Type of Posting: General Chapter Prospectus
Posting Date: 26-Apr–2024
Input Deadline: 26-May–2024
Expert Committee: General Chapters - Pharmaceutical Dosage Forms
Suggested Audience: Suppliers and manufacturers of Microsphere products, testing laboratories, QA/QC specialists, and regulatory agencies.
Estimated proposal PF: Pharmacopeial Forum 51(5)
Background and objectives:
Microparticulate systems such as microspheres, microcapsules, or any particle in a micrometer scale (usually of 1–1000 µm) are widely used as drug delivery systems, owing to their higher therapeutic and diagnostic performance compared to conventional drug delivery forms. These systems can be manufactured with many raw materials, especially polymers, most of which have been effective in improving the physicochemical and biological properties of the active compounds. Structurally, microparticles are divided into two large groups, that is, microspheres, in which the active compound and the raw material are dispersed or dissolved homogeneously, and microcapsules, in which there is a membrane enclosure delimiting and encompassing the nucleus—solid, liquid or gaseous—where the active principle is deposited. Other variants of microparticles can be manufactured with different multilayers, nuclei, or irregular shapes. There are several manufacturing techniques like phase separation, double emulsion, spray-drying and cryogenic spray-drying and the selection of a particular technique is dependent on the physicochemical properties of the active drug, polymer, and the intended use of the drug product.
Lactide and Glycolide (LG) polymers have garnered increasing attention as candidate drug delivery polymers owing to their favorable properties, including their excellent biocompatibility, biodegradability, nontoxicity, non-immunogenicity, and mechanical strength. LG polymers are specifically used as microspheres for the sustained/controlled and targeted delivery of hydrophilic or hydrophobic drugs, as well as biological therapeutic macromolecules, including peptide and protein drugs. These polymers need extensive characterization to determine the LG ratio, end group, viscosity and other tests, and have a significant impact on the microsphere drug products.
Microspheres are typically manufactured by an aseptic process because terminal sterilization (heat sterilization and gamma irradiation) results in degradation of the microspheres, loss of polymer molecular weight, and hence, performance. The in vitro release is a key quality attribute to evaluate and demonstrate acceptable product performance besides the size, shape and surface morphology in the drug product. Thus, it requires careful development of test methods and acceptance criteria for the specifications.
Description of scope and application: The focus of this General Chapter is to describe critical quality attributes and performance characteristics like universal tests, specific tests, performance tests and intended to provide guidance on acceptance limits wherever applicable that are generally necessary for Microsphere preparations as well as selected specific requirements for Microspheres not mentioned by other General Chapters.
Preliminary outline:
- Introduction
- Background
- Definitions
- Types of Microspheres
- Different LG polymers (Natural/synthetic)
- Different techniques
- Polymer Chemistry
- General Product Quality Tests
- Universal Tests:
- Aspect and Appearance
- Identification
- Assay
- Water content
- Content uniformity/Uniformity of dosage units
- Related Substances
- Residual solvents
- Particulate matter
- Bacterial Endotoxins
- Sterility
- Specific Tests:
- Polymer molecular weight distribution (Mw)/ polymer ratio
- Particle size and size distribution
- Resuspendability
- Injectability
- Performance Tests
- Invitro release methods: Dissolution
- Phase 1 Release -Initial phase
- Phase 2 Release -hydration phase
- Phase 3 Release – Primary release phase
- Discussion on discriminatory capabilities of drug product
- Microsphere–Drug Interaction
- Microsphere composition
- Drug loading and Encapsulation
- Microsphere/polymer Degradation
- Determination of glass transition temperature
- SEM/Microscopy analysis
- Morphology/Porosity/polydispersity
- Invitro release methods: Dissolution
- General considerations for Microspheres development, selection of polymers and its chemistry, drug delivery, specific requirements, and other tests
- Universal Tests:
- Glossary
- References
USP is requesting early input from stakeholders on this proposal for a new General Chapter, <1156> Product Quality and Performance Tests for Microspheres, which is planned to be published for comment in the Pharmacopeial Forum.
Anticipated implementation timing: Routine (six months after USP-NF publication)
Contact: Ravikiran.Kaja@usp.org