Outsourcing Reformulation and Lifecycle Management: The Expanding role of CROs

Recent industry discussion has focused on moving contract research organizations (CROs) from the traditional role of supplemental capacity supplier to strategic and collaborative partner with pharmaceutical companies. Increasing needs to maximize the value of existing products as well as a rise in poor clinical-trial results attributable to formulation have led to redefined CRO–sponsor relationships and a greater reliance on CRO expertise in product reformulation and lifecycle management. Traditional pharmaceutical, specialty pharmaceutical, and biopharmaceutical companies must now shift their attention to product lifecycle management tactics from as early as preclinical development throughout market life (1, 2). Forward-thinking CROs provide strong evidence for the new dynamic by offering innovative solutions to product reformulation challenges for a variety of pharmaceutical dosage forms and by working to identify and execute strategies that are closely tied to client needs at every phase of the product lifecycle.

Exploring the CRO advantage

Industry trends depict an increasing percentage of strategic outsourcing by traditional Big Pharma companies—which are well regarded as experts in integrated brand-defense strategies—electing to rely on external expertise for complex formulations and product reformulation while retaining internal core competencies such as drug discovery and product commercialization (1, 3).

Small and medium specialty pharmaceutical companies as well as some biopharmaceutical companies rely on CRO expertise as a survival strategy in all aspects of product lifecycle management. CROs that have successfully aligned their capabilities to match increasingly complex client demands are positioned to provide sponsors with a competitive edge. Beginning as early as preclinical development, these CROs offer strategies for accelerating drug development such as expedited formulation and direct-fill of active pharmaceutical ingredient (API) into capsules for early clinical proof-of-concept studies. During prelaunch and the patent exclusivity period, CROs can work with sponsors to build prelaunch awareness and develop a product launch strategy that enables sponsors to maximize initial sales and product profitability through line extensions, product reformulation, and identification of new active ingredient forms. Finally, CROs can gather competitive intelligence and work with sponsors to develop a strategic plan for extending the patent exclusivity period through product reformulation, new dosing regimens, or novel delivery mechanisms.

Lifecycle management: no longer an option

Diminishing product pipelines, soaring drug development costs, strict regulatory requirements, and a competitive environment characterized by increasing generic competition define the current situation faced by pharmaceutical companies. Pharmaceutical companies must engage in product lifecycle management to exploit the full commercial potential of existing molecules and minimize the effect of generic competition. Fortunately, product reformulation and lifecycle management often increases benefits to consumers. To extend exclusivity, new products from existing branded products must show a clear, improved clinical benefit over existing products while ensuring safety and efficacy. These advantages may include enhanced kinetics, improved patient compliance, preferred dosing regimens, novel delivery systems enabling more accurate dosing or higher efficacies, improved safety profiles, new indications, or alternative dosage choices (1, 2).

Understanding that few blockbuster products achieve top sales based solely on initial formulations and indications, pharmaceutical companies have developed systematic brand management strategies to prolong marketability and maximize product revenue and have engaged in portfolio management to deliver maximum return on investments. A recent report states that 43% of global brand teams begin lifecycle management planning as early as Phase I development. Early planning has proven most beneficial in retaining market share, defending patents, and anticipating competitive threats. Strategies for the most active pharmaceutical brands target a new product launch every year after the initial product launch, which can result in as many as 10 product formulations or indications (4–6).

The business case for early adoption of product lifecycle management

The business case for new drug development is both difficult and risky, but the effective use of product lifecycle management strategies can reduce risk and increase opportunities for innovator companies of all sizes. For product lifecycle management to be most successful, the groundwork must be integrated early in the drug development process, as opposed to added on a few years before a patent expires. A diverse, cross-functional team working at the clinical stage enables companies to:

• select the optimal therapeutic indication;

• develop effective formulation strategies;

• manage intellectual property;

• gather competitive intelligence;

• understand payer policies;

• develop marketing messages;

• develop proactive regulatory strategies;

• use lifecycle management tactics to expand beyond the base indication of the initial product launch (2, 7).

Because all pharmaceutical brands are not equal, companies often use strategic models to predict the decline rate of brand revenues resulting from generic competition or they use multi-attribute models to determine the intrinsic potential for brand expansion. Seasoned innovators have learned through bitter experience that the best candidates for lifecycle management have strong barriers to entry built into the product design (product or class attributes), which makes prescribers or consumers less likely to switch brands (8).

This increased complexity reinforces the need for CRO expertise. Although established pharmaceutical companies will likely have access to a wide array of in-house resources, small and medium specialty pharmaceutical companies and biopharmaceutical companies must increasingly look outside company walls to gain access to the requisite expertise for optimal execution of a product lifecycle management strategy.

