for Human Use Regulations, 2012

L.N. 477 of 2012

MEDICINES ACT

(CAP. 458)

Good Manufacturing Practice in Respect of Medicinal Products,

Active Substances and Investigational Medicinal Products

for Human Use Regulations, 2012

IN exercise of the powers conferred by article 106 of the

Medicines Act, the Minister of Health, the Elderly and Community

Care has made the following regulations:-

The title of these regulations is the Good Manufacturing Citation.

Practice in Respect of Medicinal Products, Active Substances and

Investigational Medicinal Products for Human Use Regulations, 2012.

These regulations, which transpose Directive 2003/94/EC and Scope.

Directive 2011/62/EU, lay down the principles and guidelines of good

manufacturing practice in respect of the manufacture of medicinal

products, active substances and investigational medicinal products for

human use.

For the purposes of these regulations and unless the Interpretation.

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 and in line with the current detailed good manufacturing

practice guidelines published by the European Union Commission;

"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 in the activities for

which the licence referred to in the Manufacture and Importation of

Medicinal Products for Human Use Regulations is required or has to

register his activities in accordance with regulation 3A of the said

regulations;

"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 Manufacture and Importation of

Medicinal Products for Human Use Regulations;

"unblinding" means the disclosure of the identity of a blinded

product.

(1) The Authority shall, by means of repeated

inspections in the case of medicinal products 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, by means of repeated inspections,

ensure that manufactures and importers of active substances,

including active substances that are intended for export, comply with

European Union good manufacturing practice for active substances.

(3) The Authority shall also take into account the

compilation, published by the Commission, of Community procedures

on inspections and exchange of information.

(4) 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

manufacturing operations, including those of medicinal products

intended only for export, and of intermediate products, active

substances and excipients, are carried out in accordance with

European Union good manufacturing practice and with the

manufacturing authorisation.

(2) It shall be the duty of the manufacturers and importers of

active substances, including active substances that are intended for

export, to comply with the current European Union good

manufacturing practice for active substances.

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

all manufacturing operations for medicinal products subject to a with

authorisation.

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 in the Clinical Trials Regulations, and as accepted by the S.L. 458.43

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 S.L. 458.43

Regulations is necessary, the application for modification shall be

submitted to the Authority.

It shall be the duty of the manufacturer to establish and Quality

implement an effective pharmaceutical quality assurance system assurance

system.

involving the active participation of the management and personnel of

the different departments.

It shall be the duty of the manufacturer to ensure that

Personnel.

(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, designed, constructed, adapted and maintained to suit the

intended 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

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 todate. 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

the Manufacture and Importation of Medicinal Products for Human S.L. 458.36

Use Regulations.

(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 Production.

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

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.

(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,

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 Work given out.

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, and by the Clinical Trials Regulations.

(1)

The manufacturer shall, in the case of medicinal Complaints,

product recall

products

and emergency

unblinding.

(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.

(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), and to

ensure that such procedure discloses the identity of the blinded

product only in so far as is necessary.

The manufacturer shall

(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.

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.

(1) Active substances shall only be imported if the

following conditions are fulfilled

(a)

the active substances have been manufactured in

accordance with standards of good manufacturing practice at

least equivalent to those laid down by the European Union

pursuant to the third paragraph of Article 47; and

(b) the active substances are accompanied by a written

confirmation from the competent authority of the exporting

third country of the following

(i) the standards of good manufacturing practice

applicable to the plant manufacturing the exported active

substance are at least equivalent to those laid down by the

European Union;

(ii) the manufacturing plant concerned is subject

to regular, strict and transparent controls and to the

effective enforcement of good manufacturing practice,

including repeated and unannounced inspections, so as to

ensure a protection of public health at least equivalent to

that in the European Union; and

(iii) in the event of findings relating to non-

compliance, information on such findings is supplied by

the exporting third country to the European Union without

any delay;

(2) This written confirmation shall be without prejudice to any

other obligations set out in the Act and regulations and, or rules made

thereunder. The requirement set out in sub-regulation (1)(b) shall not

apply if the exporting country is included in the list published by the

European Union Commission as referred to in Article 111b of

Directive 2001/83/EC, as amended.

(3) Exceptionally and where necessary to ensure the

availability of medicinal products, when a plant manufacturing an

active substance for export has been inspected by a European Union

Member State and was found to comply with the principles and

guidelines of good manufacturing practice as defined in these

regulations, the requirement set out in sub-regulation (1)(b) may be

waived for a period not exceeding the validity of the certificate of

good manufacturing practice. When such waiver is used, this shall be

communicated to the European Union Commission.

Any breach to these regulations shall be liable to penalties Offences and

penalties.

under article 99(1)(b) of the Medicines Act.

The Good Manufacturing Practice in Respect of Medicinal

Revokes the

Good

and Investigational Medicinal Products for Human Use Regulations,

Manufacturing

2004 are hereby being revoked.

Practice in

Respect of

Medicinal and

Investigational

Medicinal

Products for

Human Use

Regulations,

2004. L.N. 485 of

2004. €0.90