Quite often you will come across the use of adjuvants in the formulation of vaccines.
Adjuvants can be for example, aluminium salts, oil-in-water emulsions, saponin-based adjuvants, toll-Like Receptor (TLR) agonists or perhaps liposomes and virus-like particles (VLPs).
I’m not going to comment on how individual adjuvants work save to say that they mainly work by stimulating the body’s own immune system one way or the other and thus enhance the effect of the vaccine.
However for technology transfer purposes, should they be treated as an Active Pharmaceutical Ingredient (API) or purely as an excipient, and how should they be treated as part of the technology Transfer process?
Strictly by definitions, adjuvants are excipients rather than APIs- the EMA define an excipient as “A constituent of a medicine other than the active pharmaceutical ingredient (API), which in tun are defined as “The substance responsible for the activity of a medicine”[ https://www.ema.europa.eu/en/about-us/glossaries/glossary-regulatory-terms]
However, from the regulatory point of view, this is one of those “grey area’s”, being an ingredient that increases or modifies the activity of the other ingredients. Perhaps they should be regarded as more like a biological catalyst which on its own has little or no effect, but when in the right environment enhances the biological process.
So how should technology transfer process’s treat them?
One of the key functions of technology transfer is to ensure that the transferred process is in compliance with the appropriate regulatory authority requirement, so the real question here is, how do the regulatory authorities regard adjuvants?
Regulatory agencies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) consider adjuvants to be active immunologic components of a vaccine because they:
• Enhance immune response.
• May reduce the antigen dose required.
• May alter the immune profile.
• Can affect safety and immune system’s response to vaccination (reactogenicity).
So rather than class adjuvants as API’s pharmaceutical regulators tend treat adjuvants as critical components of vaccines – not as inactive ingredients – and they are evaluated with the same scientific rigor as the antigen itself during clinical development and expect them to be evaluated as part of a vaccine’s overall risk–benefit profile.
Regulators (e.g. FDA) assess the entire vaccine–adjuvant combination, not the adjuvant or the vaccine drug substance in isolation, and adjuvants are only approved as components of a specific vaccine formulation. The vaccine–adjuvant combination being the regulated product.
Within clinical trials, the level of adjuvant evaluation required can depend on how well any particular adjuvant is established in other products (its previous usage history), and if it is already licenced for use.
However even well-known adjuvants must be re-evaluated for use in each new vaccine. For well-established adjuvants such as aluminium salts the regulators will probably:
- Accept existing safety databases.
- Still require evaluation and safety assessments in the new vaccine formulation.
- Expect clinical data showing tolerability and immunogenicity.
If it is a novel adjuvant thathas not previously been licensed, regulators would probably require extensive preclinical data such as:
- Toxicology (repeat-dose studies).
- Biodistribution and persistence data studies.
- Local reactogenicity assessment.
- Mechanism of action data.
Phase I Clinical Trials would probably also require:
- A dose-escalation design.
- Close safety monitoring.
- Immune profiling.
- A comparison against the non-adjuvanted formulation.
The FDA would also usually require:
- Dedicated early-phase safety trials.
- Larger phase III safety databases before licensure
The European Medicines Agency (EMA)
As with the FDA, the EMA also regulates adjuvants only as part of a vaccine, but it has historically been somewhat more experienced with complex adjuvant systems and evaluates the adjuvant’s contribution to immunogenicity and safety as part of a benefit–risk assessment with strong emphasis on:
- Mechanistic immunology data.
- Comparative immunogenicity studies.
- Risk management planning.
- Long-term safety monitoring.
Both the FDA and EMA have specific guidance on:
- Adjuvant safety evaluation
- Nonclinical testing requirements
- Clinical safety monitoring
- Pharmacovigilance expectations
World Health Organisation (WHO)
The WHO also provides global policy guidance for adjuvanted vaccines, particularly for low- and middle-income (emerging system) countries.
So, how do the various regulatory agencies regard adjuvants?
| Issue | United States (FDA) | European Union (EMA) | Emerging Systems |
| Standalone adjuvant approval | No | No | No |
| Tolerance for novel adjuvants | Conservative | Moderately open | Variable |
| Phase III safety database size | Often large | Large, but flexible | Often accept global data |
| Mechanistic data emphasis | Strong | Very strong | Increasing |
| Post-marketing surveillance | Robust | Highly structured (RMP-based | Variable, strengthening |
| Reliance on foreign data | Limited | Integrated EU system | Often high reliance |
In summary, and especially with respect to products still within clinical trials, regulatory agencies tend to:
- Have an acceptance of foreign Phase III data.
- Require bridging studies in local populations.
- Require a growing but variable pharmacovigilance infrastructure.
- Place increasing emphasis on Good Clinical Practice (GCP).
Novel adjuvants often face:
- Longer review timelines.
- Requests for additional safety reassurance.
- Political sensitivity due to public vaccine confidence issues.
So overall, although strictly adjuvants are excipients (being catalyst rather than biological API’s), from the technology transfer point of view, all major regulators:
- Treat adjuvants as biologically active but not as API’s.
- Require full safety evaluation.
- Approve only the combined vaccine product.
About The Author:
Trefor Jones is a technology transfer specialist with Bluehatch Consultancy Ltd. After spending over 30 years in the pharmaceutical / biopharmaceutical industry in engineering design, biopharmaceutical processes, and scale-up of new manufacturing processes, he now specializes in technology transfer especially of biotechnology and sterile products.
He can be reached at trefor ”at” bluehatchconsultancy.com.