1. Purpose
The purpose of this procedure is to describe the accountabilities and single process for the batch confirmation, certification and release by a Qualified Person (QP) within the European Union (EU).
2. Scope and Applicability
Confirmation, certification and release processes for bulk production batches and finished product batches for supply into the EU (EC/EEA) market only.
Where national/local requirements are in place that conflict with this procedure, then these national and local requirements will apply.
3. Definitions
3.1 Bulk production batch
A batch of product, of a size described in the application for a Marketing Authorization, either ready for assembly into final containers or in individual containers ready for assembly to final packs. (A bulk production batch may, for example, consist of a bulk quantity of liquid product, of solid dosage form such as tablets or capsules, or of filled ampoules.)
3.2 Finished product batch
In the context of this procedure the term means the batch of products in its final pack for release to the market.
3.3 Part Finished production batch
In the context of this procedure the term means the different stages of manufacturing required to formulate a product batch prior to it being in its final pack for release to the market.
3.4 Certification of a finished product batch
The certification, in a register or equivalent document by a QP, as defined in Article 51 of Directive 2001/83/EC before a batch is released for sale or distribution.
3.5 Confirmation
An internal Certificate of Analysis or Certificate of Manufacture will be issued that confirms a process or test has been conducted in accordance with GMP and the relevant Marketing Authorization, as agreed in writing (QA Agreement) with the QP responsible for certifying the finished product batch before release.
3.6 Release for Sale
These are the tasks and activities performed in co-ordination with the certification of a batch by the QP. These can be performed under the delegated authority of a QP by an appropriate QA professional. These activities allow the product to be distributed. An example of such an activity is the generation and approval of a batch certificate.
3.7 Qualified Person
A Qualified Person (QP) is an individual who is accredited to release medicinal products to the European Union market, as defined in Articles 48, 49 and 51 of 2001/83/EC, and is named as such on the Manufacturer’s Authorization.
4. Responsibilities
4.1 It is the responsibility of each EU site to put in place procedures to support implementation of QP batch confirmation, certification and release, as defined in this International Procedure.
4.2 It is the responsibility of each site to communicate the accountabilities for product release to their National Inspectorate, as appropriate.
5. Guideline
Procedures are illustrated in flow sheets (appendix 1-2).
5.1 General
A QP within the EC/EEA must certify each batch of finished product before being released for sale or supply in the EC/EEA or for export. This is to ensure that the requirements of the marketing authorization for manufacture of the finished product batch have been checked.
The principles for Certification by a Qualified Person and Batch Release as outlined in Annex 16 to the EU Guide to Good Manufacturing Practice for Medicinal Products: “Certification by a Qualified Person and Batch Release” will apply. The QP when considering how to perform their duties required to certify a finished product batch will need to take into consideration the type and number of operations being performed.
On sites where the operations are many and complex and therefore it is not possible for the QP to take direct responsibility for all or some of these routine duties, the QP will rely on the knowledge and expertise of nominated delegated QA professionals known to him or her to carry out these activities.
The QP must ensure these tasks are performed satisfactorily. It has been recognized under EU legislation that, to support the QP in performing the certification of a finished product batch, the quality assurance units and systems need to be linked.
To reflect the fact that manufacture can take place over number of different manufacturing sites. This is referred to as confirmation where the QP will be dependent upon a manufacturing organization at another site outside their direct control.
The arrangements for which must be appropriately recorded between the manufacturing sites involved, with responsible QP for each stage. A batch certificate will be supplied from the intermediate sites to the final releasing site to demonstrate GMP and Licensing requirements. A register of QPs will be held centrally by QA.
5.2 Process
5.2.1 Each batch of finished product imported from a third country must be certified by a QP of the importer before release for sale in the EC/EEA.
5.2.2 Certification of a finished product batch against a relevant Marketing Authorization by a QP in the EC/EEA will not be repeated on the same batch provided that the batch has remained within the EC/EEA.