CRO strategies for accelerating drug development

Understanding that many pharmaceutical companies face aggressive drug development timelines, intelligent CROs have aligned their expertise, service offerings, and technology to accelerate the drug development process. An expedited formulation strategy is one example of a collaborative CRO–sponsor project to meet aggressive clinical development timelines through the alignment or dedication of critical formulation, analytical, and manufacturing contract resources. CROs have been able to reduce hard-capsule formulation development to 10.5 weeks to match shortened client timelines and deliver quicker first-in-human study results.

Similarly, pharmaceutical companies may seek strategic relationships with CROs to gain access to technologies for accelerating drug development. Partnering with a CRO can provide access to precision microdosing equipment that enables sponsors to move efficiently toward clinical proof-of-concept (e.g., chemical-in-capsule supplies for exploratory investigational new drug studies) or to achieve greater speed to first-in-human studies (e.g., API microdosing or over encapsulation). A recent US Food and Drug Administration guidance cites several advantages associated with exploratory investigational new drug studies, including the ability to identify promising drug development candidates earlier in the process, thereby reducing the time and resources devoted to drug development candidates that are unlikely to succeed. Direct encapsulation of API provides an expedited strategy to first-in-human studies and can be substantially more efficient than development efforts that result in a full formulation (9).

Strategies within the patent exclusivity period

Marketing, involving key opinion leaders, publication strategies, introducing new chemical entities to existing franchises, product repositioning, and making the decision to move from prescription to over-the-counter formulations are key strategies within the patent exclusivity period that often are retained internally by pharmaceutical companies. Marketing early on in the drug development process provides an opportunity for pharmaceutical companies to prepare the market and select the therapeutic indication and target segments that will maximize initial sales. Advisory boards consisting of thought leaders can provide market intelligence, identify unmet medical needs, shape clinical studies, improve message dissemination to key opinion leaders, and provide understanding of critical lifecycle issues. Postmarketing studies and publication strategies can be used to demonstrate scientific rationale and to increase consumer acceptance of existing products in new uses (6).

As the competitive landscape changes with the introduction of new chemical entities to existing franchises, companies should use product repositioning strategies to reduce the risk of cannibalizing existing product revenue streams and ensure distinct messaging. Finally, the decision to move from prescription to over-the-counter products can mitigate loss of market share to generics but can be limited to medications for nonserious conditions (10).

CRO strategies within the present exclusivity period

Pharmaceutical companies can find significant strategic advantage, however, by seeking external expertise for lifecycle management strategies, such as product reformulation, line extensions, and identification or characterization of new active ingredient forms. According to a recent report, pharmaceutical reformulation is an important defensive strategy that enables companies to maximize product return on investment in both the pre- and post-patent environment. Within the period of patent exclusivity, pharmaceutical companies can leverage CRO expertise in product reformulation to improve the manufacturing process, modify the release profile, develop alternative dosage forms, or provide access to innovative delivery technology. Potential benefits to pharmaceutical companies may include reduced operational costs because of improved manufacturing margins, the ability to add value to abandoned compounds with poor solubility or bioavailability through innovative formulations and the opportunity to extend the life of existing products by ten to fifteen years. Potential benefits to patients include options in route of administration, improved efficacy, greater tolerability, convenience, and increased compliance. In short, reformulation is one of the most classic and cost-effective strategies for maximizing product sales within the present exclusivity period (11).

Similarly, the depth and breadth of CRO experience may be used to strengthen the competitive position of pharmaceutical companies in selection of indications to maximize the label before patent expiry and for the identification and characterization of polymorphs, salt forms, co-crystals and hydrates that may have increased benefits or effectiveness with drug delivery technologies.

CRO strategies for extending the exclusivity period

Key strategies for extending the patent exclusivity period include product reformulation, alternative dosing regimens, novel delivery mechanisms, combining complementary in-house actives into a new product, combination products involving alliances between companies, creation of branded generics, and pediatric or orphan indications. A recent report indicates that product reformulation is the most cost-effective way to extend the lifeline of most brand-name therapies. With careful attention to patent expiration dates and intelligence about competitive products, sponsor pharmaceutical companies and CROs can work together to develop a strategic plan for extending the market life of an existing branded product through product reformulation. Key strategies focus on the reformulation of the drug product in novel ways and may include modifying the release profile, developing alternative dosing forms of the API for niche markets, or applying novel or proprietary delivery mechanisms to improve accuracy, efficacy, or patient compliance (6).

Combination products are another trend in the pharmaceutical industry because of rapid sales uptake, significant patent protection, and sufficient barriers for generic competitors. The complex nature of development objectives for combining complementary active ingredients into a totally new product is served particularly well by experienced CROs (5).

