Chemistry manufacturing and controls

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Chemistry, manufacturing and controls (CMC)


Chemistry, manufacturing and controls; also referred to as pharmaceutical quality/CMC.

The term covers the various procedures used to assess the physical and chemical characteristics of drug products, and to ensure their quality and consistency during manufacturing. CMC data are an important part of submissions to regulatory authorities.

Understanding Chemistry, Manufacturing and Controls (CMC)

Chemistry, Manufacturing and Controls (CMC) is critical to attaining a successful registration filing and is an integral part of any pharmaceutical product application to the US Food and Drug Administration (FDA). CMC applies to the entire product development life cycle, as it begins during drug candidate selection and continues through post-approval and beyond.

The basics of Chemistry, Manufacturing and Controls (CMC)

CMC upholds the connection between the drug used in clinical studies and the drug that is marketed commercially and made available to consumers. Chemistry, Manufacturing and Controls ensures patients have access to consistently efficacious, safe, and high-quality pharmaceutical and biopharmaceutical drug products. CMC must be tailored to the specific platform and delivery system of the drug (e.g., injectable, controlled release, inhalant, topical, solid dose, oral, etc.), as it is not “one-size-fits-all” or a list of tests that must be performed on every product.

Chemistry, Manufacturing and Controls applies to both the drug product and the facility in which the product is being manufactured:

Drug product

  • The manufacturing process;
  • Quality control release testing, and
  • Specifications and stability of the product.

Manufacturing facility

  • Design;
  • Qualification;
  • Operation, and
  • Maintenance.

Consequences of CMC regulatory non-compliance

A critical aspect of CMC regulatory compliance is ensuring all CMC practices comply with current FDA guidance and code of federal regulations, as regulatory requirements and expectations are continually evolving. For example, if an FDA-approved finished drug product does not meet the manufacturing, packing, or stability parameters detailed in the submission provided to the Agency, the marketing authorization is deemed non-compliant with manufacturing procedures. Consequences for non-compliance to CMC regulatory requirements can include:

  • Addressing gaps in data under the scrutiny of regulatory agencies;
  • Withdrawal of marketing authorization;
  • Suspension of product distribution, and/or
  • Consent decree and fines.

Considerations for partnering with a CDMO for CMC

Small and virtual pharma

Early drug development is increasingly carried out by smaller organizations, rather than large, vertically integrated biopharma companies, and many of these small organizations partner with contract development and manufacturing organizations (CDMOs) for the Chemistry, Manufacturing and Controls aspects of regulatory applications. For smaller pharmaceutical organizations, as a drug candidate moves into cGMP and CMC phases, due to limited internal resources, the experience and expertise of a CDMO is both necessary and critical to obtaining regulatory approval.

Benefits of a CMC-centric CDMO partnership

Drug product submission applicants benefit greatly from the resources made available by a CDMO partner. CDMOs have the depth of regulatory and scientific knowledge needed to prepare an effective CMC section of a regulatory submission, including specifications and justification for components and products, analytical methods and method validations, stability data, and product and process design and/or validations.

Partnering with Element’s CMC experts

Enrich the quality and efficiency of your regulatory submission and meet Agency expectations with the support and guidance of Element’s CMC experts. With decades of CMC experience and a depth of knowledge and understanding of current FDA guidance and regulatory requirements, our leaders and scientists can help you to determine the best CMC strategy for your drug product. Our commitment to applying our scientific expertise is evident in our proven track record of providing comprehensive and complete CMC support for successful regulatory applications.

Chemistry, Manufacturing, and Controls (CMC) Advice and Management

What is CMC?

CMC is an acronym for chemistry, manufacturing, and controls which are crucial activities when developing new pharmaceutical products. Beyond the processes themselves, CMC also refers to practices and specifications that must be followed and met in order to ensure product safety and consistency between batches. CMC begins after a lead compound is identified through drug discovery, and continues through all remaining stages of the drug development life cycle. In addition to the pharmaceutical product, CMC also applies to the facility where it manufacturing occurs.

What is the Purpose of CMC?

Before you’re ready to test your medicinal product on humans, you must develop a CMC process to ensure quality manufacturing standards have been established. This information is required in Module 3 of the clinical trials application (CTA), such as the investigational medicinal product dossier (IMPD) in Europe and the Food and Drug Administration’s (FDA’s) investigational new drug (IND) application in the US, as well as EU marketing authorization applications and FDA new drug applications (NDAs) or biologics license applications (BLAs). 

The primary objective of CMC is to assure the quality of the finished product during all phases of development. Regulatory authorities need to see detailed standards to ensure consistency of identity, safety, quality, stability, and strength between the product used for clinical trials and product batches produced for commercial purposes on an ongoing basis.

Are CMC Practices Required?

