EN    EN  
 EUROPEAN  
COMMISSION 
Brussels, XXX   
[…](2013) XXX  draft 
  
COMMISSION DELEGATED REGULATION (EU) No …/.. 
of XXX  
supplementing Directive 2001/83/EC of the Eu ropean Parliament and of the Council 
with regard to principles and guidelines of good manufacturing practice for active 
substances for medicinal products for human use 
(Text with EEA relevance) 
 EN 1   EN EXPLANATORY MEMORANDUM  
1. CONTEXT  OF THE  DELEGATED  ACT 
EU pharmaceutical legislation provides for a high level of public h ealth protection through 
stringent rules guaranteeing the quality, safety an d efficacy of the medicines circulating in the 
EU market. In particul ar, Directive 2011/62/EU1, amending Directive 2001/83/EC2 on the 
Community code relating to medicinal products for human use, introduces new provisions on 
the manufacturing of active substances, the activ e ingredients of medici nes. These provisions 
aim to ensure that only active substances that are safe and of high quality are used in the 
manufacturing of medi cines in the Union. 
As of 2 January 2013, the manufacturing of  active substances is subject to good 
manufacturing practice for active substances regardless of whether those active substances are 
manufactured in the Union or imported.  
With regard to the importation of active subs tances manufactured in third countries, active 
substances imported into the Union have to be  manufactured in accordance with standards of 
good manufacturing practice for active substance at  least equivalent to those of the Union. As 
of 2 July 2013, this has to be certified by the competent authority  of the third country through 
a written confirmation accompanying the imported active substance3, unless the third country 
has been listed as having a regulatory framewor k for active substances e quivalent to that of 
the EU.4 
In addition, manufacturers of  medicinal products are no w obliged to use only active 
substances manufactured in accordance with pr inciples and guideline s of good manufacturing 
practice for active substances. 
In this context, it is necessary to set EU-wid e standards with regards to the manufacturing of 
active substances and harmoni se their implementation and enforcement throughout the EU. 
To this end, the Commission is mandated5 to adopt, by means of delegated acts, measures 
supplementing the provisions of Directive 2001/ 83/EC with regards to good manufacturing 
practice for active substances. 
The principles of good manufacturing practi ce for active substances included in this 
Delegated Regulation are larg ely based on the existing technical guidelines on the 
manufacturing of active substances  published by the Commission in EudraLex – the rules 
governing medicinal products in  the European Union, volume 4 .6 In practice, this Delegated 
Regulation will not modify the current EU standards of good manufacturing practice for 
active substances but structure them into a lega l framework to facilitate their enforcement. 
This is important in the context of the recent rules on active substance importation7. The 
alignment between the content of this delegate d act and the existing guidelines implies that 
written confirmations that have been issued pr ior to this Regulation will still be acceptable 
once this Regulation enters into force. The same applies to third countries having been 
                                                 
1 Directive 2011/62/EU of the European Parliament and of the Council amending Directive 2001/83/EC 
as regards the prevention of the entry into the legal supply chain of falsified medicinal products, OJ L 174, 1.7.2011, p.74. 
2 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 use, OJ L 311, 28.11.2001, p. 67. 
3 Article 46b(2)(b) of Directive 2001/83/EC. 
4 Article 111b of Directive 2001/83/EC. 
5 Article 47, third paragraph, of Directive 2001/83/EC. 
6 http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm  
7 Articles 46b and 111b of Directive 2001/83/EC. EN 2   EN assessed as having manufacturing standards equivale nt to those in the EU according to article 
111b of Directive 2001/83/EC: these countries will still be consid ered as “equivalent” after 
the entry into force of this Regulation.  
2. CONSULTATIONS  PRIOR  TO THE  ADOPTION  OF THE  ACT 
With a view to preparing this Delegate d Regulation, the Commi ssion conducted a public 
consultation on a concept paper8 for a "delegated act on the pr inciples and guidelines of good 
manufacturing practice for activ e substances in medicinal products for human use". The 
consultation took place between January and Apri l 2012. In addition, an Expert Group "on the 
preparation of delegated acts re lating to manufacturing, import and introduction of medicinal 
products for human use and their active substances"9 was set up and met on 21 September 
2012 to discuss the concept paper and the results of the public consultatio n. The Expert Group 
was consulted a second time in writing in  September 2013. Comments stemming from both 
rounds of consultations were taken into accoun t when preparing this Delegated Regulation. 
3. LEGAL  ELEMENTS  OF THE  DELEGATED  ACT 
The legal basis for this Delegated Regulation is Article 47, third paragraph, of Directive 
2001/83/EC on the Community code relating to  medicinal products for human use.  
This Delegated Regulation supplements Dire ctive 2001/83/EC by establishing and detailing 
principles and guidelines of good manufacturing practice for activ e substances for medicinal 
products for human use. 
                                                 
8 http://ec.europa.eu/health/files/gmp/2012_01_20_gmp_cp_en.pdf  
9 http://ec.europa.eu/transparency /regexpert/index.cfm?do=groupD etail.groupDetail&groupID=2752  EN 3   EN COMMISSION DELEGATED REGU LATION (EU) No …/.. 
of XXX  
supplementing Directive 2001/83/EC of the Eu ropean Parliament and of the Council 
with regard to principles and guidelines of  good manufacturing practice for active 
substances 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 rela ting to medicinal products for human use
10, 
and in particular th e third paragraph of Article 47 thereof, 
Whereas: (1) All active substances manufactured in the Union, including active substances intended 
for export, should be manufactured in accordan ce with the principles and guidelines of 
good manufacturing practice for active substances  which at present are set out in the 
technical guidelines on manufacturing of active substances  published by the 
Commission. It is necessary to lay dow n principles and guidelines of good 
manufacturing practice for active subs tances in a legally binding act. 
(2) In order to promote the use of harmonised standards at global level, principles and 
guidelines of good manufacturing practice for active substances should be laid down 
in line with the guidelines for active substances established by the International Conference on Harmonisation of Technical  Requirements for Registration of 
Pharmaceuticals for Human Use. 
(3) Principles and guidelines of good manufacturing practice shoul d be set out in relation 
to all issues, operations and processes that are key to determining the quality of active 
substances, such as quality management , personnel, premises and equipment, 
documentation, material management, pr oduction, in-process qua lity  controls, 
packaging, labelling, laboratory controls, retu rns, complaints and recalls, contracting 
out and repackaging. In orde r to ensure compliance w ith those principles and 
guidelines, the manufacturers of active substa nces should be required to establish and 
implement an effective system for mana ging the quality of those substances. 
(4) Personnel in unsanitary conditions, wearing unsuitable clothing or practicing 
potentially contaminating activities in the manufacturing area may compromise the 
quality of the active substan ce. This should be prevente d by practicing sanitation and 
health habits that are appropriate to the manufacturing operations performed. Those 
practices should be provided for in the quality management system established by the manufacturer of th e active substance. 
                                                
 
10 OJ L 311, 28.11.2001, p. 67. EN 4   EN (5) In order to ensure an adequate quality of  the active substance, it is necessary to 
minimise potential contamination and cross-contamination by requiring the use of facilities, production processes and containers  designed for this purpose, as well as 
appropriate contamination controls. 
(6) It is of particular importance to preven t cross-contamination when producing active 
substances harmful to human health. Cont amination of other products with highly 
sensitizing active substances could pose a serious threat to public health since 
exposure to these substances very often results in the de velopment of hypersensitivity 
and allergic reactions. For that reason, ma nufacturing of those active substances 
should only be allowed to take place in se parate production areas. The use of separate 
production areas may also be necessary for the production of active substances with 
the potential to be harmful to human health because of their potency  or their infective 
or toxic nature. For those substances, the manufacturer should perform an assessment of the risks to human health and th e need for separate production areas. 
(7) In order to facilitate the tracing, iden tification and solving of potential quality 
problems as well as to verify complia nce with good manufacturing practice, the 
manufacturer should keep detailed written r ecords of all processe s he performs that 
relate to the manufacturing of active subs tances, including of deviations from those 
processes.  
(8) In order to ensure that medicinal products have the appropriate standards of quality, 
safety and efficacy and to protect public h ealth, manufacturers of an active substance 
should communicate without delay any change s which may affect the quality of the 
active substance to manufactur ers of medicinal products us ing the active substance. 
(9) It is necessary to have in place appropria te procedures to record and investigate 
quality-related complaints and perform pr oduct recalls in order to rapidly address 
quality concerns and remove from the ma rket active substances that do not meet 
quality standards or pose a seri ous threat to public health. 
(10) When the manufacturer of the active substan ce entrusts any part of the manufacturing 
to another party, it is important to clarify in  writing the responsibilities of that other 
party with regard to co mpliance with good manufactur ing practices and quality 
measures. 
(11) The application of good manufacturing practi ces to the process of repackaging and 
relabelling is necessary to avoid that activ e substances are wrongly labelled or become 
contaminated in the process. 
HAS ADOPTED THIS REGULATION: 
Article 1  
Scope  
This Regulation lays down the principles a nd guidelines of good manufacturing practice for 
active substances for medicinal products for human use, including activ e substances intended 
for export. 
Article 2 
Definitions  
For the purposes of this Regulation, th e following definitions shall apply: EN 5   EN (1) 'manufacturing' means any total or partia l operation of receipt of materials, 
production, packaging, repackaging, labelli ng, relabelling, quality control or release 
of active substances, and the related controls;  
(2) 'active substance starting material' means any substance from which an active 
substance is manufactured or extracted; 
(3) 'active substance intermediate' means a substance which is obtained during the 
production of an active substance and whic h is intended for further processing; 
(4) 'raw material' means any substance, reagent or solvent which is intended for use in 
the production of an active substance and from which th e active substance is not 
directly manufactured or extracted. 
Article 3 
Quality management 
1. Manufacturers of active substances (‘the ma nufacturer’) shall establish, document and 
implement an effective system for managing the quality of those substances during the 
manufacturing operations performed by them (the  ‘manufacturing process’). The system shall 
provide for the active participation of th e management and manufacturing personnel. 
The system shall ensure that the active substanc es meet the specifications for their quality and 
purity established in accor dance with Article 12(1). 
The system shall incorporate quality risk management.  2. The manufacturer shall appoint a quality un it that is independent  of the production 
unit to be responsible for quality assurance  and quality control.  
3. The manufacturer shall conduct regular in ternal audits and fo llow-up on the findings. 
Article 4 
Personnel 
1. The manufacturer shall ensure  an adequate number of personnel having the necessary 
qualifications acquired through education, traini ng or experience to carry out and supervise 
the manufacturing of active substances. 
2. Personnel shall practice good sanitation and hygiene in the manufacturing area. 
Personnel shall not access the manufacturing area if they: 
(a) suffer from an infectious disease or ha ve open lesions or other dermatological 
conditions on the exposed surface of the body that could negatively affect the quality 
and purity of the active substance;  
(b) wear clothing which is visibly dirty, or  does not protect the active substance from 
potential contamination coming from pers onnel, or does not protect personnel from 
exposure to active substances potenti ally harmful to human health;  
(c) at the moment of entering the manufactur ing area, are perfor ming activities that 
could contaminate or otherwise compromise  the quality of the active substance. 
Article 5 
Buildings and facilities 
1. Buildings and facilities us ed in the manufacturing of active substances shall be 
located, designed and constructed to suit the intended operations and to facilitate cleaning and EN 6   EN maintenance having regard to the type and st age of manufacturing which the buildings and 
facilities are used for.  
Facilities and the flow of material and personnel through th e facilities sha ll be designed to 
ensure that different substances  and materials are kept separate and do not contaminate each 
other. 
2. Buildings shall be properly maintained a nd repaired and kept in a clean condition. 
3. Highly sensitizing active substances shall be produced in separate production areas.   
When carrying out production operations, the manuf acturer shall assess the need for separate 
production areas for other active substances with the potential to be ha rmful to human health 
because of their potency or their infective or toxic nature. The assessment shall evaluate the 
risk to human health posed by those active substances by ta king account of the active 
substance potency, toxicity, infectivity and th e risk minimisation procedures in place. The 
assessment shall be documented in writing. 
Where the assessment shows a risk of harm to human health, the active  substance shall be 
produced in separate production areas. 
