Summary:
The United States Food and Drug Administration (FDA) and other health authorities (EMA, etc.) require a well-defined and consistent drugs and biologics development process and life cycle management. The established chemistry and manufacturing and controls (CMC) activities ensure methods are validated, raw materials are chosen and tested, and the product meets the set specifications for purity according to the established guidelines.
During product development, the CMC helps maintain the connection in quality between the drug used in clinical studies and the marketed drug as changes in manufacturing impacts drug quality according to the current Good Manufacturing Practices.
In post-approval, the CMC ensures all required criteria for quality and regulatory are met for change implementation to ensure product quality continues to meet the standards.
This blog provides emerging companies and biotech companies a significant overview of the considerations for CMC. There are a multitude of complexities and points to consider when developing an asset, and product development is at the center of all development. This blog also provides greater detail and discussion on how the right development partner can ensure there is a consistent ‘end-to-end’ process and continuity in the development of your asset.
At ICON, we work closely with our clients to understand their product and processes to ensure compliance and supply continuity while adhering to the applicable regulatory requirements. Our global teams have the expertise to assess CMC changes in major markets, are able to determine global CMC strategies, file necessary regulatory applications, and work with local affiliates and governments to establish a single point of contact and respond to queries to ensure timely approval.
CMC in drug development and life cycle management
The identification of a promising target/monoclonal antibodies (mAb)/biologic is just the start of a long journey to a successful product approval. While the focus of development is typically focused on pre-clinical and clinical aspects, an early focus on Chemistry, Manufacturing and Controls (CMC) is essential to ensure a successful product and the shortest path to approval.
This is especially important and pertinent for companies which are focusing on mAbs (and other biologics), as opposed to small molecules. MAbs cannot undergo complete characterization like in small molecules due to size, while the variable and hypervariable sections are important for antigen binding specificity. This, along with other issues which your development/CMC partner can help to identify, are critical to find early; issues found later on can be very costly in time and money.
Some of the major CMC related steps to consider are listed below:
CMC considerations
- Upstream process
- Downstream process
- Structural characterisation
- Functional characterisation
- Process/analytical
- Formulation
- Glycosylation
- Impurity profile
- Stability
Why is CMC a critical component in drug development?
As a product is developed, the manufacturing process and controls increase in complexity, so it is critical to assure all of the CMC components are captured and managed. Development of a new biologic requires overcoming a number of technical challenges, but lack of knowledge in the following areas can result in unnecessary delays in product development:
- Agency expectations for CMC data at each stage
- Knowledge of acceptable changes during development
- Comparability requirements with product scale-up
- Factors to address with manufacturing site changes
- Identification of appropriate analytical methodologies
- Defining the acceptable level of impurities/degradants
- Providing the necessary information from clinical trial formulations to commercial presentation
Why is it important to ID issues early?
It is very expensive and time consuming to have to go back and re-start development due to an issue with the chosen process or molecule. A knowledgeable partner can be a valuable resource providing understanding of the issues allowing early Agency contact to request insight and direction and help address areas such as:
- Identification of current CMC gaps
- Regulatory strategy to proactively address CMC concerns
- Identification of potential future issues with scale-up
- Conducting risk analysis and contingency plans
- Providing expert resources with multi-company and regulatory authority experience
- Adding needed technical expertise to address Agency questions
- Meeting and Briefing book preparation
Why are Contract Manufacturing Organisations (CMO) critical to success?
- A relationship where you work well with the CMO is beneficial to your supply chain – the ability to make changes or consistently meet supply chain demand can make or break a product
- Stock outs, equipment issues, methods issues, and out-of-specifications (OOS), along with the associated investigations, are crucial to be successful managing a CMO
- Response time back to clients, response time to health authorities, and top notch change control are some of the things that allow success at CMOs
- Need to understand and weigh the nuances/risk of where you want to manufacture – some CMOs with facilities that are working on the “edge of GMP” = cheaper price per unit is not always better
- The GMP facility is critical to the life of the product. CMO or internal sites – if they do not function well, then product supply is impacted, and patients are ultimately impacted.
- ICON has several GMP facilities in which they offer CMC services in a role as a small CMO under full cGMP
What are other key issues to consider?
