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Paving Your Path to CMC Testing Compliance

Introduction

CMC information is a crucial part of gaining approval for clinical trials. Drug companies are wise to begin compiling this information early in the preparation of their clinical trial application and making sure the CMC data are updated in each phase of their clinical trials.

Chemistry, manufacturing, and control (CMC) information about the production of an investigational new drug is a vital part of every application to commence clinical trials. CMC provides the regulating agency with information needed to ensure the safety, identity, quality, purity, strength, and potency of the drug substance and drug product (capsule, tablet, etc.) before approving it for clinical trials. Thus, CMC data is part of the bridge that allows a drug candidate to move from preclinical investigations to clinical trials.

Following successful clinical trials, the application for a marketing authorization must also contain CMC information for production at-scale, with subsequent compilation during clinical trials important for drug commercialization and monitoring.

The CMC information required is determined by the regulating body of each country in which approval is being sought.

For example:

  • In the European Union (EU), CMC output is part of the Investigational Medicinal Product Dossier (IMPD) Application stipulated by Regulation No. 536/2014 on Clinical Trials on Medicinal Products for Human Use.
  • In the United States (US), the requirements for an Investigational New Drug (IND) Application content and format are detailed in 21CFR 312.23(7)

Here we discuss the CMC requirements, guidelines, compliance challenges, and trends in testing.

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Overview of CMC Regulations and Supporting Guidelines

The CMC package required for a clinical trial application includes studies on the drug substance, drug product and placebos to be administered, manufacturing processes, and quality control measures.

Critical CMC elements include:

Drug Substance:

  • Physical, chemical, and biological characteristics.
  • Name and address of manufacturer and methods used.
  • Acceptable limits and analytical methods used to assure its identity, strength, quality, and purity.
  • Stability data such as shelf life, storage requirements, and shipping requirements across climatic zones.

Drug Product:

  • List of components in the product and used in manufacturing.
  • Name and address of manufacturer and methods used to prepare it.
  • Description of packaging procedure and materials.
  • Analytical methods and acceptable limits to assure the identity, strength, quality, and purity of the drug product.
  • Stability data such as shelf life, storage requirements, and shipping requirements across climatic zones.

Placebos:

  • Description of the composition, manufacture, and control of any placebo to be used in the clinical trial.

Labelling:

  • Copy of all labels and labelling instructions.

Pharmacopoeias can assist in the design of drug production processes and preparation of CMC information. Pharmacopoeias are country-specific compilations of drug substance data such as structure, molecular weight, analytical methods used for production, and reference standards for quality control. They also include monographs that can assist in the development of innovative and generic drugs. Examples of pharmacopoeias include the US Pharmacopoeia (USP), European Pharmacopeia (Ph. Eur.), and Japanese Pharmacopoeia (JP).

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Diverging pharmaceutical regulations present a challenge for companies wishing to gain approval to commercialize a new drug in multiple countries. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was formed in 1990 to help harmonize methods used in drug development across countries. The ICH brings together national regulatory authorities and pharmaceutical industry representatives to examine the scientific and technical aspects of drug development and develop guidelines that can help accelerate the drug approval process. ICH guidelines are focused on the areas of quality, safety, efficacy, and multidisciplinary matters.

Current good manufacturing practice (cGMP) for the pharmaceutical industry is critical for ensuring drug product quality and safety. In contrast to the use of CMC information in the decision-making process for clinical trial applications, cGMP gives regulators criteria for use in inspections of drug manufacturing facilities.

Regulators use cGMP to inspect:

  • Personnel
  • Quality controls
  • Facilities
  • Equipment, laboratory, components, and production controls
  • Distribution
  • Record keeping
  • Labelling

Inspections of drug manufacturing facilities are an important part of ensuring that the identity, strength, quality, and purity of drug products manufactured at the facility are accurate and consistent.

Understanding the Challenges in CMC Compliance

As the investigational new drug proceeds through the phases of clinical trials, the initial CMC information must be updated as new information is revealed and/or modifications are made to the drug composition, drug product, or manufacturing process. It is imperative that each piece of CMC information be evaluated and updated in the application for the next clinical trial phase to avoid delays in approval or trial failure.

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The majority of licensed drugs to-date are small molecules with well-understood, chemistry-based modes of action. Large-molecule drugs with complex modes of action are increasingly being developed. Their production often involves living cells, making it difficult to predict or control the effects that environmental changes may have on cellular responses. It is vital that the production environment be carefully designed, tested, and monitored to provide sufficient data to meet CMC manufacturing process requirements.

