Evolution in the Era of New Biopharmaceuticals

New formats and formulations will change CMC requirements

By Kasper Jahn, Vidyadhar Ranade, Alberto Santagostino and Tobias Silberzahn, McKinsey & Company

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In the already diverse field of biopharmaceuticals, chemistry manufacturing and control (CMC) is about to get more complex. New formats and formulations will change CMC requirements, dictated by the need to characterize products of increased complexity and the expectation of authorities that companies will keep pace with the latest technologies so as to minimize quality risks.

The potential implied changes required for an effective CMC include: more extensive information handoffs, greater cross-functional cooperation and a greater focus on relationships with regulatory agencies. These trends will demand a rethinking of the CMC setup and an appraisal of its capabilities based on a company’s product pipeline.

Overarching requirements
Chemistry manufacturing and control, also called technical development, is the process that takes a molecule from research and turns it into a product that can be manufactured in a large-scale facility. In the course of its work, the CMC function is charged with satisfying all the necessary quality and regulatory requirements as well as delivering the product at the right cost (Exhibit 1).CMC Phase tasks

As a multidisciplinary, highly technical process, CMC encompasses a significant amount of risk. Ensuring that the function’s setup is tailored to the company’s pipeline is crucial in mitigating some of the risks, particularly those incurred through either delays in launch or increases in production cost.

For innovator drug substances, the cell line expressing the molecule and any development of pre-formulation needs to be handed over from research to the CMC function. This handoff must be a smooth transition to ensure that all of the information on drug substance, drug product and analytical development is transferred without knowledge loss. The CMC function then needs to build on this base to experimentally prove the purity of the molecule and the robustness of the production process, while increasing the scale toward commercial production levels.

The biopharmaceutical industry has graduated from synthesizing small peptides to generating full-fledged protein therapeutics routinely on a large scale. The industry is familiar with recombinant proteins that mimic endogenous agonists (interferon, insulin, growth hormones and so on). It is equally familiar with the big wave of monoclonal antibodies (mAbs). Both of these recombinant protein types have become common science in CMC’s standardized development processes with the introduction of platforms such as optimized expression systems and vectors.

But the landscape is quickly changing. Many new protein therapy formats are being developed and entering the market. From 2006 through 2013, the share of these new formats reached 11 percent of the pipeline and grew 33 percent year over year. Examples of these new therapeutics include the following:

• Biosimilars, sometimes called “follow-on biologics,” growing in number because high-revenue biopharma molecules are going off patent
Innovative formats/formulations
• Advanced-formulation products, which have a complex drug delivery formulation and are intended to improve pharmacodynamics and target the drug substance to specific areas
• Covalently modified biopharma-ceuticals, which are recombinant proteins modified to enhance their pharmacokinetics (PK) and PD; these formats are complex and require new capabilities that are at the interface of chemistry and biologic processes
• Antibody-drug conjugates, a subclass of covalently modified biopharmaceuticals that are gaining particular importance; in this case, the covalent modification redefines the mechanism of action of the mAb, creating the opportunity for a new level of drug potency (less drug is needed as it is delivered right to the place where it is intended to be active).

These emerging categories of therapeutics will place new demands on CMC. In this article, we will take a close look at the factors that biopharma CMC organizations need to master in order to succeed.

New Therapeutic Molecular Formats
Advanced-formulation products and biosimilars exemplify the new protein therapy formats that require an appraisal and rethinking of the CMC setup and capabilities.

Advanced drug formulations demand a high knowledge of the drug product, the drug substance and the interplay between the two. The added layer of complexity of these novel formulations increases the variability of the final product and the parameter space that needs to be controlled. CMC’s responsibility is to create data that clearly demonstrates the safety of these products in the light of the altered PK and PD.

The CMC process will have to be much more focused on the simultaneous codevelopment of drug product and drug substance as the interplay between the two becomes much more extensive than in more traditional biopharmaceuticals. Not only does the transition of knowledge from research have to be flawless for CMC to have the right starting point, but the capabilities to develop the novel formulations and characterize the formulations are more challenging.

In the same way that CMC must more tightly align with research, so must it sustain closer dialogues with regulatory agencies in order to confidently know what scientific evidence will be demanded prior to approval of novel products. In new areas, where regulators are often seeing a given drug delivery system for the first time, the approval process can be expected to be even more cautious and conservative than usual. CMC must be prepared to satisfy unusually extensive demands for scientific evidence.

Biosimilars must show low variability of the product, robustness of the processes, and true biosimilarity beyond any reasonable doubt. This requirement demands much more capacity for analytical testing. Because the “ask” for biosimilarity is rightfully high to avoid approval of products of inferior quality, many players shoot for having smaller variances than originators for critical process parameters and product specification.

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