development of subcutaneous ( SC ) formulations which are designed to be self-administered at home . This innovation serves to reduce the burden on hospital outpatient services and enhance patient convenience . It is therefore paramount to obtain ‘ buy-in ’ from both prescribers and patients through appropriate patient-centered education and clinical support as these are likely to improve treatment adherence and ultimately better clinical outcomes .
The Affordable Care Act and the abbreviated approval process for the FDA approval of biosimilars The enactment of the 2009 Patient Protection and Affordable Care Act ( ACA ) included the adoption of the Biologics Price Competition and Innovation Act ( BPCIA ), which encouraged the drug development process geared towards manufacture of biosimilars . 4 Congressional approval was provided for an abbreviated licensure process for drug products that were demonstrated to be biosimilar to drug products already approved by the US FDA . The major driving factor for this congressional process was the need to significantly reduce US health care-associated costs and ameliorate the burden on the consumer as the end-user . At time of writing , the FDA has approved 28 biosimilars . 4
Although it takes time to collect substantial cost data regarding the use of biosimilars , studies conducted using biosimilars manufactured using the abbreviated approval process show significant gains in cost reduction . Mulcahy et al analyzed the market share for the first-ever FDA-approved biosimilar drug called filgrastim-sndz ( Sandoz ’ s Zarxio ® ), a biosimilar of the filgrastim reference biologic Amgen ’ s Neupogen ® , which was approved via the abbreviated drug approval process . The authors found that Zarxio ® , approved in 2015 , had a 30 % lower pre-rebate price than the reference biologic in 2016 . 5
Biosimilar manufacturing process Although designated as clinically equivalent to a reference biologic compound , it is important that patients understand that biosimilars should not be perceived as the equivalent of a generic drug . Manufacturing a traditional small molecular medicine might include about 50 critical tests . Up to 250 or more critical tests need to be implemented during the process of manufacturing the large molecular biosimilar medicines . Biologics are complex , structural protein molecules or mixture of molecules and , because of their complexity , are manufactured in a highly controlled environment with complicated multi-step processes using living cells . Biologics and biosimilars are produced similarly via a process using genetic and bioengineering technology , however , it is almost impossible to produce an exact copy of the product . 6 One way to reduce the overall cost and uncertainty of supplies , and control and maintain the standards and specifications is to replace the traditional ‘ batch ’ production with an ‘ end-to-end ’ holistic and integrated manufacture process ( Figure 1 ).
First , the gene of interest which produces the relevant biosimilar protein has to be identified and once this has occurred , it is isolated and inserted into an expression vector or plasmid and then introduced into host cells that produce further copies of the protein . Commercially available host cell lines include bacteria ( for example , E . coli ), yeast , and even human cells , although Chinese hamster ovary cells are commonly used . 7 The master cell lines producing the biosimilar protein are then extracted to create the cell bank and cultured to produce a much larger
FIGURE 1
End-to-end biosimilar manufacturing process
Genetic development
Purification substance production
Cell bank
Sterile filtration aseptic filling
Cell culture fermentation
Finished drug product
quantity of the protein which is recovered through either filtration or centrifugation . Then a complex series of tests and analyses ( for example , amino acid analysis , peptide mapping , mass spectrometry , nuclear magnetic resonance , X-ray crystallography , CD spectroscopy , surface plasmon resonance , and the analysis of post-translational modifications ) follows to confirm that the structure , function and chemical identity of the biosimilar harvested is uniform in its quality attributes and similar to the reference biological drug . 6 Finally , the purified drug substance is formulated with other excipients , placed in a container and stored under the appropriate conditions .
While the aim of the manufacturing process is to create a biologic drug that has a high degree of similarity to the reference product , a major disadvantage for the traditional ‘ batch ’ biosimilar manufacturer is that it does not have access to the original starting material , that is , the recombinant DNA and mast cell line or clone . In addition , the impurity profile from the biosimilar manufacturer may also be slightly different from the reference product , and any changes in the cell culture medium or production methods can have an impact on the structure of the final protein . Nevertheless , the manufacturer is required to undertake a series of analyses to ensure that any differences to the reference product , such as structural changes , or slight differences in the production process , do not impact the biosimilar ’ s safety and clinical efficacy . Given these disparities , patients need to realize that a biosimilar is ‘ like ’ the reference product , but not an identical copy of their biologic reference product , which can lead to questions and concerns by healthcare professionals and patients about extrapolation . Extrapolation allows biosimilars successfully tested for one approved indication to extrapolate the safety and efficacy for additional indications that have been tested and approved for the reference biologics . Extrapolation significantly improved the patient access to biosimilars . Nevertheless , patients can be reassured that due to the rigorous testing requirements of the FDA , a biosimilar will provide the same safety , efficacy and purity , that is , clinically equivalent , to the reference product .
32 | 2021 | hospitalpharmacyeurope . com