- Early sample retention is essential to be able to bridge early development tox/ Pharmacokinetic (PK)/Pharmacodynamics (PD) work to later manufacturing processes and improved assays
- Perform enough assay qualification to prove suitability with your product – don’t rely on what others are using
- Onsite tech transfer presence will result in fewer issues and a more successful manufacturing campaign
- Evaluate the product “for now” while also looking to the future, as most products grow and expand (i.e. do you need in-vitro in-vivo correlation (IVIVC) or Bioequivalent (BE) studies, or various zone stability studies to support future growth)
Small molecules remain prevalent in both development pipelines and on the market in today’s Pharma world and are still the majority of the therapeutic dosage forms manufactured today because they consistently deliver results to patient. It’s about a good old-fashioned organic group of small chemical compounds with a small molecular size made from synthetic chemical reactions. Small molecules do not necessarily mean old drugs, but many have been around for years, even being reinvented for new indications. The growing trend is cutting edge drugs, often tailored to fit very specific genetic subsets of patients.
One critical issue that the FDA has been more focused on is the evaluation of the chemical properties and the criticality of excipients in the formulation and when making changes. Recent experience shows that the following should be included in this type of change:
- All monograph and manufacturer specification parameters
- A comparison of these test results for the excipient pre- and post-change, to determine if there is a statistically significant difference
- A comparative evaluation of physical properties based upon the physical form of the excipient and its functionality as well as the specification between the RM manufacturer and user
- The effect of the change on bioburden, particularly for excipients susceptible to microbial growth
- Change in origin can involve the country of origin, geological origin, or species of origin for the raw material, Bovine Spongiform Encephalopathy (BSE), Transmissible Spongiform Encephalopathies (TSE), and Genetically Modified Organisms (GMO)
At ICON, our teams provide the expertise in the small molecules and large molecules/biologics space and they are able to assist organisations do the necessary work to obtain marketing authorisation and maintain products in the market. Our regulatory affairs CMC team focuses on the manufacturing and quality control changes, which include but not limited to, the following post approval changes in (1) components and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) CMC related labeling, as well as (7) miscellaneous changes and (8) multiple related changes.
Our CMC team also supports the writing of the Investigational Medicinal Product dossier (IMPD), which is an essential document that forms part of the Clinical Trials Authorisation (CTA) submitted to the EU Competent Authorities for non-authorised IMPs.
ICON Early Clinical and Bioanalytical Solutions offers CMC services in a CMO role in one of our two GMP facilities, based in US and EU, to support manufacturing, packaging, and labeling of the IP.
Conclusion
CMC is a critical component and a ‘first step’ component in the creation of a development strategy for an asset. Without a solid development plan for the investigational materials used in clinical studies, HAs will not be able to adequately assess the efficacy or safety of a product.
Your development partner will work closely with you in the development of an appropriate CMC program for your investigational product. Ideally, your development partner can provide an ‘end-to-end’ service to support manufacturing, packaging, and labeling of the IP, which will ultimately improve timings for clinical studies.
In this section
-
Digital Disruption
-
Clinical strategies to optimise SaMD for treating mental health
-
Digital Disruption: Surveying the industry's evolving landscape
- AI and clinical trials
-
Clinical trial data anonymisation and data sharing
-
Clinical Trial Tokenisation
-
Closing the evidence gap: The value of digital health technologies in supporting drug reimbursement decisions
-
Digital disruption in biopharma
-
Disruptive Innovation
- Remote Patient Monitoring
-
Personalising Digital Health
- Real World Data
-
The triad of trust: Navigating real-world healthcare data integration
-
Clinical strategies to optimise SaMD for treating mental health
-
Patient Centricity
-
Agile Clinical Monitoring
-
Capturing the voice of the patient in clinical trials
-
Charting the Managed Access Program Landscape
-
Developing Nurse-Centric Medical Communications
- Diversity and inclusion in clinical trials
-
Exploring the patient perspective from different angles
-
Patient safety and pharmacovigilance
-
A guide to safety data migrations
