Chemistry, manufacturing and controls (CMC) covers a wide range of activities relating to the synthesis of pharmaceutically active chemical compounds that are to be administered in a clinical trial and manufacture of the final product used in a clinical trial.

These activities are vital for converting an initial bioactive compound into a form that is suitable to be administered to patients, as a pill, tablet or liquid. They are also designed to ensure that the final medicinal product is synthesized, formulated and packaged to a consistently high standard and efficiently.

Key CMC factors to consider during antibiotic development include:

  • The physical properties of material synthesized (e.g. solubility).
  • The purity of material synthesized (i.e. with minimal impurities).
  • The stability of material synthesized (how rapidly it degrades under different atmospheric conditions).
  • The practicality and scalability of manufacturing processes (how easy it is to make material on a commercial scale).
  • The efficiency of manufacture (yield compared with amounts of raw ingredients).
  • The consistency of manufacture (ensuring that final material is of consistently high quality and has consistent pharmaceutical properties).

For phase 1, CMC activities fall into two main areas:

Before clinical trials can begin, regulatory approval is required, 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). Regulatory authorities provide detailed guidance on what should be included in IND applications and IMPDs.

 

API production

CMC activities in API production focus on five aspects:

  • Physical form characterization and optimization: Exploring the physical form (crystalline, liquid, solid) of the API and how these are affected by manufacturing processes. The aim is to identify the physical form that is best suited to how the final drug product will be formulated and used.
  • Process research and development: Exploring different ways in which the API can be synthesized, for example to maximize yield, minimize impurities, and optimize production of the most desirable physical form.
  • Analytical methods development and validation: Establishing methods to monitor API manufacturing processes and to demonstrate the purity and quality of API.
  • Manufacture of GMP batches for phase 1 and 2 studies: Establishing a manufacturing process to generate sufficient quantity of quality-assured material for early clinical studies, consistent with GMP standards.
  • Stability studies: Long-term studies to assess the chemical and physicochemical stability of API under different conditions (e.g. different temperatures, humidity) and the nature of degradation products.
  1. Physical form characterization and optimization

    A pharmaceutically active compound may have physicochemical properties that make it difficult to turn into a drug product suitable to be given to patients. A range of CMC activities can be undertaken to improve these properties.

  • Salt screening: Around half of all drugs are given in the form of a salt. A salt is formed when an acidic molecule is combined with a basic molecule. A charged pharmaceutically active compound can therefore be paired with a counterion to generate a salt. Careful selection of this counterion and analysis of the resulting salt can be used to optimise the physicochemical properties of the API compound. Salt screening typically involved several steps:
    • pKa measurement of the investigational compound to establish its acidity and the potential to form a salt. If salt formation is not possible, the next step is polymorph screening (see below).
    • Full physical characterization of the API compound, using a wide range of analytical techniques (e.g. differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to assess its response to temperature changes, X-ray powder diffraction (XRPD) to characterize its physical structure and crystalline properties, gravimetric vapour sorption (GVS) to determine its water absorption properties (hygroscopicity), and microscopy).
    • Solvent solubility screen to identify the best solvents to use in preparation of crystalline API, for example to maximize yield, purity and processability during manufacturing. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) classifies solvents according to their risk to health, and ICH class 1 or 3 solvents are preferred as these pose the lowest risk to health.
    • Exploratory high-performance liquid chromatography (HPLC) studies to assess salt solubility.
    • Medium-throughput salt screen with pharmaceutically acceptable counterions and different solvent systems to identify potential options for further investigation.
  • Polymorph screening: Most potential drug compounds can exist in a range of physical forms, known as polymorphs. Polymorphs typically have different physicochemical properties, so CMC efforts focus on producing the form with the optimal properties for use as a drug. Polymorph screening is carried out on a salt if available or on the original API material. Polymorph screening typically involves several activities:
    • Primary polymorph screening experiments.
    • Characterization of the physical properties of the solid forms.
    • Investigation of transitions between polymorphs.
    • Scale up of the most promising polymorph.
    • Analysis of stress stability.
    • Selection of the preferred API physical form for further development.
  1. Process research and development

