Medicines (Marketing Authorisation) Regulations, 2003

L.N. 426 of 2003

MEDICINES ACT, 2003.

(ACT NO. III OF 2003)

Medicines (Marketing Authorisation) Regulations, 2003

IN exercise of the powers conferred by article 106 of the Medicines

Act, 2003, the Minister of Health, has made the following regulations:-

(1) The title of these regulations is the Medicines (Marketing Title and

commancement.

Authorisation) Regulations, 2003.

(2) These regulations shall come into force on the 1 st May,

2004.

Regulation 16 (a).

General Conditions applicable to Authorisations

1. The authorisation holder shall report to the Authority any change of name

and/or address and any change of address at which there is carried on a business to

which the authorisation relates.

2. The authorisation holder shall ensure that any product to which the

authorisation relates is manufacture only in accordance with the methods set out in, or

furnished in connection with, his application for the authorisation and that the

specification of the constituents and of the finished product are in accordance with the

information contained in, or furnished in connection with the said application, except

insofar as may otherwise be approved by the Authority.

3. The authorisation holder shall not issue, or cause another person to issue, or

consent to the issue of any advertisement or recommendation, relating to any product

to which the authorisation relates, which contains particulars as to the uses, nature or

effects of such product or warnings or precautions in use concerning such product,

unless the terms of the advertisement or recommendation, insofar as they relate to

such particulars, warnings, or precautions in use correspond to or differ only to an

extent that is not material from those specified in the authorisation.

4. The authorisation holder shall inform the Authority of any material change

that has been made; or is proposed to be made in the particulars contained in or furnished

in connection with the application, in relation to any product to which the authorisation

relates, that is to say:-

4.1

in the composition of the product, or of any of its constituents,

4.2

in the specification of the product or of any of its constituents,

4.3 in the methods of manufacture of the product or of any of its constituents,

4.4 in the methods and procedures described in the application for ensuring

compliance with such specification,

4.5 in the arrangements described in the application for storage of the

product,

4.6 in the recommended uses, routes of administration or dosage schedules,

or

4.7

in the method of retail sale, supply or sales promotion.

5. The authorisation holder shall notify the Authority of any change proposed

to be made in the labelling or package leaflet relating to any medicinal product to

which the authorisation relates. Any such change not connected with the summary of

product characteristics, which have not been opposed by the Authority within 90 days

following the said notification shall be deemed to be approved by the Authority and

may be put into effect by the authorisation holder.

6. The authorisation holder shall inform the Authority of any additional

information received by him which may alter the validity of data provided in support

of the application, or may further the understanding of the substance and its effects or

may alter the directions for use of the medicinal product which is the subject of the

authorisation.

7. The authorisation holder shall kept a record of reports of adverse effects

associated with the use of the product to which the authorisation relates. The record

shall be available for inspection by a person authorised by the Authority who may take

copies thereof. The authorisation holder shall furnish to the Authority a copy of any

such report of which he has a record or of which he is aware.

8. The authorisation holder shall keep available for inspection by a person

authorised by the Authority durable records of his arrangements -

8.1 for obtaining materials for the purpose of the manufacture by him or

on his behalf of any product to which the authorisation relates, and

8.2 for procuring the manufacture, importation, storage, sale or supply of

any such product, and

8.3 for the tests to be carried out on any such product or on the materials

used for its manufacture,

and shall permit the person so authorised to take copies of, or to make extracts

from, such records. The records shall be retained for a period of five years from

the date on which the relevant batch of the product was released for sale or was

imported by or on behalf of the authorised holder.

9. The authorisation holder shall keep such documents as will facilitate the

withdrawal or recall from sale or supply of any product to which the authorisation

relates.

10. The authorisation holder, on being informed by the Authority that any product

to which the authorisation relates has been found -

10.1

to be harmful under normal conditions of use, or

B

10.2

to be lacking in therapeutic efficacy, or

10.3 not to be in accordance with the information contained in or furnished

in connection with the application for such authorisation, or furnished in

compliance with any of the condition set out in this Schedule, as regards the

qualitative or quantitative composition of the product, or

10.4 not to be in accordance with any conditions, other than those set out

in this schedule, which are specified in the authorisation,

shall, if so directed by the Authority withhold from sale all batches of the product

or such batch as may be specified by the Authority, and so far as may reasonably

be practicable, immediately recall all supplies of the product or of such batch of

the product as has already been issued.

11. The authorisation holder shall comply with the condition set where the

controls on the product to which the authorisation relates, or on any of its constituents,

in the course of its manufacture as indicated in or in connection with his application

for the authorisation or in compliance with the conditions set out in this Schedule,

have not been carried out.

