Chemistry, Manufacturing, and Control (CMC) readiness in the pharma and biotechnology industries is an important issue that helps deliver effective, safe, and high-quality drugs to patients. Although development and regulatory issues might attract considerable interest from stakeholders, CMC readiness becomes a major issue when there is an accelerated development timeline, manufacturing process change, or comparability assessment required for the product.

The described challenges become especially relevant in case of accelerated development programs, manufacturing process changes, comparability studies, and biosimilar development. These different circumstances require a different approach in terms of technical and regulatory aspects; however, they have one common goal of proving a consistent quality of the product with regard for the safety of patients and decision-making process.

To be ready for the CMC issue, one should do more than prepare the submission documentation.

CMC Readiness in Expedited Development Programs

Accelerated development programs seek to hasten the development and regulatory assessment of drugs addressing life-threatening or serious illnesses or medical needs. Though these programs bring great advantages to patients, they put significant pressure on the CMC teams.

The first major problem in these situations is that there is very little time left to develop, validate, and document the manufacturing process. It may happen that one will have to produce quite a lot of CMC data while conducting clinical trials and working on regulatory submissions at the same time.

Key challenges include:

• Short development schedule: Accelerated programs may not allow much time for the process optimization, analytical methods development, and stability studies.
• Incomplete manufacturing data: There might be preliminary process knowledge and little manufacturing experience when making early submissions.
• Supply chain management: Making sure that there are enough qualified raw materials, manufacturing capabilities, and facilities available can be hard during accelerated development.
• Regulatory requirements: Organizations still need to follow all the proper standards and provide the right data despite accelerated program.
  
  

In order to solve such problems, companies need to make a risk-based CMC plan early in the development phase. Cross functional cooperation between regulatory affairs, QA, manufacturing, analytical development, and supply chain departments.

Managing Manufacturing Process Changes

Changes in manufacturing process are not uncommon during the drugs entire lifecycle. They may involve any aspect of manufacturing from changes in raw material suppliers to changes in manufacturing process, technology, etc.

Although such changes will most probably make manufacturing more efficient, provide larger capacities or lower costs, they may have a negative effect on some of the product's critical quality attributes (CQAs).

In the case of biologics, small changes can influence such CQAs as protein structure, purity, potency, glycosylation, and biological activity.

The main problem when preparing CMC is whether the proposed change will have an impact on the quality, safety, and efficacy of the product. Companies must assess each change and produce necessary data for this assessment.

The typical elements of the change control process are:

• Description and justification of the change proposed.
• Identification of the quality attributes that will be potentially affected by the change.
• Evaluation of the necessity of additional analytical and other studies needed.
• Regulatory reporting requirements assessment for different markets.
• Updating of manufacturing documents and quality systems, if needed.
  
  
  

Effective change management helps organizations maintain process consistency while minimizing regulatory and operational risks.


Comparability Studies: Demonstrating Product Consistency

It is important to perform comparability studies when changes happen during manufacturing, especially for biological products. The aim of such studies is to prove that the product before the manufacturing change was comparable to the product after the change.

The comparability of two products is not just about proving that these products pass release specifications. Comprehensive comparability study may involve analytical, functional and stability data in order to detect differences that may affect the quality of the product.

Some difficulties include finding the right analytical methods, setting proper acceptance criteria, taking representative samples of pre-change and post-change products and interpreting complicated analytical data.

In the case of biologics, advanced characterization methods may be needed in order to examine structure of the molecule, impurities, biological activity and other specific product features.

Good comparability strategy should be planned before making the change. It is important to determine CQAs, find suitable and sensitive analytical methods and develop a testing plan according to scientific risk assessment.

In case if the analytical data does not provide sufficient information, additional non-clinical or clinical studies may be required.

CMC Challenges in Biosimilar Development

There are certain CMC challenges associated with biosimilar development since biologicals are quite complex and cannot generally be characterized like small molecules.

It is necessary to show the biosimilars similarity to the reference product with no clinical difference in terms of safety, purity, and potency. This can be achieved through analytical characterization of the drug, knowledge of the manufacturing process, and comparability exercise.

The key challenges are:

• Characterization of the reference product: Gathering adequate information about the quality and variability of the reference product.
• Analytical similarity: Showing similarity via sensitive and orthogonal methods.
• Manufacturing consistency: Establishing an effective manufacturing process that consistently produces the intended product.
• Process optimization: Handling any process changes that occur throughout the development without jeopardizing the similarity assessment.
• Meeting regulatory requirements: Compliance with all relevant requirements under various regulatory authorities.
  
  

Since manufacturing processes play a great role in determining the characteristics of biological products, the understanding of the manufacturing process becomes a priority in biosimilar development. The analytical data can provide the direction for the development and highlight any differences that need further investigation.

Building an Effective CMC Readiness Strategy

With expedited programs, manufacturing changes, comparability studies, and biosimilars development, preparation starts from proactive planning.

The following integrated strategy needs to be put in place involving scientific risk evaluation, regulatory planning, data integrity, and cross-functional teamwork.

Such priorities as the development of the CMC pathway, keeping the submission ready documentation, increasing analysis capacity, and putting quality management systems in place have to be addressed.

It is also necessary to do periodic CMC gap analysis to detect such aspects as the missing data, open technical issues, validation activities, and regulatory issues.

Conclusion

CMC readiness is not just about having the right documentation to meet the regulatory requirement, but is an essential element in the development and commercialization of pharmaceutical products.

There will be different challenges involved due to expedited development timeframes, changes in the manufacturing process, comparability studies, and biosimilars development. But these can be handled by way of adequate planning and scientific risk assessment in addition to cross-functional collaboration between development, manufacturing, quality and regulatory groups.

By following a proactive and risk-based approach to CMC, pharmaceutical and biotech organizations will be able to develop high-quality products and also ensure timely delivery to patients.

Join our upcoming CMC Readiness Challenge in Case of Expedited Programs, Process Changes, Comparability Studies and Biosimilars Masterclass, to learn from experts!

By Shara Najimudeen, Digital Marketing Executive, GLC Europe, Colombo Office, Sri Lanka.