Successful Steps for Outsourcing the Manufacture of Clinical Trials Materials

One result of the new European clinical trials directive¹ has been more outsourcing of the manufacturing of clinical trial materials. These materials must meet current Good Manufacturing Practice (cGMP) requirements, which leads one to use the services of a contract manufacturing organization (CMO). Choosing the CMO who will become your partner for clinical trials manufacturing can be a time-consuming process. Finding a CMO with the appropriate combination of experience, reliability, reputation, and skilled staff, who can accommodate your manufacturing requirements in terms of scale, schedule, and cost, can be a daunting task. This article is a guide to smooth the road to the clinic.

Why Outsource?

Few companies nowadays build their own cGMP manufacturing facilities for clinical trials materials because the cost of building and maintaining such a facility can be prohibitive. It is far easier (and cheaper) to outsource this element of therapeutic development. Not only does it avoid expensive outlays on special equipment and staff, but also it allows companies to benefit from the variety and range of experiences built up by CMOs.

Working early with a CMO in the preclinical development phase can reap huge rewards. Close collaboration and consultation early on with an experienced manufacturing partner can actually help direct your efforts during preclinical development, and avoid unnecessary delays in progress to the clinical trials stage.

Mapping Your Route to the Clinic

The first critical step on the way to take a therapeutic candidate into clinical trials is to draw a road map. Even a simple Gantt chart will formulate a preliminary schedule for preparing cell and viral banks, followed by manufacture of the clinical trial material, leading to safety testing of that material, and ultimately, the delivery and administration of that material at the clinical trial site.

Firm up the schedule by considering the critical milestones within the various activities outlined. For example, funding of the clinical trial may be provided in a phased manner, and may be contingent on the success of the previous milestone. In a typical contract, funding may be available for the initial cGMP manufacture of the cell and viral banks, but the funding for the activities that come later in the schedule may not be released until those banks are fully tested and released by the CMO. Therefore, establishing which parts of the manufacturing program are on the critical path is an important exercise and should be performed early in the planning stages.

Work with your CMO to agree on the critical schedules and milestones. Make use of their project management skills, which will help both parties understand what must be done, and crucially, by what date to deliver material to the clinic.

Design of the Clinical Trial

Explore the following factors with the CMO to ensure that all regulatory, quality, and logistical implications are considered in the manufacturing of clinical trail material:

• size

• location(s) of the clinical trial

• duration

• schedule

• nature of administration.

Taking each of these factors in turn will be instructive.

Size of the Clinical Trial

The size of the trial will have a bearing on the scale of manufacturing that will be required. This is probably the most important topic to discuss with your chosen CMO as early as possible in discussions about manufacturing. Consider the number of patients in the trial, the dose that each will receive (and how this dose is calculated), the number of doses that will be administered to each patient, and what overage needs to be built in (to allow for vial breakage during transit or in the hands of the clinician).

Once the CMO knows how many doses it must deliver for the actual trial, the project manager can factor in how much additional material must be manufactured to allow for product testing requirements. When the total volume required has been determined, the CMO can advise on the most suitable manufacturing strategy to deliver the requisite amount. At this stage, you should also discuss the placebo requirements for the clinical trial (as these must also be made according to cGMP guidelines).

Location of the Clinical Trial

Depending on which country (or countries) the clinical trial is due to take place in, there may be varying regulations surrounding the testing that must be performed on the clinical trial material. This can have a bearing on the manufacturing process.

Certain tests may be performed on the final product in the form in which it would be delivered to the clinic (i.e., the final product containers). However, other tests will be required on the raw materials that go into the manufacture of the clinical trial material. The possible items are a long list: the cell bank, viral seed stock, viral bank, cell culture media, reagents, fetal bovine serum, downstream purification buffers, and formulation buffers.

Some tests will also be performed on the bulk in-process material before its final processing and filling. This means that the scale of manufacturing must be sufficiently large to yield enough material for the clinical trial and also any attendant testing.

Location can also have implications for the shipping logistics that will be involved in delivering material to the clinical trial site. These are good questions to consider:

• Under what conditions will the material be stored?

• Will it be lyophilized and stable at room temperature?

• Must it be stored and shipped frozen?