12. The authorisation holder shall notify the Authority of any decision to

withdraw from sale or supply any product to which the authorisation relates and shall

state the reason for the decision.

13. The authorisation holder shall on request by the Authority -

13.1 furnish from such batch or batches as may be specified a sample of

any product to which the authorisation relates for the purpose of test, examination

or analysis, or

13.2 furnish full particulars of the tests which have been applied to such

batch or batches of such product as may be specified and the result of such tests.

14. The authorisation holder shall, if requested by the Authority, withhold from

sale any batch or batches in respect of which a sample is, or particulars are, requested

to be furnished until a certificate authorising the sale of the batch or batches has been

issued to him by the Authority.

15. The authorisation holder shall ensure that -

15.1 the product to which the authorisation relates is not sold unless it has

been manufactured in the premises in respect of which any undertaking has been

given.

15.2 such product has been manufactured in such premises and in such

circumstances as to comply with any conditions specified in such undertaking.

16. The authorisation holder shall in the event of the authorisation being revoked

surrender it to the Authority.

Mitbug[ fl-Istamperija tal-Gvern — Printed at the Government Printing Press

For the purposes of these regulations -

Interpretation.

“the Act” means the Medicines Act;

“the Authority” means the Medicines Authority established

under article 4 of the Act;

“the Agency” means the European Agency for the Evaluation

of Medicinal Products established by Regulation (EEC) No 2309/

“the Commission” means the Commission in accordance with

Council Decision 1999/468/EC of 28 th June, 1999;

“the Community” means the European Union, previously

referred to as the European Community and the European

Economic Community;

“imported” means a medicine brought into Malta for the

purpose of being placed on the market;

“Licensing Authority” means the Licensing Authority referred

to in article 3 of the Act;

“medicines” and”“medicinal products” means medicinals for

human use;

“Member State” means a State which is a member of the

European Union and shall also include Iceland, Norway and

Liechtenstein;

“provisional market authorisation” means a market

authorisation issued by the Licensing Authority for products present

on the market in Malta up till the 31st November, 2002;

“reference Member State” means the Member State, which

is granted the market authorisation on which an application for a

market authorisation is based;

“risk to public health” means all riska with regard to the

quality, safety and efficacy of the medicinal products;

“Superintendent” means the Superintendent of Public Health.

(2) The provisions of these regulations shall not apply to

(a) any medicinal product which is prepared in a pharmacy

in accordance with a medicinal prescription for an individual

patient, commonly known as the magistral formula;

(b) any medicinal product which is prepared in a pharmacy

in accordance with prescriptions of a pharmacopoeia and is

intended to be supplied directly to patients served by the pharmacy

in question, commonly known as the official formula;

(c) medicinal products intended for research and

development trials;

(d) intermediate products intended for further processing

by an authorised manufacturer;

(e)

any radionuclides in the form of sealed sources;

(f)

whole blood, plasma or blood cells of human origin.

The provisions of these regulations shall apply to industrially

produced medicinal products for human use intended to be placed on

the market in Malta.

No medicinal product, radionuclide generators, radionuclide

kits, radionuclide precursor radiopharmaceutical and industrially

prepared radiopharmaceuticals, may be imported, placed on the market

or otherwise sold in Malta unless, there is in respect of that product, a

valid market authorisation, issued by the Licensing Authority in

accordance with Council regulation No. (EEC) 2309/93 of 22 July 1993,

and such importation, placing on the market or sale is in accordance

with the terms and conditions of such market authorisation

Provided that a market authorisation shall not be required in the

case of a radiopharmaceutical prepared at the time of its use by a person

or by an establishment duly authorised to use such medicinal products

in an approved health care establishment exclusively from authorised

radionuclide generators, radionuclide kits or radionuclide precursors in

accordance with the manufacturer’s instructions

Provided further, that the Licensing Authority may, in exceptional

cases, subject to any condition it deems fit, allow the use of a medicinal

product which does not have a marketing authorisation

Provided further that, products having a provisional market

authorisation shall be allowed to remain on the market until such time

as the Licensing Authority may, in respect of such products, issue a

market authorisation.

