Understanding the Crucial Elements of RA CMC for Pharmaceutical Products

---

Introduction

When developing a pharmaceutical or biologic finished product, product specifications and characteristics must be clearly defined to ensure product safety, effectiveness, and consistency in manufacturing. These activities are commonly referred to as CMC, or Chemistry, Manufacturing and Control.

Every stage of the drug development life cycle will involve CMC, requirements becoming more complete throughout the process.

From pre- clinical drug development to clinical trials, any development process needs scale-up to make sure that larger batches are consistent, meeting the same specifications as the drug tested in previous trials. Once the manufacturing process has been qualified, lot release and in process testing must continue.

To assess the desired quality consistency, proper analytical methods must be qualified and then validated to ensure that the product is meeting expectations.

Stability testing will be conducted, with the product’s physicochemical properties being determined, and raw materials chosen then tested. As development progresses into the clinical stage, further characterization of the drug product is required.

Drug Development

A good drug development program provides sufficient assurance that any compound involved will meet the required quality and technical elements at each stage of development, ultimately facilitating effective commercialization of the drug.

Within CMC Regulatory Affairs activities throughout development of the requirements to achieve a drug product’s preparation, there is no unique path.

However in CMC Regulatory Affairs activities during development, there are a number of approaches which can be taken to help improve the chances of success.

Drug Substance General properties and composition of the related Drug Product

The physical and chemical properties of a drug substance must be fully explored and understood to develop an appropriate formulation. The purity profile for various lots should be analyzed, with HPLC being used for this analysis. Physical properties like hygroscopicity, solid-state stability, hydrate/solvate formation, polymorphism, and powder characteristics must also be analyzed. The functional qualities of each individual component (excipients) of the drug product are vital to the development rationalization of the formulation and serve as reference points in the analysis of supportive development data.

Excipients can be classified into four core categories based on their impact on drug substance stability, absorption, physical characteristics, and manufacturability.

Manufacturing process and process controls for clinical development

The manufacturing process of a drug substance and drug product must be compared against batch records from the manufacturing facility. A comprehensive analysis of the process will include a review of the required quantities of solvents, catalysts, raw materials and reagents, as well as the availability of reagents and safety concerns. Process development begins at a small scale, transitioning to a minimum of 10% before full scale production. Alterations to the manufacturing method must be detailed as the process progresses from Phase 1 studies to the final commercial process. Development studies must document the impact of process changes on CQAs associated with both intermediates and the final drug product.

For sterile products, pre-sterilization bioburden data must be conducted, while for nonsterile liquid products, microbial limits testing data must be conducted. Compatibility data must confirm that there are no deleterious effects to the product quality. Process parameters must be controlled effectively, such as order of addition of excipients, mixing or blending time, and flow rates of the blend into the tableting press. Predefined quality requirements and a thoroughly developed testing plan are essential for successful design.

Specifications, analytical procedures and procedure validation

Specifications for drug substances and products should include test methods and acceptance criteria based on the product's nature. Identification testing should distinguish between the drug substance and any closely related compounds. Additional specifications may be applicable, such as polymorphic form, particle size, melting point, loss on drying and Karl Fischer. Specifications of impurities must be consistent with drug safety study results and existing process capability. In Phase III, two identification tests should be performed, possibly one with HPLC retention time match and one with spectroscopic technique.

Additional specifications may be applicable, such as dissolution, disintegration, residual solvents, moisture, and microbial limits. Further physicochemical characteristics of the drug product may affect its performance, such as particle size, pH, clarity, color, viscosity, preservative testing, and volume of fill.

Reference standards, container closure systems and stability data

The validity of analytical results is partially reliant on the use of appropriate reference standards. Reference standards must be fully characterized and tested against a secondary reference standard to facilitate routine testing. A primary package from storage should be available and the potential for incompatibilities between the package and compound should be explored and understood. If drug substances are sensitive to environmental conditions, data on the packaging component’s qualification should be provided.

An appropriate package should be selected based on knowledge of the chemical and physical behavior of the drug product in pre-formulation and stability studies of model formulations.

Headspace analysis is used to determine the internal atmosphere of a drug formulation, and a secondary package may be required. Stability studies should demonstrate the suitability of the secondary package, and a robust stability protocol should be proposed early in development stages.

On Building your own RA CMC expertise

Our web-based RA CMC database provides our clients with innovative strategy advice and quality work products intended to enhance product development, approval, and marketing presence. Whether advocating a RA CMC strategy or developing RA CMC submission content that represent the best interests of emerging biotech, we focus on helping you solve critical CMC issues and build programs that enhance RA CMC knowledge.