Considerations When Outsourcing the Production of Clinical Material

June 1, 2008
Josée Ethier

Vice President of operations at Validapro Biosciences

Chantal Déziel

Director of business development and project management at Validapro Biosciences

BioPharm International, BioPharm International-06-01-2008, Volume 21, Issue 6

It is important to understand critical aspects of the CMO's capabilities. Only by auditing certain key areas can the sponsor be assured of the quality of the materials produced.

The selection of a contract manufacturing organization (CMO) can be a real challenge for many drug manufacturers. The situation is even more critical when clinical material is concerned, because of stringent regulations that must be followed while process development may still be in progress.

Josée Ethier

Thus, it is particularly important to understand the most critical practical aspects that must be considered when selecting a CMO for the production of clinical material.

The selection of a CMO usually is based on an audit conducted at the facility where the material is to be produced. The audit should include verification that the premises are adequate to manufacture the product at the scale required for the clinical trial, an evaluation of the quality systems in place, a review of personnel skills, and a review of the available equipment.

A few of the key areas to audit at a CMO include its containment strategy, its cleaning procedures, its change control process, its engineering department, and its management strategy.


Containment Strategy

The CMO's containment strategy should be reviewed, particularly if more than one manufacturing suite is available, and if both mammalian cells and bacteria or yeasts are used in the same facility.

The material, personnel, and waste flows should be examined to detect any possible risk of (cross-) contamination. This should include both verifying the operability of physical barriers, such as pressure cascades and airlocks, as well as the use of appropriate operation procedures designed to reduce the risks of (cross-) contamination.

Cleaning Procedures

Validated cleaning procedures must be developed for each product that will be handled by the CMO. The equipment used in biopharmaceutical processes should be dedicated to the type of host used (mammalian, bacterial, plant, etc.) to avoid any risk of cross-contamination.

The contract between the client and the CMO should specify who is responsible for developing the cleaning procedures and who is responsible for the preparation of the cleaning validation protocols.

Change Control Process

Because process development may not be completed when clinical material needs to be produced, one of the most important characteristics of a contract manufacturer is its capacity to manage process changes. The CMO must show evidence of its willingness and ability to adapt equipment, personnel, quality system, quality control, validation, and operations as needed.

For example, specific processes may require modifications in the standard operating procedures (SOPs) (e.g., modifications of environmental monitoring), so the quality system must be flexible to enable quick turnovers between product lines.

The CMO must also demonstrate flexibility in the equipment available for production. The equipment required may differ significantly depending on the process, and the sponsor should always review the scales and options available. Even if an automatic vial filler is available, for example, the CMO might not have the required adaptor for the vials used. Such a modification may also result in changes in the associated software, which would then require validation. Similarly, a bioreactor may show an adequate height-to-diameter ratio, but not be equipped with the appropriate mixing device. All those aspects should be reviewed, and the contract should specify who is responsible for acquiring the missing equipment as well as for the associated qualifications.

Engineering Department

A skilled engineering department is required to ensure the flexibility of equipment, services, and utilities. Equipment adaptation and even custom design may be required for the production of clinical material. Good contacts with suppliers of small-scale cGMP equipment, services, and utilities help perform the required modifications quickly, ensuring adherence to the established timeline. The CMO's engineering team can prepare technical specifications for modifications to be performed and either implement those changes itself or have a supplier modify the equipment accordingly.

Management Strategy

Once the CMO's compliance has been assessed and the sponsor is certain that contamination and cross-contamination can be prevented, it is time to look at the CMO's management strategy. The way a CMO is managed can seriously affect product quality as well as the cost of clinical trials.

All CMO personnel involved should be properly trained on cGMPs, technology transfer, regulatory requirements, and the management of clinical trials. A multidisciplinary team that includes representatives from all departments should be built. This team should be informed of the objectives, timelines, and budget for the project.

It is also recommended the sponsor be involved in all aspects of the technology transfer. Notwithstanding the application of the CMO's internal politics, a project manager should be on site as required and invited to observe all the steps of the manufacturing process.

The sponsor should require the CMO to demonstrate both the seniority of the personnel involved in the project and a low turnover rate of key personnel. Personnel stability is an indication of good management and ensures project continuity for the duration of the entire clinical phase.


Though challenging, choosing the right CMO is an important step in ensuring the quality of clinical materials. It is important to understand critical aspects of the CMO's capabilities. Only by auditing these key areas can the sponsor be assured of the quality of the materials produced.

Josée Ethier is the vice president of operations, and Chantal Déziel is the director of business development and project management, both at Validapro Biosciences, Laval, Quebec, Canada, 450.668.1144,