    A critical aspect of CMC is to identify the best ways to manufacture API, for example to optimize yield, purity and stability of the desired physical form. This involves comparing different routes of chemical synthesis (route scouting) and defining the optimal manufacturing process for the selected route of synthesis. Further key activities include:

  • Optimizing crystallisation of drug substance.
  • Assessing the safety of the selected synthesis process.
  • If relevant, development of HPLC methods to monitor synthesis of enantiomers, for compounds that can exist in mirror-image forms.
  • Undertaking genotoxicity risk assessments (GRA) to monitor for possible genotoxic impurities at key stages of synthesis.
  • Manufacturing of a demonstration batch, which is necessary to show that the defined process reliably produces material with the expected properties.
  1. Analytical methods development and validation

    As part of quality assurance, analytical methods are needed to monitor the synthesis process and the quality of material synthesised. These methods must comply with phase 1 trial regulatory requirements. Forced degradation studies, a type of stress testing, must also be carried out to assess the stability of API synthesized in response to a wide range of physical and environmental challenges.

Extensive structural characterization is carried out on the final API reference standard, using techniques such as elemental (CHN) analysis, counter-ion identity and stoichiometry confirmation, nuclear magnetic resonance (1H-NMR, 13C-NMR), ultraviolet/visible spectroscopy (UV-Vis), infrared spectroscopy (IR), liquid chromatography–mass spectroscopy (LC-MS), XRPD and DSC/TGA.

  1. Manufacture of GMP batches for phase 1 and 2 studies

    Once the optimal manufacturing process has been established and validated, GMP-quality batches of drug substance are produced for phase 1 and 2 clinical trials.

  1. Stability study on demonstration and GMP batches

    While initial batches of API will be used relatively quickly in clinical trials, regulatory approval will also require data on long-term stability, to establish a shelf-life and required storage conditions, and to inform labelling of the final product.

Bodies such as the ICH and WHO have established guidelines on stability studies for pharmaceuticals. These criteria establish how long studies should last (e.g. ≥ 6 months or ≥ 12 months) and the conditions under which material should be stored (e.g. different temperatures and levels of humidity). Guidelines have been established to mimic five climatic zones (e.g. temperate, hot/humid), to mimic environmental conditions in different parts of the world.

Multiple analyses are carried out during stability studies to monitor changes in chemical or physicochemical properties over time, including the appearance of potentially harmful degradation products.

Drug product

In drug product development, processes are established to convert API into a form that can be administered to patients (without affecting its chemical composition). CMC activities in drug product development focus on four aspects:

  • Clinical formulation development: Establishing the best formulation for the drug product to be given to patients – i.e. what additional materials can be included to enhance API biological activity (e.g. by increasing its bioavailability) or improve the properties of the final product (e.g. by enhancing its palatability).
  • Analytical method development and validation: Identifying and validating the tests to be used to quality assure the drug product.
  • Manufacture of clinical supplies for phase 1 studies: Preparing the materials that will be administered to patients in a clinical trial.
  • Stability study: Assessing the stability of one batch of drug product.
  1. Clinical formulation development

    Typically, formulation development takes place across three stages:

  • Pre-formulation studies to characterize the properties of drug substance of relevance to formulation development and to determine the optimal formulation technology. Properties assessed include:
    • Solubility at different pH levels.
    • Solubility in standard pharmaceutical solvents.
    • Compatibility with other ingredients commonly used in drug product development (pharmaceutical excipients), such as binding agents or lubricants.
    • The relationship between dissolvability and particle size.
  • Prototype formulation development based on the results of pre-formulation studies. Short-term stability studies (≤ 3 months) are carried out on prototype formulations to inform recommendations included on packaging materials. After further formulation development, if required, a formulation is selected for phase 1 studies. A visually matched placebo is also developed.
  1. Analytical methods development and validation

    Analytical methods are needed to monitor production of drug product.

  1. Manufacture of clinical supplies for a phase 1 study

    Batches of GMP-quality material for clinical trials are produced, as well as matching placebo. 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.

  1. Stability study

    A stability study is carried out on the selected prototype formulation and a clinical batch of drug product.