

REMOVAL OF VIRU SES 295

VALIDATION OF VIRUS REMOVAL/INACTIVATION PROCEDURES: CHOICE OF

VIRUSES 311

MINIMISING THE RISK OF TRANSMITTING AGENTS CAUSING SPONGIFORM

ENCEPH ALOPA THY VIA MEDICINAL PRODU CTS 315

TES TS ON SAM PLES OF BIOLOGICAL ORIGIN. 323

PLASMA DERIVED MED ICINAL PRODU CTS 333

PLASMA POOL TEST ING 351

HARMONISATION OF REQU IREMENT S FOR INFLUENZA VACCINES 355

ALLER GEN PRODU CTS 373

ASSESSING THE EFFICACY AND SAFETY OF HUMAN PLASMA DERIVED

FACTOR VIILC AND FACTOR IX:C PRODUCTS IN CLINICAL TRIALS IN

HAEMO PHILIACS BEFORE AND AFTER AUTHORISATION 381

ASSESSING THE EFFICACY AND SAFETY OF NORMAL INTRAVENOUS

IMMUNOGLOBU LIN PRODUCTS FOR MARKETING AUTHORISATIONS 393

I N D E X 4 0 5

V I


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QUALITY GUIDELINES


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3AQ1a

DEVELOPMENT PHARMACEUTICS AND PROCESS

VALIDATION

G u i d e l i n e T i t l e

L e g i s l a t i v e b a s i s

D a t e o f f i r s t a d o p t i o n

D a t e o f e n t r y i n t o

f o r c e

S ta tu s

P r e v i o u s t i t l e s / o t h e r

r e f e r e n c e s

A d d i t i o n a l N o t e s

D e v e l o p m e n t P h a r m a c e u t i c s a n d P r o c e s s V a l i d a t i o n

D i r e c t i v e 7 5 / 3 1 8 / E E C a s a m e n d e d

Apr i l 1988

Oc tobe r 1988

Las t r ev i s ed 1988

N o n e

T h i s n o t e f o r g u i d a n c e c o n c e r n s t h e a p p l i c a t i o n o f P a r t

2 ,

s e c t i o n s A .4 a n d Β o f t h e A n n e x t o D i r e c t i v e

75 /318 /EEC as am en de d wi th a v i e w to t he g r a n t i n g o f a

m a r k e t i n g a u t h o r i s a t i o n f o r a m e d i c i n a l p r o d u c t .

CONTENTS

D E V E L O P M E N T P H A R M A C E U T I C S

1 . I N T R O D U C T I O N

2 . C O N S T I T U E N T S

3 .

C O M P O S I T I O N

4 . C O N T A I N E R

I I P R O C E S S V A L I D A T I O N


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3AQ1a

DEVELOPMENT PHARMACEUTICS AND PROCESS

VALIDATION

I. DEVELOPMENT PHARMACEUTICS

L I N T R O D U C T I O N

Ph arm ace utic al developm ent studies may need to be carrie d out to estab lish that the type of

dosage form selected a nd the form ulation proposed are s atisfactory for the purpose specified

in the applicatio n. They also aim to identify those form ulatio n an d process ing aspects that

are crucial for batch reproducibility and which therefore need to be monitored routinely.

Because of the gre at variety in active subs tance s and dosage forms, this note for gu idanc e is

only an i llus trat ion of the type of inform ation which ha s been found useful in es tab lish ing

the factors which affect quality of a finished product.

2.

C O N S T I T U E N T S

2.1 Act ive subs tances

2.1.1 Compatibility

The com patibility of the active substance(s) w ith the excipien ts sho uld, where neces sary , be

demonst ra ted .

2.1.2 Physical charac teristics

It ma y be nec essa ry to study the effect of such par am ete rs as e.g. crysta l form, m ois tur e

content and particle size of the active substan ce on the form ulatio n. The l atte r may be of

importance in bioavailabi l i ty, content uniformity, suspension propert ies , s tabi l i ty and for

eye irr i ta t ion studies. Hav ing identif ied a param eter a s being cr i t ical , i ts control should

then be reflected in the active substance sp ecification, or dealt with by other app ropriate

m e a n s .

2.1.3 Overage

Overages are prim ari ly employed to cover losses during ma nufa cture , i .e . m an uf ac tu rin g

overage, and/or durin g shelf life, stability overage. Th e inclusio n of any overage should be

just i f ied.

2.2 Excip ient s

2.2.1 An explan ation should be provided with regard to the function of the excipients in the

formula t ion .

2.2.2 Excipient comp atibility should be estab lished where rele van t.

2.2.3 W here un us ua l excipients are used in the man ufac ture of the product, e.g. the m at ri x

of a slow release prep aratio n, full in form ation on the compo sition an d function of the


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excipient in the form ulation of the product should be furnished together with a n y

docum entat ion w hich may be avai lable to dem onstrate safety of the raw m ateria l . A new

subs tance introduc ed as an excipient will be rega rded in the sam e way as a new active

substance, unless it is already approved for use in food by the same route of administration.

3.

COMPOSITION

3.1 L i q u i d d o s a g e fo rm s

3.1.1

Physical parame ters

a ) pH

Ev iden ce shou ld be pres ente d to show tha t the effect of pH w ithin the specified ran ge of the

formulation has been investigated. Consideration should be given to the effect of pH on active

constitue nt(s), and , where releva nt, on the an tim icro bia l efficacy. Should such a study show

positive results any long-term effects would need to be investigated during stability studies.

b ) o t h e r s

Depending on the formulat ion, such para me ters as ease of dissolut ion and redis pers ion,

particle size, aggre gation , rheological properties, etc. should also be considered d u ri ng

pharmaceutical development s tudies.

In the formulation of parenteral products, consideration may have to be given to such factors

as tonicity adjustment, globule size of emulsions, particle size and shape as well as changes

in crystal form, etc.

3.1.2 Additives

- preservat ives,

- an t iox idants ,

- others.

The conc entration of additive(s) incorpo rated into the form ulation should be shown by

experimental results to be optimum for the intended usage. Consideration should therefore be

given to such factors as storage, reconstitution and dilution before use and frequency of

opening the pack when choosing suitable level(s) of additive(s ) a nd d esig nin g tests to

establis h efficacy of a preserv ative system . Larg e packs intend ed for dispen sing purpose

ma y requ ire more string ent testin g. Both an tiba cte rial and antif ung al efficacy should be

dem onstr ated and the test should include suitable positive and n egative controls. T es tin g

conditions and the results thereby obtained must be reported.

3.1.3 Com patibility with other produ cts

This is of particular importance for products to be administered intravenously.

W here the dat a sheet gives instr uctio ns for dilution before ad m ini stra tio n, dat a should be

presented to dem onstrate physical and chemical compatibi li ty w ith the recom me nde d

diluents over the recommended or anticipated period of use.


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3AQ1a

3 .2 S e m i - s o l i d d o s a g e f o r m s

3.2.1 Physical parameters

a ) pH

Ev iden ce should be pres ented to show that the effect of pH withi n th e specified ran ge of the

formulat ion, where relevant , including preservat ive act ivi ty, has been invest igated . W he re

a significan t effect is observed, any long-term effects would need to be inve stiga ted d ur in g

stability studies.

b ) o t h e r s

Wh ere the act ive substance is suspended rath er than dissolved, pa rt icle size control an d

particle size aggreg ation should be tak en into con sider ation du ring developm ent studies..

Rheology studies may also need to be carried out during the development of semi-solids.

3.2.2 Additives

- preservat ives,

- an t iox idants ,

- others.

The concen tration of additive(s) incorp orated into the form ulation should be shown by

experimental results to be optimum for the intended usage. Consideration should therefore be

given to such factors as storage, reco nstitutio n, dilution before use and frequency of op eni ng

the pack when choosing su itable level(s) of additive (s) and d esign ing tests to esta blish the

efficacy of the preservative system. In such tes ts, both ant iba cte rial and an ti fungal efficacy

should be dem onstra ted and the test should include suitable positive and nega tive con trols .

Testing conditions and the results thereby obtained must be reported.

3 . 3 S o l i d d o s a g e f o r m s

3.3.1 Dissolution

The dissolution ap par atu s used in the testi ng of both unmo dified an d modified re lea se

prep arati ons should be either of those described in the Euro pean Ph armac opoe ia. W here these

prove unsu itable, dissolution test equipment described in the Na tional Pharm acopo eia of the

Mem ber State should be adopted as second choice, or, failing this , any other m ethod.