Branded generics provide an opportunity for pharmaceutical companies to partner with generics companies to soften the blow of market share erosion through partnerships. This strategy allows both sides to benefit from their respective core competencies.

Finally, deciding to pursue pediatric or orphan indications can be a strategy to extend the exclusivity period of a drug. The potential to maximize revenues, however, is often limited because of small market size or infrequent use (8).

Case study: iontophoretic drug delivery

The following case study exemplifies the integration of efforts by the pharmaceutical development services of MDS Pharma Services, engineering services, and a customer's product vision to produce a combination product.

Applying innovative and creative thinking was instrumental in the successful development of an iontophoretic system for Transport Pharmaceuticals' medical device. (Iontophoresis is the transdermal delivery of drugs by an electrical current.) The customer had established therapeutic efficacy in a Phase II trial and was developing a new treatment system which would enable patients to self-administer treatment. The project scope included formulation development of an antiviral topical cream, followed by the design and development of a dispensing and sealing process for a unit-dose drug cartridge as part of an iontophoretic drug delivery system.

The disposable sealed cartridge components were designed for a handheld device. The customer's medical device CRO designed and manufactured the receptacles, seal lidding, dispensing nozzle tips, and induction sealing carriers. MDS Pharma Services, the device CRO, and the customer worked in collaboration to develop the process and manufacture of the final product. MDS Pharma Services and the customer collaborated to establish methods and controls for the product.

The drug cartridge consisted of a plastic receptacle with an electrode and pad, cream that fills the pad, and a foil lid. Dispensing the cream onto the pad in the disk-shaped receptacle involved a unique ensemble of equipment for recirculation, heating, and dispensing. To ensure the reliability and accuracy of the filling process through the manufacturing run, it was necessary to reduce the viscosity of the bulk cream by heating and liquefying it for smooth flowability. A recirculation loop was included to ensure homogeneity.

The cream was manually dosed from the loop into a nonwoven pad in each receptacle using a stationary micromatic pipettor equipped with a 1-mL syringe and fitted with a Luer-Lock custom nozzle. Heaters were placed around the nozzle and pipettor barrel to maintain heated conditions throughout the dispensing process. Each receptacle was situated into a grooved cylindrical holding carrier for dispensing and sealing purposes.

One of many challenges was to achieve repetitive accurate dosing with even distribution of cream on the raised portion of the padded cartridge. Overfilling or irregular syringe ejections resulted in an excess of cream overflowing the pad, which interfered with the seal integrity. Therefore, it was critical to determine the appropriate fill volume for a sealed cartridge and to define the optimal distribution of cream in the pad. A series of experiments were performed to determine the processing temperatures, target fill weights, and the rate of dispensing to achieve the most desirable filling conditions. Several nozzle configurations were evaluated to measure the spread and penetration of the cream into the pad. Consistency of filling was then monitored by performing content uniformity on individual filled receptacles manufactured throughout the process.

An induction sealer hermetically sealed the filled receptacles. Following the filling of each receptacle, a foil-tabbed lid was positioned on the surface of the cream. The carrier containing the filled receptacle was then placed under the pneumatically driven sealing head, and the induction field melted the foil seal layer, thus bonding the receptacle rim. This aspect of the process required attention to the material composition and configuration of the lid. The performance of several lidding materials was evaluated by conducting tests for burst strength, peel integrity, and weight loss on lidded receptacles. The stability of the lids under accelerated conditions as well as freeze–thaw performance were evaluated. Sealing parameters for the induction sealing cycle and air pressure also were identified. A modification of the pressure pad in the sealing head was necessary to ensure a smooth, even surface for uniform sealing.

After identifying the correct materials and processing parameters, a demonstration batch was prepared to evaluate the feasibility of producing batch sizes that would meet the customer's needs. A production rate of more than 300 units per hour was established through careful layout of unit operations and dedication of personnel. This process was transferred from the laboratory to production under good manufacturing practices for the manufacture of clinical trial materials. The product is now in Phase III clinical trials.

Conclusion

Contract research organizations that understand the increasing complexity in today's pharmaceutical industry have positioned themselves to become more than a traditional capacity supplier. By closely aligning internal capabilities to client needs, these firms can provide a true competitive advantage in accelerating the drug development process, thereby maximizing product marketability within the exclusivity period and extending patent exclusivity for maximum profitability.

Michelle Hughes is a section head, Formulation Development, at MDS Pharma Services, and Kim Black-Washington is a product manager, Pharmaceutics, Biopharmaceuticals & Pharmacology, MDS Pharma Services, tel. 425.487.8282, kim.black-washington@mdsps.com

*To whom all correspondence should be addressed.

References

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