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www.biopharminternational.com September 2019 BioPharm International eBook 15 Regulatory Sourcebook Biosimilars ESTABLISHING COMPARATIVE ANALYTICAL ASSESSMENTS The new draft guidance, which was issued to replace earlier guidance that had been withdrawn by FDA on the back of industry concerns and objec- tions (4), outlines the agency's rec- ommendations for the design and evaluation of comparative analytics studies needed to demonstrate bio- similarity between a proposed bio- similar and the reference product. The document also provides recom- mendations to sponsors on what sci- entific and technical information to include for the chemistry, manufac- turing, and controls (CMC) section of a marketing application for a pro- posed biosimilar. The document also gives guid- ance on the factors that sponsors should consider when performing comparative analytical assessment for a proposed product. Factors to con- sider include the expression system, the manufacturing process, physi- cochemical properties, functional activities, target binding, impurities, the reference product and reference standards, the finished drug product, and stability. The document gives details on how comparative analyti- cal assessments should cover these key factors. The draft guidance also empha- sizes the need for sponsors to have a thorough understanding of the reference product, which is critical for a successful biosimilar develop- ment program. Understanding the physicochemical and biological char- acteristics of the reference product, doing a full characterization, and familiarizing oneself with publicly available information on the refer- ence product are recommended approaches for forming the basis of understanding for that product. Because protein products are, by their nature, complex molecules that are manufactured in living cells and later on purified through a variety of technologies, they will naturally have inherent lot-to-lot variability in their quality characteristics. Thus, it is important to sufficiently charac- terize the lot-to-lot variability of the reference product and the proposed biosimilar through comparative ana- lytical assessment. Important to the comparative ana- lytical assessment process is the use of adequate lots from both the reference product and the proposed biosimi- lar. The draft guidance suggests that for the reference product, sponsors should acquire multiple lots of refer- ence product throughout the devel- opment program of their proposed biosimilar, and that they should be in sufficient quantity to conduct multiple physiochemical and func- tional assays. This will help ensure an accurate picture of the full range of product variability. For the pro- posed biosimilar, a sponsor should include at least 6–10 lots (including investigational-scale and commercial- scale material) of biosimilar product in the comparative analytical assess- ment. Including these lots will help ensure that characterization of the proposed biosimilar is adequate and that manufacturing variability is well understood. It will also ensure that the sponsor has an adequate com- parison to the reference product. DEMONSTRATING INTERCHANGEABILITY The final interchangeability guid- ance is informed by FDA's cumulative experience providing development- stage advice to sponsors of pro- posed interchangeable products. The agency also considered numer- ous comments on the draft inter- changeability guidance and made changes to provide increased clar- ity to stakeholders. In this final guidance, FDA gives an overview of the important scientific consid- erations that sponsors should focus on when setting out to demonstrate interchangeability between their proposed therapeutic product (i.e., proposed interchangeable biosimilar or proposed interchangeable product) with a reference product. Several factors impact the type and amount of data and information that would be needed to support a demonstration of interchangeability. The product-dependent factors that should be taken into consideration are the proposed interchangeable product's complexity and the extent of characterization—both compara- tive and functional—and product- specific immunogenicity risk (of the reference product). FDA encourages sponsors to consider these two fac- tors together to inform the type of data they should collect and the information they will need to sup- port a demonstration of interchange- ability within a particular context. Sponsors will also need to determine the data and information necessary to support interchangeability on a case-by-case basis. To demonstrate interchangeability, a sponsor typically sets up switching studies to show that the risk of safety of diminished efficacy from switch- ing between the proposed inter- changeable product and the reference product is not greater than using the reference product only. FDA's guid- ance suggests that switching stud- ies evaluate changes in treatment that result in two or more alternat- ing exposures, or switch intervals between the interchangeable product and the reference product. If a sponsor believes that these types of data are not necessary, FDA will expect the sponsor to provide a justification for their decision to not include switch study data as part of their demonstration of inter- changeability. An instance where a switching study may not be neces- sary is one where biological products (interchangeable and reference) are not to be administered to a patient