• What validation will be required to prove that shipping and storage conditions are not having deleterious effects on the clinical trial material?

• What will be the ambient temperature conditions, depending on what country the trial is taking place in?

• What distribution channels are available to ensure safe, efficient delivery of intact, functional clinical trial material?

Duration of the Clinical Trial

Estimate the duration of the clinical trial so that you can develop the right kind of stability study. This study provides supporting data for the functionality of the clinical trial material over the length of time that the investigational medicinal drug product will be held in storage before administration to the patient.

Schedule for Conducting the Clinical Trial

The target date for starting clinical testing is crucial. Work closely with the CMO to ensure you both agree on target date for delivering released product. You must also establish if the clinical trial date is a fixed date or if it is flexible. The start date may change if you need to wait until sufficient patient numbers are recruited into the trial, or if there is a delay in funding for the next milestone in the clinical development program. If the clinical trial date is not firmly fixed, you must consider the duration of the stability study that will be required to ensure that the latest possible date for patient administration will be covered by the supporting evidence.

Nature of Administration

Another crucial element of the clinical trial design for you and your CMO to discuss is how the investigational medicinal drug product will be administered to the patient. Is the CMO expected to provide the clinical trial material in the final dosage form, or will they simply manufacture the product to the stage of bulk drug substance for delivery to another company, or back to the sponsor, for the final formulation and filling stage?

Hold detailed discussions at this stage to determine the specification for the final product container, and how the CMO will ensure that the correct dose will be present in each container. For example, if a specific viral titer is to be delivered to each patient, how accurate will the volume be that is dispensed into each container, and has the extractable volume of the container been determined? If the clinical trial material is a liquid supplied in a glass vial, ask how much material will be left in the vial and in the holding volume in the syringe once the clinician has extracted the liquid from the vial.

If the trial is to take the form of a prime and boost delivery, then take appropriate measures to ensure that the stability study covers this lag phase between the first and last doses. Obviously, the manufacturing scale will also have to be larger if more than one dose is required per patient.

An area often overlooked in considering the final product container is the issue of filling validation. If the clinical trial material is to be supplied by the CMO in its final dosage form, then the CMO must undertake a filling validation to provide assurance that it is able to fill the requisite number of containers in an aseptic manner. The validation must also demonstrate that the correct volume of product is dispensed into each container, within an agreed and defined tolerance level.

Conflicting Demands of Robustness and Speed

There are always lively discussions between process development professionals and those on the business side who are overseeing the clinical development. It is understandable that the sponsoring company will be anxious to deliver the clinical trial material to the clinic as fast as possible. Many biopharmaceutical companies' entire business model is based on speeding a therapeutic candidate into the clinic as quickly as possible to establish the safety of the product and to confirm proof of principle, with the intention of partnering with a larger pharmaceutical organization to take the candidate forward into later-phase clinical trials (and hopefully through to commercial manufacture).

Compounding this need for speed is the fact that regulatory authorities do not insist on manufacturing early-phase clinical trial material using a fully validated manufacturing method. Everyone knows that validation will need to be performed for later-phase clinical trials (and certainly for commercial manufacture), but it can be tempting to avoid any extraneous expense and time in process development for a Phase 1 clinical trial.

The antidote is to use the services of the Qualified Person (QP) within the CMO to prepare for a clinical trial. The QP will help ensure that compliance is built into the manufacturing process for clinical trial material and avoid any nasty surprises with the regulators. The QP can advise on whether the proposed manufacturing strategy and proposed design of the clinical trial will be likely to be acceptable to the regulatory authorities.

Working with a QP will ensure that the trial design and manufacturing are appropriate for the stage that the therapeutic candidate has reached. The payoff is that you avoid any nightmare scenarios in which a sponsor has gone through cGMP manufacture of clinical trial material, but regulators have picked up some issue with regard to manufacturing, testing, or packaging that cannot be resolved. In the worst case, this could lead to the need to remanufacture the whole clinical trial investigational medicinal drug product, which would be a catastrophic waste of money and time.

Susan Cameron is a commercial scientist at BioReliance, Ltd., Glasgow, UK, +44.(0).141.579.3265, susan.cameron@invitrogen.com

Reference

1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official J Eur Communities 2001 Jan 5; L121:34-44.