-
Taking safety reporting to the next level with automation
-
Outsourced Pharmacovigilance Affiliate Solution
-
The evolution of the Pharmacovigilance System Master File: Benefits, challenges, and opportunities
-
Sponsor and CRO pharmacovigilance and safety alliances
-
Understanding the Periodic Benefit-Risk Evaluation Report
-
A guide to safety data migrations
-
Patient voice survey
-
Patient Voice Survey - Decentralised and Hybrid Trials
-
Reimagining Patient-Centricity with the Internet of Medical Things (IoMT)
-
Using longitudinal qualitative research to capture the patient voice
-
Agile Clinical Monitoring
-
Regulatory Intelligence
-
An innovative approach to rare disease clinical development
- EU Clinical Trials Regulation
-
Using innovative tools and lean writing processes to accelerate regulatory document writing
-
Current overview of data sharing within clinical trial transparency
-
Global Agency Meetings: A collaborative approach to drug development
-
Keeping the end in mind: key considerations for creating plain language summaries
-
Navigating orphan drug development from early phase to marketing authorisation
-
Procedural and regulatory know-how for China biotechs in the EU
-
RACE for Children Act
-
Early engagement and regulatory considerations for biotech
-
Regulatory Intelligence Newsletter
-
Requirements & strategy considerations within clinical trial transparency
-
Spotlight on regulatory reforms in China
-
Demystifying EU CTR, MDR and IVDR
-
Transfer of marketing authorisation
-
An innovative approach to rare disease clinical development
-
Therapeutics insights
- Endocrine and Metabolic Disorders
- Cardiovascular
- Cell and Gene Therapies
- Central Nervous System
-
Glycomics
- Infectious Diseases
- NASH
- Oncology
- Paediatrics
-
Respiratory
-
Rare and orphan diseases
-
Advanced therapies for rare diseases
-
Cross-border enrollment of rare disease patients
-
Crossing the finish line: Why effective participation support strategy is critical to trial efficiency and success in rare diseases
-
Diversity, equity and inclusion in rare disease clinical trials
-
Identify and mitigate risks to rare disease clinical programmes
-
Leveraging historical data for use in rare disease trials
-
Natural history studies to improve drug development in rare diseases
-
Patient Centricity in Orphan Drug Development
-
The key to remarkable rare disease registries
-
Therapeutic spotlight: Precision medicine considerations in rare diseases
-
Advanced therapies for rare diseases
-
Transforming Trials
-
Accelerating biotech innovation from discovery to commercialisation
-
Ensuring the validity of clinical outcomes assessment (COA) data: The value of rater training
-
Linguistic validation of Clinical Outcomes Assessments
-
Optimising biotech funding
- Adaptive clinical trials
-
Best practices to increase engagement with medical and scientific poster content
-
Decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
Decentralised and Hybrid clinical trials
-
Practical considerations in transitioning to hybrid or decentralised clinical trials
-
Navigating the regulatory labyrinth of technology in decentralised clinical trials
-
Biopharma perspective: the promise of decentralised models and diversity in clinical trials
-
eCOA implementation
- Blended solutions insights
-
Implications of COVID-19 on statistical design and analyses of clinical studies
-
Improving pharma R&D efficiency
-
Increasing Complexity and Declining ROI in Drug Development
-
Innovation in Clinical Trial Methodologies
- Partnership insights
-
Risk Based Quality Management
-
Transforming the R&D Model to Sustain Growth
-
Accelerating biotech innovation from discovery to commercialisation
-
Value Based Healthcare
-
Strategies for commercialising oncology treatments for young adults
-
US payers and PROs
-
Accelerated early clinical manufacturing
-
Cardiovascular Medical Devices
-
CMS Part D Price Negotiations: Is your drug on the list?
-
COVID-19 navigating global market access
-
Ensuring scientific rigor in external control arms
-
Evidence Synthesis: A solution to sparse evidence, heterogeneous studies, and disconnected networks
-
Global Outcomes Benchmarking
-
Health technology assessment
-
Perspectives from US payers
-
ICER’s impact on payer decision making
-
Making Sense of the Biosimilars Market
-
Medical communications in early phase product development
-
Navigating the Challenges and Opportunities of Value Based Healthcare
-
Payer Reliance on ICER and Perceptions on Value Based Pricing
-
Payers Perspectives on Digital Therapeutics
-
Precision Medicine
-
RWE Generation Cross Sectional Studies and Medical Chart Review
-
Survey results: How to engage healthcare decision-makers
-
The affordability hurdle for gene therapies
-
The Role of ICER as an HTA Organisation
-
Strategies for commercialising oncology treatments for young adults
-
Blog
-
Videos
-
Webinar Channel