However, just i f icat ion for the use of a method other tha n Europ ean Pha rmac opoeia mu st be

put forward.

a) Un m o di f i ed re l ease prep arat ions

Dissolution tests mu st be performed du ring developm ent and stability stud ies in order to

establish whether such testing would need to be done during stability studies and routinely as

pa rt of th e finished product specification.

b) M od i f ied re l ease prep arat io ns

The choice of dissolution test cond itions and relea se ra tes adopted for a sse ssi ng batch

reproducibility n eeds to be justified. Th is should take account of in vivo studies carried out to

establish the release and absorption profile of the product and would, if feasible, consist of a

study corr elatin g in vitro release rate s to in vivo res ults to allow me anin gfu l batch

reproduc ibility evalu ation. Such a corre lation would be of pa rtic ula r im porta nce for


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me dicinal products containin g act ive substances with a narrow therapeutic window. A

significant ch ange in composition, me thod or site of ma nufa cture or equip me nt, control tests

on sta rti ng m ate ria ls or finished produ ct ma y however nece ssitate further in vitro

correlation studies or in vivo bioavailability studies.

3.3.2 Homogeneity

The European Pharm acopoeia includes a require me nt for uniformity of content of s ingle-

dose pre par atio ns w here the am oun t of active con stituent is less th an 2 mg per dose or les s

tha n 2% by ma ss of the total m ass. Notw ithstandin g this requ ireme nt , the adequacy of the

mixing process in obtain ing the requ ired hom ogeneity of the m ixtur e ought to be con side red

for all solid dose forms i.e., tablets, powders, etc.

4.

C O N T A I N E R

App ropriate studies should be performed to dem ons trate th e integ rity of the con taine r an d

closure. A possible interaction between product and container may need to be considered.

4.1 So rpt ion to co nta ine r

Da ta should be presen ted to show tha t conside ration ha s been given to the possibility of

sorption of the active constituent(s) an d additive(s) from liquid or semi-solid form ulation s if

relevant to safety or stability. These phenomena are known to occur with rubber closures and

with both glass and plast ic contain ers and a dm inistr at ion sets . Where evidence exists for

significa nt sorption to ad m ini stra tio n sets, the data sheet should include an approp riate

reference to this fact.

4 .2 Leach ing

Da ta should be presen ted to show tha t there is no significa nt leach ing of any pac k

compo nent, inclu din g label adhe sive, into liquid or finely divided solid pre para tion s over

the shelf life period, where relevant.

4.3 Dose reproducib i l i ty

If a dosing device is used, evidence should be presented that a reproducible dose of the product

is delivered under testing conditions, which, as far as possible, are relevant for the use of the

product by the patient.

8


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3 A Q l a

II.

PROCESS VALIDATION

W here as development pharm aceutics is concerned w ith estab l ishing that the proposed

form ulation is satisfactory for the purpose specified, process valid atio n is inten ded to

establ ish that the proposed manufacturing process is a sui table one and yields consistent ly a

produc t of the desired quality. W hile process val idat ion is gene rally a concept mo re closely

associated with Good Ma nufactu ring Pract ice (GMP) and therefore fal l ing into the area of

insp ectio ns, if a non-s tand ard metho d of m anu fact ure is used or if cer tain aspects of the

metho d of m anu factu re are crucial for product quality , efficacy or safety but can no t

necessari ly be detected by analyt ical mean s, da ta on process val idat io n may be required in

applicat ions for m ark et in g autho risat ion for a med icinal product . Area s m ostly con cerne d

are process environmen t, process equipm ent and the ma nuf actu ring process

itself,

the lat ter

being the most important one. Thus data may be required to establ ish e .g. that :

- non -stand ard ster i lisat ion condit ions provide an acceptable level of assu ranc e of

product sterility,

or

- the m an ufa ctu ring process for a modified releas e system will only va ry to an extent

that will still yield a product of the desired quality and not have any effect on product

efficacy or safety.


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3AQ2a

MANUFACTURE OF THE FINISHED DOSAGE FORM



Da te o f f i r s t a do p t io n

M a n u f a c t u r e o f t h e F i n i s h e d D o s a g e F o r m

D i r e c t i v e 7 5/ 31 8 /E E C a s a m e n d e d

S e p t e m b e r 1 9 9 5

Da te o f en t r y i n to M ay 1996

f o r c e

S ta tu s


r e f e r e n c e s


T h i s v e r s i o n r e - i s s u e d i n A p r i l 1 99 6

N o n e / C P M P / Q W P / 4 8 6 / 9 5


2, sec t i o n D o f t h e A nn ex t o D i r e c t i ve 75 /318 /EEC a s

a m e n d e d , w i t h a v i e w t o t h e g r a n t i n g o f a m a r k e t i n g

a u t h o r i s a t i o n f or a n e w m e d i c i n a l p r o d u c t .

CONTENTS

1.

I N T R O D U C T I O N

2 . T H E A P P L I C A T I O N F O R M A R K E T I N G A U T H O R I S A T I O N A N D G M P

3 .

M A N U F A C T U R I N G F O R M U L A

4 . D E S C R I P T I O N O F T H E M A N U F A C T U R I N G P R O C E S S

5 . D E S C R I P T I O N O F T H E M A N U F A C T U R I N G C H A I N

6 . V A L I D A T IO N O F T H E M A N U F A C T U R I N G P R O C E S S

7 . SPEC I AL I TEM S

11


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3AQ2a

MANUFACTURE OF THE FINISHED DOSAGE FORM

L INTRODUCTION

According to Direct ive 65/65/EEC, an applicat ion for a m ark et in g autho risat ion sh al l

contain a brief description of the method of preparation.

This is described in more detail in the Annex, Part 2 of Directive 91/507/EEC, which states:

The description of the m ethod of prep aratio n [. ..] sh all be drafted in such a way as to give a n

adequate synopsis of the nature of the operations employed.

For this purpose it shall include at least:

men tion of the various s tages of ma nufa cture , so that an a ssessm ent can be ma de of

whe ther the processes employed in producing the phar ma ceutica l form migh t hav e

produced an adverse change in the const i tuents ,

in the case of continuous ma nufac ture, ful l d etai ls concerning precaution s take n to

ens ure th e homogeneity of the finished p roduct,

the actual ma nufa cturin g formula, with the quan ti tat ive par t icula rs of al l the

substances used, the quan ti t ies of the excipients , however, being given in appro xim ate

term s in so far as the pharm aceutica l form ma kes this necessary; me ntion shal l be

made of any substances tha t may disappear in the course of ma nufa cture; any ove rage

shall be indicated and justified,

a s tateme nt of the s tages of ma nufac ture at which sam pling is carr ied out for in-

process control test s, where other data in the docum ents supporting the application show

such tests to be necessary for the quality control of the finished medicinal product,

exper imenta l s tud ies va l ida t ing the ma nufac tur ing process , where a no n-s t and ard

method of manufacture is used or where it is critical for the product,

for sterile prod ucts, details of the steri lisat ion processes and/or aseptic pro cedu res

used .

This note for guidance provides guidance on the backg round and the interpre tat ion of some

aspects of the text of the Directive.

Th is note for guidance does not per tain to biological m edic inal products such as v ac ci ne s,

sera, toxins and al lerge ns, products derived from hu m an blood and plasm a as well a s

medicinal products prepared biotechnological ly.

2.

T H E A P P L I C A T I O N F O R M A R K E T IN G A U T H O R I S A T I O N

A N D G M P

Medicinal products on the market in the EC should be produced under the EC Rules for Good

Manufacturing Practice (GMP), see Directive 91/356/EEC.

Many genera l elem ents of GMP and quali ty as sura nce do not need to be described in the

application for m ark et in g authorisat ion . Examples are qual ificat ions of key per son nel ,

1 3


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3AQ2a

cleanin g procedures for the production equipment and production are as, f inal pa ck ag ing

and labelling procedures etc.

In general, the dossier for marketing authorisation should contain only those elements of the

qua lity assuran ce which are specific for the m edicin al product, wh erea s non product related

elem ents of the quality assuran ce fall with in the field of GM P, conseque ntly, no d escription

is necessary in the applicat ion for a market ing authorisat ion.

This note for guida nce add resse s th e item s tha t should be prese nted in the application for a

m ark et in g authorisat ion. F or i tems not to be covered by the applicat ion for a m ar ke t in g

authorisation, the obligation for adherence to the EC GMP principles is implicit.

3. M A N U F A C T U R I N G F O R M U L A

The intended batch size should be indicated.

An application for a varia ble and/o r alte rna tive batch size should be justified. Con sistent

conformity of the finished product to all the specifications should be made plausible.

The nam es and quan tities of all ingre dients used in the course of the m anu fac ture should be

stated. This includes ingredients which are removed from the product during the production

process, such as solvents . Substances that may not always be used should also be mentioned,

such as acids and alkal is for pH adjustmen t . Overages mu st be indicated in qua nti tat iv e

terms and just i f ied in the sect ion on Development Pharmaceutics .

