Comparability Exercise: Biosimilars Manufacturing Process Change

<p><strong>INTRODUCTION&nbsp;</strong></p><p>Process Change is the key element of life cycle of biologic product development. Biopharmaceutical manufacturers especially Biosimilars manufacturers frequently make changes to the manufacturing processes of products both during product development and after approval. Biologic drugs are highly complex molecules produced by living cells and The key characteristics of these molecules, known as critical quality attributes (CQAs), can vary during the manufacturing process change hence, it is expected that multiple changes in the manufacturing process could impact drug product quality, safety, and efficacy.&nbsp;</p><p>A comparability exercise generally needs to perform that products have highly similar quality attributes before and after manufacturing process changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred. This conclusion can be based on an analysis of product quality attributes. In some cases, nonclinical or clinical data might contribute to the conclusion.&nbsp;</p><p><strong>&ldquo;WHY&rdquo; PROCESS CHANGE </strong>&nbsp;</p><p>There could be many reasons a manufacturer considered manufacturing process change. These might include but is not limited to;&nbsp;</p><p>1.   Improving Manufacturing Process Step&nbsp;</p><p>2.   Changing Manufacturing Site&nbsp;</p><p>3.   Increasing Manufacturing Scale&nbsp;</p><p>4.   Improving Product Stability&nbsp;</p><p>5.   Changing Equipment Type&nbsp;</p><p>6.   Complying with changes in regulatory requirements&nbsp;</p><p><strong>GOAL POST OF PROCESS CHANGES&nbsp;</strong></p><p>The goal of &ldquo;Process Change&rdquo; is to fulfill the needs of business, product and regulatory. Generally, quality data on the pre-and post-change product are generated and a careful evaluation is performed based on the existing product knowledge to predict all foreseeable consequences to ensure that any differences in quality attributes have no adverse impact upon quality, safety or efficacy of the drug product Pre- &amp; post-change in Biotechnology or biologics or biosimilars product.&nbsp;</p><p><strong>THE KEY TO PROCESS CHANGE IS COMPARABILITY&nbsp;</strong></p><p>The key to process change is comparability, based on appropriate comparison of relevant quality attributes, pre-and post-change products are highly similar and considered comparable, i.e., no adverse impact on safety or efficacy profiles is foreseen.&nbsp;</p><p><strong> &ldquo;IS BIO-SIMILARITY AND COMPARABILITY&rdquo; THE SAME?&nbsp;</strong></p><p> &ldquo;Comparability differs from Bio-similarity&rdquo; which can be understood as;&nbsp;</p><p>&bull;      Bio-similarity Different manufacturer, new product compared with reference biologic.&nbsp;</p><p>&bull;      Comparability Same manufacturer, same product tested before and after change.&nbsp;</p><p><strong> &ldquo;HOW MUCH COMPARABILITY DO WE NEED TO DEMONSTRATE&rdquo;?&nbsp;</strong></p><p>A determination of comparability can be based on a combination of analytical testing, biological assays, and, in some cases, nonclinical and clinical data. Following possibilities, a manufacturer could face once they perform the comparability!&nbsp;</p><p>1.  <strong><em> The analytical procedures used are not enough</em></strong> to discern relevant differences that can impact the safety and efficacy of the product. The manufacturer should consider employing additional testing / orthogonal tests (e.g., further characterization) which may help to understand the residual uncertainty post-process changes to reach a definitive conclusion&nbsp;</p><p>2.   <strong><em>Some differences have been observed in the quality attributes of the pre-change and post-change product,</em></strong> but it can be justified that no adverse impact on safety or efficacy profiles is expected, based on the manufacturer&rsquo;s accumulated experience, relevant information, and data. In these circumstances, pre-and post-change product can be considered comparable. For example; Quality Drift has been observed of bG2 glycan structure by Sandoz in many batches of commercial product distributed by the originator in the EU (light blue) and the US (dark blue).&nbsp;</p><p><img style="display: block; margin-left: auto; margin-right: auto;" src="" alt="" width="419" height="272" /></p><p>Fig: 1; Analysing complex product attributes over time. The expiry date of the product batches is listed on the x-axis and the relative amount of product attribute enrichment is listed on the y-axis. Pre-shift quality refers to the content of the attribute prior to a manufacturing change and post-shift quality after the manufacturing change.