With this evolving landscape and the focus being on HPAPIs, the challenges in handling and manufacture of these molecules has also increased and so have the investments in terms of specialized containment areas and procedures to prevent exposure of personnel and the environment.HPAPIs are molecules which can exert therapeutic effects at very low concentrations. A pharmaceutical molecule is termed to be “potent” if the molecule demonstrates an effect at 15µg or less per kilogram of body weight or a daily dose of 1 mg or less.
With respect to exposure, a molecule is deemed to be potent if an eight hour time weighted average occupational exposure limit (OEL) is 10 µg/m3 or less. While most HPAPIs are oncology therapeutics, they are also used to formulate drugs for the treatment of cardiovascular, central nervous system, musculoskeletal, hormonal imbalance and eye diseases.3
Handling of HPAPIs is the primary concern and needs specialized equipment to avoid cross contamination, product protection and to ensure operator and environmental safety. One of the biggest challenges is choosing an appropriate solution that achieves a balance in prioritizing protection, whilst maintaining productivity and operability.
Further, extending capabilities can mean upgrading/investing in new equipments that poses a significant challenge for smaller manufacturers. In addition to various equipments and systems, other critical requirements of HPAPI include focus on standard operating procedures, personnel training, risk analysis of processes and periodic assessments.
The cardinal change has been on how these solutions have advanced over the years, offering higher levels of protection and less reliance on personal protection equipment (PPE) and respirators8.
The pharmaceutical industry classifies molecules into four categories based on the occupation exposure bands (OEB) levels which are determined by the toxicology and potency of compounds. OEBs decide the handling and manufacturing approaches to be adopted for the compounds.
Category 1 compounds are low toxicity with OEL>100 mg/m3. They have minimal acute or chronic health effects and good warning properties. These products will have no genetic effects and will not be sensitizers. Absorption will be slow, and no medical intervention will be required following exposure to them.
Category 2 include compounds which can cause reversible health effects. They include sensitizers and have an OEL of 10 µg/m3 to 1mg/m3. They have moderate acute or chronic toxicity, but their effects are reversible. They may be weak sensitizers. Most have fair warning properties, a moderate absorption rate, and no genic effects, but medical intervention may be required after exposure to them.
Category 3 compounds involve special hazards such as cytotoxicity, mutagenic and teratogenicity. Category 3A compounds have OEL of 1µg/m3 to 10µg/m3 whereas 3B compounds have OEL in the range of 10 ng/m3 to 1µg/m3 elevated potency, with high acute or chronic toxicity. These effects may be irreversible. The products may be moderate sensitizers, and their warning properties are likely to be poor or absent. Their absorption rates may be rapid, they may have suspected or known genic effects, and moderate to immediate medical intervention will be required.
Category 4 compounds have high potency and extremely toxic, Acute and chronic toxicity. They cause irreversible effects and are likely to be strong sensitizers, with poor or no warning properties and a rapid absorption rate. These products will have known genic effects and require immediate medical intervention. Their OEL is <1 ng/m3.
Products falling into category 3 and 4 are termed as highly potent molecules. Requirements for containment
Occupational exposure levels (OELs) set by scientific committees and institutes are increasingly strenuous and containment performance can go as low as 10ng/m3, eight-hour time weighted average (TWA). Traditional restricted access barrier system (RABS), laminar flow cabinet or fume hood do not provide such a strict controlled environment, but high containment technologies do.
Containment technologies such as isolator and glovebox fulfil the above requirement at any scale. The International Society for Pharmacoepidemiology (ISPE) defines containment technology as a “leak-tight enclosure designed to protect operators from hazardous/potent processes or protect processes from people or detrimental external environments or both”10.
Isolator and Glovebox11
A high containment isolator is generally operated under negative pressure to ensure maximum operator and environment safety. In other words, should the containment envelope be breached, the outside air will be pulled inside the isolator avoiding product exposure for the operator. The negative pressure is typically –100 Pa and must be electronically controlled.
For the same reason, the air in the isolator must not exchange with that of the surrounding environment. HEPA filters are used to circulate the room air with a ‘push-push’ system for safe remote change. High containment gloveboxes are usually purged with nitrogen for higher safety or for air-sensitive product requirements.
Safety features should be integrated; for example, interlocked doors and windows with safe guard glove ports after start of operation. All levels should be displayed to indicate in real time the status of the isolator (pressure, nitrogen, etc.). This type of isolator is typically classified as ISO 7 (Class 10,000 at rest, Grade C) and as part of the recommended use, all materials exiting the isolator must be cleaned or contained using rapid transfer ports (RTP) or airlocks.
