November 1, 2015 (Vol. 35, No. 19)
A Nip Here, a Tuck There Can Keep Critical Quality Attributes from Sagging
With the first U.S. biosimilar approval, for Zarxio (filgrastim-sndz) in March, it is still too early to write a “lessons learned” article on the manufacture of molecules formerly known as “follow-on biologics.”
According to the Generics and Biosimilars Initiative, the manufacture of biosimilars is more challenging than for small-molecule generics because investments and operating costs for biosimilars, coupled with the risk of failure, are significantly higher than for generics. Thus the relatively small discount for biosimilars compared with generics. Manufacturers are expected to discount biosimilars by 15% to 35%, compared with up to 90% for small-molecule generics. Still, experts predict that biosimilars could save the U.S. healthcare system as much as $40 billion over the next decade.
GEN readers are familiar with the other main manufacturing hurdle for biosimilars, that relatively minor changes in manufacturing processes may significantly affect product quality and/or safety, or the criteria by which similarity is determined. “The process is the product” revisited.
As with their reference biologics, biosimilars are complex molecules derived from living cells with inherent variability. Developing biosimilars involves several steps, including the selection of an appropriate reference biologic, understanding its key molecular attributes, and designing a suitable manufacturing process. EMA and FDA guidances require that biosimilars undergo rigorous evaluation for similarity in lieu of conducting extensive preclinical and clinical studies. Demonstrating similarity is an extensive comparability exercise, while achieving and maintaining similarity requires a tightly controlled manufacturing process.
“Molecularly, to develop a biosimilar of an advanced biologic, scientists conduct an in-depth analysis of the originator biologic and steadily isolate the critical quality attributes (CQAs) that define the safety and efficacy of the active ingredient,” says Mourad Farouk Rezk, M.D., senior director, global head medical affairs biosimilars at Biogen.
Establishing Comparability Criteria
The measured ranges for an originator’s CQAs form the basis for establishing comparability criteria for the biosimilar product. The process continues by selecting and engineering an appropriate cell line that expresses a protein to match the CQAs as closely as possible. “All these steps occur before manufacturing can even begin,” says Dr. Rezk, who adds that at Biogen, the selected cell line moves into process development, which designs a robust process that delivers product consistently.
According to Dr. Rezk, “Many regulators, including the EMA, have established clinical guidelines to support the development of biosimilars, putting forth requirements for demonstrating molecular and functional comparability, together with comparable pharmacokinetics, efficacy, safety, and immunogenicity.” This is achieved through Phase I pharmacokinetic studies and Phase III controlled, randomized trials in sensitive patient populations.
Biosimilars are not shortcuts to new products in the same vein as generic small-molecule drugs. Since biosimilars are manufactured in complex expression systems, product and process development take years. “What’s more, biosimilars of advanced biologics are more complex than first-generation biosimilars such as insulin or growth hormone therapies,” points out Dr. Rezk. “Each step of the manufacturing process has the potential to modify the product, and the process requires controlling hundreds of input parameters that can each affect the safety and efficacy of the final product.”
This manufacturing complexity can lead to a high degree of variability, which established biomanufacturers like Biogen have mastered through experience with originator biologics. “We have learned to isolate and control these factors during manufacturing,” emphasizes Dr. Rezk. “We have developed extensive statistical models and process controls that improve every step of the manufacturing process for producing both our originator biologics and biosimilars of advanced biologics.”
Assessing biosimilarity requires the totality of data gathered from physico-chemical and biological characterization of the bulk drug substance and drug product, coupled with evaluation of the molecule alongside the innovator in nonclinical models and clinical pharmacology studies,” says Linda Randall, Ph.D., director for process science at Actavis Biologics. “Only through the totality of this data can one demonstrate biosimilarity to the innovator product.”
Actavis, for example, employs orthogonal analytical methods combining physicochemical and functional analyses because single tests may not reflect subtle differences between the biosimilar and the innovator.
Another criterion to consider within any biosimilar development program is how much data is sufficient to characterize and determine batch-to-batch variability within the innovator product. “Sourcing sufficient batches from the marketplace can be challenging and costs can be very steep, so this is an important tactical element to build into the design of your development program,” explains Dr. Randall.
For any biosimilar, cost, speed, and quality are of paramount importance and at times demand careful balancing. Actavis utilizes lean manufacturing principles and focuses on state-of-the-art process intensification to design processes that are cost-effective and allow control over cost of goods.
“We have found that similarity can be controlled or modified to achieve a closer match to the innovator in the cell-line development stages, in the bioreactor processes where the cells are producing the biological molecule, and even during purification,” says Dr. Randall. “Understanding the effect of process on the CQAs through application of design-of-experiment methodologies on small-scale process models, having scientists who are innovative in providing solutions, and having a toolbox of process modifications to achieve closer physico-chemical and biological attributes and subsequently control those from batch to batch are all important assets.”
Regulators want to see statistically meaningful data from the product produced at the final manufacturing scale, which can be challenging during clinical development.
“At Actavis, we establish our process design and development for our biosimilar product with the end in mind,” notes Dr. Randall. “This means we set out with a clear focus on the critical quality attributes we need to achieve and a clear understanding of the anticipated commercial scale, and, therefore the target scale for our clinical batches. Manufacturing flexibility and agility are essential components for success. Minimizing changeover times, for example through use of single-use equipment and process intensification methods reduce costs of goods and reduce facility footprint.”