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Formulation strategy is an important consideration when selecting and managing outsourced biopharmaceutical development programs.
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.
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:
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 1. Formulation options for taking a parenteral biopharmaceutical drug product through early-stage clinical trials
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.
Table 2. Models for contracting out a pharmaceutical development program to a contract manufacturing organization (CMO)
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.
Although currently a relatively small percentage, more biopharmaceuticals are being developed for indications such as wound healing or certain allergies that would require topical or local administration. A growing number of monoclonal antibody (MAb) derived molecules also are being developed. This is a trend that is expected to increase. Although MAbs have many benefits as therapeutic agents, the development of full-sized MAbs is not without significant challenges and disadvantages, from the high cost of goods, to the limited options for delivery to patients. The development of smaller MAb fragments offers the possibility of alternative routes of administration, which, in turn, require the development of suitable formulations.
Manufacturing a nonparenteral dosage form requires the consideration of other factors that would not arise with the manufacture of parenteral drug products. These factors include the required form of the drug substance (solid or liquid), differences in the approach to formulation development, revalidation of analytical methods, and manufacture.
Requirements of the Drug Substance
For parenteral preparations, the drug substance will be provided in a liquid form, which may need to be reformulated for the drug product. With other more conventional dosage forms, the drug substance may have to be supplied as a solid for use in manufacture. This raises two questions for the innovator organization.
First, the solid form for the drug substance must be considered. Is it best to supply the drug substance as bulk lyophilized or spray-dried material? Is the drug substance sufficiently stable so that it can be processed into the required solid form? It may be that the importance of selecting the most appropriate solid form of the drug substance for a given program must to be established on a case-by-case basis, taking into account both the ability to formulate and manufacture the drug substance into the solid and the compatibility of the bulk solid form with the formulation and manufacture of the required dosage form. This is an area that is relatively uncharted and could therefore pose unknown challenges.
The second question is whether the biopharmaceutical drug substance manufacturer has the capabilities to produce the required (intermediate) form of the material in the quantities required for clinical trials supply and beyond.
Requirements for Formulation Development
These formulations are likely to be more complex than the relatively simple buffer systems typically developed for parenteral products. It is very unlikely that a drug substance manufacturer will have the expertise and the capabilities to formulate a wider range of dosage forms. In this situation, the formulation development and subsequent activities, including re-validation of the analytical methods, would be best placed with a CMO which has the required specialist capabilities.
Analytical methods for nonparenteral dosage forms will almost certainly need to be redeveloped and revalidated. In all likelihood, the formulation will not be readily compatible with the methods commonly used for protein analysis. There is a strong possibility of matrix components interfering with the analysis. The development of a suitable method of extraction of the drug substance from the matrix also may be required. The innovator organization may be faced with a choice in relation to where the method (re-)development and (re-)validation activities for drug product are now best carried out.
If the initial method development and validation for drug substance have already been carried out by an analytical contractor laboratory or a drug substance CMO (models 1 and 2 in Table 2, respectively), then the cost and time taken for methods transfer to a drug product CMO (model 3 in Table 2) must be assessed against the potential benefit of bringing together all of the drug product development and manufacturing activities under one roof.
Currently, it is unlikely that a drug substance CMO also will have the capabilities to manufacture drug product for clinical trials in the potentially wide range of formulations or presentations that may be required for nonparenteral dosage forms. For parenteral products, the final step of drug substance manufacture would involve concentration and exchange into a suitable buffer. Typically, the drug substance solution can then be filled directly into vials, requiring dilution with the formulation buffer beforehand. The additional manufacturing capabilities required for the production of nonparenteral dosage forms are likely to be beyond those that are to be found with drug substance CMOs.
When embarking on a pharmaceutical development program, an innovator organization will have to make decisions about how key development operations are contracted out. These decisions can be complex because CMOs will have complementary and partially overlapping capabilities, and constraints in terms of scale of manufacture. The initial choice of CMO to provide drug substance and drug product may be sufficient for early-stage clinical trials. Often, for parenteral dosage forms, formulation development, analytical method development, and validation, release, and stability testing are carried out by the drug substance manufacturer, and the fill–finish operations are performed by the CMO. The amount of effort spent trying to optimize the formulation and presentation of the drug product so that it is fit for purpose for early-stage clinical trials must be considered in the broader context of business and resource constraints. This arrangement is common and may work for early-stage development. However, should the pharmaceutical development program progress beyond Phase 1–2 clinical trials, the innovator organization faces a further set of decisions. It is at this stage, when there is confidence in the potential efficacy of the drug, that changes to the formulation and presentation are likely to be made so that they are more suitable for late-phase clinical trials or for a marketed product.
To ensure regulatory compliance, these changes also will require revalidation of analytical methods. The requirements of increased scale of manufacture must considered. The innovator organization must determine whether its CMO network can meet the requirements for later stage clinical trials and beyond, or if the balance of manufacturing or development activities must be shifted.
Roman Hlodan is a biopharmaceutical specialist in pharmaceutical development services at Patheon UK Ltd., Swindon, UK, +44 (0)1793 501273, firstname.lastname@example.org.