Points to Consider for Establishing Biotechnological/Biological Product Comparability

January 21, 2019 Becky Hurt

Authored By: Mo Heidaran, Mark Levi, Kurt Brorson and Robert Iser

Making changes to the manufacturing process/product is an inevitable part of process development with the goal of making a better product.  There is a risk if manufacturing changes are made late in the clinical trials that they could potentially change the product’s critical characteristics. For this reason, manufacturers are encouraged to 1) introduce major manufacturing changes as early as feasible during the product development life cycle, and 2) demonstrate that the products pre and post change are highly similar.

In reality, manufacturers often introduce major manufacturing changes very late in the product development life cycle for a variety of business and logistical reasons. Some of these common changes include scale up and automation. 

Foreign regulatory authorities as well as FDA have broadly adopted the requirements defined in ICH Q5E:  Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process for establishing product comparability. The comparability study is defined as a prospective study protocol designed to demonstrate that two products are comparable before and after the change. In some cases the Agency may ask the IND sponsor or applicant to submit the comparability study for assessment and review prior to the data collection and analysis. 

In ICH Q5E comparability is defined as a conclusion that products are highly similar before and after manufacturing process changes with no predicted adverse impact on the quality, safety, or efficacy of the drug product. This conclusion is most often based on an analysis of product quality attributes. In some cases where subtle analytical changes are seen, nonclinical or even clinical/immunogenicity data might be indicated. When this document was written in the 1990’s, biological (biotech) products were within scope, unfortunately cell and gene therapy products were not because this product sector was in its infancy. Fortunately, the minimal elements of a good comparability study for this emerging product class have been defined in several public presentations by FDA/CBER. Based on available information1 the following are considered by FDA to be the critical elements of a good prospective comparability study for cell and gene therapy products:

  1. Description of the proposed change(s)

  2. Risk Assessment

  3. Rationale for the proposed change(s )

  4. Comparability study design for the proposed change(s)

  5. Comparative assessment of Quality Attributes before and after change (side-by-side comparison is preferred)

  6. Justification for well-defined acceptance criteria for establishing comparability

  7. Detailed analytical procedures, sampling plan, statistical methods and analysis

  8. Reporting commitment

PAREXEL’s consulting group can provide our clients with a predictable process to develop comprehensive comparability study protocol based on number of criteria including: What is the nature of the proposed change?, What is the risk of a change impacting product quality?, Why the proposed changes are being introduced, and finally, When in the product lifecycle is the proposed change going to be introduced?


1 FDA public presentation https://cdn.ymaws.com/www.casss.org/resource/resmgr/cmc_no_am_jul_spkr_slds/2017_CMCS_HeidaranMo.pdf)

No Previous Articles

Points to Consider When Mitigating Biopharmaceutical Virus Risk
Points to Consider When Mitigating Biopharmaceutical Virus Risk