Products intended for use in clinical trials (late Phase II and Phase III studies) should as far as possible be manufactured at a licensed facility, e.g.:
• A pilot plant, primarily designed and used for process development.
• A small-scale facility (sometimes called a "pharmacy")1 separate both from the company's pilot plant and from routine production.
• A larger-scale production line assembled to manufacture materials in larger batches, e.g. for late Phase III trials and first commercial batches.
• The normal production line used for licensed commercial batches, and sometimes for the production of investigational pharmaceutical products if the number, e.g. of ordered ampoules, tablets or other dosage forms, is large enough.
1 Some manufacturers use the term "pharmacy" to designate other types of premises, e.g. areas where starting materials are dispensed and batches compounded.
The relation between the batch size for investigational pharmaceutical products manufactured in a pilot plant or small-scale facility to the planned full-size batches may vary widely depending on the pilot plant or "pharmacy" batch size demanded and the capacity available in full-size production.
The present guidelines are applicable to licensed facilities of the first and second types. It is easier to assure compliance with GMP in facilities of the second type, since processes are kept constant in the course of production and are not normally changed for the purpose of process development. Facilities of the remaining types should be subject to all GMP rules for pharmaceutical products.
Administratively, the manufacturer has yet another possibility, namely to contract out the preparation of investigational products. Technically, however, the licensed facility will be of one of the above-mentioned types. The contract must then clearly state, inter alia, the use of the pharmaceutical product(s) in clinical trials. Close cooperation between the contracting parties is essential.
Validated procedures may not always be available during the development phase, which makes it difficult to know in advance what critical parameters and in-process controls would help to control these parameters. Provisional production parameters and in-process controls may then usually be deduced from experience with analogous products. Careful consideration by key personnel is called for in order to formulate the necessary instructions and to adapt them continuously to the experience gained in production.
For sterile investigational products, assurance of sterility should be no less than for licensed products. Cleaning procedures should be appropriately validated and designed in the light of the incomplete knowledge of the toxicity of the investigational product. Where processes such as mixing have not been validated, additional quality control testing may be necessary.
Packaging and labelling
The packaging and labelling of investigational products are likely to be more complex and more liable to errors (which are also harder to detect) when "blinded" labels are used than for licensed products. Supervisory procedures such as label reconciliation, line clearance, etc., and the independent checks by quality control staff should accordingly be intensified.
The packaging must ensure that the investigational product remains in good condition during transport and storage at intermediate destinations. Any opening of, or tampering with, the outer packaging during transport should be readily discernible.
In the preparation of "blinded" products, in-process control should include a check on the similarity in appearance and any other required characteristics of the different products being compared.