Enhanced Risk? EMA Issues New Guidance For OSD Co-processed Excipients
By Tim Sandle, Ph.D.

Many pharmaceutical products contain excipients: inactive substances acting as a medium for a drug product.1 For many products, particularly biologics, excipients are necessary in formulating the dosage form by enhancing the manufacturability, stability, and delivery of the drug product.2 These can include coloring agents, preservatives, and fillers, and they range from inert and simple to active and complex substances. In recent years there has been a drive toward the use of co-processed excipients to aid leaner manufacturing. This has prompted the European Medicines Agency (EMA) to develop a new guidance document titled “Questions and Answers regarding co-processed excipients used in solid oral dosage forms (H & V).”3 The parenthetical “H & V” stands for “human and veterinary”. This document is in draft form for public consultation until the end of 2024.
Co-processed excipients are combinations, so-called “all-in-one solutions,” achieving synergistic effects. The definition is not the same as blending two or more excipients. Co-processed excipients have intended functionalities, such as improved compaction characteristics, that cannot be achieved by combining two individual excipients during drug manufacturing. The objective is to minimize the number of ingredients and, hence, processing requirements during pharmaceutical manufacturing. An additional advantage beyond reducing manufacturing complexity is enabling faster development of new products.
As many new pharmaceuticals become more complex, the larger number and greater diversity of APIs require the development of novel multifunctional excipients.
Why Is The Guidance Needed?
Although guidance exists for excipients, the EMA has taken the view that specific guidance is required for co-processed excipients in pharmaceutical formulations, based on the risk profile. The increased risk is related to:
- complexity of composition, such as inherent variability and unpredictable interactions4
- quality control, such as challenges for analytical methods and batch to batch consistency
- formulation development, such as complexity of optimization studies and challenges with scaling up production
- stability issues from the combination of different materials.
Selection processes for a suitable vendor need to be in place. There may need to be a requirement for specifications for single excipients (before introducing them in the co-processed excipient). This includes, for example, specifications for particle size, viscosity, degree of polymerization, and so on.
Risk Assessment
The main part of the guidance is dedicated to a risk assessment process. The objective is to categorize co-processed excipients into one of three groups:
- Category A: high risk
- Category B: medium risk
- Category C: low risk
The risk assessment is based on a review of those critical quality attributes (CQAs) of the finished product that can be impacted by the material attributes of the co-processed excipient. The CQAs are derived from the quality target product profile (QTPP) of the product, based on the dosage and target population.
In general, the higher the number of excipients having different functions and/or physicochemical characteristics, the higher the risk.5 This is because it may become increasingly difficult to achieve consistent quality. Processes that lead to modification of the physicochemical properties of excipients, including moisture content, density, surface area, surface morphology, porosity, viscosity, cohesiveness, crystallinity, hygroscopicity, structural properties, and molecular properties, can substantially alter the finished product quality6. The more excipients there are, and the greater the interaction between them, the greater the complexity of manufacturing control becomes.
The types of CQAs that could be impacted by co-processed excipients include:
- appearance
- assay
- content uniformity
- release of the active substance
- stability
- impurity profile
- impact on bioavailability.
To assess the above, suitable validated assays are required. Assays need to be able to measure functional characteristics, material identification, degradation products (impurities), elemental impurities, and residual solvents.
The above CQAs can be influenced by the material attributes of the co-processed excipient, such as:
- function, for example, filler, lubricant, stabilizer, surfactant, antioxidant, disintegrant, or release rate controlling agent
- physicochemical properties, which also can influence critical process parameters (such as particle size, particle morphology, density, and flowability). Predictable material properties reduce the risk of mass flow deviations from their set point, minimizing alarms and process downtime and maximizing process efficiency.7
- composition of the co-processed excipient (i.e., the number of excipients)
- the interaction between the co-processed excipient and any other excipients included in the composition of the finished product.