For each ingredient, the allowed upper and lower acceptance limits for the actual quantity of

each ingredie nt from the nom inal quan ti ty of the batch ma nufa ctur ing formula should be

stated.

For active ingre die nts , these acceptance lim its should be with in 95 to 105% of the no m in al

qua ntity ; for excipients, acceptance lim its of 90 to 110% of the no m ina l qua ntity ar e

acceptable without further justification.

W ider acceptance lim its m ay be acceptable but should be justified by showing that batches

with a composition close to the upp er and lower proposed acceptance limits r em ain within the

finished product specifications.

Wh en th at the quan tity of an active ingred ient to be used is calcu lated from the actua l as sa y

value of the batch of that active i ngr edie nt ( factorisation ), this ha s to be indica ted. If

ano ther ingredien t is used to keep the total ma ss per batch equal to the quan tity provided for

in the batch manufacturing formula, this should also be indicated.

4.

D E S C R I P T I O N O F T H E M A N U F A C T U R IN G P R O C E S S

A description of the manufacturing process should be given.

A proposal to allow alte rna tive steps in the m an ufa ctu ring process (for in stan ce: two

alterna t ive s ter i l isat ion methods for the container) should be accompanied by evidenc e

showing th at all processes proposed will co nsistently produce a finished product in

compliance with the specifications.

If rele van t (see below), the ap par atu s to be used h as to be described. The in-process controls

and corresponding acceptance limits need to be described as well, when relevant (see below).

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The various s teps in the m anu factu ring process and correspon ding in-process controls

should also be shown in a flow-chart.

The presented data on the m anu fact urin g process, app aratu s and in-process controls ar e

bindin g for the future manu fact urin g of the me dicinal product, unle ss autho risat ion for

changes is given by the Competent Authority.

I t is in the interest of both the applicant and the regulatory authori t ies to avoid un ne ce ss ary

applicat ions for varia t ions . Very detai led descript ions of the m anu factu ring process,

apparatus and in-process controls should therefore be avoided.

In selecting the necessary level of detail the following should be considered:

the testi ng at release of the finished product,

the description of the man ufacturing process and a pp arat us,

the in-process controls and validated acceptance limits.

Toge ther these should provide a high degree of probability tha t each u nit of every batch of the

finished product, will be in conformity with the specifications.

So , if the consistent qua lity of a med icinal product can be fully safeguarde d by the im pl ic it

production und er G MP and t esti ng of the finished product at rele ase , th e description of the

ma nuf actu ring process need not be comp rehensive, a nd app aratu s and in-process controls

need not to be described.

However, many quali ty pa ram eter s that are tested at release do not provide suff icient

certa inty of the qua lity of the whole batch from a statistical p oint of view, becaus e the qu ali ty

parameter may not necessari ly be homogeneous within the batch.

An example is the homogeneous distr ibut ion of the act ive ing redien t in sol id and sem i-sol id

dosage forms, i .e. content unifo rm ity. Te sting at relea se alon e does not provide sufficien t

certainty for the content uniformity of the whole batch from a statistical point of view.

So , the appara tus to be used and the appropriate in-process controls (i .e. m ixing t ime, m ix in g

speed etc.) and the validated acceptance lim its for these in-process c ontrols (see below) m us t

be proposed in the application file.

Another example is s ter i l isat ion. For al l s ter i l isat ion processes, appropriate in-process

controls and their acceptance limits are to be described in the application file, see below.

5.

DESC RIPTION OF THE MANUFACTURING CHAIN

An account shall be given of the sites at which each stage of the m an uf ac tu rin g a n d

assembly operat ions takes place. Different ma nuf actu ring si tes belonging to the sam e

company shal l be men tioned as separate units . The company responsible for the f i na l

approval of the release of the product onto the market shall be specified.

6. VALIDATION DATA OF THE MA NUFACTU RING PR OC ES S

Validat ion studies that are used to identify cr i t ical s teps in non -stan dard m an uf ac tu rin g

processes are part of the Developm ent Pharm ace utics , and should be described in P ar t IIA of

the application file.

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3AQ2a

Examples are: new dosage forms, the manufacturing of liposomes, etc.

Irrespect ive of these Development Phar ma ceutic al process val ida t ions, process Va lida t ion

resu lts of the actu al production process m ust be described in Pa rt IIB if conform ity to the

finished product specifications cann ot be gua ran teed to an acce ptable degree of statisti cal

certa inty by testi ng the finished product at releas e. Th is holds also for st an da rd

manufac tur ing processes .

Exam ples are mixing , g ranu lat ion and emulsifying processes of solid and semi-sol id

dosage forms and non-pharmacopoeial sterilisation procedures, see below.

Process validation data obtained with closely related medicine products may be acceptable.

Please note that notw ithstand ing a successful process val idat ion, the qual i ty par am eter s

related to the valid ated process should be specified un de r the release specifications and en d

of shelf life specifications. For insta nce , ste rility should alw ays be specified at release an d

end of shelf life, no tw iths tan din g a successful valid ation of the ster ilisa tion process. Also ,

the content unifor mity of solid and semi-solid dosage forms should be specified in the

release and end of shelf life specifications, no twi thsta nd ing a successful process val id ati on

with respect to homogeneity.

It may be acceptable to refrain from the routine testing at relea se of such a specificatio n

( param etric release ), see the note for guidan ce Specifications and C ontrol Tests on the

Finished Product. With respect to parametric release in relation to sterilisation, the text of the

Ph. Eur. Methods of pre para tion of sterile products is to be observed.

7.

S P E C I A L I T E M S

7.1 M etho d of s te r i l i s at io n

The choice of the meth od of sterilis ation should be justified un de r Deve lopm ent

Pharmaceut ics , Par t I IA.

According to the text of the Ph . Eu r.: Methods of prep aratio n of sterile products , t er m in al

sterilisatio n in th e final con taine r is to be preferred. Refraining from t erm ina l ste rili sat ion

in the final contain er should be justified in the application file.

In Part IIB the actual sterilisation process to be applied should be described.

All sterilisation processes should be carried out accordin g to the ins truc tion s of the Ph. Eu r.

In the application file, an explicit state m ent should be ma de that the instr uct ion s of the Ph.

Eur. are followed.

According to the Ph. Eur., all sterilisation procedu res should be vali date d and be carrie d out

un de r the EC GM P-rules. How ever, in the application file for ma rk eti ng auth oris ation for

some sterilisatio n proce dures no, or only limited valid ation da ta and d ata on the biobu rden

of the product prior to the sterilisation need to be presented , see below.

In the case of term inal s ter i l isat ion in the f inal container by heat using a reference

condition of the Ph . Eur., only the time and tem pera ture of the cycle an d the a cceptan ce

limits of the corresponding in-process controls need to be provided in the application file.

So , this holds for sterilisation by satu rate d steam at a minim um of 121 °C for 15 min . and by

dry heat at a minimum of 160 °C for at least 2 hours.

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3AQ2a

In accordance with the Ph. Eur. , these condit ions should be met within al l un i ts . How ever,

the val idat ion data showing th at al l uni ts are subjected to these condit ions are norm ally not

requ ired in the application file. They ma y be requ ested by the com petent autho rities in

cer ta in c i rcumstances .

For term inal s ter i l isat ion cycles in the f inal container by heat with a t ime an d/o r

tem per atu re below the valu es of the reference cond itions of the Ph. E ur., not only the

acceptance lim its for the in-process controls for time an d tem pe ratu re sho uld be stated, but

also the maximum acceptable bioburden before sterilisation.

The re sult s of the vali datio n of the ster ilisa tion cycle w ith reg ard to the effectiveness in

terms of the Sterility Assurance Level (SAL) obtained should be presented in the application

file.

For sterilisatio n by filtration th e m axim um acceptable bioburd en prior to the filtration m us t

be stated in the application . In m ost situa tion s NM T 10 CFU's/100 ml w ill be acceptab le,

dep end ing on the volume to be filtered in relat ion to the dia m eter of the filter. If this

requ irem ent is not met , i t is necess ary to use a pre-f il t ration through a ba cte r ia- ret ain ing

filter to obtain a sufficiently low bioburden.

The type of bacte ria-rete ntive filter, an d its pore size shou ld a lso be described in the

application . Pore sizes of 0.22 um or less are acceptable without furthe r justi ficati on, in

accordan ce with the Ph. Eu r. A proposal to use a larg er pore size in com binatio n with a n

additional sterilisation step has to be validated and justified in the application file.

Results of media filling fall within the field of GMP and need not be presented routinely i n

the applicat ion for ma rket ing au thorisat ion bu t may be requested by the competent autho ri t ies

in certain circumstances.

