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Regulatory CMC Changes – Challenges and Management



Abiding by the national laws and regulations is a necessity for biopharma organizations towards the development, manufacture and selling of their pharmaceutical products. Prior to entering the market, every biopharma product needs a marketing sanction from the health authority. Issuance of this authorization depends on the assessment results from the data that is submitted indicating that the product is safe, quality controlled and effective for specified conditions. 

Manufacturers and applicants at times require making some variations in the product, process of production, quality, and equipment, in charge person or labeling recognized in an approved application for certified biological products or facilities for varied reasons. Because of global regulatory requirements, several changes cannot be implemented unless the health authority scrutinizes and approves them.

Regulatory necessities for post-approval modifications depend on the country regulations. It is a tough and expensive process for applicants to handle changes of the approved regulatory folder of documents over the lifecycle of the product when it gets registration in multiple countries. 

Medical authorities often have innumerable questions at the time of their reviews and a manufacturer has to prepare keeping all these in mind for a number of rounds of replies. Numerous reviews of the identical information can soar the costs, a more intricate supply chain and a need for refined systems to sustain regulatory compliance which in turn can result in an increase in number of errors that affect regulatory conformity, difficulty in managing costs and resource reduction as well as increase in the possibility of a hindrance in supply of drug products.


The importance of Change is varied like process improvement, cost reduction, improve competency, minimize possible failures and meet advanced processes or to improve conformity with regulations / Good Manufacturing Process (GMP). However, creating changes is highly intricate and requires methodical preparation, documentation and synchronization to the manufacturers in inclusion with quality and regulatory departments. The change management system should incorporate the following as might be deemed appropriate for the lifecycle stages:

  • Quality risk management (as per ICH Q9) should be put into use for the evaluation of anticipated changes. The exertion and formality level of the evaluation should be in correspondence with the risk level.
  • The proposed changes should be evaluated in relation to the market sanction, with the inclusion of design space, place of establishment, and/or knowledge of present product and process. An assessment should be conducted to determine whether an alteration to the regulatory filing is necessary under local requirements. As stated in ICH Q8, operating within the design space is not held as a change (from the perspective of regulatory filing). However, a pharmaceutical quality system states that a company’s change management system should evaluate all the changes. 
  • Evaluation of proposed changes should be performed by specialist teams having apt expertise and understanding from pertinent areas (e.g. Pharmaceutical development, Manufacturing, Quality, Regulatory Affairs and Medical), to certify that the change is technically acceptable. Plausible evaluation methodology for a proposed change should be laid down. 
  • Once implemented, an assessment of the change should be conducted to validate that the change objectives were attained and that there was no harmful impact on product quality.