for Human Use Regulations, 2004

L.N. 485 of 2004

MEDICINES ACT

(ACT NO. III OF 2003)

Good Manufacturing Practice in Respect of Medicinal and

Investigational Medicinal Products

for Human Use Regulations, 2004

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

Act, 2003, the Minister of Health, the Elderly and Community Care has

made the>-

The title of these regulations is the Good Manufacturing

Practice in Respect of Medicinal and Investigational Medicinal Products

for Human Use Regulations, 2004.

These regulations, which transpose Directive 2003#94#EC, lay

down the principles and guidelines of good manufacturing practice in

respect of the manufacture of medicinal and investigational medicinal

products for human use.

For the purposes of these regulations and unless the context

otherwise requires>-

“the Authority” means the Medicines Authority<

“blinding” means the deliberate disguising of the identity of

an investigational medicinal product in accordance with the

instructions of the sponsor<

“good manufacturing practice” means the part of quality

assurance which ensures that products are consistently produced

and controlled in accordance with the quality standards appropriate

to their intended use<

“investigational medicinal product” means a pharmaceutical

form of an active substance or placebo being tested or used as a

reference in a clinical trial, including products already having a

marketing authorization but which are used or assembled

(formulated or packaged) in a way different from the authorised

form, or when used for an unauthorised indication, or when used

to gain further information about the authorised form<

“manufacturer” means any person engaged the activities for

which the licence referred to in the Manufacture of Medicinal

Products for Human Use Regulations, 2004, Legal Notice 143, is

required<

“medicinal product” means any product as defined in Article

1(2) of Directive 2001#83#EC<

“pharmaceutical quality assurance” means the total sum of

the organised arrangements made with the object of ensuring that

medicinal products or investigational medicinal products are of

the quality required for their intended use<

“qualified person” means any person who is a qualified person

as provided by regulation 9 of the Manufacture of Medicinal

Products for Human Use Regulations, 2004, Legal Notice 143.

“unblinding” means the disclosure of the identity of a blinded

product.

(1) The Authority shall, by means of repeated inspections Inspections.

in the case of medicinals for human use and by means of inspections in

the case of investigational medicinal products, ensure that manufacturers

respect the principles and guidelines of good manufacturing practice

laid down by these regulations.

(2) The Authority shall also take into account the

compilation, published by the Commission, of Community procedures

on inspections and exchange of information.

(3) For the interpretation of the principles and guidelines

of good manufacturing practice, the Authority and the manufacturers

shall take into account the detailed guidelines referred to in the second

paragraph of Article 47 of Directive 2001#83#EC, published by the

Commission in the “Guide to good manufacturing practice for medicinal

products and for investigational medicinal products”.

(1) It shall be the duty of the manufacturer to ensure that Conformity with

manufacturing operations, including those of medicinal products good

practice.

intended only for export, are carried out in accordance with good

manufacturing practice and with the manufacturing authorisation.

(2) It shall be the duty of the importer to ensure that>

(a) in the case of medicinal products and investigational

medicinal products imported from third countries, these have been

manufactured in accordance with standards which are at least

equivalent to the good manufacturing practice standards laid down

by the Community<

(b) in the case of medicinal products , such products have

been manufactured by manufacturers duly authorised for the

purpose< and

(c) in the case of investigational medicinal products, such

products have been manufactured by a manufacturer notified to

the competent authorities and accepted by them for that purpose.

(1) It shall be the duty of the manufacturer to ensure that all

manufacturing operations for medicinal products subject to a marketing

authorisation are carried out in accordance with the information provided

in the application for marketing authorisation as accepted by the

Licensing Authority.

(2) In the case of investigational medicinal products, the

manufacturer shall ensure that all manufacturing operations are carried

out in accordance with the information provided by the sponsor as

provided the Clinical Trials Regulations, 2004 and as accepted by the

Licensing Authority.

(3) It shall be the duty of the manufacturer to review

regularly his manufacturing methods in the light of scientific and

technical progress and the development of the investigational medicinal

product.

(4) If a variation to the marketing authorisation dossier or

an amendment to the request provided for in the Clinical Trials

Regulations, 2004 is necessary, the application for modification shall

be submitted to the Authority.