For s ter i l isat ion by gam ma and electron rad iat ion , see the note for guidance The Use of

Ionisation Ra diation in the Manufacture of Medicinal Products.

For sterilisa tion by ethylen e oxide, the provisio ns laid down in the note for gu id an ce

Limitations to the use of Ethylene Oxide in the Manufacture of Medicinal Products should be

followed, i .e. its use as a ste rilisa tion metho d is only acceptable if no other metho d of

ster i l isat ion is avai lable.

The applicat ion for market ing authorisat ion should contain a descript ion of the apparatus,

qu ant itativ e data on the mi xtu re of gases to be used, da ta on the biobu rden prior to

ster i l isat ion, the t ime of exposure of the gas, the temp erature and hum idity prior to an d

during the sterilisation cycle, and the conditions for the removal of ethylene oxide. All these

condition s should be mo nitored by suitable in-process controls th at are to be descr ibed

together with the acceptance limits for these in-process controls.

Resu lts of the process validation shou ld be pres ente d to justify th ese acceptanc e lim its for the

in-process controls . The resul ts should demon strate both an acceptable as sura nce , of s ter i l i ty

and removal of ethylene oxide to an acceptable level.

Lim its of NMT 1 ppm of ethyle ne oxide (if applicable, mea sure d by m ean s of a sim ulate d use

extract ion method) and NM T 50 ppm of ethylene c hlorhyd rin (or an y other ha loge nated

ethylen ehyd rin) are acceptable without further just i f icat ion, once ster i l isat ion by ethylene

oxide has been justified.

No twi thsta nd ing successful process vali datio n, a limit for resi du al ethy lene oxide, an d the

corresponding val idated a naly t ical method, should be included in the product release- an d

end of shelf life specifications.

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7.2 Re -process in g of res id ua l pro du ct

Proced ures for the re-proce ssing of residu al produ ct of non-biological medicinal prod ucts fall

within the field of GMP and need not to be described in the marketing authorisation dossier.

7.3 Re m ova l of solve nts or gases

If toxic gases or solvents are used in the ma nu factu re of the finished product, relea se an d

end of shelf life specifications for ma xim um acceptable resid ues of these solvents or ga se s

should be proposed for the product. A justificatio n for the proposed limits can be presen ted

i f

requ ired in P ar t HA, Pa rt IIB or HE of the file. Both toxicological and technological aspects

should be discussed in this justification.

Stages of the ma nufa cturin g process which affect the levels of such ma ter ial s in the product

should be controlled by in-process controls a nd the acceptance lim its for these in-proc ess

controls should be validate d. The resu lts of these process valida tion s should be presen ted i n

the application for marketing authorisation; see the paragraph in 7.1 above on ethylene oxide

s te r i l i sa t ion .

7.4 Clean ing of p r im ary packa g ing m a te r i a l

Wa shing procedures of the prim ary containe rs and closures norm ally fall within the f ield

of GMP and are not needed routinely in the applicat ion for ma rke t ing authorisa t ion but

may, in certain circumstances, be requested by the Competent Authori ty.

7.5 S t e r i l i s a t ion of p r im ary packa g ing m a te r i a l

Where applicable, the s ter i l isat ion procedure of the prim ary contain ers and closures should

be described, and, when necessary, validated according to the paragraph on sterilisation.

7 .6 P roduc t i on a r eas

Details on the production a rea, i .e. specifications for the microbiological qua lity of the a re as

and freedom from particles in the air nor ma lly fall w ithin the field of GMP an d are not

needed routinely in the application for m ark et in g authorisa t ion but may , in cer tain

circumstances, be requested by the Competent Authority.

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3AQ3a

LIMITATIONS TO THE USE OF ETHYLENE OXIDE IN

THE MANUFACTURE OF MEDICINAL PRODUCTS

Guide l ine Ti t l e

Legis la t ive bas is

Date of first adoption

Date of entry in to

force

Status

P re v i ous t i t l e s / o t he r

re fe rences

Addi t iona l Notes

Lim ita t io ns to the use of Eth ylen e Oxide in the

M anufa c ture of Med ic ina l P ro du c t s

Direct ive 75/318/EEC as amended

December 1993

June 1994

Last revised February 1994

N one / I I I / 9261 / 90

This no te for guid anc e deals wi th the use of e th yl en e

oxide in the man ufac ture of me dic ina l pro duc t s . I t

should be read in conjunc t ion wi th Volume IV of Th e

Rules Governing Medic ina l P roduc t s in the European

Union , pa r t i cu la r ly the annex on manufac ture of s t e r i l e

me d i c i na l p roduc t s

CONTENTS

1 TOXICOLOGICAL BACKGROUND

2 CATEGORIES OF USE OF ETHYLEN E OXIDE

3 SPECIFICATIONS/TEST PROCED URES

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LIMITATIONS TO THE USE OF ETHYLENE OXIDE IN

THE MANUFACTURE OF MEDICINAL PRODUCTS

This note for guidance deals with the use of ethylene oxyde in p harm aceu tical raw

materials , f inished products and containers.

1 T O X I C O L O G I C A L B A C K G R O U N D

Eth ylen e oxide is a substanc e w hich, due to its epoxide stru cture , is counted am ong the ve ry

react ive compounds. This react ivi ty also includes organic stru ctures within cells an d cel l

nuclei . In this case, alkylat ion and react ions with DNA, RNA and proteins occu r.

Cytotoxicity, carcin ogen icity and m utag eni city of ethylen e oxide, which have been

demonstrated by many in vi tro and in vivo tests , are at t r ibuted to these propert ies .

Epidemiological data from many sources indicated that workers exposed to ethylene oxide at

their working place had an increased incidence of leukae mia and other tum our s.

In view of the known positive potential of ethy lene oxide for genotoxic carcin oge nicity , it is

recommended th at use is acceptable only when pharm aceu tical ly absolutely necessary, an d

then at a limit of 1 ppm. Th is lim it is based on the cur ren t lim it of detection for ethy lene

oxide.

Any deviat ion upwards from this l imit mu st be just i f ied and defended, t akin g into account

the cl inical r isk/benefi t assessment for the part icular products under considerat ion.

2 .

C A T E G O R I E S O F U S E O F E T H Y L E N E O X ID E

Ethylene oxide is used in the synthesis of pharmaceutical raw materials and as a s ter i lant .

Since it is effective only as a surface ster ialn t it should be used only for ste rilis ing jus tifie d

and val idated on an individual basis .

Ethylene oxide sterilisation should be used only where safer alternatives cannot be used.

3. S P E C I F I C A T I O N S / T E S T P R O C E D U R E S

Due to the above mentioned consid erat ions, the l imits are f ixed on a m ass /m ass basis an d

not on a daily inta ke basis. If no official test procedure (e.g. Pha rma cop oeia) is availa ble a

valid ated test procedure m ust be proposed by the applic ant (see also note for guid anc e on

Validation of Analytical Procedures: Methodology).

3.1 Ra w m ater ia l s

Specification:

Eth ylen e oxide: 1 μg/g

Ethylene chlorhydrin (or any other halogenated ethylenehydrine): 50 ug/g.

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3 .2 F in i shed p roduc t

If the residual ethylene oxide originates from its use in the raw material, its content must be

l imited in the raw material .

Specification (when used on the finished product):

Eth ylen e oxide: 1 μg/g

Ethylene chlorhydrin (or any other halogenated ethylenehydrine): 50 μg/g.

3 .3 Con ta ine r s

Specification (based on simulated use):

Eth ylen e oxide: 1 μ§/πι1 (conta iner volume)

Ethylene chlorhydrin (or any other halogenated ethyleneh ydrine): 50 μg/ml (con taine r

volume) .

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3AQ4a

THE USE OF IONISING RADIATION IN THE

MANUFACTURE OF MEDICINAL PRODUCTS




Da te o f en t r y i n to

f o r c e

S ta tu s


r e f e r e n c e s


T h e u s e o f I o n i s i n g R a d i a t i o n i n t h e M a n u f a c t u r e o f

M e d i c i n a l P r o d u c t s


D e c e m b e r 1 9 9 1

Ju ly 1992

L a s t r e v i s e d D e c e m b e r 1 9 9 1

N o n e / I I I / 9 1 0 9 / 9 0

T h i s n o t e fo r g u i d a n c e d e a l s w i t h t h e u s e o f i o n i s i n g

r a d i a t i o n i n t h e m a n u f a c t u r e o f m e d i c i n a l p r o d u c t s . It

s h o u l d b e r e a d i n c o n j u n c t i o n w i t h V o l u m e TV of Th e

R u l e s G o v e r n i n g M e d i c i n a l P r o d u c t s i n t h e E u r o p e a n

U n i o n , p a r t i c u l a r l y t h e a n n e x o n i o n i s i n g r a d i a t i o n .