The entire isolator must be cleanable in a reproducible and quantifiable manner to avoid cross-contamination. Swab tests and tracer substances should be used during qualification. Ergonomics are therefore an important part of the design to allow operators to reach and wipe every part of the cabinet.
To qualify the containment isolator, a series of tests needs to be performed during the Factory Acceptance Test (FAT) and Installation and Operation Qualifications on site. It is highly recommended to test the OEL level during the FAT, or once installed on site to verify that it meets the specified design OEL. A third party usually performs all the operations in the isolator using a placebo, allowing airborne particle concentrations on the operator and in the room to be measured to certify that the OEL level has been achieved.
The effective containment is always better than personal protective equipment or systems which rely on human behavior, and showed how to calculate the degree of containment required based on occupational exposure limits (OELs), acceptable daily intakes (ADIs) and cross contamination limits 12.
The overall materials handling concept for potent APIs is the controlling factor in determining the containment performance of the entire installation. There are two basic choices: stainless steel or disposable systems 12.
Recent Innovations for Manufacturing and Handling of Highly Potent Drugs are illustrated in below table12
|BUCK® MC Valve||Split butterfly valves ensure the protection of both people and products when charging and discharging highly potent APIs.||The docking system comprises two half valves that are able to independently seal two different containers. A corresponding actuator ring is used to lock and activate the two half valves, which then allows contained powder transfer.|
|BUCK® Sampler||Based on split valve technology, the BUCK® Sampler was specifically developed for gravity based process sampling applications in combination with commonly used product sampling equipment in processes such as granulation and drying.||The sampler offers a fully contained sampling process, even maintaining a process-related pressure resistance during all stages of docking, sampling and undocking.|
|Hicoflex® disposable containment technology||It comprises two identical couplings that are joined together to seal the external faces. Hicoflex® Consumables can be operated using specially engineered equipment.||Provides dust-tight product transfer|
|Vibroflow™||Prevents product segregation Vibroflow™ technology allows IBCs to discharge poorly flowing product in a reliable and repeatable manner. With product containment and operator safety being of paramount importance, it is no longer acceptable for operators to intervene and open the IBC to remove blockages.||Vibroflow™ is a proven discharge technology that has been thoroughly tested by leading pharmaceutical manufacturers and installed successfully in a number of primary and secondary API plants|
IBCs (intermediate bulk containers) with split butterfly valves are the material handling systems most commonly used for potent APIs. Split butterfly valves offer a proven solution for make-and-break connections. They are available in different performance levels, In this case the entire material required for a batch is loaded into an IBC in the dispensing area, typically under a laminar-flow booth.
The IBC is moved into the granulation area where it is docked using a split butterfly valve connection to, say, a discharge station. The raw material is then loaded into the granulator by either gravity (if the room height allows) or a vacuum conveyor, with a mill to remove lumps in between12.
If a disposable solution is preferred, one of the option is- Hicoflex flexible container system. Excipients are handled in a conventional container, while the API is weighed inside a glovebox and then transferred via a funnel into a Hicoflex bag below. Both containers are connected via an integrated mill to the granulator inlet12.
Using process isolation and containment equipment is the most important means of protection. By ensuring that an entire manufacturing process is carried out in closed systems — from raw materials to product packaging — the chances of employee exposure can be minimized.
In summary, the product development and manufacture of highly potent drug substances and their products bring a number of challenges, but not insurmountable obstacles.
Technologies to ensure safe handling procedures have now become widely available (e.g. isolators, split butterfly valves).
Technological advances will drive future change in all manufacturing facilities. Given the risks involved with operator exposure to high potency drug products, however, there are certain technologies that we can expect to eliminate the potential risks — namely the use of robotics that will remove the operator from physically working with harmful substances.
- High Potency Active Pharmaceutical Ingredients (APIs) Market Analysis by Product (Synthetic, Biotech), Manufacturer (In-house, Outsourced), Drug Type, Therapeutic Application (Oncology, Hormonal, Glaucoma, Others), and Segment “Highly Potent APIs – Markets, Myths and Manufacturing.” Cambrex. Nov. 2017. Web.
- O’Connell, David. “High Potency Drugs – from Molecule to Market.” PCI Pharma Services. Aug. 2013. Web.
- High Potency API/HPAPI Market Size worth $34.8 Billion by 2025.Grand View Research. Jul. 2017. Web.
- High Potency APIs /HPAPI Market worth 26.84 Billion USD by 2023.Markets and Markets. Apr. 2018. Web.
- High Potency Active Pharmaceutical Ingredients Market by Type (Innovative HPAPI, Generic HPAPI), Synthesis (Synthetic HPAPI, Biotech HPAPI), Therapeutic Application (Oncology, Hormonal Imbalance, