Tag Archives: Good manufacturing practice

Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

Outline of the Community (European Union) legislation about Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

Topics

These categories group together and put in context the legislative and non-legislative initiatives which deal with the same topic.

Internal market > Pharmaceutical and cosmetic products

Good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use

Document or Iniciative

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

Summary

Commission Directive 91/356/EEC laid down the principles and guidelines of good manufacturing practice* only for medicinal products* for human use. The majority of the provisions in Directive 91/356/EEC therefore had to be amended, extended and adapted in order to cover good manufacturing practice for investigational* medicinal products for human use. This Directive therefore repeals Directive 91/356/EEC in order to lay down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.

The principles and guidelines of good manufacturing practice relate mainly to personnel, premises and equipment, production, documentation, quality control and labelling, work contracted out, inspections, complaints and product recalls.

Quality assurance system: personnel, premises and equipment

The manufacturer implements an effective pharmaceutical* quality assurance system, involving the management and personnel of the various departments concerned.

At each manufacturing site, the manufacturer has personnel with the skills to achieve the pharmaceutical quality assurance objective.

The personnel receives regular training covering the theory and application of quality assurance and good manufacturing practice and the requirements for the manufacture of investigational medicinal products.

Hygiene programmes that are adapted to the activities to be carried out must be established. These must include procedures relating to the health, hygiene practice and clothing of personnel.

Premises and manufacturing equipment must also be subject to extremely strict hygiene standards in order to avoid contamination and any adverse effect on the quality of the product.

Moreover, premises and equipment used for manufacturing operations which are critical for the quality of the products must be subjected to appropriate validation.

Production

Production must be carried out in accordance with good manufacturing practice and must follow the pre-established instructions and procedures. Process deviations and product defects must be documented and investigated.

Technical and/or organisational measures must be taken in order to avoid, in particular, cross-contamination. In the case of investigational medicinal products, particular attention must be paid to the handling of products during and after any blinding operation*.

For medicinal products, new manufacturing processes and those that have been substantially changed must be validated, and critical phases of the manufacturing process must be regularly revalidated.

In the case of investigational medicinal products, at least the critical process steps, such as sterilisation, and if necessary the manufacturing process in its entirety must be validated.

Documentation

The manufacturer must set up a system of documentation covering the various manufacturing operations carried out. These documents trace the history of the manufacture of each batch and the changes introduced during the development of an investigational medicinal product.

Electronic or other data processing systems may replace written documents. In this case, the manufacturer must prove that the data will be appropriately stored during the period in question.

Quality control and labelling

The manufacturer must set up a quality control system. This system is placed under the authority of a person who has the requisite qualifications and is independent of production. This person has access to quality control laboratories in order to carry out the necessary examination of the starting materials and packaging materials and the testing of intermediate and finished products. Contract laboratories may be used if authorised.

During the final control of the finished product before its release, the quality control system must take into account the production conditions, the results of in-process controls, the examination of the manufacturing documents and the conformity of the product to its specifications.

Samples of each batch of finished medicinal product must be retained for at least one year after the expiry date. In the case of investigational medicinal products, samples of each batch of bulk formulated product and of key packaging components used for each finished product batch must be retained for at least two years after completion of the last clinical trial in which the batch was used.

In addition, samples of certain raw materials used in the manufacturing process must be retained for at least two years after the release of the product. This period may be shortened in certain cases.

For investigational medicinal products, labelling must be such as to ensure protection of the subject and traceability, facilitate proper use of the investigational medicinal product and allow identification of the product and trial.

Work contracted out

Any manufacturing operation must be the subject of a written contract between the contract giver and the contract acceptor. This contract sets out the responsibilities of each party. The contract acceptor must respect the principles and guidelines of good manufacturing practice and must submit to inspections carried out by the competent authorities.

Complaints, product recall and emergency unblinding*

Member States must set up inspections in order to ensure that manufacturers* respect the principles and guidelines of good manufacturing practice laid down by this Directive. They must also take into account Community procedures on inspections and exchange of information.

The manufacturer must ensure that manufacturing operations are carried out in accordance with good manufacturing practice and with the manufacturing authorisation, including medicinal products intended for export. Regular self-inspections must be conducted in order to monitor compliance with good manufacturing practice and, if necessary, to propose corrective measures.

For the purposes of interpreting the principles and guidelines of good manufacturing practice, the manufacturers and the competent authorities must refer to the guidelines set out in the “Guide to good manufacturing practice (GMP) for medicinal products and for investigational medicinal products” , published by the Commission.

With regard to medicinal products and investigational medicinal products imported from third countries, importers must ensure that their manufacture conforms to standards equivalent to the good manufacturing practice developed by the Community. Moreover, an importer of medicinal products must ensure that the persons manufacturing these are authorised manufacturers, and an importer of investigational medicinal products must ensure that their manufacturer is notified to the competent authorities and accepted by them.

