Frequently Asked Questions about HPAPIs

A Highly Potent Active Pharmaceutical Ingredient (HPAPI) is usually defined as an API with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average.

Cytotoxics are a subcategory of HPAPIs; cytotoxic drugs are highly potent but not all highly potent drugs are cytotoxic.
Early chemotherapy drugs (such as alkylating agents, anti-metabolites and topoisomerase inhibitors) interfered with the structure or function of DNA. The generalized cell-killing action of these compounds led to them being labelled as ‘cytotoxic’.

HPAPIs are usually classified in Occupational Exposure Bands (OEB), representing different level of toxicity and requiring different levels of containment. The lower and upper toxicity limits of each band is associated with a maximum and minimum Occupational Exposure Level (OEL).

The classification of a compound is based on the evaluation of qualitative and quantitative toxicity data available such as the mechanism of action, the therapeutic dose, the OEL, etc. In the absence of toxicity data, the classification can be made by default, based on the chemical structure of the compound by analogy with other compounds.

Various OEB banding systems are used by the industry and it is important to specify the system used and the actual OEL when sharing information on a compound.
Novasep usually refers to the 4 band Safebridge approach:

Many HPAPIs are in the oncology field, but HPAPIs may also be found in other therapeutic areas (e.g. respiratory).

Novasep’s Le Mans site is Novasep’s center of excellence for Highly Potent APIs & offers more than 30 years’ experience in the production of HPAPIs & cytotoxics. The site offers specific expertise in the field of ADC payloads, and also offers ADC conjugation services from development to commercial manufacturing.

Novasep’s sites at Chasse-sur-Rhône (Lyon, F) and Leverkusen (Cologne, D) offer large scale production of oncology products such as kinase inhibitors.

To learn more about the level of potency Novasep can handle:

Novasep’s specialist HPAPI site, Le Mans (France), is specifically equipped to handle compounds for Band 3 & 4 compounds (Safebridge). The site is a leading producer of ADC payloads & equipped to handle OELs below 30 ng/m3/8hrs for R&D, clinical & commercial production.

Novasep evaluates periodically the containment of each HPAPI workstation in R&D, QC and production in order to define the minimum acceptable OEL at the station. The evaluation is made by experimental measurements and uses qualified methods. It integrates human variability and other safety factors. The data generated for over ten years now demonstrate that products with an OEL as low as a few ng/m3/8hr can be handled.

Our ability to execute a specific manufacturing process for a specific HPAPI will depend on the workstations to be used, depending on the unit operations involved and the production scale. It is a case by case evaluation that we perform at the beginning of each project and revisit whenever new information is available.

To learn more about our experience in producing HPAPIs:

Novasep is able to handle a wide range of chemistry. Low and high temperature reactions, as well as reduction or oxidation processes can be run in our HPAPI facilities.
For safety reasons, the only limitations are processes involving hydrogen gas or involving high energy chemistry.

Novasep’s Le Mans HPAPI site is equipped with a wide range of chromatography equipment from development to commercial scale & benefits from more than 30 years’ experience in combining synthesis & purification of HPAPIs.

Discover our preparative chromatography solutions on our dedicated webpage.

Many HPAPIs are complex molecules either originating from, or related to, natural compounds, for example taxanes & ADC Payloads. At the same time, a high level of purity is expected for APIs used in injectable drugs. Preparative HPLC is a key technology to achieve the purity target.

A facility equipped with laboratory and production equipment offering an appropriate level of containment is a pre-requisite, however it is far from sufficient; it will not meet the safety standards expected for HPAPI unless it is operated by qualified people with the know-how that only a long experience can bring.

You should therefore look for an ‘HPAPI culture’, combining an experienced team of experts & a strong HSE process.

The partner should be able to demonstrate a successful track record in cGMP manufacturing of HPAPIs (number of clinical and commercial batches) & a history of regulatory compliance (number of audits & outcome).

CDMO outsourcing projects begin with technical & analytical transfer followed in most cases by process development. Clearly the partner must have the appropriate technical expertise and capacity.