CONTENTS


2 . A D M I N I S T R A T I V E D A T A

3 . M A N U F A C T U R I N G P R O C E S S

4 . V A L I D A T I O N O F T H E I R R A D I A T I O N P R O C E D U R E

G L O S S A R Y

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3AQ4a

THE USE OF IONISING RADIATION IN THE

MANUFACTURE OF MEDICINAL PRODUCTS

L INTRODUCTION

This note for guidance is intended for applicants wishing to use ionising radia t ion in the

ma nufactu re of medicinal products . I rrad iat ion m ay be used for microbial de con tam ina tion ,

ster i l isat ion or other t reatm ents . Different m ateria ls or products may be irrad iated : s ta r t in g

materials , packaging materials , intermediate products , bulk products and f inished products .

Information should be given in sufficient detail to enable the competent authority to evaluate

wh ether or not the m an ufa ctu rin g subprocess is effective and the product is safe for the

patient.

M anufa cturers us ing ionising ra diat ion in the ma nufa cture of me dicina l products should

refer to the Guide to Good M anu fact urin g Prac tice (Volume IV of

"The Rules Governing

Medicinal Products in the European Union") and in par t icu la r to the annex on io n is ing

radiat ion used in the ma nufactu re of med icinal products and, w here releva nt , to the an ne x

on manufacture of s ter i le medicinal products .

2.

ADM INISTRATIVE DATA

a) The nam e and descript ion of the product ( includin g i ts pack aging m ateria l) to be

irra dia ted should be given. Its shap e, size and composition (type and qu ant ity of

substances) should be described in detai l . Furthermore, i t should be made clear whether

star t in g ma teria ls , packag ing m ate rials , interm edia te p roducts , bulk products or the

finished p roduct are irrad iate d. Sizes of production batches an d of irr ad iat io n batches

should be defined. In the case of a continuo us process, a batch comp rises all th e un its

processed in a given period of time.

b) The purpose of the irrad iation should be stated. Both the m in im um dose to achieve this

purpose and the maximum permissible dose should be stated.

c) In addit ion to the nam es and addresses of al l ma nuf actu rers involved in the

ma nufactu re of the product, the nam e a nd addre ss of the i rrad iat io n plant should be

given, making clear which operations are to be conducted at which site.

d) A copy of the auth orisa tion referred to in Directive 75/319/EEC as ame nde d an d

covering the irradiation plant should be attached to the application.

3. MANUFACTURING PRO CE SS

Irradiation of a medicinal product is part of its manufacturing process and the description of

that part of processing should be sufficiently detailed. Th e applica tion should inclu de the

fol lowing information:

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3AQ4a

3.1 D escr ip t ion of th e i r ra d ia t io n p l an t

a ) Ty p e ( r ad io n u c l id e so u r ce , e l ec t r o n g en e r a t o r ) an d b u i ld e r o f t h e p l an t ;

b ) wo r k in g mo d e ( b a tch - o r co n t in u o u s mo d e) ;

c ) au t h o r i sed an d ac tu a l ac t iv i ty o f th e r ad io n u c l id e in th e r ad ia t i o n so u r ce ( GB q ) , o r t h e

m a x i m u m a n d m i n i m u m e l e c t r o n e n e r g y (M e V ) o f t h e g e n e r a t o r a s a p p r o p r i a t e ;

d ) co n c i se d esc r ip t io n o f th e p l an t i n c lu d in g d r a w in g s , sh o win g c l ea r ly th e co u r se o f th e

p r o d u c t wi th in th e p l an t , t h e p o s i t io n an d g eo me t r y of th e i r r ad ia t io n so u r ce a n d th e

c o n v e y o r s y s t e m i n c l u d i n g t h e s o u r c e p a s s m e c h a n i s m .

3.2 D escr ip t io n of the i r ra d ia t ion proc ess

a ) a d esc r ip t io n o f th e m a te r i a l t o b e i r r a d ia t ed sh o u ld b e g iv en , i n c lu d in g l im i t s ( i f a n y )

o n b io b u r d e n an d an y p r o cess a im ed to l im i t o r co n t r o l t h e b io b u r d en . Ac t io n to b e

tak en wh en p a r t i cu la r b io b u r d en l im i t s a r e ex ceed ed sh o u ld b e s t a t ed ;

b ) th e n u m b e r an d p o s i t io n s o f th e i r r a d ia t io n co n ta i n e r s in r e l a t i o n to th e p o s i t io n o f th e

so u r ce d u r in g th e wh o le d w e l l in g t im e , an d th e me th o d of mo v in g th e m th r o u g h th e

ch amb er , sh o u ld b e d esc r ib ed ;

c ) t h e m a t e r i a l a n d d i m e n s i o n s o f t h e i r r a d i a t i o n c o n t a i n e r s h o u l d b e d e s c r i b e d ;

d ) t h e m a x i m u m t o t a l i r r a d i a t i o n t i m e a n d t h e m a x i m u m d w e l l i n g t i m e of t h e p r o d u c t i n

t h e i r r a d i a t i o n c h a m b e r s h o u l d b e s t a t e d ;

e ) r e s u l t s of d o s e m a p p i n g s t u d i e s u s i n g a d u m m y p r o d u c t a r e r e q u i r e d ;

f ) t h e lo ad in g p a t t e r n of th e p r o d u c t m u s t b e s t a t ed f or each i r r a d ia t io n co n ta in e r . I f t h e

lo ad co n s i s t s o f mix ed p r o d u c t s , t h e co m p o s i t io n of th e lo ad m u s t b e d e sc r ib e d

i n c l u d i n g t h e i r s t a t e d p o s i ti o n i n t h e i r r a d i a t i o n c o n t a i n e r . T h e m e a n d e n s i t y o f t h e

lo ad an d th e accep tab le m ax im u m d en s i ty sh o u ld b e g iv en . A mo d i f i ca t io n o f th e

l o a d i n g p a t t e r n m a y b e a c c e p t a b l e p r o v i d e d a n e w do s e m a p p i n g i s p e r fo r m e d , s h o w i n g

t h a t t h e s t a t e d m i n i m u m a n d m a x i m u m d o s e s a r e n o t e x c e e d e d ;

g ) w h e n t h e l o a d i n g p a t t e r n of t h e p r o d u c t w i t h i n t h e i r r a d i a t i o n c o n t a i n e r h a s b e e n

d e f in ed , d o se m ap p in g sh o u ld b e p e r f o r m ed wi t h a su f f i c ien t n u m b e r of ap p r o p r i a t e

d o s im e te r s to sh o w th e d i s t r ib u t i o n o f th e ab so r b e d do se wi th in th e lo ad ed i r r a d i a t io n

c o n t a i n e r a n d to s h o w t h e p l a c e s o f m i n i m u m a n d m a x i m u m d o s e s . T h i s d o s e

m a p p i n g s h o u l d b e c a r r i e d o u t f or a r e p r e s e n t a t i v e n u m b e r o f i r r a d i a t i o n c o n t a i n e r s to

d e t e r m in e th e v a r i ab i l i t y o f t h e ab so r b ed d o se in th e lo ad of o n e co n ta in e r an d th e

d i f f e r e n c e s b e t w e e n s e v e r a l c o n t a i n e r s .

No te : Se p a r a t e d o se m ap p in g ex e r c i se s sh o u ld b e ca r r i ed o u t f or eac h p r o d u c t o r d i s t in c t

ca t eg o r y o f p r o d u c t s an d each p a th w ay to b e u sed f o r p r o cess in g p r o d u c t s .

h ) a w r i t t e n s t a n d a r d o p e r a t i n g p r o c e d u r e s h o u l d b e e s t a b l i s h e d i n c l u d i n g t h e f o l l o w i n g

m i n i m u m i t e m s :

- t h e lo ad in g p a t t e r n o f p r o d u c t ( s ) wi th in th e i r r ad ia t io n co n ta in e r ;

- t h e ty p e , n u m b e r an d lo ca t io n o f r o u t in e d o s im e te r s wi t h in o n e i r r ad ia t io n b a tch

or w i th in a s ta t ed per io d of t im e in th e case of a con t inu ous p rocess ;

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- any adjustme nts to be applied to the routine dosimeter m eas ure m ent s to convert

them into the absorbed dose at both minimum and maximum posi t ions;

- the s ta ted min imu m and max imum absorbed dose inc luding exp er im enta l ly

determined errors of dosimeters;

- wh ether or not repeated tre atm en t is acceptable; for the product conce rned, the

circum stances in which such repeated treatm ent is al lowed, and the num ber of

occasions on which it is allowed for a particular batch;

- in the case of electron beam irrad iator s electron energy, average beam curre nt ,

beam width and conveyor speed should be stated with acceptable limits.