It shall be the duty of the manufacturer to establish and

implement an effective pharmaceutical quality assurance system

involving the active participation of the management and personnel of

the different departments.

(1) It shall be the duty of the manufacturer to ensure that>

(a) there is at each manufacturing site, a sufficient number

of competent and appropriately qualified personnel at his disposal

to achieve the pharmaceutical quality assurance objective<

(b) the duties of the managerial and supervisory staff,

including the qualified persons, responsible for implementing and

operating good manufacturing practice, are defined in the job

descriptions<

(c) the hierarchical relationships of the manufacturer’s staff

are defined in an organisation chart<

(d) the organisation charts and job descriptions are approved

in accordance with the manufacturer’s internal procedures<

(e) the staff have sufficient authority to discharge their

responsibility correctly<

(f) the personnel receives initial and ongoing training, the

effectiveness of which shall be verified, covering in particular the

theory and application of the concept of quality assurance and good

manufacturing practice, and, where appropriate, the particular

requirements for the manufacture of investigational medicinal

products<

(g) the hygiene programmes adapted to the activities to be

carried out shall be established and observed and such programmes

shall, in particular include procedures relating to health, hygiene

practice and clothing of personnel.

(1) Premises and manufacturing equipment shall be located, Premises and

designed, constructed, adapted and maintained to suit the intended equipment.

operations.

(2) Premises and manufacturing equipment shall be laid out,

designed and operated in such a way as to minimise the risk of error

and to permit effective cleaning and maintenance in order to avoid

contamination, cross contamination and, in general, any adverse effect

on the quality of the product.

(3) Premises and equipment to be used for manufacturing

operations, which are critical to the quality of the products, shall be

subjected to appropriate qualification and validation.

(1) (a) It shall be the duty of the manufacturer to establish Documentation.

and maintain a documentation system based upon specifications,

manufacturing formulae and processing and packaging instructions,

procedures and records covering the various manufacturing operations

performed.

(b) Documents shall be clear, free from error and kept up to

date. Pre-established procedures for general manufacturing

operations and conditions shall be kept available, together with

specific documents for the manufacture of each batch. Such set of

documents shall enable the history of the manufacture of each batch

and the changes introduced during the development of an

investigational medicinal product to be traced.

(2) (a) For a medicinal product, the batch documentation

shall be retained for at least one year after the expiry date of the batches

to which it relates or at least five years after the certification referred to

in Manufacturing of Medicinal Products for Human use, Regulations

2004. (b) In the case of an investigational medicinal product, the

batch documentation shall be retained for at least five years after

the completion or formal discontinuation of the last clinical trial

in which the batch was used. The sponsor or marketing

authorisation holder, if different, shall be responsible for ensuring

that records are retained as required for marketing authorisation in

accordance with the Annex I to Directive 2001#83#EC, if required

for a subsequent marketing authorisation.

3. (a) When electronic, photographic or other data

processing systems are used instead of written documents, the

manufacturer shall first validate the systems by showing that the data

will be appropriately stored during the anticipated period of storage.

(b) Data stored by those systems shall be made readily

available in legible form and shall be provided to the competent

authorities at their request.

(c) The electronically stored data shall be protected,

by methods such as duplication or back-up and transfer on to another

storage system, against loss or damage of data, and audit trails shall be

maintained.

(1) (a) The different production operations shall be carried

out in accordance with pre-established instructions and procedures and

in accordance with good manufacturing practice.

(b) Adequate and sufficient resources shall be made

available for the in-process controls.

(c) All process deviations and product defects shall be

documented and thoroughly investigated.

(2) Appropriate technical or organisational measures shall

be taken to avoid cross contamination and mix-ups. In the case of

investigational medicinal products, particular attention shall be paid to

the handling of products during and after any blinding operation.

(3) In the case of medicinal products, any new manufacture

or important modification of a manufacturing process of a medicinal

product shall be validated and the critical phases of manufacturing

processes shall be regularly re-validated.

(4) In the case of investigational medicinal products, the

manufacturing process shall be validated in its entirety in so far as is

appropriate, taking into account the stage of product development. The

critical process steps, such as sterilisation, shall be validated and all

steps in the design and development of the manufacturing process shall

be fully documented.

(1) (a) It shall be the duty of the manufacturer to establish Quality control.

and maintain a quality control system placed under the authority of a

person who has the requisite qualifications and is independent of

production.

