Outsourcing Batch Release Testing

The provisions of article 20(b) of Directive 2001/83/EC as amended by point 18 of Directive 2004/27/EC allow the batch testing noted above to be contracted out to third parties provided the laboratories have been verified by the competent European authorities. Laboratories used for contract testing may be located in any European country or any country with a relevant MRA. European-based contract laboratories offer this service to virtual companies using contract manufacturing organizations based outside the region and to larger companies that do not possess the facilities or capacity to conduct the testing themselves. This is particularly true for biological products for which testing capacity is often located at the single site performing the worldwide manufacture, frequently in the US.

The facility that will conduct European batch release testing must be identified in the marketing authorization application (MAA) for the product. Therefore, if a company will need to outsource batch release testing, it must start the process of laboratory selection well in advance of the intended product launch. This selection process will follow the usual procedures for choosing an outsourcing partner, such as questionnaires, audits, and bid proposals, but also must include an assessment of the laboratory's accreditation under European GMPs and its suitability to handle the particular product type and its analytical tests.

Once the laboratory has been selected, the process of method transfer can start. The methods and specifications that will be used by the contract laboratory will be those detailed in the MAA; the manufacturer must maintain control of these documents throughout the testing period because any change made by the contracting laboratory could require regulatory approval. The first stage of maintaining this control is for the manufacturer to add the contractor to its in-house circulation list for methods and specifications. Thus, if any revision to these documents is required by the manufacturer, the revised document is automatically circulated to the contractor to ensure that it is using the current version. The timeliness of this circulation is critical.

Next, the contractor must have established procedures for preventing any deviation from the methods as supplied. If local instructions are needed by the contractor, for example to allow alternate suppliers of reagents, these instructions must require approval by the manufacturer.

The method transfer process itself can take a considerable period, potentially longer than the MAA review if complex, specialized assays are necessary. Establishing banks of cells required for in vitro potency testing or the purchase and validation of specialized equipment and software can be particularly time consuming. The partnership between the contract laboratory and the manufacturer must ensure that sufficient staff are trained to perform all the batch tests within the required time period throughout the year. This can be accommodated in the initial transfer, or an initial pool of staff can be trained with cascade training as the marketed batches start being tested. Whatever the approach, cascade training will be required during the lifetime of batch testing; there will be staff turnover and hopefully increasing market share for the product will mean more batches will require testing. Managing this cascade training is essential to ensure that there is no drift in the application of the methods.

Technical and Quality Agreements

Technical and quality agreements are a requirement of European GMPs, but the documents often are used to cover business aspects of the relationship as well. Agreements between the parties must define delivery notice periods and turnaround times for reporting results. The lines of communication, particularly for unexpected or out-of-specification results and deviations, must be clearly stated.

The agreement must be long term in nature, to protect both parties. For the contractor, a substantial commitment in resources will be made for the routine testing of batches, and a standard termination clause may not give the contractor time to replace the work. For the manufacturer, changing the testing laboratory would require an amendment to the MAA, so the termination clause must allow sufficient time for the manufacturer to do that. It is thus important to reflect the nature of the business in the termination clause. The agreement also must have a built-in review mechanism and establish a maximum period between reviews.