Here you will find answers to the following questions:
- What does the EC GMP Guideline mean by "release"?
- How is certification by a qualified person and release in accordance with appendix 16 of the EC GMP Guideline regulated?
- Which stages of the release procedure are there in practice?
In the EC GMP Guideline, the release relates to a designated batch of a medicinal product, which displays the results of a manufacture and control in accordance with the submission documents for marketing authorisation. Figure 14.J-1 release in the sense of the EC GMP Guideline is an active process carried out on the basis of a process description that must be documented within the analytical report and for which a responsible person is appointed.
Figure 14.J-1 The term" release" in the GMP Guideline
The term "release" in the GMP Guideline
Release as a component of quality assurance
"The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that medicinal products are not sold or supplied before a Qualified Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products;"
"The basic requirements of Quality Control are that no batch of product is released for sale or supply prior to certification by a Qualified Person that it is in accordance with the requirements of the Marketing Authorisation;" (chapter 1.4 VII)
"Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by the Qualified Person(s) in accordance with the requirements of Article 51 of Directive 2001/83/EC" (chapter 4.24)
Release of finished products
"Finished products should be held in quarantine until their final release under conditionsestablished by the manufacturer."
"The evaluation of finished products and documentation which is necessary before release ofproduct for sale are described in Chapter 6 (Quality Control)."
"After release, finished products should be stored as usable stock under conditionsestablished by the manufacturer" (Chapter 5.58-5.60)
Release as a component of test protocols
"The tests performed should be recorded and the records should include at least the following data: ...
h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person." (Chapter 6.17)
Release within contract manufacture/analysis
"The contract should describe clearly who is responsible for purchasing materials, testing and releasing materials, ...". (Chapter 7.12)
In the context of GMP however, facilities and equipment are also "released" for routine manufacture once maintenance, cleaning or qualification has been carried out (compare for example the supplementary guideline no. 15 for manufacture of medicinal gases: release of fill lines after cleaning), procedures and reports are "released" (compare PIC/S Pi 006, see chapter F.1 Recommendations on Validation Master Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning Validation (PIC/S PI 006)) or an "release" for further processing takes place for intermediate products after the in-process controls.
14.J.1 Certification by a Qualified Person and release
in accordance with EC GMP Guidelines
Appendix 6 of the EC GMP Guideline (see chapter C.6.16 Annex 16 Final Version: Certification by a Qualified Person and Batch Release - Certification by a Qualified Person and Batch approval) has been regulating details for the batch release procedure since January 2002.
To facilitate understanding, it is now wise to present the relevant EC directive regulations. EC directives are directives with very high enforceability. It is an obligation to transfer them within a national legal system.
Directive 2001/83/EC is concerned with a codification, in other words, it summarises several directives already issued in the area of medicinal products without making changes to their contents. The requirements quoted under chapter 14.J.1.1 Regulations contained in Directive 2001/83/ECof article 51 of Directive 2001/83/EC are already found in article 22 of Directive 75/319/EEC and are therefore more than 25 years old. The codification has not created new contents, it has just clarified the legislation that had to be adopted as national law.
14.J.1.1 Regulations contained in Directive 2001/83/EC
The guarantor function of a qualified person is within the manufacture and checks and in placing medicinal products on the market:
Qualified Person, shortened to: Q. P.).
The requirements for qualification of the qualified person can be found in Article 49. The requirement is an academic qualification including theory-based and practical study for a period of at least four years in the fields of pharmacy, medicine, veterinary medicine, pharmaceutical chemistry and technology or biology and at least two years in a company authorised to manufacture, working in the field of quantitative analysis of active pharmaceutical ingredients and further trials and testing to guarantee the quality of the medication. Credit is given for the amount of time spent in a company with such an authorisation to produce. Each member state must specify the corresponding minimum qualification that the qualified person must have. Furthermore, penalties must also be implemented against the qualified person (Article 52).
Even those applying for authorisation to produce must have at least one qualified person (Article 41 c), with the subsequent bearer of the authorisation unaffected (Article 48). This must be checked by the competent supervisory authority. The qualified person must be enabled to fulfil their tasks by the holder of the authorisation to manufacture. Excipients must be supplied for this purpose (Article 46).
The qualified person's tasks can be found in Article 51 of Directive 2001/83/EC. This directive ensures:
- that every batch of medicinal product produced in an EU member state is produced and checked in compliance with the law in force and in accordance with the market authorisation requirements.
- that quality standards are observed if the products are imported.
- that a document is produced to show this and that this certification is entered in a register or similar document.
Once this certification has been obtained and entered in a register, the batch may be released.
14.J.1.2 Objectives of appendix 16
Appendix 16 gives a detailed description of the procedure (in accordance with Article 51 of Directive 2001/83/EC) of the certification of a batch of finished medicinal products. The specific approach taken is the procedure which would apply when there are several companies/plants involved.
It is therefore no longer necessary to conduct the procedure in the member state for which the batch is going to be released. It is also permissible to conduct the release procedure in another EC/EEA member state, with which the EC has an MRA agreement.
The qualified person certifying the batch and the batch protocol must be quick and clear when a shortcoming is discovered or a batch is recalled.