Article 6 
Equipment 
1. Equipment used in the manufacturing of active substances shal l be appropriately 
designed, sized and located for its intend ed use, cleaning, maintenance and, where 
appropriate, sanitization . 
Equipment shall be constructed and operated so th at surfaces that come into contact with raw 
materials, active substance starting material s, active substance intermediates or active 
substances do not alter the quality  of the raw materials, the active substance starting materials, 
the active substance intermediate s or the active substa nces to the extent that they no longer 
comply with the specifications establ ished in accordance with Article 12(1). 
2. The manufacturer shall establish written pr ocedures for the cleaning of equipment and 
the subsequent verification of its suitabil ity for use in the manufacturing process. 
3. Control, weighing, measuring, monitoring an d test equipment that is critical for 
assuring the quality of the active substance sha ll be calibrated in accordance with written 
procedures and an established schedule. 
Article 7 
Documentation and records 
1. The manufacturer shall establish and ma intain a documentation system and written 
procedures covering the ma nufacturing process.  
All documents in relation to the manufacturing process shall be prepared, reviewed, approved 
and distributed in accordance with written procedures. 
The manufacturer shall maintain records of at le ast the following elements in relation to the 
manufacturing process: 
(1) equipment cleaning and use; 
(2) origins of raw materials, active substance starting materials and active substance 
intermediates;  EN 7   EN (3) controls in relation to raw materials, ac tive substance starting materials and active 
substance intermediates; 
(4) use of raw materials, active substance starting materials and active substance 
intermediates; 
(5) labelling of the active substances and of the packaging materials; 
(6) master production instructions;  
(7) batch production and control; 
(8) laboratory controls. 
The issuance, revision, replacement and w ithdrawal of documents related to the 
manufacturing process shall be controlled, an d records of their revision, replacement and 
withdrawal  shall be kept. 
2. All quality related activities carried out  during the manufacturing process shall be 
recorded at the time they are performed. Any de viation from the written procedures referred 
to in Article 7(1) shall be documented and expl ained. Deviations affecting the quality of the 
active substance or preventing the active substan ce from meeting the specifications referred to 
in Article 12(1) shall be investigated, and th e investigation and its conclusions shall be 
documented. 
3. After carrying out production and control operations, the ma nufacturer shall retain all 
production and control records for at  least one year after the expi ry date of the batch. For an 
active substance with retest dates, the manufactur er shall retain records for at least three years 
after the complete batch ha s been placed on the market. 
Article 8 
Material management 
1. The manufacturer shall have written pro cedures in place for ensuring the quality of 
incoming material covering the following elements:   
(1) receipt; 
(2) identification;  
(3) quarantine; 
(4) storage; 
(5) handling; 
(6) sampling;  
(7) testing; 
(8) approving; 
(9) rejection. 
2. The manufacturer shall have a system in place for evaluating suppliers of critical 
materials. EN 8   EN Article 9 
Production and in-process control 
1. Production operations shall be subject to cont rols in order to monitor and adjust the 
production process or verify that the active subs tance conforms to the specifications of quality 
and purity pursuant to Article 12(1). Production operations which are critical to  ensure that 
the active substance meets the qu ality specifications referred to in Article 12(1) shall be 
carried out under the visual superv ision of qualified personnel or  subjected to an equivalent 
control. 
2. Weighing and measuring of ra w materials and active substance starting materials shall 
be accurate and shall be conducted in a manner wh ich does not affect their suitability for use. 
3. Production operations, including any opera tion after purificat ion of the active 
substance intermediates or the active substance, shall be conducted in a manner that prevents 
raw materials, active substance starting materials, active substance intermediates and active substances from being contaminated by other materials. 
Article 10 
Packaging and labelling 
1. Containers shall provide adequate protecti on against deterioration or contamination of 
the active substance from the moment the active substance is packaged to the moment it is 
used in the manufacturi ng of medicinal products. 
2. Storage, print and use of labels on the packaging of active s ubstances shall be 
controlled. Labels shall contain the information necessary to assure the quality of the active substance.  
Article 11  
Placing  on the market  
An active substance shall only be placed on the market after it has been released for sale by 
the quality unit. 