To derive the overall risk, the guidance sets out a risk evaluation procedure. This is a holistic approach and requires each risk factor to be considered together. Account must also be taken of the special characteristics of the finished product.
The risk evaluation process needs to demonstrate that processing of the individual excipients into the co-processed excipient does not introduce any covalent bonds. This needs to be shown through suitable characterization techniques, backed up by data, to show that the chemical structure of each excipient is preserved.
For medium- and high-risk co-processed excipients, where individual excipients are removed from the co-processed excipient during the process (such as solvents or water), the quantity (range), function, and reference to relevant standard need to be understood, including verification of the absence of these excipients from the final co-processed excipient in the finished product. An additional requirement is the demonstration that a sufficiently homogenous co-processed excipient quality has been established through a review of all relevant quality attributes.
Process Requirements
Where co-processed excipients are used, the manufacturer is required to have in-process controls in place that can ensure that the single excipients comply with their respective specification (such as in relation to a pharmacopeial monograph).
Additional Guidance
To complete the risk evaluation, there are established EMA guidelines that need to be consulted. These are:
- EU/ICH guideline Q8 (R2) on pharmaceutical development (EMA/CHMP/ICH/167068/2004)
- EU guideline on development pharmaceutics for veterinary medicinal products (EMA/CVMP/QWP/684556/2022)
- EU guideline on excipients in the dossier for application for marketing authorisation of a medicinal product (R2) (EMEA/CHMP/QWP/396951/2006)
- EU guideline on excipients in the dossier for application for marketing authorisation for veterinary medicinal products (EMA/CVMP/QWP/307647/2023).
License Applications
When making new license applications within the European Union for products containing co-processed excipients, the applicant will need to provide a copy of the risk assessment together with the following details about the co-processed excipient:
- brand name
- grade
- quantity present (mg/unit and %/unit)
- function
- reference to relevant standard.
This is required for the overall co-processed excipient and for each individual excipient that makes up the co-processed excipient. A justification is required for the use of a co-processed excipient instead of using special grades of single excipients.
Moving Forward
The EMA draft provides a process through which a pharmaceutical organization can demonstrate it has adequate understanding and control of not only the finished product buts also its excipients. The guidance structures an evaluation of the impact of any co-processed excipients on the finished product. This includes an evaluation during pharmaceutical development and then developing an adequate control strategy to ensure the finished product is of consistent quality, safety, and efficacy.
References
- Shesky PJ, Cook W, Cable CG. Handbook of Pharmaceutical Excipients. Pharmaceutical Press and American Pharmaceutical Association; 2020
- Walsh G. Pharmaceutical biotechnology: concepts and applications: John Wiley & Sons; 2013
- EMA. Questions and Answers regarding co-processed excipients used in solid oral dosage forms (H & V), EMA/CHMP/CVMP/QWP/422493/2024: https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-regarding-co-processed-excipients-used-solid-oral-dosage-forms-h-v_en.pdf
- Zarmpi P., Flanagan T., Meehan E., Mann J., Fotaki N. Biopharmaceutical aspects and implications of excipient variability in drug product performance. Eur. J. Pharm. Biopharm. 2017;111:1–15
- Ruban O., Pidpruzhnykov Y., Kolisnyk T. Excipient risk assessment: Possible approaches to assessing the risk associated with excipient function. J. Pharm. Investig. 2018;48:421–429
- Zhou D., Law D., Reynolds J., Davis L., Smith C., Torres J.L., Dave V., Gopinathan N., Hernandez D.T., Springman M.K. Understanding and managing the impact of HPMC variability on drug release from controlled release formulations. J. Pharm. Sci. 2014;103:1664–1672
- ICH. Q13 Continuous Manufacturing of Drug Substances and Drug Products, Step 4 (ICH, Nov. 16 2022): https://database.ich.org/sites/default/files/ICH_Q13_Step4_Guideline_2022_1116.pdf
About The Author:
Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.