All companies with investigational products are required to follow the specific details of their CMC for every phase of the product lifecycle, including lifecycle management activities, eg, technology transfer and line extensions. A critical element is knowing which steps and variables in the manufacturing process need to be controlled and why in order to obtain a comprehensive understanding of the manufacturing process and the necessary control strategy.

If CMC practices are not followed or if they do not meet current regulatory requirements, the marketing authorization will be considered non-compliant and will be withdrawn. The consequences of this include fines, suspension of distribution, and any data gaps will have to be addressed under scrutiny of the appropriate regulatory agencies.

Should You Work with a Consultant to Develop Your CMC Plan? 

Working with a global partner experienced in regulatory strategy and CMC development can help you appropriately analyze and document the manufacturing processes, active substance and drug product characteristics, and testing to ensure the product is safe, effective, and consistent.

From early-stage development and at every point through commercialization, ProPharma Group partners with our clients to tackle complex CMC challenges. We help ensure the regulatory authorities see the control and robustness of your process and product from a documentational and operational perspective. As your CMC partner, we can smooth the path to marketing authorization application (MAA)/new drug application (NDA) approval and commercialization, balancing cost, risk, and speed to help you ensure quality manufacturing and effective controls for the health and safety of patients.

Science-Focused Regulatory CMC Experts

At ProPharma Group, our regulatory CMC experts are scientists first and foremost. Our team of PhDs and MDs have decades of global regulatory and quality experience, allowing us to provide a unique level of service when developing your Chemistry, Manufacturing, and Controls plan:

  • Our unmatched global reach means we can work with you to prepare your marketing applications (MAA or NDA) in parallel, saving you time and money
  • Our science-first approach to understanding your product, combined with first-hand insights of regulatory expectations and requirements, help support the successful design of your CMC plan — including process and formulation development, analytical development identifying Critical Quality Attributes (CQA) and Critical Process Parameters (CPP), developing control strategies, establishing quality testing methods and reviewing validation protocols and reports
  • Our 30+ years of providing regulatory sciences services means we’ve seen how submission requirements and expectations are constantly evolving. Our frequent contact and extensive experience with regulatory agencies ensure you will be following the latest FDA and European Medicines Agency (EMA)/national agencies guidance
  • Our understanding of the regulatory world means that we can interpret the regulatory landscape and translate this into a successful regulatory CMC strategy. We can also provide scientific advice and prepare, coordinate, and participate in meetings with the regulators of interest
  • Our unique standing as a single-source provider of regulatory, life science consulting (including quality assurance), pharmacovigilance, and medical information services offers you a cohesive, multidisciplinary extension of your team through every phase of the product lifecycle

CMC Development Strategies include:

Drug Product Development

  • API and Excipient Sourcing
  • Analytical Development
  • Analytical Testing and Validation Management
  • Formulation Development Management
  • Report Documentation
  • Analytical and Formulation Vendor Selection and Management
  • Project Management

Clinical Trial Material

  • Planning and Oversight of CTM Manufacturing
  • Oversight of Packaging and Labelling
  • Management of CTM Inventory and Distribution Logistics

Supply Chain and Manufacturing Strategy

  • Technology Transfer Planning and Management
  • Vendor and Facility Selection
  • Manufacturing Strategy
  • Manufacturing Process Development and Validation
  • Process Assessment and Optimization
  • Manufacturing Scale-Up
  • Material Sourcing

Quality and Compliance

  • Gap and Risk Assessments
  • Technical and Process Auditing
  • Pre-Approval Inspection Preparation and Remediation
  • Process Optimization and Validation
  • Cleaning Validation
  • Sterility Validation
  • Quality Management System Development

Our early involvement in the drug development process saves you substantial time and money. From API and formulation sourcing, to manufacturing, scale-up and packaging, we provide invaluable strategic guidance and CMC Development Services.

An introduction to Chemistry, Manufacturing and Controls (CMC) regulatory strategy

Regulatory strategies in the field of drug development can be understood as science-driven assessments of a product’s specific development options, key considerations and anticipated regulatory outcomes. A robust regulatory strategy should encompass the whole product lifecycle from initial development through to modifications planned post-marketing.

A product’s regulatory outcome will have a wider impact because it will ultimately link to its potential for patient access, its commercial acceptability and uptake, and any potential business outcomes.

A comprehensive regulatory strategy should include a combination of regulatory requirements and business objectives. It will typically be defined by a global regulatory expert, who will seek input from a diverse cross-functional clinical, nonclinical and technical team.

