Specifications (for starting materials, primary packaging materials, intermediate and bulk products and finished products), master formulae, and processing and packaging instructions may be changed frequently as a result of new experience in the development of an investigational product. Each new version should take into account the latest data and include a reference to the previous version so that traceability is ensured. Rationales for changes should be stated and recorded.
Batch processing and packaging records should be retained for at least 2 years after the termination or discontinuance of the clinical trial, or after the approval of the investigational product.
The order may request the processing and/or packaging of a certain number of units and/or their shipping. It may only be given by the sponsor to the manufacturer of an investigational product. It should be in writing (though it may be transmitted by electronic means), precise enough to avoid any ambiguity and formally authorized, and refer to the approved product specification file (see below).
Product specification file(s)
A product specification file (or files) should contain the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release, storage conditions and/or shipping. It should indicate who has been designated or trained as the authorized person responsible for the release of batches (see reference 2, page 18). It should be continuously updated while at the same time ensuring appropriate traceability to the previous versions.
In developing specifications, special attention should be paid to characteristics which affect the efficacy and safety of pharmaceutical products, namely:
• The accuracy of the therapeutic or unitary dose: homogeneity, content uniformity.
• The release of active ingredients from the dosage form: dissolution time, etc.
• The estimated stability, if necessary, under accelerated conditions, the preliminary storage conditions and the shelf-life of the product.1
1 See Annex 5.
In addition, the package size should be suitable for the requirements of the trial.
Specifications may be subject to change as the development of the product progresses. Changes should, however, be made in accordance with a written procedure authorized by a responsible person and clearly recorded. Specifications should be based on all available scientific data, current state-of-the-art technology, and the regulatory and pharmacopoeial requirements.
Master formulae and processing instructions
These may be changed in the light of experience, but allowance must be made for any possible repercussions on stability and, above all, on bioequivalence between batches of finished products. Changes should be made in accordance with a written procedure, authorized by a responsible person and clearly recorded.
It may sometimes not be necessary to produce master formulae and processing instructions, but for every manufacturing operation or supply there should be clear and adequate written instructions and written records. Records are particularly important for the preparation of the final version of the documents to be used in routine manufacture.
The number of units to be packaged should be specified before the start of the packaging operations. Account should be taken of the number of units necessary for carrying out quality controls and of the number of samples from each batch used in the clinical trial to be kept as a reference for further rechecking and control. A reconciliation should be carried out at the end of the packaging and labelling process.
The information presented on labels should include:
• The name of the sponsor.
• A statement: "for clinical research use only".
• A trial reference number.
• A batch number.
• The patient identification number.1
• The storage conditions.
• The expiry date (month/year) or a retest date.
1 This is not necessarily inserted at the manufacturing facility but may be added at a later stage.
Additional information may be displayed in accordance with the order (e.g. dosing instructions, treatment period, standard warnings). When necessary for blinding purposes, the batch number may be provided separately (see also "Blinding operations" on p. 106). A copy of each type of label should be kept in the batch packaging record.
Processing and packaging batch records
Processing and packaging batch records should be kept in sufficient detail for the sequence of operations to be accurately traced. They should contain any relevant remarks which increase existing knowledge of the product, allow improvements in the manufacturing operations, and justify the procedures used.
Coding (or randomization) systems
Procedures should be established for the generation, distribution, handling and retention of any randomization code used in packaging investigational products.
A coding system should be introduced to permit the proper identification of "blinded" products. The code, together with the randomization list, must permit proper identification of the product, including any necessary traceability to the codes and batch number of the product before the blinding operation. The coding system must permit determination without delay in an emergency situation of the identity of the actual treatment product received by individual subjects.