(1) A market authorisation may only be granted or renewed Grant or renewal of

market

if the General Conditions applicable to authorisations and the conditions authorisation.

set out under Directive 2001/83/EC on the Community Code relating

to medicinal products for human use and subsequent amendments

thereto, are fulfilled as follows:-

(a) an application for market authorisation shall be made to

the Licensing Authority which shall refer such application to the

Authority for processing;

(b) a marketing authorisation may only be granted to an

applicant established in the Community;

(c) the application shall be accompanied by the following

documents and particulars to be submitted in accordance with

Annex I of Directive 2003/63/EC:-

(i) the name or corporate name and permanent address

of the applicant and, where applicable, of the manufacture;

(ii) the name of the medicinal product;

(iii) the qualitative and quantitative particulars of all

the constituents of the medicinal product in usual terminology,

but excluding empirical chemical formulae, with mention of

the international non-proprietary name recommended by the

World Health Organisation (WHO) where such name exists;

(iv)

a description of the manufacturing method;

(v) therapeutic indications, contra-indications and

adverse reactions;

(vi) posology, pharmaceutical forms method and route

of administration and expected shelf life;

(vii) if applicable, reasons for any precautionary and

safety measures to be taken for the storage of the medicinal

product, its administration to patients and for the disposal of

waste products, together with an indication of any potential

risks presented by the medicinal products for the environment;

(viii) a description of the control methods employed

by the manufacturer (qualitative and quantitative analysis of

the constituents and of the finished product, special tests, such

as sterility tests, tests for the presence of pyrogenic substances,

the presence of heavy metals, stability tests, biological and

toxicity tests, controls carried out at an intermediate stage of

the manufacturing process);

(ix) results of physico-chemical, biological or

microbiological tests, toxicological and pharmacological tests

and clinical trials;

(x) a summary, in accordance with regulation 8, of the

product characteristics, one or more specimens or mock-ups

of the outer packaging and the immediate packaging of the

medicinal product with a package leaflet;

(xi) a document showing that the manufacturer is

authorised in his own country to produce medicinal products;

and

(xii) copies of any authorisation obtained in another

Member State or in a third country to place the medicinal

product on the market, together with a list of those Member

States in which an application for authorisation submitted in

accordance with the provisions of these regulations is under

examination. Copies of the summary of the product

characteristics proposed by the applicant in accordance with

regulation 8 or approved by the competent authorities of the

Member State. Copies of the package leaflet proposed.

Details of any decision to refuse authorisation, whether in

the community or in a third country, and the reasons for such

a decision.

(2) The information under paragraph (c) of subregulation

(1) hereof shall be updated on a regular basis.

In the case of an application for a market authorisation for a Application for

radionuclide

radionuclide generator, the application shall also contain

generator.

(i) a general description of the system together with a

detailed description of the components of the system which may

affect the composition or quality of the daughter nucleid

preparation; and

(ii) qualitative and quantitative particulars of the eluate of

the sublimate.

(1) The applicant shall not be required to provide the results Details to be

provided.

of toxicological and pharmacological tests or the results of clinical trials

if he shows to the satisfaction of the Authority that

(a) either the medicinal product is essentially similar to

another already authorised in Malta, and that the holder of the

marketing authorisation of such similar product has consented to

the toxicological, pharmacological and, or clinical references

contained in the file of such product being used for the purpose of

examining the application in question; or

(b) the constituent or constituents of the medicinal product

have a well established medicinal use, with recognised efficacy

and an acceptable level of safety by means of a detailed scientific

bibliography; or

(c) the medicinal product is marketed in Malta and is

essentially similar to another product which has been authorised

within the Community, in accordance with the Community

provisions in force, for not less than six years, which period shall,

in the case of high technology, be extended to ten years

Provided that where the medicinal product is intended for a different

therapeutic use from that of the other medicinal products marketed, or

is to be administered by different routes or in different doses, the results

of appropriate toxicological and pharmacological tests and or the

appropriate clinical trials must also be provided.

(2) In the case of new medicinal products which contain

known constituents not hitherto used in combination for therapeutic

purposes, the results of toxicological and pharmacological tests and of

clinical trials relating to that combination must be provided, provided

that it shall not be necessary to provide references relating to each

individual constituent.

The summary of the product characteristics shall contain the

following information:-

a) the name of the medicinal product;

b) the qualitative and quantitative composition in terms of

the active substance and constituents of the excipient, knowledge

of which is essential for proper administration of the medicinal

product, in such manner that the usual common name or chemical

description shall be used;

c) pharmaceutical forms;

d) pharmacological properties and, in so far as this

information is useful for therapeutic purposes, pharmacokinetic

particulars;

e) clinical particulars

(i)

therapeutic indications,

(ii) contra-indications,

(iii)

adverse reactions (frequency and seriousness),

(iv) special precautions for use and, in the case of

immunological medicinal products, any special precautions

to be taken by persons handling such products and

administering them to patients, together with any precautions

to be taken by the patient,

(v) use during pregnancy and lactation,

(vi) interaction with other medicaments and other

forms of interaction,

(vii) posology and method of administration for adults

and, where necessary, for children,

(viii) overdose (symptoms, emergency procedures,

antidotes),

(ix)

special warnings

(x) effects on ability to drive and to use machines;