5.2.3 The overall manufacturing supply chain of a particular batch of product, regardless of how many sites are involved, will be understood by the QP who certifies that finished product batch before release. He/ She must be aware of the sites involved and be assured of the existence of QA agreements for the different intermediates.
5.2.4 Each QP who certifies a finished product batch for release will rely on confirmations by other QPs upstream in the supply chain for that finished product batch. This reliance will be based on confidence and knowledge of the corporate quality system.
5.2.5 Finished product batches will not be shipped ahead of QP certification, unless by prior agreement between QPs and only if adequate controls and agreements are put in place.
5.2.6 Each QP who confirms a bulk production batch or certifies a finished product batch for release is accountable for putting in place a QA Agreement with the receiver (i.e. production site for bulk production batches and registration holder for finished product batches). This is to ensure that QA accountabilities are clear, any local regulatory requirements are met and the key points of this procedure are recorded.
5.2.7 Each site will have in place a QP who is accountable for ensuring that there is a quality system in place. Before a batch is confirmed or certified for release(finished product batch) the QP or his nominated delegate is, for their stage of manufacture, accountable for ensuring that:
– The requirements laid down by Marketing Authorization Application (MAA)and Manufacturer’s Authorization (MA) requirements for the medicinal product have been met for the batch concerned.
– The principles and guidelines of good manufacturing practice as laid down indirective 91/356 and interpreted in the EC Guide to GMP have been followed.
– The principal manufacturing and testing processes have been validated.
– All the necessary checks and tests have been performed and account taken of the production condition and manufacturing records.
– Any planned changes or deviations in manufacturing or quality control have been notified in accordance with a well-defined reporting system before any product is released.
– Any deviations in manufacturing or quality control have been investigated in accordance with a well-defined system before any product is released.
– Any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes or deviations.
– All necessary Production and QC documentation have been completed and endorsed by Line Management, trained in appropriate disciplines.
– Appropriate audits, self-inspections and spot checks are being carried out by experienced staff.
– All relevant factors have been considered including any observations not specifically associated with the batch under review (e.g. sub-division to output batches from a common input, factors associated with continuous production runs and environmental controls).
– A finished product batch certification register is in place and retrievable.
– Information on batch confirmation when performed is to be retained and retrievable to support the finished product batch certification by the QP
– The legal requirements regarding imported products have been fully met.(Reference: 2001/83/EC, Article 51). This includes ensuring testing is performed within the EU/EEA to the requirements of the marketing authorization. Unless there is a mutual recognition agreement in place that allows for the acceptance of a manufacturing batch certificate.
– The arrangements in the QA agreement with the supplying site are verified and agreed.
5.2.8 Release for sale activities performed on behalf of the QP must be done in accordance with local procedures that have been reviewed and approved byte QP. Where deemed appropriate the name of the delegate performing the activity should be recorded. For example, the generation of a batch certificate.
5.2.9 Each Site will have the responsibility for ensuring the accuracy of the QP register for those individuals who are accredited as a QP.
5.2.10 The receiving warehouse will implement receipt procedures for verifying receipt order versus consignment, verifying transportation conditions and inspection for damage. Released bulk production batches and/or finished product batches will then be accepted without further checks, except those necessary to confirm that local legal requirements have been met.
5.2.11 The receiving warehouse will refer any inconsistency with respect to section 5.2.12 to the QP of the releasing site.
5.2.12 The QA function responsible for the batch release arrangements as described
in the Marketing Authorization holder will remain the key contact for the market and will be accountable for utilizing the appropriate systems designated in the relevant compliance Manual and in Quality Assurance Agreements.
5.2.13 Whatever particular arrangements are made for certification and release of
batches, it should always be possible to identify and recall without delay all products which could be rendered hazardous by a quality defect in the batch.
Appendix 1. Flow sheet: When all manufacture occurs at a single authorized site.
Appendix 2. Flow sheet: Different stages of manufacture are conducted at different sites.