Chemistry, Manufacturing & Control (CMC)

Our CMC team’s expertise ranges from small molecules to cell therapies. We are ready to execute a single CMC task or create and implement a full CMC strategy that is appropriate for you and your company.

Balancing Risk, Time, Quality & Budget

A well-thought-out CMC strategy is key to project success as it ensures sufficient drug is available. CMC is the sum of, first, the definition of the properties of the final drug and methods to measure and quantify them (chemistry); second, the processes by which the drug is made and an understanding of the steps that critically affect product quality (manufacturing); and third, a control strategy, based on molecule and process understanding, that ensures consistency between batches (control).

Many different aspects contribute to CMC, some of which are highlighted below. The more these aspects are considered parts of a whole, the higher the likelihood of a successful CMC strategy. In addition, it is critical to properly integrate a CMC strategy with regulatory, clinical, preclinical, and quality strategies. 

Any CMC strategy needs to be a function of the company executing it, the indication they are pursuing, and the particular details of the drug. At 3D-PharmXchange, we have extensive experience with many different drugs, for different indications and administration routes, in different companies. We have worked with our own pre-clinical, clinical, and regulatory colleagues, or with those in other companies. We bring all this experience to help you craft the best approach for your company.

Phase-appropriate CMC Strategy

From start to finish, CMC represents a lot of work by different departments, on different aspects that ultimately result in a robust process producing a drug of consistent quality. The more of this work is done early, the less likely it is there will be delays because a batch unexpectedly fails. The more is postponed to a later phase, however, the quicker a drug can move into the clinic where it can be determined if there are signs of efficacy. Balancing these two pressures, of increasing understanding early vs. failing early in the clinic without expending enormous resources, involves setting a strategy where the risks are identified and decisions are taken of when it is appropriate to take those risks. This will differ from project to project and company to company. The CMC experts at 3D-PharmXchange have each done this multiple times on many projects and together with you will use their expertise to craft a risk strategy that is appropriate for the specifics of your drug, indication, and company.

Formulation & Stability – Understanding Your Molecule.

A formulation is developed to allow the drug to be dosed via the chosen administration route, at the right dose, and resulting in the desired pharmacokinetic profile in the patient. The drug needs to be stable in the formulation under the chosen storage conditions, to allow for appropriate shelf life. Additionally, stability needs to be demonstrated during the preparation of the drug for patient administration. The formulation may need to be changed during development, for example, when new clinical information suggests a different dose is required.

As development enters late stage, it becomes necessary to understand more about the formulation, for example how changes in pH or excipient concentration or grade affect stability. Coupled with more data becoming available, this leads to a better understanding of the molecule: a fundamental part of demonstrating control over the manufacturing process.

Administration routes – Choosing The Right Path

The choice of administration route has a profound effect on CMC. Not all drugs can be delivered to the patient in all ways and sometimes significant formulation work needs to be done to identify a formulation that maintains stability and allows for the chosen administration route. Changes in administration route during development may require a lot of rework: often stability data needs to be collected again and it needs to be shown that the new formulation results in a similar molecule and safety and pharmacokinetic profile in the patient.

In light of this, it is important that there is close collaboration between the CMC, pre-clinicalclinical, and commercial colleagues so that potential changes can be anticipated. The better the view to long-term plans, the better a CMC strategy can be tailored to anticipate and derisk upcoming changes upfront. The 3D-PharmXchange experts have worked on most traditional administration routes (e.g. IV or oral) and the corresponding drug product presentation, as well as on a number of novel routes (e.g. nasal or intraocular).

CDMO Selection – Finding Your Match

Depending on your company, there are more or fewer activities you can do in-house: method development can be outsourced, for example, as can formulation, stability, and process development. Clinical manufacturing is typically outsourced and in anticipation of the commercial stage, a commercial CMO needs to be identified in time. At 3D-PharmXchange, we have a network of trusted C(D)MOs and we have helped many clients work on requests for proposals from C(D)MOs, assessed and compared responses, and given advice on the choice.

