Chemistry Manufacturing & Controls

Chemistry Manufacturing & Controls

QBit QA Consulting provides expert Chemistry Manufacturing & Controls (CMC) guidance to companies navigating the complex landscape of drug development, manufacturing processes, and regulatory submissions, helping them achieve efficiency, compliance, and product integrity.

Regulatory agencies require detailed CMC documentation to demonstrate that a drug product is consistently produced and meets quality standards. Failure to comply with CMC requirements can lead to delays in drug approval, costly rework, or even regulatory rejection. Effective CMC management reduces risks, ensures product safety and efficacy, and accelerates time-to-market.

CMC is a term used when drug developers define their investigative drug substance, establish manufacturing methods for that drug, and develop a strategy for controlling the quality and stability of the product from early phases through post-approval production.

CMC STRATEGY

A CMC strategy is a science-based plan for ensuring a product’s quality and safety throughout development. It is often tailored to the specific product, its delivery method, and its development timeline. It’s also important to engage with regulatory authorities to ensure that the strategy meets their expectations.

Elements of a CMC Strategy:

Quality attributes: Identifying characteristics that must be monitored, such as safety, purity, and strength
Analytical methods: Developing methods to measure quality attributes
Manufacturing processes: Optimizing processes to ensure consistent production
Supply chain controls: Implementing controls to ensure consistent supply
Risk assessment: Identifying and managing potential risks
Regulatory compliance: Ensuring compliance with regulatory requirements

Understanding the regulatory requirements for CMC information for an Investigational New Drug (IND) application and for a New Drug Application (NDA) will be an important factor for the development of a CMC Strategy.

Throughout the development process CMC information is collected and analyzed, resulting in increased product and process understanding. The CMC information required for an IND application often leverages existing data to establish the identification, quality, purity and strength of the investigational drug product for a phase 1 study, while the CMC information required for an NDA statistically demonstrates the specific controls for the product and process at full scale commercial production.

As more CMC information is collected throughout the development process, the CMC Strategy may change, based on the increased product and process understanding.

IND CMC REQUIREMENTS

Initially and at each phase of the clinical study sufficient CMC information is required to be submitted to assure the proper identification, quality, purity and strength of the investigational drug product. The amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available.

Required CMC Information:

Drug Substance

A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy relevant requirements in this paragraph.

Drug Product

A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product’s stability during the planned clinical studies. Reference to the current edition of the United States Pharmacopeia—National Formulary may satisfy certain requirements in this paragraph.

Placebo

A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial.

Labeling

A copy of all labels and labeling to be provided to each investigator.

Environmental analysis requirements

A claim for categorical exclusion under 21 CFR Part 25, § 25.30 or 25.31 or an environmental assessment under § 25.40.

NDA CMC REQUIREMENTS

Required CMC Information:

eCTD Module 3, Quality

Drug Substance (3.2.S)
- General Information
- Manufacture
- Characterization
- Control of Drug Substance
- Reference Standards
- Container Closure System
- Stability

Drug Product (3.2.P)
- Description and Composition of Drug Product
- Pharmaceutical Development
- Manufacture
- Control of Excipients
- Control of Drug Product
- Reference Standards or Materials
- Container Closure System
- Stability

Appendices (3.2.A)
- Facilities and Equipment
- Adventitious Agents Safety Evaluation
- Excipients

Regional Information (3.2.R)
- Executed Batch Records (US)
- Method Validation Package (US)
- Comparability Protocols (US)
- Process Validation Scheme for the Drug Product (EU)
- Medical Device (EU)

QUALITY By DESIGN (QbD)

Quality by design (QbD) is a concept first outlined by quality expert Joseph M. Juran in publications, most notably Juran on Quality by Design, 1992. QbD is a proactive, science-based approach to product and process development that focuses on understanding the relationships between critical process parameters (CPPs) and critical quality attributes (CQAs) to ensure a product meets its intended use. The approach aligns with the eCTD format, covering the elements required for a successful regulatory submission. By using the QbD approach, development can be accelerated and resources can be used more effectively.

The quality by design model consists of the following steps:

Establish the project design targets and goals.
Define the market and customers that will be targeted.
Discover the market, customers, and societal needs.
Develop the features of the new design that will meet the needs.
Develop or redevelop the processes to produce the features.
Develop process controls to be able to transfer the new designs to operations.

Elements of Pharmaceutical Development

Defining the quality target product profile (QTPP) as it relates to quality, safety and efficacy, considering e.g., the route of administration, dosage form, bioavailability, strength, and stability;
Identifying potential critical quality attributes (CQAs) of the drug product, so that those product characteristics having an impact on product quality can be studied and controlled;
Determining the critical quality attributes of the drug substance, excipients etc., and selecting the type and amount of excipients to deliver drug product of the desired quality;
Selecting an appropriate manufacturing process ;
Defining a control strategy
A systematic evaluation, understanding and refining of the formulation and manufacturing process, including;
- Identifying, through e.g., prior knowledge, experimentation, and risk assessment, the material attributes and process parameters that can have an effect on product CQAs;
- Determining the functional relationships that link material attributes and process parameters to product CQAs;
Using the enhanced product and process understanding in combination with quality risk management to establish an appropriate control strategy which can, for example, include a proposal for a design space(s) and/or real-time release testing.

Quality Target Profile (QTP)

The quality target product profile forms the basis of design for the development of the product. Considerations for the quality target product profile could include:

Intended use in clinical setting, route of administration, dosage form, delivery systems;
Dosage strength(s);
Container closure system;
Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed;
Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product.

Critical Quality Attributes (CQA)

A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product.

Risk Assessment

Risk assessment is a valuable science-based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained.

Design Space

The relationship between the process inputs (material attributes and process parameters) and the critical quality attributes can be described in the design space.

Control Strategy

A control strategy is designed to ensure that a product of required quality will be produced consistently. The elements of the control strategy should describe and justify how in-process controls and the controls of input materials (drug substance and excipients), intermediates (in-process materials), container closure system, and drug products contribute to the final product quality. These controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical process parameters and material attributes.

Product Lifecycle Management and Continual Improvement

Throughout the product lifecycle, companies have opportunities to evaluate innovative approaches to improve product quality. Process performance can be monitored to ensure that it is working as anticipated to deliver product quality attributes as predicted by the design space. This monitoring could include trend analysis of the manufacturing process as additional experience is gained during routine manufacture. For certain design spaces using mathematical models, periodic maintenance could be useful to ensure the model’s performance. The model maintenance is an example of activity that can be managed within a company‘s own internal quality system provided the design space is unchanged. Expansion, reduction or redefinition of the design space could be desired upon gaining additional process knowledge. Change of design space is subject to regional requirements.