Note: The stated min im um dose is that requ ired for the inten ded purpose, the stated

ma xim um dose is limited by unacceptable changes induced by irrad iat io n in the product

and/or the packaging, or imposed by official restrictions.

A m inim um absorbed dose of 25 kGy ma y be rega rded as ade qua te for the purpose of

ster i l is ing phar ma ceutica l com ponents or products which have a low ini t ia l bioburden an d

no rad iore sista nt spores. Oth er doses ma y be used provided that a biological v alid atio n ha s

been performed.

4 . V A L I D A T IO N O F T H E I R R A D I A T I O N P R O C E D U R E

4.1 Va l ida t i on w i th r eg a rd t o t he i r r ad i a t i o n p roce du re and dose

a ) with electron irrad iatio n, if the maxim um electron energy exceeds 10 MeV, it should be

demonstrated that no radionuclides develop in the product;

b) information derived from expe rime ntal invest igat ions into the acceptable varia t ion in

the loading pattern should be given;

c) information should be included on the erro rs due to the type of dosim eters used and on

the influence of their position;

d) inform ation on the rela tion ship between the absorbed doses in the extrem e position s

within the load and the positions of routine dosimeters should be given.

4.2 Va l ida t ion w i th re ga rd to th e pu rp os e of i r r ad ia t io n ( see sec t ion

2.b)

For reduction of biobu rden and /or ste rilisatio n:

a) Wh ere appropriate , informa tion on the bioburden of the product before i rra di at io n

should be given with da ta from sev eral batche s to show the usu al bioburd en levels an d

types of organisms usual ly present;

b) data on the reduction of bioburd en du ring the irra dia tio n with different doses,

including the minimum dose, should be given for at least 2 batches;

c) an inactiva tion curve derived from the above da ta should be subm itted. If the test

specimen itself ha s a low bioburd en, it should be artificially con tam inat ed with

> 107 cfu/single u nit preferably w ith a mi cro org anis m orig ina lly occu rring in the

product and with a minimum D-Value of 3 kGy;

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d) the bioburden limit on the product prior to irra dia tio n should be based on da ta de rive d

from a) - c).

In other cases, exp erim enta l resu lts should show that the purpose of irra dia tio n ha s been

achieved.

4.3 V al ida t ion w i th re ga rd to th e qua l i ty of th e p rod uc t

a) Information should be given about any quali tat ive and quanti tat ive changes in the

product, including its packaging, as a result of irradiation;

Note: Methods used for quan ti tat ive deter min at ions should be val idated in

accordance with the note for guidance Validation of Analytical Proced ures:

Methodology.

b) Inform ation should be given about the formation of radio lysis products or other

degradat ion or interact ion produc ts . Whenever possible , the radiolysis products should

be identified;

c) the resu lts of the studies carried out with high doses of rad iatio n to dete rm ine the

maximum dose should be given;

d) as asse ssm ent of the significance of any observed chan ges should be included;

e) inform ation should be given abo ut th e effect of irra dia tio n on th e stab ility of the p roduct

and therefore stability studies should be performed on products which have received the

maximum absorbed dose.

Note: The relevance of any changes in the product induced by irrad iat io n as

reg ard s qua lity of the product as well as he alth an d safety of the patie nt should be

discussed. The toxicological ris ks caused by products of irra dia tio n (see section 3.3.b)

should be evaluated . Safety of the irrad iated product for the patien t should be disc uss ed

in the expert report.

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GLOSSARY

Absorbed Dose

The qua nti ty of radiat io n energy imp arted per unit m ass of m ater ial . The un it of absorbed

dose is the G ray (Gy) where 1 Gray is equiv alent to absorption of 1 Joule p er kilo gra m (J.k g-

1).

Batch

A defined qua nti ty of s tar t in g ma teria l , p acka ging ma teria l or product processed in one

process or series of processes so th at. it could be expected to be hom ogeneous.

Note: To complete certain stage s of ma nuf actu re, it may be necess ary to divide a batch into

a numb er of subb atche s, which are later brou ght together to form a final hom ogeneo us batch.

In the case of continuou s ma nufa cture , the batch m ust correspond to a defined fraction of the

production, character ised by i ts intended homogeneity.

For control of the finished product, the following definition ha s been given in Dire ctive

75/318/EEC as amended: 'For the control of the finished product, a batch of a proprietary

me dicinal product comprises al l the units of a pharm aceutica l form which are ma de from

the same in i t ia l mass of mate r ia l and have undergone a sing le se r ies of m an ufa c tu r ing

operations or a single sterilisation operation or, in the case of a continuous production

process, all the units manufactured in a given period of time'.

Bioburden

The total nu m be r of all viable aerobic bac teria, ye asts an d m oulds expres sed a s colony

forming units (cfu) per unit or gram of product.

Bulk Product

Any p roduct which ha s completed all proc essing stage s up to, but not inclu din g, fin al

packag ing .

Dose Mapping

An exercise conducted within the i rrad iat io n equipm ent to determ ine the distr ibut ion of

absorbed dose throu gho ut a load of product or sim ulated p roduct of specified de nsity ( du m m y

product ) arranged in the i rradiat ion container in a defined configurat ion.

Dosimeter

A device or system havin g a reproducible me asura ble response to radia t ion, which can be

used to measure the absorbed dose in a given material.

Dummy Product

Homogeneous material of known density for filling the irradiation container for the purpose

of carrying out dose distr ibut ion experiments with ionising radiat ion.

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Finished Product

A medicinal product which has undergon e al l s tages of production including packaging.

Intermediate Product

Part ly processed material which must undergo further manufacturing steps before i t becomes

a bulk product.

Irradiation Container

The outermost container in which the products are i r radiated.

Packaging Material

Any ma terial employed in the packa ging of a product, excluding any outer pack aging used

for t ranspo rtat ion or shipm ent. Packa ging m ater ials are referred to as pr imary or

secon dary according to wh ether or not they are inte nde d to be in direct contact w ith the

product.

Starting Material

Any substance used in the production of a product, but excluding packaging materials.

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CHEMISTRY OF ACTIVE SUBSTANCES



Da te o f f i r s t a do p t io n


f o r c e

S ta tu s


r e f e r e n c e s


C h e m i s t r y o f A c t i v e S u b s t a n c e s


October 1987

Oc tobe r 1987

Las t rev ised 1987

Chemistry of Active Ingredients


2, sec t i on C of t h e A nn ex t o D i r e c t i v e 75 /318 /EEC a s

a m e n d e d w i t h a v i e w to t h e g r a n t i n g o f a m a r k e t i n g

a u t h o r i s a t i o n f o r a m e d i c i n a l p r o d u c t . T h e s e c t i o n o n

i m p u r i t i e s i s r e p l a c e d b y t h e g u i d e l i n e

Impu rities in

New Active Substances f o r n e w a c t i v e s u b s t a n c e s . F o r

a b r i d g e d a p p l i c a t i o n s , b i o t e c h n o l o g i c a l / b i o l o g i c a l

p r o d u c t s a n d o t h e r p r o d u c t s e x e m p t e d f r o m t h e

i m p u r i t i e s g u i d e l i n e , t h e s e r e q u i r e m e n t s c o n t i n u e t o

a p p l y .

CONTENTS


2 . I D E N T I T Y O F M A T E R I A L S

3 .

M A N U F A C T U R E

4 . D E V E L O P M E N T C H E M I S T R Y

5 .

I M P U R I T I E S

6 . A C TD 7E S U B S T A N C E S P E C I F I C A T I O N

7. BATC H ANA LYSI S

8 . R E F E R E N C E S T A N D A R D S

9 . R A D I O L A B E L L E D P R O D U C T

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CHEMISTRY OF ACTIVE SUBSTANCES

1 INTRODUCTION

The purpose of this note for guid ance is to set out the type of inform ation requ ired for the

control of new active substances used for the first time in a medicinal product, which are not

described in the European Pharmacopoeia or a pharmacopoeia of a Member State .

2. IDENTITY OF MATERIAL

This sect ion deals with the identi ty, no me nclatu re and chemical s tructure of the act ive

substan ce which is the subject of the application for mar ke tin g au tho risat ion . Only brie f

details of physical chara cter istics should be stated, as full details and proof of stru ctu re a re

required later .

2 .1 N o m e n c l a t u r e

- In te rna t ion a l Non-Propr ie ta ry Name ( INN) ,

- Nationa l Approved Nam es, ( )

US Adopted Name (USAN),

- Lab oratory Code(s),

- System atic Chem ical Nam e(s) ,

- Othe r Nam es (e .g. Proprie tary) .