Gene therapy drug research has experienced rapid growth in the last five years. The US FDA recently released an updated guidance document for human gene therapy IND applications. A few of the novel CMC considerations for such applications are:

  • Development of use and testing protocols for cells and vectors.
  • Development of product-specific titer assays and biologically relevant potency assays.
  • Use of ultrahigh grade reagents.
  • Testing of biologically-derived reagents for pathogens.

Most regulatory agencies encourage companies to engage with them early to allow discussion of CMC information preparation, development milestones, and other items specific to human gene therapies.

Current Trends

One of the strongest trends today is the continued increase in the outsourcing to contracted companies for different steps in the drug development and approval process. Roughly 10 years ago, contract research organizations (CRO) were hired by drug companies to prepare their regulatory paperwork for clinical trial applications. CROs then began expanding their expertise in best processes and machinery for drug and drug product manufacturing. This enabled them to take on more tasks including manufacturing design and the actual manufacturing. From this, house CROs that undertook downstream manufacturing and/or operations processes became known as contract manufacturing organizations (CMOs).

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Eventually, CMOs added drug development tasks to their capabilities, such as cellular and in vivo modelling, pharmacology and toxicology testing, and other preclinical activities. Thus began the contract development and manufacturing organization (CDMO) that offers a broad range of capabilities to drug companies.

The increased availability of CMO/CDMO fills a need for drug companies that may lack in-house expertise for the timely completion of design, regulatory applications and filings, or product manufacturing. The use of CMO/CDMO often helps companies get a new drug into clinical trials and obtain licensure for commercialization of the drug product more quickly. New, small drug companies can benefit by using CMO/CDMO to control the amount of investment needed for infrastructure and operations.

Generic manufacturers must submit an Abbreviated New Drug Application (ANDA in the US) for generic drug approval. The generic drug product must be bioequivalent to the patented drug product, i.e., it must deliver the same amount of active ingredient to the bloodstream in the same amount of time. Thus, the research and development of a new generic drug typically begins up to five years before the original drug patent expires.

ANDA also requires CMC information on the raw materials, processes, and equipment to be used in the drug production. A CMO/CDMO can complete the research, development, manufacturing design, and regulatory paperwork for a generic drug company so the ANDA is ready to submit when the patent expires. This greatly reduces the time required to get the generic drug to market.

Future Trends

Much consideration is being given to converting drug production from batch manufacturing to continuous process manufacturing. A primary driver of this trend is the increased efficiency that can be realized by having one process—from raw ingredients to final packaged product—all in one location. The time from raw materials to final product shipping is shortened with the continuous process model, and costs are decreased by eliminating transport of materials to multiple step-specific facilities.

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Such a conversion will require the development of innovative and robust quality control measures to (1) ensure the quality of the product and (2) enable problem correction early in the process to prevent downstream waste. A few of the quality controls that will be required are:

  • Detailed process and QA/QC SOPs and training in their implementation.
  • Continuous, in-line monitoring throughout the process.
  • Real-time reporting to enable immediate remediation of problems.

The increased use of digital technology and advanced analytical techniques is another emerging trend in development. Implementation of these technologies will enable the following and other advances:

  • In silico prototyping in research and development efforts.
  • Deep learning for predictive modelling of molecule activity and drug formulations.
  • Real-time batch monitoring for the conversion to continuous process manufacturing.

Efforts are also underway to develop and make available biological reference standards to support CMC testing. This will be very supportive in the advancement of cell and gene therapies. Pharmacopoeias do not currently have many monographs for cell and gene therapy drugs, although work is underway to add chapters that characterize the properties of the target cells and genes.

Biological reference standards are very specific to each biological therapy, as opposed to one chemical reference standard that may apply to multiple chemical therapies. The development of such biological reference standards will require some time to complete for therapies already developed and will need to be included in the development of new cell and gene therapies.

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Summary

CMC information is a crucial part of gaining approval for clinical trials. Drug companies are wise to begin compiling this information early in the preparation of their clinical trial application and making sure the CMC data are updated in each phase of their clinical trials. CMC needs must also be an integral part of the development of new types of drug therapies, such as cell and gene therapies, and the emergence of new technology innovations such as continuous process manufacturing and advanced analytical technologies.

References

  1. Clinical trials - Regulation EU No 536/2014. https://ec.europa.eu/health/human-use/clinical-trials/regulation_en
  2. Investigational New Drug Application. 21CFR 312.23(7). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.2
  3. US Pharmacopoeia (USP). https://www.usp.org/
  4. European Pharmacopeia (Ph. Eur.). https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-10th-edition
  5. Japanese Pharmacopoeia (JP). https://www.pmda.go.jp/english/rs-sb-std/standards-development/jp/0019.html
  6. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. https://www.ich.org/
  7. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/chemistry-manufacturing-and-control-cmc-information-human-gene-therapy-investigational-new-drug