CHAPTER II GOOD MANUFACTURING PRACTICE

Article 3 Conformity with good manufacturing practice
1. The manufacturer shall ensure that manufacturing operations are carried out in accordance with good manufacturing practice for investigational medicinal products specified in this Regulation and subject to an authorisation as referred to in Article 61(1) of Regulation (EU) No 536/2014.
2. When importing an investigational medicinal products, the holder of the authorisation referred to in Article 61(1) of Regulation (EU) No 536/2014 shall ensure that the products have been manufactured by applying quality standards at least equivalent to those laid down by this Regulation and in Regulation (EU) No 536/2014, and that the third country manufacturer is authorised or entitled to in accordance with the laws of that country to manufacture that investigational medicinal products in that third country.

Article 4 Compliance with clinical trial authorisation
1. The manufacturer shall ensure that all manufacturing operations for investigational medicinal products are carried out in accordance with the documentation and information provided by the sponsor pursuant to Article 25 of Regulation (EU) No 536/2014 and as authorised in accordance with the procedure laid down in Chapter II, or if documentation and information was subsequently amended, in Chapter III of abovementioned Regulation (EU) No 536/2014.
2. The manufacturer shall regularly review his manufacturing methods in the light of scientific and technical progress and experience gained by the sponsor during the development of the investigational medicinal product.
The manufacturer shall inform the sponsor of his reviews of the manufacturing methods.
Where, following a review, an amendment to the clinical trial authorisation is necessary, the application for the amendment shall be submitted in accordance with Article 16 of Regulation (EU) No 536/2014 where the change to the clinical trial is a substantial modification or the amendment shall be carried out in accordance with Article 81(9) of that Regulation where the change to the clinical trial is not a substantial modification.

Article 5 Pharmaceutical quality system
1. The manufacturer shall establish, implement and maintain effective organised arrangements to ensure that the investigational medicinal products are of the quality required for their intended use. Those arrangements shall include the establishment of a good manufacturing practice and a quality control.
2. Senior management and personnel from different departments shall participate in the establishment of the pharmaceutical quality system.

Article 6 Personnel
1. At each manufacturing site, the manufacturer shall have a sufficient number of competent and appropriately qualified personnel at his disposal to ensure that the investigational medicinal products are of the quality required for their intended use.
2. The duties of managerial and supervisory staff, including the qualified persons, responsible for implementing and operating good manufacturing practice shall be set out in their job descriptions. Their hierarchical relationships shall be set out in an organisation chart. The organisation chart and the job descriptions shall be approved in accordance with 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 ongoing training covering in particular the following areas:
(a) the theory and application of the concept of pharmaceutical quality;
(b) good manufacturing practice.
The manufacturer shall verify the effectiveness of the training.
5. The manufacturer shall establish hygiene programmes, including procedures relating to health, hygiene practice and clothing of personnel. The programmes shall be adapted to the manufacturing operations to be carried out. The manufacturer shall ensure that the programmes are observed.

Article 7 Premises and equipment
1. The manufacturer shall ensure that premises and manufacturing equipment are located, designed, constructed, adapted and maintained to suit the intended operations.
2. The manufacturer shall ensure that the premises and manufacturing equipment are laid out, designed and operated in such a way as to minimise risk of error and permit effective cleaning and maintenance in order to avoid contamination, cross contamination and any other adverse effect on the quality of the investigational medicinal product.
3. The manufacturer shall ensure that those premises and equipment to be used for manufacturing operations which are critical to the quality of the investigational medicinal products are subjected to appropriate qualification and validation.

Article 8 Documentation
1. The manufacturer shall establish and maintain a documentation system recording the following, where appropriate having regard to the activities undertaken:
(a) specifications;
(b) manufacturing formulae;
(c) processing and packaging instructions;
(d) procedures and protocols, including procedures for general manufacturing operations and conditions;
(e) records, in particular covering the various manufacturing operations performed and batch records;
(f) technical agreements;
(g) certificates of analysis;
The documents specific to any investigational medicinal product shall be consistent with the product specification file as relevant.
2. The documentation system shall ensure the data quality and integrity. Documents shall be clear, free from error and kept up to date.
3. The manufacturer shall retain the product specification file and batch documentation for at least five years after the completion or discontinuation of the last clinical trial in which the batch was used.
4. When documentation is stored using electronic, photographic or other data processing systems, the manufacturer shall first validate the systems to ensure that the data will be appropriately stored during the period of storage laid down in paragraph 3. Data stored by those systems shall be made readily available in readable form.
5. The electronically stored data shall be protected against unlawful access, loss or damage of data by techniques such as duplication, back-up and transfer onto another storage system. Audit trails, meaning records of all relevant changes and deletions in those data, shall be maintained.
6. The documentation shall be provided to competent authority upon request.

Article 9 Production
1. The manufacturer shall carry out production operations in accordance with pre-established instructions and procedures.
The manufacturer shall ensure that adequate and sufficient resources are made available for the in-process controls and that all process deviations and product defects are documented and thoroughly investigated.
2. The manufacturer shall take appropriate technical or organisational measures to avoid cross contamination and unintentional mixing of substances. Particular attention shall be paid to the handling of investigational medicinal products during and after any blinding operation.
3. The manufacturing process shall be validated in its entirety, as far as is appropriate, taking into account the stage of product development.
The manufacturer shall identify the process steps that ensure the safety of the subject, such as sterilisation, and the reliability and robustness of the clinical trial data generated in the clinical trial. Those critical process steps shall be validated and regularly re-validated.
All steps in the design and development of the manufacturing process shall be fully documented.

