Study of Critical Material Attributes (CMAs) of RLD

Introduction of Critical Material Attributes (CMAs)

A stable source of raw materials in the development and production of generic drugs is a crucial link. A CMA is a physical, chemical, microbiological or biological property or characteristic of a material, and it can significantly impact pharmaceutical unit operations, process consistency, and product quality attributes. Therefore, in the consistency evaluation of generic drugs, according to FDA requirements, CMAs should be within an acceptable range, limit or distribution to ensure that the quality of raw materials and excipients is consistent with RLD. Therefore, in the consistency evaluation of generic drugs, FDA emphasizes on the identification of CMAs of Reference Listed Drugs (RLDs) through QbD, so as to prevent them from adversely affecting the drug product or drug substance.

Figure 1. The strategy of controlling CMAs. (Mohammed, A. Q.; et al. 2015)

Due to the large number of unit operations and media complexity in the manufacturing process of generic drugs, it is easy to overlook the CMAs that may affect the variation of API and drug product. Failure by the manufacturer to identify these CMAs will result in unexplained variability in unexplainable variation during batch processing and lot acceptance. Alfa Chemistry's comprehensive consistency evaluation services will deepen your understanding of the generic drug manufacturing process and final product, and identify the source of drug variation. Our experts help you to correctly select raw materials consistent with RLDs in the manufacturing process of generic drug by identifying the CMAs of raw materials (such as purity, solubility, crystal form, etc.).

Application of the Study of CMAs

• Identify sources of variability that can affect product quality: The identification of CMAs of RLDs helps to understand the sources of variation and its impact on downstream process, in-process materials, and drug product quality
• Ensure the stability of the manufacturing process: Preliminary determination of the prescription and manufacturing process of generic drugs
• Risk assessment of the production process: After identifying the CMAs of RLDs, the risk assessment of the entire drug production process can be carried out to determine the process steps (CPP) that may affect the critical quality attributes of the final product

Our Services

Based on the comprehensive understanding of formulations and manufacturing process of generic drugs, our experts are able to provide services for the identification of CMAs of RLDs.

Our Workflow of Determining the CMAs

1. Determine CQAs for drugs substances and products
2. Identify API, excipients, process, materials and container closures
3. Define unit operations and sequence of process operations for the generic drug production
4. Define all product and process specification limits and acceptance criteria
5. Validation of all analytical methods
6. Identify unit operations with risks to CQA
7. For at-risk unit operations, complete low-level factor/response selections for all factors, interactions, quadratics, and materials
8. Generate designs of experiments (DoEs) for unit operations or materials with risk
9. Use DoE or other multivariate methods to explore the design space for all key factors identified during the risk assessment
10. Determine all CMAs

Some Important CMAs Affecting Function and Performance:

CMAs of RLDs are the QbD elements that have an impact on the manufactured generics drugs, and are used to obtain material characteristics consistent with RLDs. Alfa Chemistry provides the identification and analysis of the following CMAs:

• Particle size/shape
• Particle size distribution
• Fines
• True density
• Conhesive/adhesive properties
• Electrostatic properties
• Moisture content
• Hardness
• Viscoelasticity
• Solid form/polymorph
• Granule density
• Melting point
• Glass transition temp
• Density
• Tablet dimensions/defects
• Membrane thickness
• Polymer type