Chemistry, manufacturing and controls (CMC)

Chemistry, manufacturing and controls (CMC) activities are designed to optimize the delivery of a pharmaceutically active compound to patients and ensure the quality of medicinal products throughout product development and manufacturing.

Much of the focus of CMC is at the phase 1 trial stage, to establish manufacturing processes that consistently generate GMP-standard materials in the required form to give to patients. However, additional CMC activities are carried out at later stages, for example to refine and scale-up manufacturing processes.

As for phase 1, CMC activities for phase 2 and 3 focus on two areas:

Before phase 2 or 3 trials can begin, regulatory approval must be obtained, and regulatory assessment covers CMC activities. CMC is therefore an important component of the documentation that must be submitted for regulatory approval (an Investigational New Drug (IND) application to the FDA in the US and an Investigational Medicinal Product Dossier (IMPD) in the EU).

These documents must include summaries of information related to manufacturing and quality assurance for all materials to be administered in a trial (including placebos or existing products used as controls, as well as the investigational drug product).

Guidance on what should be included in IND applications and IMPDs has been provided by the FDA and EMA, respectively.

API production

CMC activities focus on three main areas at phase 2/3:

  • Manufacturing processes: Scale up, process optimization and quality assurance.
  • Specifications: Defining requirements relating to API quality and manufacturing processes.
  • Stability studies: Long-term studies of changes to the physical and physicochemical properties of API manufactured for phase 2/3 trials.
  1. Manufacturing processes

    Building on the process established for initial API production, modifications are made to support larger-scale manufacturing, to further optimize manufacturing, and to assure quality at this larger scale. Key activities include:

  • Process optimization and scale up: Modifying existing manufacturing process to generate the larger quantities of material required for bigger trials and to enhance efficiency or yield.
  • Quality by design (QbD) assessment: Applying a systematic approach to assure the quality of manufactured materials based on a thorough understanding of (a) the critical properties of the material being made (critical quality attributes, CQAs) and (b) the most important aspects of the manufacturing process that might influence these attributes (critical process parameters, CPPs).
  • Impurity control strategy definition: Defining the approach need to minimize the presence of impurities and degradation products in batches of API.
  • Regulatory starting material characterization: Analysis of the raw ingredients that will be used in the API manufacturing process, to identify any issues that could have implications for regulatory approval.
  • Potential genotoxic impurities assessment: Studies to identify the potential presence of contaminants with mutagenic potential.
  • Nitrosamine risk assessment: An analysis of the potential for contamination with nitrosamines, potential human carcinogens, during API manufacture.
  • Manufacture of a pilot batch: Testing of manufacturing and control processes through a test run.
  • Manufacture of a GMP batch to support phase 2/3 studies: Production of GMP-quality material that will be used in clinical trials.
  1. Specifications

    A key CMC function is to define the product and manufacturing process specifications that must be adhered to in order to assure quality. These specifications should also cover acceptable impurity levels. The analytical methods used to assess whether specifications are being met must be validated. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance is available on validation of analytical methods.

  2. Stability studies

    Long-term stability studies on API batches, in line with those carried out at phase 1.

Drug product

CMC activities focus on five main areas at phase 2/3:

  • Clinical formulation development: Optimizing the formulation of the final drug product
  • Manufacturing processes: Scale up, process optimization and quality assurance for drug product manufacture.
  • Specifications: Defining requirements relating to assurance of drug product quality and manufacturing processes.
  • Manufacture of clinical supplies: Manufacture and packaging of batches of drug product for use in clinical trials.
  • Stability studies: Long-term studies of drug product stability under different environmental conditions.
  1. Clinical formulation development

    Optimization of product formulation to establish a form of drug product delivering the desired dosage that can be taken through subsequent stages of commercialization.

  2. Manufacturing processes

    As for API manufacturing, undertaking a quality by design (QbD) assessment and defining a control strategy for critical quality attributes CQAs and critical process parameters (CPPs). Following process optimization and scale up, pilot batches of drug product are manufactured.

  3. Specifications

    As for API manufacturing, defining the product and manufacturing process specifications that must be adhered to in order to assure quality of the drug product. ICH guidance is available on validation of analytical methods used to monitor adherence to these specifications.

  4. Manufacture of clinical supplies

    Batches of GMP-quality drug product are produced for use in clinical trials. Clinical batches are packaged and labelled as material for use in clinical trials. These final materials must be certified by a qualified person (QP), a suitably trained and qualified individual ultimately responsible for the quality of manufactured pharmaceuticals. Clinical trial materials are distributed to clinical trial sites by specialist couriers, with temperature monitoring throughout transit.

  5. Stability studies

    Stability studies are carried out on a clinical batch of drug product to assess changes to the physical and physicochemical properties of API manufactured for phase 2/3 trials.