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CLINICSECTION TITLEAL RESEARCH


Table 1. Changes to the Manufacturing Process*


Manufacturing Step


Cell expansion Cell production Purification


Storage Shipping


Formulation Sterilization


Filling, packaging, and release


N/A = Not applicable.


*This table is an example and does not represent a thorough list of all changes that may be applicable. †


The Working Cell Bank is not yet established.


old and new product. Variability of the process may be identified by analyzing a larger than usual number of samples included for release, in-process, and stability testing.


Lastly, the sponsor wishes to rely on the existing safety data from Phase I to proceed with Phase II studies. In order to avoid performing additional clinical studies with the new product and relying on the existing safety data, cross-functional discussions will focus on the review of the product's toxicity, safety data, and release data from phase 1 batches. The outcome of this discussion for this case study is the calculation of the overall benefit/risk and ability to demonstrate comparability through analytical data only, without having to perform additional toxicity studies.


The CMC, Clinical, and Non-clinical team representatives are now in a position to present to the Management an estimate of resources required to implement the scale-up efforts, and additional studies which have to be performed (characterization, method validation, and stability) in addition to the justification for not performing added toxicity or safety studies. In this case study, the Management team determines a positive ratio for only a small portion of the patient population (eg, adults and not the children), and concludes that investment in building the scientific knowledge of the product is needed irrespective of the need for scale-up. Therefore, a comparability protocol will be written for submission and discussions with FDA.


Conclusion


While confronting changes, we often turn to the CMC team for answers, but we have to be aware that there is not a CMC answer to every question raised as a result of a change. Consideration of CMC data is a necessary part of addressing changes, but it may not be sufficient to address all concerns. Developing a product is a well-planned journey that takes into account the influence of scientific, economic, and human factors.


The CMC team has a role to play in consideration of these


factors. When unexpected turns present themselves, the team is well positioned to provide scientifically sound data to evaluate the quality of a product; and establish analytical comparability between the old and new products, which is often the most economical approach. Product


quality has a direct impact on risk to the patients, which is only one aspect of the human factor. The other dimension of the human factor involves the level of risk the Management is willing to take as a part of change implementation which is beyond the reach of CMC and varies among sponsor and drug candidates.


References


1. Commission Regulation (EU) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. Official Journal of the European Union. 2012;(L209):4-14. Available at: http://ec.europa.eu/health/files/eudralex/vol-1/ reg_2012_712/reg_2012_712_en.pdf. Accessed February 25, 2015.


2. U.S. Food and Drug Administration. CFR-Code of Federal Regulations Title 21. Biologics Licensing, Changes to An Approved Application. 21 CFR § 601.12. 2014. Available at: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=601.12. Accessed February 26, 2015.


3. U.S. Food and Drug Administration. CFR-Code of Federal Regulations Title 21. Applications For FDA Approval To Market a New Drug, Supplements and other changes to an approved application. 21 C.F.R § 314.70. 2014. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.70. Accessed February 26, 2015.


4. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for Industry: CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports. 2014. Available at: http:// www.fda.gov/downloads/Drugs/.../Guidances/UCM217043.pdf. Accessed February 26, 2015.


5. European Medicines Agency Inspections. Committee for Medicinal Products for Human Use (CHMP). Guideline on The Requirements to The Chemical And Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials. 2006. Available at: http://ec.europa.eu/health/files/eudralex/vol-10/18540104en_en.pdf. Accessed February 26, 2015.


6. U.S. Food and Drug Administration. Center for Biologics Evaluation and Research. Center for Drug Evaluation and Research. Demonstration of Comparability of Human Biologics Products Including Therapeutic Biotechnology-derived Products. 1996. Available at http:// www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122879. htm. Accessed February 26, 2015.


Jilla K. Boulas is a Senior Regulatory Consultant with Complya Consulting Group, LLC, in Woburn, Massachusetts, USA, involved in assisting/consulting clients in the design and implementation of CMC strategies throughout the lifecycle of pharmaceutical and biopharmaceutical medicinal products. Her recent activities include the design of comparability protocols/reports, post- approval change management protocols, change control process management, and regulatory strategies for CMC technical issues.


pharmoutsourcing.com | 45 | March/April 2015


Current Process (Old)


T-flasks (15 mL) 150 L


4-step column purification process


Overnight Temperature control Stabilizing agent Filter sterilization 50 vials


Proposed Process (New)


T-flasks (2 X 15mL) 300 L


5-step purification step


Overnight Temperature control Stabilizing agent Filter sterilization 100 vials Changes Drug Substance


Number of vials of the master of cell bank (MCB)


Changes in the duration and volume of the production step


Added a new step


N/A N/A


Drug Product


Increased volume and duration


Larger surface area Increased vials of finished drug product


Allows for a change in the scale of finished drug product.


Allows for the increased scale


Increase number of vials to allow for a larger clinical study


Extra vial of MCB† production vessel.


is used in the preparation for use of a larger


Allow for a larger volume of the active substance.


Process improvement: Addition of a new step to improve the safety profile of the drug substance


N/A N/A


Justification for Change


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