To place a medicinal product on the market in a Member State, a marketing authorisation must be granted by the competent authority of that Member State or by the European Agency for the Evaluation of Medicinal Products. The manufacturer must ensure that medicinal products are manufactured in accordance with the information provided in the application for marketing authorisation as accepted by the competent authorities.

With regard to investigational medicinal products, the manufacturer must ensure that they are manufactured in accordance with the information provided by the sponsor and accepted by the competent authorities.

For both medicinal products and investigational medicinal products, the manufacturer must examine and record complaints regarding a defect. He must inform the competent authority of any defect that could result in a recall or restriction on supply and indicate the country of destination. In the case of investigational medicinal products, he must also indicate the trial sites.

For investigational medicinal products, the sponsor must implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall. The sponsor must also ensure that the procedure discloses the identity of the blinded product only in so far as is necessary.

Key terms in the Act
  • Good manufacturing practice: the part of quality assurance which ensures that medicinal products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.
  • Medicinal product: any product as defined in Article 1(2) of Directive 2001/83/EC.
  • Investigational medicinal product: any product as defined in Article 2(d) of Directive 2001/20/EC.
  • Manufacturer: any person engaged in activities for which the authorisation referred to in Article 40(1) and (3) of Directive 2001/83/EC or the authorisation referred to in Article 13(1) of Directive 2001/20/EC is required.
  • Pharmaceutical quality assurance: 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.
  • Blinding: the deliberate disguising of the identity of an investigational medicinal product in accordance with the instructions of the sponsor.
  • Unblinding: the disclosure of the identity of a blinded product.

References

Act Entry into force Deadline for transposition in the Member States Official Journal
Directive 2003/94/EC 20 days after publication in the Official Journal (04.11.2003) 30.04.2004 OJ L 262, 14.10.2003

Related Acts

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency [Official Journal L 136, 30.04.2004].

Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use [Official Journal L 136, 30.04.2004].

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 [Official Journal L 311, 28.11.2001].

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use [Official Journal L 121, 01.05.2001].

Good manufacturing practice for veterinary medicinal products

Good manufacturing practice for veterinary medicinal products

Outline of the Community (European Union) legislation about Good manufacturing practice for veterinary medicinal products

Topics

These categories group together and put in context the legislative and non-legislative initiatives which deal with the same topic.

Internal market > Pharmaceutical and cosmetic products

Good manufacturing practice for veterinary medicinal products

Document or Iniciative

Commission Directive 91/412/EEC of 23 July 1991 laying down the principles and guidelines of good manufacturing practice for veterinary medicinal products.

Summary

Veterinary medicinal products manufactured or imported into the Community, including those intended for export, must be manufactured in accordance with the principles and guidelines of good manufacturing practice *.

The principles and guidelines primarily concern personnel, premises and equipment, production, documentation, quality control, contracting out, and inspections, complaints and product recall.

Quality assurance system: personnel, premises and equipment

Manufacturers * must set up an effective pharmaceutical quality assurance system *, involving the management and personnel of the various services concerned.

At each manufacturing site, the manufacturer must have persons responsible for implementing the good manufacturing practice, who have the expertise required to achieve the objective of pharmaceutical quality assurance.

Personnel must receive regular training, covering the theoretical and practical aspects of quality assurance and good manufacturing practice.

Hygiene programmes adapted to the activities must be established, including procedures relating to health, hygiene and clothing of personnel.

Premises and equipment must also be subject to strict hygiene standards in order to prevent contamination and any adverse effect on the quality of products. Moreover, premises and equipment to be used for manufacturing operations which are critical for the quality of the products must be checked for suitability.

Production

Production must be carried out in accordance with good manufacturing practice and must follow the pre-established instructions and procedures.

Technical or organisational measures must be taken in order to avoid, in particular, cross-contamination.

New manufacturing processes and those that have been substantially changed must be validated, while critical phases of the manufacturing process must be regularly revalidated.

Documentation

Manufacturers must use a system of documentation covering the various manufacturing operations performed. These documents trace the history of the manufacture of each batch.

Electronic or other data processing systems may replace written documents. In this case, the manufacturer must prove that the data will be appropriately stored during the period in question.

Quality control

Manufacturers must have a quality control department at their disposal. This department must be placed under the authority of a person independent of the other departments and having the required qualifications. It must have at its disposal one or more quality control laboratories appropriately staffed and equipped to carry out the necessary testing of the raw materials and packaging materials and the intermediate and finished products. Resorting to outside laboratories may be authorised.

During the final control of finished products before their release for sale or distribution, the quality control department must take into account, in particular, production conditions, results of in-process controls, the examination of the manufacturing documents and the conformity of products with their specifications.

Samples of each batch of finished products must be retained for at least one year after the expiry date. In addition, samples of certain raw materials must be retained for at least two years after the release of the product. This period may be shortened in certain cases.