Once a partner organization is picked, 3D-PharmXchange has significant experience with the tech transfer of an existing process to a partner and subsequently (daily) management of further work.

Characterization & Stability – Designing A Product That Lasts. 

At the root of any CMC work are the proper definition and physicochemical properties of the molecule, both the drug substance/API and the drug product. An understanding of the critical properties of the molecule leads to the definition of critical quality attributes and specifications. These will be further refined during development, but this knowledge underlies all other CMC work.

To accurately measure different critical aspects of the molecule, it is necessary to develop analytical methods. These are often specific to each project and molecule and during development will go from qualified status to being fully validated.

Quality By Design – Determining Your qTTP & CQA

To demonstrate the safety of a drug, it is critical to have control over the process and the final drug product administered to the patient. This implies an understanding of what aspects of the drug are critical (the critical quality attributes), what the final drug should look like (the quality target product profile), and what steps and factors in the manufacturing processes affect these the most (the critical process parameters). To understand the interplay between these factors, Quality by Design is often used as a strategy.

This consists of taking the existing knowledge of a product and manufacturing processes and using this to plan further experiments to increase the knowledge and understanding of the product and processes. It is an iterative approach, often amplified with statistical techniques such as design of experiments, to do this more efficiently. Taking a holistic approach to CMC development, rather than seeing it as the sum of individual activities that need to be performed, greatly enhances the ability to bring true understanding, and control, to manufacturing.

Phase-appropriate CMC Strategy

From start to finish, CMC represents a lot of work by different departments, on different aspects that ultimately result in a robust process producing a drug of consistent quality. The more of this work is done early, the less likely it is there will be delays because a batch unexpectedly fails. The more is postponed to a later phase, however, the quicker a drug can move into the clinic where it can be determined if there are signs of efficacy. Balancing these two pressures, of increasing understanding early vs. failing early in the clinic without expending enormous resources, involves setting a strategy where the risks are identified and decisions are taken of when it is appropriate to take those risks. This will differ from project to project and company to company. The CMC experts at 3D-PharmXchange have each done this multiple times on many projects and together with you will use their expertise to craft a risk strategy that is appropriate for the specifics of your drug, indication, and company.

Formulation & Stability – Understanding Your Molecule.

A formulation is developed to allow the drug to be dosed via the chosen administration route, at the right dose, and resulting in the desired pharmacokinetic profile in the patient. The drug needs to be stable in the formulation under the chosen storage conditions, to allow for appropriate shelf life. Additionally, stability needs to be demonstrated during the preparation of the drug for patient administration. The formulation may need to be changed during development, for example, when new clinical information suggests a different dose is required.

As development enters late stage, it becomes necessary to understand more about the formulation, for example how changes in pH or excipient concentration or grade affect stability. Coupled with more data becoming available, this leads to a better understanding of the molecule: a fundamental part of demonstrating control over the manufacturing process.

Administration routes – Choosing The Right Path

The choice of administration route has a profound effect on CMC. Not all drugs can be delivered to the patient in all ways and sometimes significant formulation work needs to be done to identify a formulation that maintains stability and allows for the chosen administration route. Changes in administration route during development may require a lot of rework: often stability data needs to be collected again and it needs to be shown that the new formulation results in a similar molecule and safety and pharmacokinetic profile in the patient.

In light of this, it is important that there is close collaboration between the CMC, pre-clinicalclinical, and commercial colleagues so that potential changes can be anticipated. The better the view to long-term plans, the better a CMC strategy can be tailored to anticipate and derisk upcoming changes upfront. The 3D-PharmXchange experts have worked on most traditional administration routes (e.g. IV or oral) and the corresponding drug product presentation, as well as on a number of novel routes (e.g. nasal or intraocular).