This cross-functional team is an essential part of the regulatory process and should be comprised of experts who are able to:

  • Provide information on regional regulatory requirements and up-to-date regulatory intelligence on expectations, precedents, and potential competition
  • Liaise with local regulatory authorities
  • Facilitate appropriate document management and submission processes
  • Provide specific functional expertise around issues such as labeling, nonclinical and clinical trials and CMC

Understanding the CMC component of regulatory strategy

The overall aim of any regulatory strategy is to allow patient access to vital drugs. It is just one element of the new Drug Application marketing application (NDA), and it is within this specific context that a CMC regulatory expert is required to deliver a suitable CMC regulatory strategy.

The strategy must include key CMC milestones and decision points as well as considering regulatory CMC objectives, hurdles, the current regulatory landscape and any relevant precedents. It must also explore and outline any risks to potential success in delivering a specific regulatory outcome.

Drug sponsors should have significant input into the development plan throughout the product’s lifecycle – from the preclinical development phase through to post-marketing activities.

A company’s internal regulatory knowledge is combined with expertise via outside consultants to provide feedback on the likely acceptability of the planned evidence package. This evidence package is compiled for the regulator and subsequent stakeholders and will include information on specific regulatory requirements for product development, product labeling, regulatory submission management, regulatory intelligence, advertising and promotion and post-marketing.

Internal and external business considerations will also feed into a specific CMC regulatory strategy’s development. For example, internal examples may include the product’s intellectual property status or the organization’s financial situation, while external examples may include the drug sponsor’s investor community or business partners.

Establishing the product development strategy

A CMC Drug Development program will be primarily focused on factors such as the drug substance and drug product’s formulation and its process development considerations. It will also consider presentation, process controls and the specifics of manufacturing facility.

In order to be comprehensive, the CMC development program must consider a number of aspects, including the development phase and any specific regional requirements.

The CMC regulatory strategy should ideally be linked and integrated with the wider regulatory strategy to ensure an appropriately formulated product is available that meets the requirements of the development stage.

The three core factors impacting the CMC development program are time, quality and cost. These factors are all related to one another, and the chosen pathway will also be dependent on the risk tolerance of the sponsor.

For example, an organization may initially opt to save time to get the first patient for a given clinical study. This decision may ultimately incur higher costs and additional time, but could potentially result in a target product profile that is less satisfactory to patients; for example, a product may have short storage conditions because of a lack of stability data.

A non-GMP drug substance will be acceptable for nonclinical studies so long as the impurity profile does not lead to a potential toxicity risk in later development stages where limits around impurity are stricter. It is generally the case that only the drug substance is necessary for initial toxicology and pharmacology studies.

It is necessary to evaluate formulation effects. However, nonclinical studies may be required should the product need a complex formulation due to the drug substance’s physicochemical properties, for example, low membrane permeability, solubility, stability, or interactions with formulation excipients.

Recognizing clinical trial product requirements

As the product begins to move into clinical studies, the CMC regulatory strategy must account for clinical trial product requirements in countries where studies are planned. In the majority of countries, comprehensive GMP compliance is required for every clinical study phase. Some countries do permit the use of a non-GMP product for a first-in-human study with healthy volunteers.

Drug product presentation should also be consistent with the clinical development strategy to ensure the dosage dose and form unit meet protocol requirements.

It is typically accepted that early in development, clinical studies may be conducted with a simple formulation, but later clinical studies must be conducted with the actual product planned for marketing.

Should substantial manufacturing or formulation changes be made in the late stages of development, bridging studies may be necessary in order to verify that the changes have not changed the product’s efficacy or safety profile in any way.

A number of other clinical study CMC considerations exist, including requirements around the use of a placebo product identical in appearance to the active product in double-blind studies. Should the active drug substance possess characteristics which are difficult to emulate with an inactive substance (for example, smell or taste), placebo development may be difficult.

The availability of clinical trial supply is a central factor in study start-up times and must be organized in partnership with the clinical development team. While batch records may be necessary for study approval, manufacture timing should strive to ensure that enough stability data is available to avoid any requirement to change batches throughout the study.

Devising the CMC regulatory filing strategy

As a product development program begins to approach marketing approval, it is vital that the CMC team is fully aware of the regulatory filing strategy, desired product profile for patients and priority target countries. These factors are important in ensuring that regulatory dossier CMC sections adhere to the specific format and content requirements for each individual country.

Marketing teams may also be required to accommodate country- or region-specific requirements in order to promote commercial success; for example, in many regions a pack size equivalent to one month’s supply is the maximum quantity permitted to be dispensed or reimbursed on each occasion.

Guidelines from the International Council on Harmonization (ICH) support manufacturers in developing a core CMC dossier, but many countries have specific requirements for the non-CTD format, labeling, packaging and stability studies across temperature zones.

Specific product type guidelines in place in a number of jurisdictions require different or additional product specifications.

Building the regulatory modules

ICH provides structure and content guidelines for Modules 2–5. Module 2 – Quality Overall Summary (QOS) includes summaries of the organization’s position on available data. It also includes summaries of quality (QOS), safety (CSS) and efficacy (CSE).