(b) Such person shall have at his disposal, or shall have

access to, one or more quality control laboratories appropriately

staffed and equipped to carry out the necessary examination and

testing of the starting materials and packaging materials and the

testing of intermediate and finished products.

(2) (a) In the case of medicinal products, including those

imported from third countries, contract laboratories may be used if

authorised in accordance with regulation 13 of these regulations.

(b) In the case of investigational medicinal products,

the sponsor shall ensure that the contract laboratory complies with

the content of the request referred to in the Clinical Trials

Regulations, 2004 and accepted by the Authority

Provided that when such products are imported from third

countries, analytical control shall not be mandatory.

(3) During the final control of the finished product, before

its release for sale or distribution or for use in clinical trials, the quality

control system shall take into account, in addition to analytical results,

any essential information such as the production conditions, the results

of in-process controls, the examination of the manufacturing documents

and the conformity of the product to its specifications, including the

final finished pack.

(4) (a) In the case of a finished medicinal product, samples

of each batch shall be retained for at least one year after the expiry date.

(b) In the case of an investigational medicinal product,

sufficient samples of each batch of bulk formulated product and

of key packaging components used for each finished product batch

shall be retained for at least two years after completion or formal

discontinuation of the last clinical trial in which the batch was

used, whichever period is the longer.

(c) In the case of samples of starting materials, other

than solvents, gases or water, used in the manufacturing process,

such samples shall be retained for at least two years after the release

of the product>

Provided that such period may be shortened if the period of

stability of the material, as indicated in the relevant specification,

is shorter.

(d) All such samples shall be maintained at the disposal

of the competent authorities.

(1) Any manufacturing operation or operation linked

thereto which is given out shall be the subject of a written agreement.

(2) The agreement shall clearly define the responsibilities

of each party and shall define, in particular, the observance of good

manufacturing practice to be followed and the manner in which

the qualified person responsible for certifying each batch is to

discharge his responsibilities.

(3) A party to the agreement shall not subcontract any of

the work entrusted to him under the agreement without written

authorisation from the other party.

(4) Such party shall comply with the principles and

guidelines of good manufacturing practice and shall submit to

inspections carried out by the competent authorities as provided by the

Medicines Act, 2003 and by the Clinical Trials Regulations, 2004.

(1) The manufacturer shall, in the case of medicinal products>

(a) implement a system for recording and reviewing

complaints together with an effective system for recalling, promptly

and at any time, medicinal products in the distribution network<

(b)

record and investigate any complaint concerning a

defect<

(c) inform the competent authority of any defect that could

result in a recall or abnormal restriction on supply and, in so far as

is possible, indicate the countries of destination.Any recall shall

be made in accordance with the requirements referred to in the

Medicines Act, 2003<

(2) In the case of investigational medicinal products, the

manufacturer shall>

(a) in cooperation with the sponsor, implement a system

for recording and reviewing complaints together with an effective

system for recalling promptly and at any time investigational

medicinal products which have already entered the distribution

network<

(b) record and investigate any complaint concerning a defect

and shall inform the competent authority of any defect that could

result in a recall or abnormal restriction on supply<

(c) identify all trial sites and, in so far as is possible, indicate

the countries of destination.

(3) In the case of an investigational medicinal product for

which a marketing authorisation has been issued, the manufacturer of

the investigational medicinal product shall, in cooperation with the

sponsor, inform the marketing authorisation holder of any defect that

could be related to the authorised medicinal product.

(4) It shall be the duty of the sponsor to implement a

procedure for the rapid unblinding of blinded products, where this is

necessary for a prompt recall referred to in sub-regulation (2) of this

regulation, and to ensure that such procedure discloses the identity of

the blinded product only in so far as is necessary.

The manufacturer shall>

Self-inspection.

(a) conduct repeated self-inspections as part of the quality

assurance system in order to monitor the implementation and

respect of good manufacturing practice and to propose any

necessary corrective measures< and

(b) maintain records of such self-inspections and any

corrective action subsequently taken.

B

Labelling.

In the case of an investigational medicinal product, labelling

shall be such as to ensure protection of the subject and traceability, to

enable identification of the product and trial, and to facilitate proper

use of the investigational medicinal product.

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