Drug Readiness: The Role of CMC (Effective Chemistry, manufacturing, and control)

According to Austin and Hayford (2021), only in 2019, the pharmaceutical industry spent approximately 83 billion dollars on research and development (R&D) for drugs and medical products, which is 10 times what the pharmaceutical industry spent per year in the 80s.

Standardizing the processes involved in developing a new drug or medical product through a well-defined CMC is crucial for pharmaceuticals, as it allows them to reduce R&D processes and overall healthcare costs while simultaneously increasing their revenue, allowing labs to deliver safe and high-quality results every time.

The Role of CMC

CMC stands for chemistry, manufacturing, and control. It refers to all the activities involved in all stages of the drug development cycle, developing a guideline that will help control the quality and stability of a new drug or medicinal product from the beginning through post-approval production. 

Each word represents a vital component of the drug developmental process:

• Chemistry: Involves the detailed chemical composition of a drug, including the active pharmaceutical ingredients (APIs) and other components. 
• Manufacturing: Includes all the practical processes necessary to develop the drug, involving all manufacturing protocols and the establishment of production methods, for small and large-scale production while preserving the drug’s integrity. 
• Control: Comprises all the quality control measures implemented throughout the drug’s manufacturing process to ensure its standardization and quality.

CMC processes must be consistently defined to ensure the drug's safety and effectiveness and the same manufacturing quality for all products, from the investigational phase to their approval to be released to the public.

What are CMC Regulatory Agencies?

A Well-defined CMC, also referred to as pharmaceutical quality, is critical for allowing an Investigational New Drug (IND) to be approved by regulatory health authorities like the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

Every country has a regulatory authority that regulates the drug development process, manufacturing, licensing, and registration. These authorities have different regulations and laws regarding investigational New Drugs (INDs) or investigational medicinal products (IMPs).

The regulatory authorities are responsible for enforcing regulations and development guidelines for pharmaceuticals and labs to ensure INDs/IMPs are high-quality and safe to use, ensuring pharmaceuticals comply with all regulations and laws to allow a drug to be launched into the market. Furthermore, national authorities are regulated by international health authorities, like the World Health Organization (WHO) and the Panamerican Health Organization (PAHO).

Drug Developmental Process in the United States

The drug developmental process in the United States involves five key stages that ensure any IND/IMP is safe to use, and each stage must be followed chronologically according to the FDA:

1. Discovery and Development: The starting phase begins in the laboratory, which includes all activities related to the discovery of the drug and its manufacturing process. 
2. Pre-clinical Research: This phase required the drugs to undergo lab testing to answer safety questions. 
3. Clinical Research: The drugs are tested on people to validate their safety and effectiveness. 
4. FDA reviews: The regulatory agency thoroughly reviews all the data related to the IND/IMP and its manufacturing. This stage includes the possible approval of the drug to start its distribution to the general public. 
5. Post-market safety monitoring: The FDA follows a continuous evaluation of all approved products available for public use.

Drug Development Challenges

The drug development phase starts in the laboratory and includes all the activities involving the active pharmaceutical ingredient (API) discovered in the discovery phase to develop the final product that can be marketed and publicly used after being approved by regulatory health authorities. 

According to Austin and Hayford (2021), “consumer spending on brand-name prescription drugs has risen, but R&D spending has risen more quickly.” The development phase accounts for over half of the total research and development (R&D) expenses. This fact makes it necessary to reduce this phase as much as possible to potentially reduce the final product costs that determine sales revenue.

The increasing costs of the drug development phase have significantly impacted small and emerging biopharmaceuticals. Moreover, creating a CMC strategy that ensures regulatory agency approval has become more demanding as regulations have become more strict. 

To this situation, the Director of CMC & Quality from Small Biopharma, Small Molecules and Biologics agrees that budgeting is an issue and “Most of our challenges are related to funding, getting the money, because making this stuff isn't all that complicated, but you still need to pay for it.”

The pharmaceutical industry is aware of how the drug development phase can significantly impact a drug's production costs and, consequently, its marketability and use in the population. However, over the last two decades, the duration of the drug development phase has increased, mainly due to stronger regulations, leading to higher development costs.

CMC’s Five Pillars: Ensuring IND/IMP Approval

The rationale behind the development of any IND/IMP is to reach its final approval to start its use on individuals who can benefit from it, which is the post-clinical phase of the drug developmental process. CMC is a crucial part of achieving this goal, supporting their regulatory approval by standardizing five critical areas according to the FDA, which are known as the five CMC pillars of standardization:

• Drug Identity: The active pharmaceutical ingredient (API) and its physicochemical characterization (appearance and physical form, particle size distribution, polymorphism, and others).
• Quality: Manufacturing, quality controls, critical quality attributes (CQAs), operating parameters, and in-process controls.
• Safety: Lab trials, safety testings, identification of impurities, and toxicology.
• Purity: Potential impurities, residual solvents, and overall sterility of the drug. 
• Strength/Potency: Its dissolution, strength against solvents, and excipients content.