CDMO Selection – Finding Your Match

Depending on your company, there are more or fewer activities you can do in-house: method development can be outsourced, for example, as can formulation, stability, and process development. Clinical manufacturing is typically outsourced and in anticipation of the commercial stage, a commercial CMO needs to be identified in time. At 3D-PharmXchange, we have a network of trusted C(D)MOs and we have helped many clients work on requests for proposals from C(D)MOs, assessed and compared responses, and given advice on the choice.

Once a partner organization is picked, 3D-PharmXchange has significant experience with the tech transfer of an existing process to a partner and subsequently (daily) management of further work.

Characterization & Stability – Designing A Product That Lasts.

At the root of any CMC work are the proper definition and physicochemical properties of the molecule, both the drug substance/API and the drug product. An understanding of the critical properties of the molecule leads to the definition of critical quality attributes and specifications. These will be further refined during development, but this knowledge underlies all other CMC work.

To accurately measure different critical aspects of the molecule, it is necessary to develop analytical methods. These are often specific to each project and molecule and during development will go from qualified status to being fully validated.

Quality By Design – Determining Your qTTP & CQA

To demonstrate the safety of a drug, it is critical to have control over the process and the final drug product administered to the patient. This implies an understanding of what aspects of the drug are critical (the critical quality attributes), what the final drug should look like (the quality target product profile), and what steps and factors in the manufacturing processes affect these the most (the critical process parameters). To understand the interplay between these factors, Quality by Design is often used as a strategy.

This consists of taking the existing knowledge of a product and manufacturing processes and using this to plan further experiments to increase the knowledge and understanding of the product and processes. It is an iterative approach, often amplified with statistical techniques such as design of experiments, to do this more efficiently. Taking a holistic approach to CMC development, rather than seeing it as the sum of individual activities that need to be performed, greatly enhances the ability to bring true understanding, and control, to manufacturing.

Maarten Nieboer

Maarten Nieboer

Maarten leads the CMC team at 3D-PharmXChange. His team has on average 10 years+ experience in development of CMC for all different products – small molecules and biologicals in all stages of Drug Development.

Interested?

Contact us for enquiries regarding our CMC expertise.

e info@3d-pxc.com
t +31 1 353 482 72

Maidstone 48a, 5026 SK Tilburg,
The Netherlands

Pivot Park, RK Building, room 2326,
Kloosterstraat 9,
5349 AB Oss,
The Netherlands

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Our solutions

Navigating milestones successfully is critical for your drug development program to move forward. Besides a focus on quality, our teams aim to ensure that your plans are executed efficiently, cost-effectively, and are ready to partner with you to develop a program customized to your needs. 

Our senior experts can also take on leadership roles to answer to your development program’s specific requirements. Whether they are Non-Clinical, Clinical, CMC, or Regulatory experts they all have hands-on experience with leading large development teams and toward market approval.

Read more about our Leadership Roles.

Non-Clinical

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CMC

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Clinical

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Regulatory Affairs

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Leadership Roles

Our senior experts are selected based on their ability to answer to your development program’s specific requirements. Whether they are Non-Clinical, Clinical, CMC, or Regulatory experts they all have hands-on experience with leading large development teams and toward market approval.

Without exception, we are concerned with the seniority and experience of our candidates required to lead multi-disciplinary teams and to provide you with a balanced expert collaboration that matches your needs.

About us

A company where small dedicated teams and a high level of ownership are the key to success. That is why we treat our clients’ project as if they are our own. From a genuine interest we maintain a close relationship with our clients, in which we value open and honest communication, in order to provide high quality tailored solutions.

Main Office
Maidstone 48a
5026 SK Tilburg
The Netherlands

Satellite Office
Pivot Park RK Building Room 2326
Kloosterstraat 9
5349 AB Oss
The Netherlands

Careers at 3D

No drug is developed by a single person. We understand that it takes teamwork, perseverance to realize something this big. The 3D team works hard with room to laugh and is looking to expand.

At 3D, we believe knowledge needs to be shared to further develop clinical programs, increase market access, and to meet unmet patient needs. This is why we share publications, blogs, and other insights here. Feel free to leave us a message if you’d like more information on a certain topic.