2 . 2 D e s c r i p t i o n

- phys ical form,

- s tru ctu ral formula,

- mo lecular formula,

- relat ive molecu lar ma ss.

A brief description should be given of the app eara nce of the m ate ria l. W here possible, the

structu ral formula should be given dia gra m m atic al ly with al l known stereoch emistry

indicated conventional ly, with molecular formula and relat ive molecular mass; otherwise a

detailed description of the nature of the substance should be given.

The relat ive mo lecular ma ss of the therapeutical ly act ive m oiety should also be incl ude d,

where appropriate .

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3. M A N U F A C T U R E

A concise bu t com prehensive account of the m anu fac ture of the active s ubstan ce should be

provided. The headings given below should be followed where the active substance concerned

is a totally synthetic product. Some modification may be required where the molecule is only

partially synthetic e.g. penicillin-derivatives.

3.1 Manufac tur ing process

W hen a complete or part ial chem ical syn thesi s is involved, this should be repre sente d by

diagrams of the chemical reactions in the form of a flow sheet.

3.2 D esc r ipt io n of pro cess

An app ropriate description should be given of each stage of the ma nu fact ure , in cl ud in g,

where applicable:

- solvents and reag ents used,

- cata lysts used,

- conditions of reactions where these are critical,

- inform ation on inter me diate s which are isolated and purified,

- deta ils of the final purification and solvents involved.

The description of the process should indic ate the scale of ma nuf act ure . It is often helpful if

an indication of the yield produced at each stage is given.

The description must normally fully define the method of synthesis. However, if alternative

steps or solve nts a re proposed these should be just ified and show tha t the final q ual ity of

material obtained does not differ significantly.

3.3 Qu al i ty con t ro l du r in g synthes i s

3.3.1 Starting materials

Describe the analyt ical controls which are applied to ensure that the s tar t ing m at er ial s ,

which mak e a s ignif icant contr ibution to the molecu lar formula, and any reagen ts are

correctly identified and are shown to be of a satisfactory quality. An indication of the content

of significa nt imp urities in sta rtin g m ate ria ls sho uld be given. Specifications for s olve nts

used in the final stages of synthesis, crystallisation and/or washing should be submitted.

The crite ria for accepting or rejecting b atches of these mate rial s should be indica ted. Th e

control of sta rtin g mat erial s should be designed to detect isomeric or other im pur ities which

are potentially reactive and could be carried through to the final product of the synthesis.

3.3.2 Intermediate control

The quality control checks w hich are carried out at each stage of the process and on the

isolated inte rm ed iate s should be described. A state m ent of the test procedure(s) and cr ite ria

for acceptance should be given for each stage, where appropriate.

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4.

D E V E L O P M E N T C H E M I S T R Y

T h i s s e c ti o n s h o u l d i n d i c a t e t h e r e s e a r c h a n d d e v e l o p m e n t p r o g r a m m e w h i c h h a s b e e n

u n d e r t a k e n o n t h e n e w a c t i v e s u b s t a n c e s t o i n v e s t i g a t e t h e e v i d e n c e of s t r u c t u r e a n d t h e

c h e m i c a l a n d p h y s i c o - c h e m i c a l p r o p e r t i e s .

Th e f ind ings des cr ib ed in th is sec t io n should be ref lec ted in the contro l tes ts on the ac t iv e

su b s tan ce b y wh ich b a tc h - to - b a tch u n i f o r m i ty i s co n t r o l l ed .

4.1 Ev iden ce of chem ica l s t ru c t ur e

A sc ien t i f i c d i scu ss io n o f th e ch e m is t r y of th e ac t iv e su b s t an ces m o lecu le sh o u ld b e g iv en

a n d s h o u l d i n c l u d e , w h e r e a p p li c a b l e , u n e q u i v o c a l p r oo f of s t r u c t u r e , c o n f i g u r a t i o n ,

c o n f o r m a t i o n a n d p o t e n t i a l i s o m e r i s m . T h i s s h o u l d i n c l u d e a p r e s e n t a t i o n o f t h e s t e r e o

c h e m i c a l p r o p e r t i e s o f t h e m o l e c u l e , e .g . g e o m e t r i c i s o m e r i s m ( c i s / t r a n s , E / Z ), n u m b e r o f

c h i r a l c e n t r e s a n d c o n f i g u r a t i o n a t e a c h c e n t r e . A s u m m a r y a n d d i s c u s s i o n of t h e

u n eq u iv o ca l pr o o f o f s t r u c tu r e b y th e e x p e r t s i n v o lv ed in th e Ex p e r t R ep o r t can o f ten p r o v id e

u s e fu l a d d i t i o n a l b a c k g r o u n d i n f o r m a t i o n . C a r e s h o u l d b e t a k e n t h a t t h e v i s u a l e v i d e n c e o f

sp ec t r a i s co mp le te ly l eg ib le wh en r ep r o d u ced in th e co p ie s o f t h e ap p l i c a t io n . I t i s im p o r t a n t

th a t t h e ev id en ce o f s t r u c tu r e sh o u ld b e r e l a t ed to th e ac tu a l m a t e r i a l t o b e u se d in th e

m a r k e t e d p r o d u c t , e s p e c i a l l y fo r h i g h l y c o m p l e x m o l e c u l a r s t r u c t u r e s . W h e r e t h e d a t a

in c lu d ed in th i s su b - h ea d in g a r e fr om a so u r ce of sy n th e t i c p r o cess o th e r th an t h a t co v e r ed b y

th e ap p l i c a t io n (i . e . d i f f e r en t r o u te s ) , ev id en c e ma y b e r eq u i r e d to co n f i r m th e s t r u c tu r a l

i d e n t i t y o f t h e d i f fe r e n t m a t e r i a l s . T h i s i s p a r t i c u l a r l y i m p o r t a n t w h e r e to x i c i ty w o r k h a s

b een ca r r i ed o u t o n m a t e r i a l f r o m a d i f f e r en t so u r ce ( see a l so i t em 7 ) . W h e r e th e sy n th e t i c

r o u te an d s t r u c tu r e o f th e in t e r m ed ia t e s a r e c i ted a s ev id en ce of s t r u c tu r e , r e f e r en c es to

r e l e v a n t p u b l i s h e d p a p e r s i n t h e l i t e r a t u r e w o u l d b e h e l p fu l . W h e r e r e l e v a n t , t h e i n f o r m a t i o n

mig h t in c lu d e su ch ev id en ce a s :

- e l e m e n t a l a n a l y s i s w i t h t h e o r e t i c a l v a l u e s ,

- i n f ra - r e d s p e c t r a w i t h i n t e r p r e t a t i o n ,

n u c l e a r m a g n e t i c r e s o n a n c e s p e c t r a w i t h i n t e r p r e t a t i o n i n c l u d i n g C 1 3 d a t a w h e r e

r e l e v a n t ,

- d i s c u s s i o n o n U V c h a r a c t e r i s t i c s i n c l u d i n g p H d e p e n d e n t s h i ft s ,

- m a s s s p e c t r u m w i t h i n t e r p r e t a t i o n a n d d i s c u s s i o n o f r e s u l t s ,

- d i scu ss io n o f th e sy n t h e t i c r o u te a s ev id en ce of s t r u c tu r e ,

- ev id en ce of s t r u c tu r e o f k ey in t e r m ed ia t e s o f sy n th e s i s ( e .g. u s i n g I R , NM R , e t c . ) ,

ch a r ac t e r i s t i c ch emica l r eac t io n s wh ich a r e d i ag n o s t i c of t h e s t r u c tu r e of th e m o lecu le ,

- X- r ay c r y s t a l lo g r a p h y wi th in t e r p r e t a t io n an d d i scu s s io n o f r e su l t s ( r e f e r t o 4 .2 .3 ) ,

o p t i ca l r o t a t io n wi th d i scu ss io n o f o p t i ca l p u r i ty in th e ca se o f i so m er i s m. ( Ab sen ce o f

o p t ic a l r o t a t i o n s h o u l d b e r e p o r t e d w h e n t h i s s e r v e s t o i l l u s t r a t e t h a t a n a s y m m e t r i c

mo lecu le i s r acemic ) ,

e v i d e n c e of t h e i n d i c a t e d r e l a t i v e m o l e c u l a r m a s s .

Th e r e l ev an c e of th e i so m er to ac t iv i ty sh o u ld b e d i sc u sse d .

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4 .2 Phys i co -chemica l cha rac t e r i s t i c s

Info rma tion set out un der the relev ant hea din gs below should cover aspec ts of physico-

chemical characteristics which have been investigated, whether or not they are include in the

monograph for the active substance.