By upholding these five pillars, CMC ensures a structured and consistent approach to submitting a New Drug Application (NDA) to the FDA in the case of the United States.

CMC Healthcare Impact

A standardized CMC proves to be the most efficient way to allow individuals to access innovative and high-quality treatments faster. This is a positive outcome for healthcare and pharmaceutical industries alike, as it increases the possibility of better outcomes for many health conditions due to more affordable and accessible treatments, which can also improve preventive medicine strategies and reduce healthcare costs, consequently improving health equity.

CMC Challenges

From evolving regulations to complex manufacturing processes, pharmaceutical companies face a range of challenges that impact drug quality and availability, as well as delay the approval and release date. Here are some of the most common CMC obstacles pharmaceuticals are facing today:

• Regulatory Compliance: Pharmaceuticals must keep up and learn to adapt to the continuously evolving global regulations and new requirements from health authorities nationwide and across different countries.
• Product Complexity: Producing biologics, like genetic therapies, involves more complex processes that require specialized knowledge and expertise to maintain drug consistency and high quality.
• Global Supply Chain Obstacles: A worldwide supply chain means that pharmaceutical operations are on a bigger scale, and they must manage logistics, transportation, and coordination challenges globally.
• New Technologies: Tech advances bring opportunities for efficiency and quality improvements in manufacturing, but they also present challenges in implementation and complicate the validation processes, ensuring drugs comply with the country's regulations.
• Data Integrity & Management: Data integrity must be achieved throughout the CMC process, which aims to ensure data accuracy, completeness, reliability, and consistency.
• Lifecycle Management: Changes to manufacturing processes, formulations, or facilities during a product’s lifecycle require careful regulatory coordination and management to minimize disruptions and ensure a continuous, high-quality drug supply.

Overcoming these challenges is essential for delivering safe and effective medications to the public. To effectively address these challenges, a mix of scientific insight, regulatory knowledge, and a dedication to quality at every step of the drug development and manufacturing journey is needed for the pharmaceutical company and drug success.

CMC Non-Compliance

CMC non-compliance is a prevalent challenge in drug development. Many factors can intervene in the manufacturing process of an IND, like the solid-state attributes of the API and its potential polymorphism. If the polymorphism is high, it means the API state is unstable, making the manufacturing process non-compliant with CMC standards, and making the drug unsafe due to uncontrollable results.

Although time is crucial for developing a detailed CMC process that ensures the standardization of the R&D phase of new drugs, some situations collide against CMC principles, attempting against regulatory agencies' regulations, such as epidemiological emergencies.

Specialists are still working on a better risk-based approach to CMC when working on critical epidemiological situations, like the COVID-19 pandemic, which required the fast development and approval of a highly effective vaccine that could reduce the disease's mortality rate and lower the transmission rate. The COVID-19 pandemic made many individuals realize how vital drug control is when creating safe vaccines and other therapies for humans, making CMC crucial for pharmaceutical organizations, especially in crises. 

The Path Forward: Continues Improvement in CMC Practices 

Pharmaceutical organizations must recognize that producing a high-quality drug or medicinal product is based on a standardized and well-defined CMC process. This process ensures the consistent generation of the IND/IMP under the same conditions every time, under the appropriate health regulations. It also highlights the need for continuous improvement in CMC practices to comply with the continuously evolving regulatory standards and ensure drug safety and effectiveness. 

Securing CMC Compliance

By working with a CMC compliance specialist, all CMC-related activities and practices meeting regulatory compliance will be guaranteed, and the company won’t experience any delays or failed submissions of the product. At Viltis, we will help you identify compliance gaps in the early stages by saving your time and resources and ensuring the product’s quality, safety, and efficacy. CMC compliance specialists are updated with global regulatory standards, which will allow you to adapt to new requirements. Our specialist will work with your team to create a CMC and regulatory approach that expedites the regulatory approval procedure, which will allow you to get market access more quickly and consistently.

Get in touch with Viltis today!

Viltis is a Consulting Firm in the Pharmaceutical, Biologics, Life Science, & Medical Device space headquartered in San Diego, CA. We provide support to our clients across the US in regulatory compliance consulting in the field of FDA standards for pharmaceutical and medical device quality. Our mission is to provide high-quality and expert solutions to our clients. With ethics at the heart of our business, we stand by every project we set out on and ensure our solutions are to the complete satisfaction of our clients.

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