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Tools help improve understanding of excipient risk in formulating OSD drugs.
New tools for formulators of oral solid-dosage (OSD) drugs are being developed to improve understanding of the properties and variability of excipients and, thus, reduce risk. These tools include guidelines from the International Pharmaceutical Excipients Council Federation (IPEC), databases of excipient properties, and a new software program.
IPEC, in collaboration with the Parenteral Drug Association (PDA), published a joint technical report in December 2019 that formalizes a risk assessment for excipients (1). The report discusses the types of supply chains, and risks from these, and presents options for evaluating and mitigating risk. IPEC is also preparing to publish a guideline on quality by design (QbD) that will, among other topics, provide guidance on incorporating excipient variability into QbD formulation projects and assist users in addressing the impact of excipient variability on finished product quality in development and control strategy, explained Brian Carlin, director of QbD and Regulatory at DFE Pharma, in a presentation at IFPAC (2). “A certificate of analysis (CoA) is not enough,” said Carlin. “A CoA might not specify attributes that are crucial for your particular process, for example, the water binding capacity of microcrystalline cellulose when used in wet granulation.” He also noted the importance of working collaboratively with suppliers to set specifications for critical material attributes and recommended having a range rather than a fixed level of excipient with a CMA to ensure consistent finished product critical quality attributes. Continuous multivariate monitoring of the process can help identify “drift” caused by the inevitable cumulative changes in product, process, or excipient, he added. Drift may cause an otherwise innocuous excipient variability to interact with a finished product criticality, causing special cause variation.
Considering the role of excipients in a formulation is particularly important in continuous manufacturing, noted Chris Moreton, vice-president of Pharmaceutical Sciences at FinnBrit Consulting and a member of the Pharmaceutical Technology editorial advisory board, at the conference (3). He emphasized designing more robust formulations using QbD and the benefit of using process analytical technology (PAT), possibly with feedforward control, to make process adjustments to cope with variability.
Researchers at Rutgers, The State University of New Jersey, are developing a database of excipient properties for direct compression as part of their work on continuous manufacturing with the C-SOPS industry consortium, said Doug Hausner, associate director at C-SOPS (4). The team has set up a digitized system for collecting material characterization data, so that the material data can be analyzed in conjunction with process data and used for process modeling.
Researchers with the National Institute for Pharmaceutical Technology & Education (NIPTE) at the University of Maryland are developing an excipient database as a risk determination tool. The goal is to create an information management system using failure modes and effects analysis to identify risk, explained Steve Hoag, professor at the University of Maryland (5). The initial database, with a limited number of excipients, was developed using a grant from FDA to NIPTE and is publicly available, said Hoag. The group hopes to obtain funding to add more excipients to the database.
BASF has introduced a “virtual pharma assistant” web-based tool for aiding excipient selection that considers excipients and their interactions with APIs (6). ZoomLab, which is available on BASF Pharma Solutions’ website, is intended to eliminate pre-formulation trial and error by predicting potential tablet formulations for API parameters that are input by the user. The database used by the tool includes a range of excipients, fillers, and binders and combinations of these. In the initial version, data are included for processability in direct compression, but the company intends to expand the tool to consider other critical properties and other processes. The first version can be used for APIs in BCS Class I and III.
A new digital tool from BASF named RegXcellence aims to simplify the compliance process. The regulatory and quality portal gives customers the ability to instantly download documents, find audit information, and have a compliance overview of the customer’s portfolio, says the company (6). The virtual assistant provides a faster way to maintain documentation.
1. PDA, IPEC, Technical Report No. 54-6: Formalized Risk Assessment for Excipients (Dec. 2019).
2. B. Carlin, “Impact of IPEC Excipient QbD Guide on Design of Pharmaceutical Products,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
3. C. Moreton, “An Introduction to Excipients and Excipient Variability,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
4. D. Hausner, “Updates on Material Property Database Activities,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
5. S. Hoag, “Excipient Variability and Risk Mitigation,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
6. BASF, “BASF to Present Three New Digital Solutions for the Pharma Industry During CPhI 2019,” Press Release, Nov. 5, 2019.
Supplement: Solid Dosage Drug Development and Manufacturing
When referring to this article, please cite it as J. Markarian, “Mitigating Risk in Formulating with Excipients,” Solid Dosage Drug Development and Manufacturing Supplement (April 2020).