The manufacture and inspection in stages and at various locations is seen to be the normal case. Duplicated work should be avoided if possible when trying to maintain the same level of medication safety. A repeat analysis on an imported product can be waived if certain prerequirements are met.
It is possible to transfer parts of the total responsibility for the batch, but only if other qualified persons then take the responsibility on and this was prearranged in writing.
In addition to the qualification in accordance with Article 49 of Directive 2001/83/EC, special knowledge and experience possessed by the qualified person about the product or the product group for which they are responsible for certifying are also expected. There is therefore an obligation to undergo further training before commencing a role with regard to a new product or pharmaceutical form.
Furthermore, any information relating to quality shortcomings in the batch must be forwarded to the qualified person who has undertaken to certify the batch. The qualified person is responsible for introducing the corresponding measures. Two key terms in appendix 16 have central importance: Confirmation and certification.
For the batch, a qualified person confirms that it was produced and checked in accordance with the law in force and the market authorisation requirements. The focal point of this confirmation will be details on the system according to which the medicinal product was manufactured. This confirmation can only cover a chapter: for example, when allocating bulk manufacture or an analytical procedure by proxy, the contract acceptor's qualified person can issue a confirmation for the chapters covered.
Appendix 16 states the minimum requirements for the confirmation.
Figure 14.J-2 Minimum requirements for the confirmation
Minimum requirements for the confirmation
- The batch and its manufacture must comply with the market authorisation requirements, and if necessary, an authorisation to introduce the product must also be held.
- The manufacture must have taken place in compliance with GMP.
- The most important manufacture and inspection processes must have been validated. The current conditions and protocols comply with specifications.
- Change Control procedures have been established and if necessary correctly carried out. If changes made during market authorisation or granting of manufacturing authorisation require official release, this has been issued.
- The manufacturing and inspection documentation is complete and has been signed by the people responsible.
- All quality audits were carried out in accordance with the requirements of the QA system.
- Any possible special occurrences were taken into account.
Certification of the finished product batch
A qualified person will carry out the procedure for a batch of finished medicinal products in accordance with Article 51 of Directive 2001/83/EC. The qualified person can obtain help from one or more Confirmations or one or more qualified persons, or perform the confirmation procedure himself. If all chapters have been confirmed), the certification will be made by making an entry in the register or a similar document. The batch in question is then released.
14.J.1.3 Cases of application
Various cases of co-operation with other qualified persons are set out in appendix 16 by way of example (see figure 14.J-4). A clear limitation of responsibilities must always be set out beforehand, e.g. in an SOP or in a contract.
Figure 14.J-3 Cases of application for appendix 16
Cases of application for appendix 16
- Manufacture in a production plant within the EC
- Manufacture in several production plants of a company or group within the EC
- Manufacture in several production plants owned by various legal persons within the EC
- Batches imported from third countries
- with MRS agreement
- without MRA agreement
Manufacture in a production plant within the EC
The company's appointed qualified person is responsible for the certification. It may be worked towards by other qualified persons who will then assume part of the responsibility, as far as this is possible in the QA system.
Manufacture in several production plants of a company or group within the EC
A qualified person must be appointed for each chapter, regardless of whether the companies are listed in one or several manufacturing permits.
The certification is carried out by the plant's qualified person, appointed by the holder of the permit.
The qualified person who undertakes the certification can assume total responsibility for all chapters or can use confirmations from other qualified persons. If various legal persons are involved, a contract will be required.
Manufacture in several production plants owned by various legal persons within the EC
A contract is required.The contract acceptor's qualified person can also use a confirmation issued by the contract giver's qualified person in this case. The qualified person is then, however, responsible for ensuring that the contract acceptor complies with the stipulations in the contract. The certification shall then be carried out by the contract giver's qualified person.
Batches imported from third countries
An importer must also have a permit and a qualified person.
- If the batch is imported from a country with which the EC has formed a mutual recognition (MRA) agreement, the qualified person for the importer can then rely on the confirmation issued by the manufacturer. A repeat analysis is not strictly necessary. The qualified person must also scrutinise the transport and storage conditions. The entry may not be made in the registry until the batch has arrived with the importer and it is confirmed that a negative influence on the batch during transport and storage has not taken place.
- If no MRA agreement has been made, an analytical investigation of samples in the EC/EEA will be a requirement before the qualified person can issue the confirmation for the batch. Importing, sampling, analytical investigations and if necessary further processing and certification may be carried out in various member states to do this.
14.J.2 Responsibility for issuing the release
The EC GMP Guideline shall transfer the release issued by the "qualified person", the PIC GMP Guideline shall transfer the release from the "authorised person". The release is a purely formal act, during which a check should be made to ensure that the production and quality control managers have signed their protocols correctly. In practice, the release is frequently transferred to the quality control manager, since this person normally has the total batch documentation once the manufacture and inspection are complete and can then conduct the checks to ensure that the final designations are correct. Naturally, the release can also be issued by the quality assurance department, which administers the batch documentation in many companies. In any case, the persons entitled to issue the release must be authorised to do so in writing, e.g. within the workspace designation (see chapter 2.A Place of work and job descriptions).