&nbsp;</p><p>3.   <strong><em>Some differences have been identified in the comparison of quality attributes and a possible adverse impact on safety and efficacy profiles</em></strong> cannot be excluded. In such situations, the generation and analysis of additional data on quality attributes are unlikely to assist in determining whether pre- and post-change product are comparable. The manufacturer should consider performing nonclinical and/or clinical studies.&nbsp;</p><p><strong>DEMONSTRATION OF COMPARABILITY DURING PRODUCT DEVELOPMENT&nbsp;</strong></p><p>During product development, it is expected that multiple changes in the manufacturing process will occur that could impact drug product quality, safety, and efficacy.&nbsp;</p><p>Comparability studies conducted for products in development are influenced by factors such as;&nbsp;</p><p>1.    the stage of product development,&nbsp;</p><p>2.   the availability of validated analytical procedures,&nbsp;</p><p>3.   and the extent of product and process knowledge,&nbsp;</p><p>When process changes are introduced in the late stages of development and no additional clinical studies are planned to support the marketing authorization, the comparability exercise should be as comprehensive and thorough as one conducted for an approved product. Some outcomes of the comparability studies on quality attributes can lead to additional nonclinical or clinical studies. Here, we can understand the &ldquo;comfort Index&rdquo; of process change applied to the development stage.&nbsp;</p><p><strong>Fig: 2; Comfort Index of process changes for a manufacturer&nbsp;</strong></p><p><img style="display: block; margin-left: auto; margin-right: auto;" src="" alt="" width="602" height="266" /></p><p><strong>MANUFACTURING PROCESS CONSIDERATIONS&nbsp;</strong></p><ol><li>When changes are made to a process, the manufacturer should demonstrate Consistent performance of the process post process changes.&nbsp;</li><li>The modified process steps should be re-evaluated and/or re-validated, as appropriate.&nbsp;</li><li>that the associated process controls, including any new ones, provide assurance that the modified process will also be capable of providing comparable products.&nbsp;</li><li>Demonstration of state of associated process control to be still capable of providing comparable product even after modified/changed manufacturing process. This might include, but is not limited to, such items as:&nbsp;</li></ol><ul><li>Establishment of modified specifications for raw, source and starting materials, and reagents;&nbsp;</li><li>Appropriate bioburden and/or viral safety testing of the post-change cell banks and cells at the limit of in vitro cell age for production;&nbsp;</li><li>Adventitious agent clearance;&nbsp;</li><li>Removal of product- or process-related impurities, such as residual host cell DNA and proteins; and Maintenance of the purity level.&nbsp;</li></ul><p><strong>CONCLUSION&nbsp;</strong></p><p>Process change can be applied to any stage of its product development life cycle starting from early stage development to post-market authorization approvals. Biological Manufacturer needs to demonstrate comparability pre- and post-change in terms of product quality, safety and efficacy. The level of complexity to determine the comparability to prove residual uncertainty of product quality depends on the product life cycle stage in which process change happens.&nbsp;</p><p>The manufacturer needs to assess the impact of process change on physiochemical &amp; biological characterization and stability of product at each key manufacturing stage e.g., Critical Intermediates, Drug Substance, Drug Product.&nbsp;</p><p>Fig: 3; COMPARABILITY EXERCISE STRATEGY&nbsp;</p><p><img style="display: block; margin-left: auto; margin-right: auto;" src="" alt="" width="602" height="338" /></p><p> If a manufacturer establishes the relationship between quality attributes and safety and efficacy through analytical &amp; biological characterization of product and is able to predict the residual uncertainty (potential differences in product-related substances and product-related impurities) by either accelerated or stress conditions or in degradation pathways of the product; then nonclinical or clinical studies with the post-change product are not warranted.&nbsp;</p><p>&nbsp;</p>
KR Expert - Praveen Gupta

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