EN    EN 
 
 
 EUROPEAN  
COMMISSION   
Brussels, XXX   
[…](2015) XXX  draft  
  
COMMISSION DIRECTIVE (EU) .../…  
of XXX  
supplementing Directive 2001/83/EC of the European Parliament and of the Council as 
regards the principles and guidelines of good manufacturing practice for medicinal 
products for human use  
(Text with EEA relevance)    
EN 2   EN COMMISSION DIRECTIVE (EU) .../…  
of XXX  
supplementing  Directive 2001/83/EC of the European Parliament and of the Council as 
regards the principles and guidelines of good manufacturing practice for medicinal 
products for human use  
(Text with EEA relevance)  
THE EUROPEAN COMMISSION,  
Having regard to the Treaty on the Functioning of the European Union,  
Having regard to Directive 2001/83/EC of the European Parliament and of the Council of 6 
November 2001 on the Community code relating to medicinal products for human use1, and 
in particular  the first paragraph of  Article 47 thereof,  
Whereas:  
(1) Commission Directive 2003/94 EC2 applies to  both medicinal products for human use 
and investigational medicinal products for human use . 
(2) In accordance with Article 63(1) of Regulation (EU) No 536/2014  of the European 
Parliament and of the Council3 the Commission is empowered to adopt  a delegated  act 
laying down principles of good manufacturing practice for investigational medicinal 
products for human use . It is therefore necessary to adapt the provisio ns of Directive 
2003/94/EC by deleting the references to investigational medicinal products  for human 
use. 
(3) The definition of a pharmaceutical quality system and some terminology should be 
updated  to reflect the international developments or the actual usag e of that 
terminology of inspectors and manufacturers.  
(4) All medicinal products for human use manufactured or imported into the Union, 
including medicinal products intended for export, should b e manufactured in 
accordance with the principles and guidelines o f good manufacturing practice.  
However, for the manufacturer to be able to comply with those principles and 
guidelines , cooperation between the manufacturer and the marketing authorisation 
holder, when they are different legal entities,  is necessary. The o bligations of the 
manufacturer and marketing authorisation holder  vis-à-vis each other should  be 
defined in a technical agreement between them .  
                                                 
1 OJ L 311, 28.11.2001 , p. 67. 
2 Commission Directive 2003/94 EC of 8 October 2003 laying down the principles and guidelines of 
good manufacturing practice in respect of medicinal products for human use and investigational 
medicinal products for human use ( OJ L 262, 1 4.10.2003, p. 22 ). 
3 Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on 
clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC  (OJ L 158, 
27.5.2014, p.1 ).  
EN 3   EN (5) The manufacturer of medicinal products has to ensure that they are fit for their 
intended use, comply with the requirements of the marketing authorisation and do not 
place patients at risk due to inadequate quality. To achieve this quality objective 
reliably the manufacturer must implement a comprehensively designed and correctly 
implemented pharmaceutical quality system  incorporating good manufacturing 
practice and quality risk management.  
(6) In order to ensure conformity with the principles and guidelines of good 
manufacturing practice, it is necessary to lay down detailed provisions on inspections 
by the competent authorities and on certain obligations of manufacturer.  
(7) It is necessary to ensure that all medicinal products available on the EU territory 
comply with the same  quality standards, therefore m edicinal products imported into 
the Union should be manufactured in accordance with standards which are at least 
equivalent to the good manufacturing practice standards laid down in the Union.  
(8) In order to  ensure the consistent application of the principles of good manufacturing 
practice,  manufacturers of medicinal produ cts for human use and inspectors should 
consider the guidelines referred to in the second paragraph of Article 47 of Directive 
2001/83/EC . However, for advanced therapy medicinal products, the guideline 
referred in Article 5 of Regulation (EU) No 1394 /20074 should be applied . Principles 
and guidelines of good manufacturing practice for medicinal products for human use 
should be set out in relation to quality management, personnel, premises and 
equipment, documentation, production, quality control, outsource d operations , 
complaints, product  recall, and self -inspections . As regards the advanced therapy 
medicinal products those principles and guidelines should be adapted to the specific 
characteristic of those products in accordance with the risk -based approach .   
(9) Since many of the provisions of Directive 2003/94/EC need to be adjusted, for the 
sake of clarity, that Directive should be rep ealed . 
(10) The measures provided for in this Directive are in accordance with the opinion of the 
Standing  Committee  for Medicinal Products for Human Use , 
HAS ADOPTED THIS DIRECTIVE:  
Article 1  
Subject -matter  
This Directive lays down the principles and guidelines of good manufacturing practice in 
respect of medicinal products for human use whose manufacture or import requires the 
authorisation referred to in Article 40 of Directive 2001/83/EC.  
Article 2 
Definitions  
For the purposes of this Directive, the following definitions shall apply:  
(1) 'manufacturer' means any person engaged in activities for which the authorisation 
referred to in Article 40(1) and (3) of Directive 2001/83/EC is required;  
                                                 
