Roman Hlodan
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After an innovator organization decides to take a candidate drug through to clinical trials, it faces key decisions relating
to managing the production and supply of material to the clinic. The requirements for progressing a drug through to clinical
trials include analytical characterization of the molecule, production of drug substance, manufacture of drug product, analytical
method development and validation, and formulation development of drug substance and drug product.
These requirements also must be managed so timelines for entry into the clinic are not compromised. Finding and managing a
supplier network that can meet all of these needs, through all of the phases of the clinical development program, raises the
challenge of managing a series of complex operations. It is highly unlikely that a single contract manufacturing organization
(CMO) will be able to provide all of the capabilities required to get a drug into clinical trials. Manufacturers who have
the expertise and capabilities to produce sufficient quantities of drug substance may have limited capabilities in the secondary
manufacture (fill–finish) of drug product. Conversely, companies with the expertise to manufacture the required dosage form
for the clinic will not necessarily be able to manufacture the drug substance. Having made its initial decisions about which
CMO to use, a company will have to consider potential limitations in any one contractor's capabilities as the pharmaceutical
development program progresses.
In managing its supplier network, an innovator organization may have to shift the balance of certain activities during the
course of a development program to make optimum use of the CMOs' strengths. In this article, we discuss the important factors
that a company will have to consider to alter the balance of activities between suppliers whose capabilities may be complementary
during the development program. Any changes to the formulation or the presentation of the biopharmaceutical product are an
important consideration in assessing when, or whether, such a change is necessary.
PARENTERAL PRODUCTS
Currently, the majority of biopharmaceutical products are parenterals. However, as discussed later in this article, a small
but increasing number of products are being developed for nonparenteral use.
With small (and in many cases, virtual) innovator companies developing parenteral biopharmaceutical products, the strategy
adopted tends to be enforced by the need to quickly obtain proof-of-concept data. This shapes the operations of a pharmaceutical
development program. The strategies for pharmaceutical development programs can be diverse, influenced by a number of factors.
These include:
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the nature of an organization and available resources. The constraints on a small or virtual biotechnology company are very different from those faced by a large pharmaceutical
company.
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the business model used by the organization. Is the intention to partner or sell the drug after successful completion of early-stage clinical trials, or does the organization
plan to commercialize the product?
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attitude to risk. A major concern is the risk to product stability while clinical trials are ongoing.
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the formulation of competitor products. In general, stable liquid formulations are more desirable than lyophilized formulations. Therefore, if a competitor product
already on the market is in a liquid form, then lyophilization may not be a viable option.
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timelines. A company typically is required to meet milestones and stakeholder expectations.
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cost. Limited funds may be available, especially in the current economic climate.
Table 1. Formulation options for taking a parenteral biopharmaceutical drug product through early-stage clinical trials
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A summary of the formulation options for taking a parenteral product into early-stage clinical trials, with some of the key
advantages and disadvantages of each, is provided in Table 1. When the selected formulation is a liquid, release testing and
stability studies typically will reside with either the drug substance manufacturer or the analytical services provider. For
early-stage programs, there is little point in incurring the additional costs of transferring analytical methods, or adding
to the complexity of a program in which timelines are invariably tight, especially if the drug product manufacturer has the
necessary skills to complement the competencies of the drug substance supplier and analytical services provider (models 1
and 2 in Table 2). Inevitably, this model may need to be reconsidered as the development program progresses through clinical
trials.
Table 2. Models for contracting out a pharmaceutical development program to a contract manufacturing organization (CMO)
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A formulation that may be adequate for early-stage clinical trials, such as a frozen liquid, is not necessarily suitable for
later-stage clinical trials and the marketed product. Also, a change in presentation may be required. In this case, a company
will not only need to decide which CMO is best placed to carry out the redevelopment of the formulation, but also the other
activities which may need to change as a consequence. Reformulation will require the revalidation of analytical methods to
establish their fitness for purpose in the new formulation. A new manufacturing process will need to be developed and validated.
A shift toward model 3 (Table 2) may, therefore, represent a better fit between the innovator company's requirements and the
CMOs' capabilities.
When the selected formulation is a lyophile, it is more likely that the formulation development will be carried out by the
drug product manufacturer. Consequently, to support the formulation development activities, an innovator company may have
more options and decisions to make about where it would be more practical and advantageous to revalidate analytical methods,
as well as carry out the subsequent release and stability testing. Formulation requirements for parenteral products are a
pivotal consideration in deciding how to manage the activities performed by CMOs. A proper understanding of their capabilities
is important in determining if, or when, to change the balance of activities from one CMO to another to try and achieve as
seamless a manufacturing process flow as possible.