Article 10 Quality control
1. The manufacturer shall establish and maintain a quality control system under the authority of a person who has the requisite qualifications and is independent of production.
That person shall have access to one or more quality control laboratories appropriately staffed and equipped to carry out the examination and testing of starting materials and packaging materials and the testing of intermediate and finished investigational medicinal products.
2. The manufacturer shall ensure that the quality control laboratories comply with information provided in the application dossier, referred to in Article 25(1) of Regulation (EU) No 536/2014, as authorised by Member States.
3. When investigational medicinal products are imported from third countries, analytical control in the Union shall not be mandatory.
4. During the final control of the finished investigational medicinal product, and before its release by the manufacturer, the manufacturer shall take into account:
(a) analytical results;
(b) production conditions;
(c) the results of in-process controls;
(d) the examination of the manufacturing documents;
(e) the conformity of the product with its specifications;
(f) conformity of the product with the clinical trial authorisation;
(g) examination of the final finished packaging.

Article 11 Retention of samples used for quality control
1. The manufacturer shall retain sufficient samples of each batch of bulk formulated product, of key packaging components used for each finished investigational medicinal product batch and of each batch of finished investigational medicinal product for at least two years after the completion or discontinuation of the last clinical trial in which the batch was used.
Samples of starting materials, other than solvents, gases or water, used in the manufacturing process shall be retained by the manufacturer for at least two years after the release of the investigational medicinal product. However, this period may be shortened where the period of stability of the starting material, as indicated in the relevant specification, is shorter.
In all cases samples shall be maintained by the manufacturer at the disposal of the competent authority.
2. Upon application of the manufacturer, the competent authority may grant a derogation from paragraph 1 in relation to the sampling and retention of starting material and for certain products manufactured individually or in small quantities, or when their storage could raise special problems.

Article 12 Responsibilities of the qualified person
1. The qualified person referred to in Article 61(2)(b) of Regulation (EU) No 536/2014 shall be responsible for the following:
(a) where investigational medicinal products are manufactured in the Member State concerned, verifying that each production batch has been manufactured and checked in compliance with the requirements of good manufacturing practice for investigational medicinal products laid down in this Regulation and the information provided pursuant to Article 25 of Regulation (EU) No 536/2014, taking into account the guidelines referred to in Article 63(1) of that Regulation;
(b) where investigational medicinal products are manufactured in a third country, verifying that each production batch has been manufactured and checked in accordance with quality standards at least equivalent to those laid down in this Regulation and the information provided pursuant to Article 25 of Regulation (EU) No 536/2014 taking into account the guidelines referred to in Article 63(1) of that Regulation.
The qualified person shall certify in a register or equivalent document provided for that purpose that each production batch complies with the requirements laid down in paragraph 1.
2. The register or equivalent document shall be kept up to date as operations are carried out and shall remain at the disposal of the competent authority for at least five years after the completion of or the formal discontinuation of the last clinical trial in which the product batch was used.

Article 13 Outsourced operations
1. Where a manufacturing operation or operation linked thereto is outsourced, the outsourcing shall be the subject of a written contract.
2. The contract shall clearly lay down the responsibilities of each party. It shall lay down an obligation for the party to whom the operations are outsourced to follow good manufacturing practice and set out the manner in which the qualified person responsible for certifying each batch is to discharge his responsibilities.
3. The party to whom the operations are outsourced shall not subcontract any of the operations entrusted to him under the contract without written consent from the contract giver.
4. The party to whom the operations are outsourced shall comply with the principles and guidelines of good manufacturing practice applicable to the operations concerned and shall submit to inspections carried out by the competent authority pursuant to Article 63(4) of Regulation (EU) No 536/2014.

Article 14 Complaints, product recall and emergency unblinding
1. The manufacturer shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints together with an effective system for recalling investigational medicinal products which have already entered the distribution network promptly and at any time. The manufacturer shall record and investigate any complaint concerning a defect and shall inform the sponsor and the competent authority of the Member States concerned of any defect that could result in a recall or abnormal restriction on supply.
All trial sites shall be identified and, in so far as possible, the countries of destination shall be indicated.
In the case of an authorised investigational medicinal product, the manufacturer shall, in cooperation with the sponsor, inform the marketing authorisation holder of any defect that could be related to that product.
2. Where blinding of investigational medicinal products is required by the protocol of a clinical trial, the manufacturer in conjunction with the sponsor shall implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall as referred to in paragraph 1. The manufacturer shall ensure that the procedure discloses the identity of the blinded product only in so far as it is necessary.

Article 15 Self-inspection by the manufacturer
The manufacturer shall conduct regular inspections as part of the pharmaceutical quality system in order to monitor the implementation and respect of good manufacturing practice. He shall take any necessary corrective action and to put in place any necessary preventive measures.
The manufacturer shall maintain records of all such inspections and any corrective action or preventive measures subsequently taken.

Article 16 Advanced therapy investigational medicinal products
The good manufacturing principles shall be adapted to the specific characteristics of the advanced therapy medicinal products when used as investigational medicinal products. Investigational medicinal products, which are at the same time advanced therapy medicinal products, shall be manufactured in accordance with the guidelines referred to in Article 5 of Regulation (EC) No 1394/2007.