In the manufacturing contract between the contract giver and the contract acceptor, the responsibility for issuing the release must be clearly set out in the contract. If the release is issued by the contract giver, the contract acceptor must send them the manufacturing and inspection protocols so that the contract giver can ensure before the release that the production and quality control managers have signed correctly.
Regardless of all internal company regulations for the release, the public and legal responsibility for placing only released goods onto the market remains with the pharmaceutical company.
14.J.3 Publication of release
The publication of the "release" may not be carried out until both protocols have been properly signed. "Publication" means the physical identification of containers in situ and electronically changing the status of the goods, by connecting them to a stock management program, for example.
The change of status from "quarantine" to "released" is a critical step in a batch's history. Misidentifying a batch or changing the status of a batch prematurely can have serious consequences. For this reason, the release procedure in particular must be accurately described in procedural instructions and educated to others, like when changing the status of a batch in situ or in an electronic system.
If goods are physically identified in situ using a green label, for example, then the medicinal product name, the batch, the release date and the signature of the responsible person must be entered on the release label, so that if the label accidentally becomes loose, the batch is not misidentified.
If the batch is released using a computer-assisted system this process must by law be validated (see chapter 9 Computer Validation). The time when the release was issued, the person who issued the release and the status of the goods before their release must be stored in the system so that the release process can be understood at a later stage.
If several release labels are used, e.g. release for further processing, release for dispatch, release for investigational purposes, etc., the release for placing the product on the market must be clearly unmistakable from this other release.
The release documentation can be attached in the form of a special explanation of the batch documentation. Figure 14.J-4 contains an example of this.
Figure 14.J-4 Release documentation in accordance with section 7 of the Pharmaceutical Companies Ordinance
14.J.4 Release procedures in practice
For company reasons, it can be necessary to delegate the release to qualified persons in accordance with the general legal conditions. In large companies, the QA can be divided between several areas ("satellite system"). Accordingly, authorisations to take decisions on sections (raw materials, active pharmaceutical ingredients and excipients, intermediate products, packaging materials, semi-finished and finished products) is regulated separately. The responsibilities must be specified in an SOP. This SOP could look like this (figure 14.J-5.)
Figure 14.J-5 Responsibilities assigned per material
Responsibilities assigned per material
Active pharmaceutical ingredients
QC-P = QC for pharmaceutical products
QC-C = QC for active pharmaceutical ingredients
QC-PM:QC for packaging materials
For each section it will be necessary to set out the release procedure (content and responsibilities) in an SOP. Practice has shown that the release is best divided into different decision levels (release levels).
- Level technical decision
- Level 2 primary decision
- Level 3 secondary decision
The meanings of the above are:
Technical decision: Release on the testing laboratory level must be issued by the laboratory manager. This is confirmation that the batch was checked in accordance with released analytical procedures, all tests were conducted and all results were within spec. This is not a release for the market. It is imply a confirmation of the analytical section. The documentation should preferably be carried out using a computer system and (automatically) pointed analysis report.
Primary decision: This is a release issued by the QP (Qualified Person) or by a representative whom he has authorised to do this. It is confirmation that
- the manufacturing documentation is complete and no critical deviations occurred during the manufacture (deviation report)
- the batch record review is available and has been released
- the technical release has been issued, in other words, all the analyses have been carried out and none of the results are out of specification.
A computer-assisted system makes this documentation easier. In addition, an (automatic) printout of the certificate for the decision (certificate of analysis) was produced and has been signed and dated.
Secondary decision: If the batch is not released because there are deviations from the specified quality requirements (OOS) and/or manufacturing conditions (deviation report) (see chapter 14.H Out-of-specification results, chapter 11 Production, chapter 15 Documentation), an application for reconsideration can be justified and made. The Qualified Person (QP) or the person whom he has authorised can then take a secondary decision based on the results.
Decision to issue release: The material can then be released, quarantined or rejected at any stage. Further subcategories can be created within the company. It must be possible at all times to follow who carried out which status change at which point. In addition, the goods must be correspondingly marked and stored.
The change of status from "quarantine" to "released" is a critical step in a batch's history.
The EC GMP Guideline transfers the release from a "qualified person". Appendix 16 provides a detailed description of the release procedure which a finished medicinal product batch must undergo in accordance with Article 51 of Directive 2001/83/EC (or Article 22 of Directive 75/319/EC) before it is placed on the market. Elements of Directive 91/356/EC (quality assurance, documentation contract manufacturing) are taken into consideration for this purpose. The qualified person (QP) is assigned the main role in this procedureWays of avoiding duplication when several companies or factories are involved in manufacturing and/or analysing the product are shown to those involved.
A prerequisite to be satisfied before the decision to issue the release is taken is that the manufacture and analysis documentation must have been checked for completeness and to make sure that any deviations were recorded: all tests must be carried out and none of the results may be out of specification.
Three decision levels (release levels) can be distinguished. technical decision at level 1 = laboratory release; primary decision at level 2 = decision to issue release for market; secondary decision at level 3 = decision to issue release for market after an application for the batch to be reconsidered has been made.
The batch can be released, placed in quarantine or rejected.