Reconstitution is the simple process of dissolving, dispersing, diluting, or mixing a pre-existing investigational medicinal product (IMP) with a vehicle immediately prior to its administration to a study participant. It is not treated as manufacturing in the EU guidelines and therefore does not fall under their GMP scope for IMPs. Nevertheless, it must be described in the clinical trial application dossier and in the documentation available at the clinical site.
Action at the Point of Administration
Reconstitution takes place close to the time of administration. Typical cases include dissolving a lyophilized product, diluting a concentrate, or dispersing a medicinal product for the specified application. The process is not intended to create a new IMP, but rather to make an existing product ready for use by the study participant.
The fact that reconstitution is not considered manufacturing does not mean that it may be carried out in an unstructured manner. Instructions for it must be defined in the clinical trial submission documents and be available to the clinical site. There, the responsible personnel require precise information on the solvent or vehicle, handling, and timing relative to administration that is suitable for the specific dosage form.
This distinction prevents the incorrect classification of activities. If actions at the site are blanketly assessed as manufacturing, they could be confused with the GMP obligations of the manufacturing site. Conversely, if they are treated as mere preparation without defined instructions, the basis for ensuring uniform administration and traceability within the trial process is lacking.
Documentation at the Clinical Site
For reconstitution, the description must not reside solely in a technical manufacturing file. It also belongs in the documentation available at the clinical site. This ensures that administration follows the same approved procedure, even if personnel change or multiple sites use the same dosage form.
Planning must take the practical workflow into account. A product that is only diluted shortly before administration may require different roles, facilities, and timing than a ready-to-use solution for injection. The clinical documentation should therefore clearly separate the action intended in the study from transport, storage, removal from packaging, and the actual administration.
In the event of a change to the intended reconstitution, it cannot be assumed that this only affects a local work instruction. Because the guideline lists reconstitution as part of the application dossier, the relationship to the approved trial status must be reviewed. This is significant, for example, if a different dilution volume, a different vehicle, or a different sequence of steps is intended.
Distinction from the Manufacturing of an IMP
Reconstitution presupposes that the IMP already exists before the process. Combining several components, including the active substance, to first manufacture the IMP is therefore not reconstitution. The rules on GMP, manufacturing and import authorization, and the associated batch documentation apply to this manufacturing process.
This distinction is particularly important for mixtures. Adding a vehicle to an existing IMP for administration can be reconstitution. If, on the other hand, the active substance and other ingredients are combined for the first time to form a product, the IMP is only created through the process. The designation therefore depends on the function and initial state, not on whether both activities colloquially appear to be “mixing.”
Relevance for clinical trials
Unclear reconstitution instructions can lead to different preparations and time intervals until administration between study sites. This directly affects the consistent implementation of the protocol and can complicate the assessment of administration processes. Particularly for products with a narrow time window after dissolution, the site documentation must be so specific that preparation is not based on individual interpretation.
Full-service CROs like Mediconomics provide support in transferring the approved reconstitution description into working documents suitable for clinical sites, in aligning them with training materials, and in checking that the protocol, application manual, and study logistics specify the same conditions. This helps to organize the activity—which is not classified as manufacturing—in a uniform and traceable manner.
The distinction also does not exempt the study site from training the persons performing the action. It merely characterizes the regulatory nature of the process and does not shift the responsibility for its correct application back to the GMP manufacturer.
Frequently Asked Questions (FAQ)
Is the dilution of an IMP always reconstitution?
It can be reconstitution if an existing IMP is diluted with a substance as a vehicle for administration. The process must take place close to the time of administration and be described in the study documents.
Why is reconstitution part of the application dossier?
The clinical trial must present the intended preparation of the product before use in a traceable manner. Furthermore, the corresponding information should be available to the clinical site.
Is the clinical site allowed to mix the active substance with other ingredients?
If this is what first creates the IMP, it is not reconstitution. This activity is to be classified as manufacturing and cannot be covered by a reconstitution instruction alone.
Regulatory References
- Detailed Commission guidelines C(2017) 8179 final, Section 1 – defines reconstitution and its boundary with manufacturing.
- Regulation (EU) No 536/2014, Article 2 – contains the definition of manufacturing for clinical trials.
- Regulation (EU) No 536/2014, Articles 61 and 63 – classifies manufacturing and GMP requirements for IMPs.