4.2.1 Solubility

The solubility in wa ter, including pH depend ence, and in other solvents should be given as

numerical values with part icular reference to the formulat ion and test procedures.

4.2.2 Physical character is t ics

An indication should be given as to whether the substance is crystalline, amorphous, etc. and

where relevant, information on particle size, solvation, melting point, boiling point etc.

4.2.3 Polymorphism

Where relevant, the presence of polymorphic forms and the methods of detection and control

should be discussed, or their absence confirmed.

4.2.4 pKa and pH values

W here rele van t, the plia valu es of the active substan ce and the pH in solutions of de fined

con centra tion should be given. In the case of a salt, this inform ation for the corre spo ndi ng

base or acid should be given.

4.2.5 Other characteristics

Any other rele van t inform ation should be given (for oil/water partitio n coefficient,

numerical values should be presented) .

4 .3 Ana ly t i ca l deve lopment

Any cri t ical aspects of analyt ical development relevant to the act ive substance mo nograp h

should be me ntioned . Th e discussion here should highligh t an y un us ua l aspe cts of the tests

for identity, physico-chemical characteristics and content which are used in the monograph.

(Tests for purity and freedom from co nta m ina tion can be discussed und er the section on

imp uritie s). Discussio n of the precision and ac curacy of test procedu res is p art icu lar ly

applicable to substances where biological control is necessary.

5.

I M P U R H T E S

A broad outline should be given of the research program me which has been un der take n to

dem ons trate that the test procedures u sed for im pur ity control in the active substan ce

specification are valid in clud ing limit of detection an d limit of qua ntifica tion. Ne gativ e

information can sometimes be important .

5.1 Impur i t i es

- by-products of the synth esis ari sin g from side reac tion s, im pur ities in the sta rti ng

materials or isomerisat ion,

- residual solvents and reage nts ,

- trace elem ents arising from the use of cataly sts or from other sources,

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- deg rada tion products (see note for guid ance Stability Tests on Active Substanc es and

Finished Products).

A list and brief description of the products which have been considered as potential

im pu ritie s ari sin g from the syn the sis should be given. In each case, it should be stated

whether actual samples of such impuri t ies have been synthesised for test purposes and which

of the analytical methods described under 5.2 have been used to detect those impurities.

Possible rou tes of deg rada tion should also be discusse d on the bas is of results of

inv estig atio ns on exposure of the sub stanc es to stress cond itions (such as he at, light, pH,

moisture and other relevant factors) .

5.2 Tes t pr oc ed ur es

The analytical methods with limits of detection of the test procedures which have been used to

detect each of the likely im pu rities considere d in 5.1 above or other rela ted im pu rities , the

exact iden tities of which may be un kn ow n, should be described. Copies of rele va nt

chromatograms should be provided.

5.3 Su m m ary of res u l t s

A sum ma ry should be given of the na ture and levels of imp uri t ies which h ave been detected

in the batch sam ples of the m ate ria l. The E xpert Report should prov ide a justific ation for

selecting the limits (based on findings from toxicity testing) and methods used for impurity

control in the specification.

6 . A C T I V E S U B S T A N C E S P E C I F I C A T I O N

6.1 The test s applied and the limits there by imposed should be sta ted for:

- physical cha racte r is t ics ,

- tes ts for identity,

- s tan dar ds for puri ty and l imitat ion of imp uri t ies ,

- sta nd ard s and tes ts for potency.

6.2 Ana lytical me thod s employed should be described in deta il.

7.

B A T C H A N A L Y S I S

Data should be provided in this section to illus trate the actu al re sul ts wh ich hav e been

obtained from routin e quality control of the active substan ce. Resu lts should be given, if

possible, for:

- batche s of m ate ria l used in the toxicity tests and clinical tri als reported in support of

the application,

- recent consecutive batch es (5) which are repr esen tative of the product which will be

supplied for the purposes covered by the m ark eti ng aut ho risa tion to show that the

proposed me thods will give routine production m ate ria l which falls with in the

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specification lim its cited. Inform ation on production batch es should be provided, if

necessary on an on-going basis.

7.1 B atch ana lys i s res u l t s

The results should include:

- date of ma nufactu re,

- batch size and num ber,

- place of m anu fac ture ,

- resul t s of analyt ical determ inat ion s,

- use of batch es.

As far as possible, the resu lts should give actual figures for tests on, for exam ple, im pu rity

levels. Resu lts which mere ly state that the m ate ria l complies with the test are not

sufficiently info rma tive, especially where a relative ly wide limit is allowed in the

specification.

The batch ana lys es should include all the tests set out in the specification. Th ere m ay ,

however, be cases where ear lier b atches of m ate rial were tested usi ng a slightly differen t

specification. In these cases, a brief explanatory note should be included.

7.2 Discussion of resul ts

Any apparently inconsistent or anomalous resul ts in the batch analyses should be explained.

8. R E F E R E N C E S T A N D A RD S

The cr i ter ia for establ ishing the reference substances (primary and secondary) for routin e

analysis should be given with full analytical profiles.

9 . R A D I O L A B E L L E D P R O D U C T

Information on radiolabelled material should be compatible with the above guidelines.

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SUBSTANCES





f o r c e

S t a t u s


r e f e r e n c e s


R e q u i r e m e n t s i n r e l a t i o n t o A c t i v e S u b s t a n c e s

D i r e c t i v e 7 5/ 31 8 /E E C a s a m e n d e d

Oc tobe r 1991

Apr i l 1992

Las t r ev i s ed 1991

N o n e / I I I / 8 3 1 5 / 8 9

T h i s n o t e f o r g u i d a n c e c la r i f i e s t h e r e q u i r e m e n t s t o b e

i n c l u d e d i n a m a r k e t i n g a u t h o r i s a t i o n f o r a n a c t i v e

s u b s t a n c e d e p e n d i n g o n t h e d e s c r i b e d c l a s s i f ic a t i o n .

CONTENTS

1. CLA SSI FI CAT I ON OF ACI TVE SUBS TAN CES

2 . N E W A C T P 7 E S U B S T A N C E S

3 . EXI STI NG ACTRHE SUBST ANC ES NO T I NCLU DED IN TH E P h . E u r . OR TH E

P H A R M A C O P O E I A O F A M E M B E R S T A TE

4 . P H A R M A C O P O E I A L A C T P 7 E S U B S T A N C E S

D E C I S I O N T R E E S H O W I N G S E L E C T I O N O F R E G U L A T O R Y P R O C E D U R E F O R

ACTDTE SUBSTANCES

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REQUIREMENTS IN RELATION TO ACTIVE

SUBSTANCES

L C L A S S I F I C A T I O N O F A C T I V E S U B S T A N C E S

Active substances may be classified into:

- new act ive substan ces;

- existin g active sub stanc es not includ ed in the Ph . Eu r. or the pharm acop oeia of a

Member State;

- pharmacop oeial active substances included in the Ph. Eur. or the pharma copoeia of a

Member State .

2.

N E W A C TD 7E S U B S T A N C E S

For new chemical act ive substance s, the requ irem ents are set out in the note for gu ida nc e

Chemistry of the Active Substance.

For biotechnologically derived new active sub stanc es, the req uir em en ts are described in the

specific biotechnology guidelines.

The information may be supplied ei ther as part of the ma rke t ing autho risat ion (MA )

applicat ion or using the European Drug Master Fi le procedure.

3. E X I S T I N G A CTD VE S U B S T A N C E S N O T I N C L U D E D I N T H E

P H . E U R . O R T H E P H A R M A C O P O E I A O F A M E M B E R

S T A T E

The requirements are as set out as above for new chemical active substances.

W here appro priate, inform ation ma y be omitted in rela tion to proof of stru ctur e (e.g. wh ere

this can be carrie d out by specific identific ation tests in relatio n to a reference sub stan ce

fully described in the dossier, where necessary).

Evidence of the stability of the active substan ce ma y be provided from the litera tur e (see no te

for guidance on Stability Tests on Active Substances and Finished Produ cts).

The information may be supplied either as part of the MA application or using the European

Drug Master Fi le procedure.

4.

P H A R M A C O P O E I A L A C T IV E S U B S T A N C E S

Pharmacopoeial act ive substances may be divided into:

- inorganic sub stanc es;

- vegetable substances and vegetable substance prepa rat ions;

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- biotechnologically derived sub stan ces ;

- organic substanc es (extracted from m ateria l of anim al or hum an origin);

- organic substances (manufactured or extracted) .

Each batch of substances must comply w ith the current require me nts of the Ph. E ur. or

pharmacopoeia of a Member State.

In each case, evidence should be prese nted to the competent auth orities to dem ons trate the

sui tabi l i ty of the pharmacopoeial monograph for materia l from t

eudralex 3a

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