Work contracted out

Any manufacturing operation must be the subject of a written contract between the contract giver and the contract acceptor. This contract must set out the responsibilities of each party. The contract acceptor must respect the principles and guidelines of good manufacturing practice and must submit to inspections carried out by the competent authorities.

Inspections, complaints and product recall

Member States must set up regular inspections in order to ensure that manufacturers respect the principles and guidelines of good manufacturing practice laid down by this Directive.

Manufacturers must ensure that the manufacture of medicinal products complies with good manufacturing practice and with the manufacturing authorisation. Regular self-inspections must be conducted in order to monitor the respect of good manufacturing practice and, if necessary, to propose corrective measures.

The competent authorities of each Member State must prepare reports on the observance of good manufacturing practices, which must be communicated upon request to the competent authorities of another Member State.

For the interpretation of the principles and guidelines of good manufacturing practice, the manufacturers and the competent authorities must refer to the guidelines set out in the “Good manufacturing practice guidelines” (EN).

With regard to veterinary medicinal products imported from third countries, importers must ensure that their manufacture conforms to standards equivalent to the good manufacturing practice developed by the Community. In addition, they must ensure that the persons manufacturing these are authorised manufacturers.

Manufacturers must set up a system for recording and reviewing complaints together with an effective system for recalling promptly the veterinary medicinal products in the distribution network. They must examine and record complaints regarding a quality defect, and must inform the competent authorities of any quality defect that may result in a recall or abnormal restriction on the supply. They must also indicate the countries of destination.

Key terms in the Act
  • Good manufacturing practice: 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.
  • Manufacturer: any holder of the authorisation referred to in Article 44 of Directive 2001/82/EEC.
  • Pharmaceutical quality assurance: the sum total of the organised arrangements made in order to ensure that veterinary medicinal products are of the quality required for their intended use.

References

Act Entry into force Deadline for transposition in the Member States Official Journal
Directive 91/412/EEC 20 days after publication in the Official Journal 23.07.1993 OJ L 228, 17.08.1991.

Related Acts

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency [Official Journal L136, 30.04.2004].

Directive 2004/28/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/82/EC on the Community code relating to veterinary medicinal products [Official Journal L 136, 30.04.2004].

Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use [Official Journal L 311 of 28.11.2001].

Good manufacturing practice for materials and articles intended to come into contact with food

Good manufacturing practice for materials and articles intended to come into contact with food

Outline of the Community (European Union) legislation about Good manufacturing practice for materials and articles intended to come into contact with food

Topics

These categories group together and put in context the legislative and non-legislative initiatives which deal with the same topic.

Food safety > Contamination and environmental factors

Good manufacturing practice for materials and articles intended to come into contact with food

Document or Iniciative

Commission Regulation (EC) No 2023/2006 of 22 December 2006 on good manufacturing practice for materials and articles intended to come into contact with food.

Summary

This Regulation establishes “good manufacturing practice *” for materials and articles intended to come into contact with food.

“Good practice” harmonises manufacturing procedures in the European Union for the aforementioned materials at all stages of production, from manufacture to distribution.

Manufacturers must establish a quality assurance system and a quality control system (see below) following the detailed manufacturing regulations, for example the processes involving printing inks.

Materials in contact with food include objects such as containers and packaging, but also all materials in contact with foodstuffs, such as paper and cardboard or those which could possibly transfer their constituents to food, for example inks and adhesives.

Annex 1 to Regulation (EC) No 1935/2004 includes a list of the materials covered by this Regulation: active and intelligent objects, adhesives, ceramics, cork, rubbers, glass, ion-exchange resins, metals and alloys, paper and cardboard, plastics, printing inks, regenerated cellulose, silicones, textiles, varnishes and coatings, waxes and wood.

Quality assurance system and quality control system

This Regulation includes an obligation for manufacturers to implement a quality assurance system (taking account of the personnel required to put the system in place and the size of the business), as well as a quality control system. The latter provides for measures to be taken should a business fail to comply with good manufacturing practice.

In addition, manufacturers shall create and maintain documentation regarding the specifications, manufacturing formulae and product processing which are important for the compliance and safety of the finished article, as well as those related to the various manufacturing operations. They are required to make the documentation available to the competent authorities at their request.

Key terms of the Act
  • ‘good manufacturing practice (GMP)’ means those aspects of quality assurance which ensure that materials and articles are consistently produced and controlled to ensure conformity with the rules applicable to them and with the quality standards appropriate to their intended use by not endangering human health or causing an unacceptable change in the composition of the food or causing a deterioration in the organoleptic characteristics thereof.

References

Act Entry into force Deadline for transposition in the Member States Official Journal
Regulation (EC) No 2023/2006

18.1.2007

OJ L 384 of 29.12.2006

AMENDMENTS TO THE ANNEXES

Annex – Detailed rules on good manufacturing practice
Regulation (EC) No 282/2008 [Official Journal L 86 of 28.3.2008].