Article 12 
Laboratory controls 
1. The manufacturer shall establish specifications  for the quality and pu rity of the active 
substances he manufactures and for the raw mate rials, active substance starting materials and 
active substance intermediates used in that process. 
2. Laboratory tests shall be conducted to ve rify compliance with  the specifications 
referred to in the first paragraph. 
The manufacturer shall i ssue certificates of analysis fo r each batch of active substance upon 
the request of: 
(a) the competent authorities of a Member State; 
(b) manufacturers of active substances supplied directly or indirectly with the active 
substance for the purpose of further processing, packing, repacking, labelling or relabelling the active substance; 
(c) distributors and brokers of active substances; EN 9   EN (d) manufacturers of medicinal pr oducts supplied directly or indirectly with the active 
substance. 
3. The manufacturer shall monito r the stability of the activ e substance through stability 
studies. Dates for the expiry or retest of activ e substances shall be set on the basis of an 
evaluation of data derived from the stability studies. Appropriately identified samples of the 
active substance shall be retained in accordance with a sampling plan established on the basis 
of the shelf-life of the active substance.  
Article 13 
Validation 
The manufacturer shall set up and implement a validation po licy for those processes and 
procedures that are critical to  ensure that the active substance meets the quality and purity 
specifications established in accordance with Article 12(1). 
Article 14 
Change control 
1. The manufacturer shall evaluate the poten tial impact on the qua lity of the active 
substance of any changes to the manufacturing process  that may affect the production and 
control of the active substance be fore implementing those changes.  
2. Changes to the manufacturing process  that negatively affect the quality of the active 
substance shall be not be implemented.  
3. The manufacturer of an activ e substance shall notify wit hout delay the manufacturers 
of medicinal products which he  supplies with the active substance of any changes to the 
manufacturing process  that may impact the quality of the active substance.  
Article 15 
Rejection and returns 
1. Batches of active substances and active subs tance intermediates failing to conform to 
the specifications established in accordance with Article 12(1) shall be rejected, labelled as 
such and quarantined.  
2. The manufacturer who reprocesses or reworks rejected batches of an active substance 
that do not conform to specificati ons, or recovers raw materials and solvents for re-use in the 
manufacturing process, shall follow the proced ures established in accordance with Article 
7(1) and shall perform appropriate  controls to ensure that:  
(a) the reprocessed or reworked active substance meets the quality specifications 
established in accordance with Article 12(1);  
(b) the recovered raw materials and solvents are suitable for their intended use in the 
manufacturing process. 
3. Returned active substances shall be  identified as such and quarantined. 
Article 16 
Complaints and recalls 
1. The manufacturer shall record and investigate all quality related complaints. EN 10   EN 2. The manufacturer shall estab lish procedures for the recall of active substances from 
the market.  
3. In the event of the recalled active substa nce posing a serious thre at to public health, 
the manufacturer shall inform the co mpetent authorities without delay. 
Article 17 
Contract manufacturing 
1. A manufacturing operation or an  operation linked thereto whic h is to be carried out on 
behalf of the manufacturer of  the active substance by another party (‘the contract 
manufacturer’) shall be the subject of a written contract. 
The contract shall clearly define the responsibil ities of the contract ma nufacturer with regards 
to good manufacturing practice.  
2.  The manufacturer of the active substance sh all control that operat ions carried out by a 
contract manufacturer comply with good manufacturing practice.   
3. A manufacturing operation or an  operation linked thereto wh ich has been entrusted to 
a contract manufacturer shall not be subcontracted to a third pa rty without the written consent 
of the manufacturer of  the active substance. 
Article 18 
Repackaging 
Where the active substance is repackaged by a ma nufacturer in a contai ner which differs from 
the original container with regard to its volume, or the material it is made of, or its opaqueness 
to light, he shall conduct stability studies on the active substance and assign an expiration or 
retest date for it on the basis of those studies. 
Article 19 
Entry into force 
This Regulation shall enter into  force on the twentieth day follo wing that of its publication in 
the Official Journal of  the European Union . 
It shall apply from [6 m onths after publication]. 
This Regulation shall be binding in  its entirety and directly applicable in all Member States. 
 
Done at Brussels, 
 For the Commission 
 The President