(f)

pharmaceutical particulars

(i)

major incompatibilities,

(ii) shelf life, when necessary after reconstruction of

the medicinal product or when the immediate packaging is

opened for the first time,

(iii)

special precautions for storage,

(iv)

nature and contents of the immediate packaging,

(v) special precautions for disposal of unused

medicinal products or waste materials derived from such

medicinal products, if appropriate;

(g) name or corporate name and permanent address of

the marketing authorisation holder;

(h) for radiopharmaceuticals, full details of internal

radiation dosimetry, additional detailed instructions for

extemporaneous preparation and quality control of such preparation

and, where appropriate maximum storage time during which any

intermediate preparation such as an eluate or the ready-to-use

pharmaceutical will conform with its specifications.

The Authority shall take all the necessary measures to ensure Experts to formulate

and sign documents.

that the documents and particulars listed in the preceding regulations

are drawn up and signed by experts with the necessary technical or

professional qualifications.

It shall be the duty of experts to:-

Duty of experts.

(a) to perform tasks falling within their respective disciplines

(analysis, pharmacology and similar experimental sciences, clinical

trials) and to describe objectively the results obtained (qualitatively

and quantitatively);

(b) to describe their observations in accordance with Annex

I of Directive 2003/63/EC, and to state, in particular

(i) in the case of the analyst, whether the medicinal

product is consistent with the declared composition, giving

any substantiation of the control methods employed by the

manufacturer;

(ii) in the case of the pharmacologist or the specialist

with similar experimental competence, the toxicity of the

medicinal product and the pharmacological properties

observed;

(iii) in the case of the clinician, whether he has been

able to ascertain effects on persons treated with the medicinal

product which correspond to the particulars given by the

applicant in accordance with the provisions of these

regulations, whether the patient tolerates the medicinal product

well, the posology the clinician advises and any contra-

indications and adverse reactions; and

(c) where applicable, to state the grounds for using the

bibliography referred to under regulation 7(1)(b) hereof.

Detailed reports by the experts shall be deemed to form part

of the particulars accompanying the application submitted by the

applicant.

It shall be the duty of the Authority to ensure that an

application for a marketing authorisation is processed within a period

of 210 days from the date of its submission

Provided that this period shall be suspended when the processing

of the application stops for any reason deemed necessary by the

Authority, which reason shall be communicated in writing to the

applicant.

In those cases where an application is already under

examination in a Member State, the Authority shall suspend the

examination of the application, await an assessment by the

aforementioned State and inform that State and the applicant of its

decision to suspend.

The Authority shall within 90 days of receipt of the

aforementioned assessment report, either recognise the decision and

the summary of product characteristics as approved by that Member

State or, if it deems that there is a risk to public health, it shall inform

the applicant, the Agency and the reference Member State and other

Member State concerned by the application

Provided further, that the provision of this regulation shall not be

applicable to medicinal products present on the market in Malta up till

the 30th November, 2002.

Examination of

In order to examine the submitted application, the Authority:- application.

(a) shall verify whether the particulars submitted by the

applicant are in terms of the provisions of these regulations and

examine whether any condition for issuing a market authorisation

are complied with;

(b) may submit the medicinal product, its starting materials

and, if need be, its intermediate products or other constituent

materials, for testing by a State laboratory or by a laboratory

designated for that purpose in order to ensure that the control

methods employed by the manufacturer and described in the

particulars accompanying the application are satisfactory, in which

case the period of 210 days referred to under regulation 12 is

suspended;

(c) may, where appropriate, require the applicant to

supplement the particulars accompanying the application in respect

of the items and, in such case, the 210 days referred to under

regulation 12 hereof shall be suspended until such time as the

supplementary information required has been provided. Likewise,

these time limits shall be suspended when the applicant is given

the opportunity of an oral or written explanation.

(a) When the marketing authorisation is issued it shall be Information

holder.

subject to the general conditions in the Schedule to these regulations

and the holder shall be informed by the Authority of the summary

of the product characteristics as approved by it.

(b) The Authority shall take all necessary measures to ensure

that the information given in the summary is in conformity with

that accepted when the marketing authorisation is issued or

subsequently.

(c) A copy of the authorisation together with the summary

of the product characteristics shall be forwarded to the Agency.