In this section, regulators will ask the sponsor to provide its own assessment of the product’s overall benefit-risk balance, alongside any unaddressed uncertainties in terms of either risk or benefit from the initial regulatory review.

Module 3 includes information on the product’s development and manufacturing processes and evidence of product stability under storage conditions (standard and stressed). Data is also required to confirm that the product can be manufactured reproducibly and analyzed to generate a reproducible product.

The Quality Overall Summary (QOS) is also a good place to note things that may be absent or potentially not necessary or the reasons why certain guidelines were not followed.

In Modules 2 and 3, sponsors have a degree of autonomy in terms of how data is presented and how key messages are formatted during the compilation of a CTD application.

Knowing the regulatory authority

Organizations must be aware of written regulatory requirements, but it is also important to have a good understanding of any unwritten requirements, such as the personal preferences of agency reviewers reviewing their dossiers.

Regulatory agencies expect companies to be honest, transparent, collaborative, science-based and patient-focused in every interaction.

It is advisable for regulatory personnel to interact with regulators during new product development, although it may not be possible or practical to meet with all relevant agencies.

These interactions can assist an organization in developing relationships with an agency review team, helping that team become more familiar with the product’s innovative aspects while gaining input on any proposed strategies.

The manufacturing development program has evolved for many drugs, so much so that notable differences may exist between a drug substance or product in the early stages of development versus that which is proposed for marketing.

One common challenge in the construction of a cohesive and coherent Module 3 is the issue of generated CMC data coming from a variety of sources.

In some circumstances, all CMC development is undertaken in-house, but it is commonplace that the module relies on a mix of data contributions from in-house and external parties.

As drug development accelerates, there is an increased pressure to generate batches of drug substances and drug products for nonclinical and clinical trials. GMP standards remain strict and documentation on the analytical and stability programs supporting manufacturing must be robust and comprehensive.

Technical experts in manufacturing will continue to explore more efficient process schemes, often prompting them to look to alternate contractors to reduce costs and avoid being constrained within a single-sourced strategy.

All of these process changes necessitate the maintenance of detailed documentation and evidence of control. This should ideally commence at the initiation of the project and be proactively planned as far ahead as possible.

When compiling Module 3, it is especially important to get it right from the beginning. It is extremely difficult to go back in time to a primary source and try to reconstruct data after the fact. This is even more difficult if the people responsible are no longer available, or other links are missing.

The challenge in the description of manufacturing development data and changes is persuading FDA reviewers that it is appropriate to consider and integrate nonclinical and clinical data obtained at different points during development, having studied drugs that may have been notably different at these points.

It is important to tell a story – a much easier task when the history of changes has led to improved purity and tightening of release specifications, for example.

Where this is not the case, a degree of creativity may be necessary. Pharmaceutical development reports must incorporate drug substance (active ingredient), drug product and analytical reports. These reports need to detail the story of the evolution of these three development aspects as a product has continued to develop.

Should these development reports be unconvincing or poorly prepared, this may lead to an ongoing cycle of agency queries and sponsor responses, extending the review cycle and delaying approval times.

Regulatory Expertise in All Areas of CMC Development

PPD’s chemistry, manufacturing and controls (CMC) group provides regulatory guidance in setting specifications, method development and validation and also conducts stability studies. In addition, we identify contract manufacturers, arrange contract laboratory services and conduct good manufacturing practice (GMP) audits.

Product Development and Regulatory Strategies

  • Fast-to-clinic and first-in-man strategies to minimize drug use via compounding in clinic
  • Regulatory documentation and due diligence reviews prior to compound purchase
  • CMC regulatory strategies and advice from lab bench to pharmacy shelves
  • Formulation, analytical and manufacturing process development advice on formulations and drug delivery approaches

CMC Regulatory Services

  • Preparation and review of regulatory submissions, including:
    • Investigational new drug (IND)
    • Clinical trial authorization (CTA)
    • Investigational medicinal product dossier (IMPD)
    • New drug application (NDA)
    • Marketing authorization application (MAA)
    • Abbreviated new drug application (ANDA)
  • Authoring of annual reports, drug master files, dossier amendments and supplements
  • Preparation, publication and submission of electronic common technical documents (eCTD) applications
  • Direct interactions and negotiations with U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) and national agencies

Active Pharmaceutical Ingredients (API) and Clinical Trial Material Sourcing and Management

  • Scientific/project-specific site visits and cGMP audits to evaluate vendor staff and facility capabilities to execute the program
  • Interpretation of scientific results
  • Alternative approaches to keep clinical development programs on schedule
  • Advice on setting appropriate specifications, assigning product shelf-life and conducting failure investigations

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