and Active Substances for Human Use Regulations, 2018

L.N. 161 of 2018

MEDICINES ACT

(Cap. 458)

Good Manufacturing Practice In Respect Of Medicinal Products

and Active Substances for Human Use Regulations, 2018

IN EXERCISE of the powers conferred by article 106 of the

Medicines Act, the Minister responsible for Public Health, after

consultation with the Licensing Authority has made the following

regulations:-

The title of these regulations is Good Manufacturing Citation.

Practice in Respect of Medicinal Products and Active Substances for

Human Use Regulations, 2018.

These regulations, which transpose Directive 2017/1572 Scope.

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

good manufacturing practice in respect of the manufacture of

medicinal products and active substances for human use.

For the purposes of these regulations and unless the context Interpretation.

otherwise requires

"the Authority" means the Medicines Authority;

"good manufacturing practice" means the part of quality

assurance which ensures that products are consistently produced,

imported 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;

"manufacturer" means any person engaged in the activities

for which the licence referred to in the Manufacture and S.L. 458.36.

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 system" means the total sum of the

organised arrangements made with the object o f ensuring that

medicinal products or active substances 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.

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

in the case of medicinal products for human use, 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 manufacturers 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". In the

case of advanced therapy medicinal products, the guidelines on good

manufacturing practice specific to advanced therapy medicinal

products referred to in Article 5 of Regulation No. 1394/2007/EC on

advanced therapy medicinal products shall be taken into account.

(5) The Medicines Authority shall establish and implement in

its inspectorate a properly designed quality system that shall be

complied with by inspectorates' personnel and management. The

quality system shall be updated as appropriate.

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

manufacturing operations, including those of medicinal product

intended only for export, and 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.

(3) For medicinal products imported from third countries, the

importer shall ensure that the products have been manufactured in

accordance with standards which are at least equivalent to the good

manufacturing practice standards laid down in the Union and that such

products have been manufactured by manufacturers duly authorised to

do so.

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

his manufacturing methods in the light of scientific and technical

progress.

(3) If a variation to the marketing authorisation dossier is

necessary, the application for modification shall be submitted to the

Authority.

It shall be the duty of the manufacturer to establish, Pharmaceutical

implement and maintain an effective pharmaceutical quality assurance quality system.

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 or import 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,;

(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 or import 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 on system based upon specifications,

manufacturing formulae and processing and packaging instructions,

procedures and records covering the various manufacturing operations

performed. The documentation system shall ensure data quality and

integrity.

(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 batchto be traced.

(2) 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

Use Regulations, whichever is the longer period.

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

processing s y stems 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 unlawful access, 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 an d 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.

(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.

(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 system.

person who ha s t h e 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) In the case of medicinal products, including those im ported

from third countries, contract laboratories may be used if authorised in

accordance with regulation 13.

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

release for sale or distribution, 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 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.

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

of the competent authorities.

(d) Other conditions may be defined, by agreement with

the competent authority, for the sampling and retaining of

starting materials and certain products manufactured

individually or in small quantities, or when their storage could

raise special problems.

(1) Any manufacturing operation or import operation or

operation linked thereto which is outsourced shall be the subject of a

written contract.

(2) The contract shall clearly define the responsibilities of each

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

manufacturing practice to be followed by the contract-acceptor and the

manner in which the qualified person responsible for certifying each

batch is to discharge his responsibilities.

(3) The contract-acceptor shall not subcontract any of the work

entrusted to him under the contract without written authorisation from

the contract-giver.

(4) The contract-acceptor shall comply with the principles and

guidelines of good manufacturing practice applicable to the operations

concerned laid down in the European Union and shall submit to

inspections carried out by the competent authorities as provided by the

Medicines Act.

(1)

The manufacturer shall

(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 and, if applicable, the

marketing authorization holder 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.

The manufacturer shall

Self-inspection.

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

quality system in order to monitor the implementation and

respect of good manufacturing practice and to propose any

necessary corrective measures and/or preventive actions; and

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

corrective action subsequently taken.

(1) Active substances shall only be imported if the Importation of

active

following conditions are fulfilled

substances.

(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 Medicines 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

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

Publication of these regulations shall repeal the Good

Manufacturing Practice in Respect of Medicinal Products, Active

Substances and Investigational Medicinal Products For Human Use

Regulations.

€0.72