(d) It shall be duty of the Authority to draw up an assessment

report and comments on the dossier as regards the results of the

analytical and pharmacotoxicological tests and the clinical trials

of the medicinal product concerned. The assessment report shall

be updated whenever new information becomes available which

is of importance for the evaluation of the quality, safety or efficacy

of the medicinal product concerned.

(1) In exceptional circumstances, and following

consultation with the applicant, an authorisation may be granted subject

to certain specific obligations, including:-

(a) the carrying out of further studies following the granting

of authorisation; and

(b) the notification of adverse reactions to the medicinal

product.

(2) Such exceptional decisions may be adopted only for

objective and verifiable reasons and shall be based on one of the causes

referred to in part 4 (G) of Annex I of Directive 2003/63 EC.

After an authorisation has been issued, the authorisation

holder must, in respect of the methods of manufacture and control, take

account of any scientific and technical progress and introduce any

changes which may be required to enable the medicinal product to be

manufactured and checked by means of generally accepted scientific

methods accepted by the Authority.

An authorisation shall be valid for five years and shall be

renewable for five-year periods, on an application by the holder at least

three months before the expiry date, and after consideration by the

Authority of a dossier containing in particular, details of the data on

pharmacovigilance and other information relevant to the monitoring of

the medicinal product.

An authorisation shall not affect the civil and criminal liability

of the manufacturer and, where applicable, of the marketing authorisation

holder.

(1) The marketing authorisation shall be refused if, after

verification of any particulars and documents submitted to it, the

Authority deems that

a) the medicinal product is harmful in the normal conditions

of use, or

b) its therapeutic efficacy is lacking or is insufficiently

substantiated by the applicant, or

c) its qualitative and quantitative composition is not as

declared.

(2) Authorisation shall likewise be refused if the particulars

and documents submitted do not comply with the provisions of these

regulations.

(a) (i) Before submitting an application for the Mutual recognition.

recognition of a marketing authorisation in Malta, the holder

of the authorisation shall inform the Authority in a reference

Member State that an application is to be made in accordance

with this regulation and shall notify it of any additions to the

original dossier.

(ii) The holder of the authorisation shall submit an

application to the Authority and shall testify that the dossier

is identical to that accepted by the reference Member State,

or shall identify any additions or amendments it may contain.

In the latter case, the holder shall certify that the summary of

the product characteristics proposed by him in accordance

with regulation 8 is identical to that accepted by the reference

Member State in accordance with regulation 16 hereof.

(iii) The Authority shall recognise the marketing

authorisation granted by the reference Member State within

90 days of receipt of the application and the assessment report.

It shall inform the reference Member State which granted the

initial authorisation, the other Member States concerned by

the application, the Agency, and the marketing authorisation

holder

Provided that this shall not apply when the Authority has

reason to believe that the marketing authorisation of the medicinal

product may present a risk to public health. In such case the

Authority shall inform the reference Member State, the applicant

,any other Member State concerned with the application and the

Agency, giving reasons for its decisions and advising what action

to be taken to correct any defect in the application.

(iv) The Authority shall endevour to reach an

agreement with all the Member States concerned regarding

the action to be adopted. If agreement is not reached within

90 days the matter shall then be referred to the Agency.

(v) The Authority and any other Member State

concerned shall also provide the Committee within 90 days

of receipt of the application, with a report giving the reasons

for disagreement. This report shall be copied to the applicant

who on receipt of such report shall forward to the Committee

a copy of the information and particulars referred to under

regulations 5, 7(1) and 8.

(b) (i) In those cases where Malta is the Reference

Member State, the Authority may require the applicant to

provide it with all the particulars and documents necessary to

enable it to check that the dossiers filed are identical.

(ii) The Authority, upon request by the holder of the

authorisation shall prepare an assessment report in respect of

the medicinal product concerned, or, if necessary, shall update

any existing assessment report. The Authority shall prepare

the assessment report, or update it within 90 days of the receipt

of the request.

(iii) The Authority shall then forward the assessment

report to the Member State or Member States concerned at

the same time as the application is submitted.

A market authorisation holder may apply to vary the

marketing authorisation and such application shall be submitted to that

Authority and to all other Member States which have previously

authorised the medicinal product concerned.

When the Licensing Authority is of the opinion that the

variation, suspension or withdrawal of the marketing authorisation is

necessary in the interest of public health it shall refer the matter to the

Agency

Provided that when urgent action needs to be taken in the interest

of public health the Licensing Authority may suspend the marketing

and use of the medicinal product concerned and inform the Commission

and other Member States within 24 hours giving reasons for its decision.

B