4 Regulation  (EC) No 1394 /2007 of the European Parliament and of the Council of 13 November 2007 
on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 
726/2004, (OJ L  324, 10.12.2007 , p.121)   
EN 4   EN (2) 'pharmaceutical quality system' means the total sum of the organised arrangement 
made with the objective of ensuring that medicinal products are of the quality 
required for their inten ded use;  
(3) 'good manufacturing practice' means the part of the quality assurance which ensures 
that medicinal products are consistently produced , imported  and controlled in 
accordance with the quality standards appropriate to their intended use. ] 
Article 3  
Inspections  
1. By means of the repeated inspections referred to in Article 111(1a)  of Directive 
2001/83/EC , the Member States shall ensure that manufacturers  authorised in 
accordance with Article 40(1) and (3) of Directive 2001/83/EC  respect the principles 
and guidelines of good manufacturing practice laid down by this Directive.  
Member States shall also take into account the compilation, published by the 
Commission, of Union procedures on inspections and exchange of information.  
2. For the interpretation of the principles and guidelines of good manufacturing 
practice , manufacturers and the competent authorities shall take into account the 
detailed guidelines referred to in the second paragraph of Article 47 of Directive 
2001/83/EC.  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 (EC) No 1394/2007 of the European  Parliament 
and of the Council on advanced therapy medicinal products  shall be taken into 
account.  
3. Member States shall establish and implement in the ir inspectorates a properly 
designed quality system that shall be complied with  by inspectorates' personnel  and 
management . The quality system shall be updated as appropriate.  
Article 4  
Conformity with good manufacturing practice  
1. The Member States shall ensure  that the manufacturing operations are carried out by 
manufacturers in accordance with good manufacturing practice and with the 
manufacturing authorisation. This provision shall also apply to medicinal products 
intended only for export.  
2. For medicinal products imported from third countries, the Member States shall 
ensure that the importer has manufactured the products 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.  
Article 5  
Compliance with marketing authorisation  
1. The Member S tates shall ensure that  all manufact uring  or import  operations for 
medicinal products subject to a marketing authorisation are carried out by 
manufacturers in accordance with the information provided in the application for  that 
marketing authorisation.   
EN 5   EN 2. The Member S tates shall oblige t he manu facturer to regularly review his 
manufacturing methods in light of scientific and technical progress.  
If a variation to the marketing authorisation dossier is necessary, the variation shall  
take place by the arrangements established in accordance with Article 23b of 
Directive 2001/83/EC.  
Article 6  
Pharmaceutical quality  system  
The Member S tates shall ensure that t he manufacturer s establish, implement and maintain an 
effective pharmaceutical quality system, involving the active participation of the senior 
management and the personnel of the different departments.  
Article 7  
Personnel  
1. The manufacturer shall be obliged to have at each manufacturing o r import site  a 
sufficient number of competent and appropriately qualified personnel at his disposal 
to achieve the  objective of the  pharmaceutical quality system . 
2. The duties of the managerial and supervisory staff, including the qualified persons  
referred to in Article 48 of Directive 2001/83/EC , resp onsible for implementing and 
operating good manufacturing practice, shall be defined in job descriptions. Their 
hierarchical relationships shall be defined in an organisation chart. Organisation 
charts and job descriptions shall be approved in accordance w ith the manufacturer's 
internal procedures.  
3. The staff referred to in paragraph 2 shall be given sufficient authority to discharge 
their responsibility correctly.  
4. The personnel shall receive initial and on -going 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.  
5. Hygiene programmes adapted to the activities to be carried out shall be established 
and observed. These programmes shall, in particular, include procedures relating to 
health, hygiene practice and clothing of personnel.  
Article 8  
Premises and equipment  
1. As regards the premises and manufacturing equipment the manufacturer shall be 
obliged to ensure that they are  located, designed,  constructed, adapted and 
maintained to suit the intended operations.  
2. The Member States shall require that the p remises and manufacturing equipment are 
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. Premise s and equipment to be used for manufacturing  or import  operations, which 
are critical to the quality of the products, shall be subjected to appropriate 
qualification and validation.   
EN 6   EN Article 9  
Documentation  
1. The manufacturer shall be obliged 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 . The documentation system shall  ensure data quality  and integrity . 
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. That 
set of documents shall enable the history of the manufacture of each batch  to be 
traced . 
The manufacturer shall  be required to  retain  the batch documentation for at least one 
year after the expiry date of the batches to which it relates or at least five ye ars after 
the certification referred to in Article 51(3) of Directive 2001/83/EC, whichever is 
the longer period.  
2. When electronic, photographic or other data processing systems are used instead of 
written documents, the manufacturer shall  be required to  first validate the systems by 
showing that the data will be appropriately stored during the anticipated period of 
storage. Data stored by those systems shall be made readily available in legible form 
and shall be provided to the competent authorities upon  request. The electronically 
