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The way regulatory data is generated has continued to evolve in line with the ongoing development of supporting technologies such as the increasing use of electronic data capture, automation of systems and use of remote technologies; and the increased complexity of supply chains and ways of working, for example, via third party service providers. Systems to support these ways of working can range from manual processes with paper records to the use of fully computerised systems. The main purpose of the regulatory requirements remains the same, i.e. having confidence in the quality and the integrity of the data generated (to ensure patient safety and quality of products) and being able to reconstruct activities.

This Annex to the Guide to Good Manufacturing Practice for Medicinal Products (“the GMP Guide”) gives guidance on the taking and holding of reference samples of starting materials, packaging materials or finished products and retention samples of finished products.

This Annex provides guidance on the certification by a Qualified Person (QP) and on batch release within the European Union (EU) of medicinal products for human or veterinary use holding a marketing authorisation (MA) or made for export. The principles of this guidance also apply to investigational medicinal products (IMP) for human use, subject to any difference in the legal provisions and more specific guidance published by the European Commission.

Sampling is an important operation in which only a small fraction of a batch is taken. Valid conclusions on the whole cannot be based on tests which have been carried out on nonrepresentative samples. Correct sampling is thus an essential part of a system of Quality Assurance.

The manufacture of radiopharmaceuticals shall be undertaken in accordance with the principles of Good Manufacturing Practice for Medicinal Products Part I and II. This annex specifically addresses some of the practices, which may be specific for radiopharmaceuticals.

The manufacture of sterile products covers a wide range of sterile product types (active substance, excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.

Self inspections should be conducted in order to monitor the implementation and compliance with Good Manufacturing Practice principles and to propose necessary corrective measures.

Any activity covered by the GMP Guide that is outsourced should be appropriately defined, agreed and controlled in order to avoid misunderstandings which could result in a product or operation of unsatisfactory quality. There must be a written Contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. The Quality Management System of the Contract Giver must clearly state the way that the Qualified Person certifying each batch of product for release exercises his full responsibility.

In order to protect public and animal health, a system and appropriate procedures should be in place to record, assess, investigate and review complaints including potential quality defects, and if necessary, to effectively and promptly recall medicinal products for human or veterinary use and investigational medicinal products from the distribution network. Quality Risk Management principles should be applied to the investigation and assessment of quality defects and to the decision-making process in relation to product recalls corrective and preventative actions and other risk-reducing actions. Guidance in relation to these principles is provided in Chapter 1.

Quality Control is concerned with sampling, specifications and testing as well as the organisation, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control.