Finally, the partner must be easy to work with; efficient Project Management is key.

Novasep has a dedicated team of experienced Project Managers, based on each site, responsible for the execution of each project from initial assessment & planning to final delivery & close-out. The Project Manager is the primary point of contact for the customer, coordinating & monitoring all project activities & communicating the status both internally and externally.

To learn more about technical transfer at Novasep:

Novasep offers a full range of QC services to support CDMO activities from development through to commercial production. These include analytical transfer, method development & validation, in process control, release testing & stability studies.

Our capabilities include:
- HPLC, GC, Karl Fischer & Potentiometry
- IR, UV, LC-MS, NMR, HR-MS & XRPD (outsourced)

The main classes of ADC payloads are Maytansines (DMx), Auristatins, Pyrrolobenzodiazepines (PBD dimers).

ADC payloads are usually complex structures produced through a 10-20 steps synthesis process or by hemisynthesis.

The production of these compounds with a high purity is the main challenge. Payloads and payload linkers are usually unstable and controlling the purity while scaling-up the process requires considerable knowhow, which Novasep has developed over the past 10 years.

The small quantity available to develop the process is, in itself, also very challenging and requires a good expertise to generate robust data to support the production while working on mg or g scale during the development phase.

Discover examples of processes developed by Novasep that have been published: 
PBD-Dimer Payloads for ADCs
Scale-up Synthesis of Tesirine

ADCs are inherently complex APIs and difficult to characterize. To support the filing of the ADC, the fate of the impurities coming from the payload will have to be evaluated. The use of high purity payload as starting material for the ADC will facilitate this work and can help to accelerate the filling of the ADC.

To learn more about the type of payloads Novasep can work with:

Find out more about proprietary payloads at Novasep:

Novasep’s Le Mans (France) site offers a full range of ADC payloads manufacturing services, from clinical batches to commercial manufacturing. A dedicated team, led by an experienced Project Manager, will be assigned to your project from the early development activities to commercial manufacturing.

Discover our case study about the successful process development and manufacturing of an ADC payload to learn more about our expertise!

Discover the smallest amount we can produce under cGMP:

The advantages associated with having ADC payload manufacturing and ADC bioconjugation on the same site are as follows:

- Simplified supply chain
- Optimization of timeline and cost
- One global development contract and quality agreement
- Reduction of risks (no shipment of the highly potent material, no border to cross, etc.)

The characteristics of payloads and payload linkers may vary widely from one ADC to another. Having developed the manufacturing process of the payload to be conjugated allows to fully understand its reactivity and stability. This data is very useful to select the appropriate process for conjugation. They will help to develop a more robust process and to speed up the development phase.

To discover the best containment strategy for HPAPIs:

To discover how we safely scale up the synthesis of an HPAPI drug substance:

To discover how we assess the toxicity of products:

To be properly managed, risks need to be identified using a formal methodology. It is better done with a multi-function team of people.

The Novasep site of Le Mans has an excellent safety track record with more than 2975 days without a loss time accident (recorded on 05/01/2021).

To discover how we ensure the health of our employees:

To discover how we manage wastes:

Samples and bulk products are transported contained in at least two level of packaging (the primary and secondary packaging, sometimes more).
All containers are labelled to show the product safety information required by the regulation applying to the transportation of hazardous goods.

Our HPAPIs facilities are regularly audited by the FDA, the ANSM or the AFSSAPS (every 5 years between 1994 and 2010, then every 3 years until today).

Download our brochure to discover our full regulatory track record!

Regulatory inspections consist in a plant tour during which the authorities approve our quality assurance and quality control procedures.
They also check if the documents match with the processes.

To discover how we manage cleaning for manufacturing areas and equipment:

Our employees receive Health & Safety, Quality and Technical introduction upon their arrival at Novasep, from the Quality Assurance (QA) and EHS teams.
The QA department also delivers cGMP trainings every year, to endorse the ICH Q7 requirements.