stored data shall be protected, by techniques  such as duplication or back -up and 
transfer to another storage system, against  unlawful access,  loss or damage o f data, 
and audit trails shall be maintained.  
Article 10  
Production  
1. The Member S tates shall ensure that the manufacturers carry out the different 
production operations in accordance with pre -established instructions and procedures 
and in accordance with good manufacturing practice. Adequate and sufficient 
resources shall be ma de available by the manufacturer for the in -process controls. All 
process deviations and product defects shall be documented and thoroughly 
investigated.  
2. The manufacturers shall be required to take a ppropriate technical and organisational 
measures to avoid  cross contamination and mix -ups. 
3. Any new manufacturing or important modification of a manufacturing process of a 
medicinal product shall be validated. Critical phases of manufacturing processes 
shall be regularly re -validated.  
Article 11  
Quality control  
1. The manufacturer shall be obliged 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.  
That person shall have at his disposal, or shall have access t o, one or more quality 
control laboratories appropriately staffed and equipped to carry out the necessary  
EN 7   EN examination and testing of starting materials and packaging materials and the testing 
of intermediate and finished  medicinal  products.  
2. For medicinal p roducts, including those imported from third countries, contract 
laboratories may be used if authorised in accordance with Article 12 of this Directive 
and point (b) of Article 20 of Directive 2001/83/EC . 
3. During the final control of the finished medicinal product before its release for sale 
or distribution, the quality control system shall take into account, in addition to 
analytical results, 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. Samples of each batch of finished medicinal product shall be retained for at least one 
year after the expiry date.  
Samples of starting mater ials, other than solvents, gases or water, used in the 
manufacturing process shall be retained for at least two years after the release of the 
product. That period may be shortened if the period of stability of the material, as 
indicated in the relevant sp ecification, is shorter. All those samples shall be 
maintained at the disposal of the competent authorities.  
Other conditions may be defined, by agreement with the competent authority, for the 
sampling and retaining of starting materials and certain produc ts manufactured 
individually or in small quantities, or when their storage could raise special 
problems.  
Article 12  
Outsourced operations  
1. The Member States shall require that a ny manufacturing or import operation or 
operation linked thereto which is outsourced  is the subject of a written contract.  
2. The contract shall clearly defined 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  referred to in Article 
48 of Directive 2001/83/EC  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 
Union  and shall submit to inspections carried out b y competent authorities pursuant 
to Article 111 of Directive 2001/83/EC.  
Article 13  
Complaints and product recall  
1. The Member States shall ensure that manufacturers  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. Any 
complaint concerning a defect shall be recorded and investigated by the 
manufacturer. The manufacturer shall  be required to  inform the competent authority  
and, if applicable, the marketing authorisation holder  of any defect that could result  
EN 8   EN in a recall or an abnormal restriction on supply and, in so far as possible, indicate the 
countries of destination.  
2. Any recall shall be made in accordance with the requirements referred to in Article 
123 of Directive 2001/83/EC.  
Article 14  
Self-inspection  
The manufacturer shall be required to conduct repeated self -inspections as part of the 
pharmaceutical 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 . Records shall be maintained of such self -inspections and any corrective actions 
subsequently taken.  
Article 15 
Repeal of Directive 2003/94/EC  
Directive 2003/9 4/EC is repealed  with effect  from six months after the date of publication in 
the Official Journal of the European Union of the notice referred to in Article 82(3)  of 
Regulation (EU) No 536/2014 or 1 April 2018, whichever is the later. . 
References to the repealed Directive shall be construed as references to this Directive  and to 
Commission Delegated Regulation xx5 and read in accordance with the correlation table in the 
Annex . 
Article 16 
Transposition  
1. Member States shall adopt and publish, by [ 31 March  2018 ] at the latest, the laws, 
regulations and administrative provisions necessary to comply with this Directive. 
They shall forthwith communicate to the Commission the text of those provisions.  
They shall apply those provisions from six months after the date of publication in the  
Official Journal of the European Union of the notice referred to in Article 82(3)  of 
Regulation (EU) No 536/2014  or 1 April 2018, whichever is the later .  
When Member States adopt those provisions, they shall contain a reference  to this 
Directive or be accompanied by such a reference on the occasion of their official 
publication. Member States shall determine how such reference is to be made.  
2. Member States shall communicate to the Commission the text of the main provisions 
of national law which they adopt in the field covered by this Directive.  
Article  17 
Entry into force  
This Directive shall enter into force on the twentieth  day following that of its publication in 
the Official Journal of the European Union . 
                                                 
5 Commission Delegated Regulation xx on principles and guidelines on good manufacturing practice for 
investigational medicinal products for human use and arrangements for inspections, (OJ L xx, 
dd.mm.yyyy, p. xx)   
EN 9   EN Article  18 
Address ees 
This Directive is addressed to the Member States.  
Done at Brussels,  
 For the Commission  
 The President  
  
  
 On behalf of the President  
  
 [Position]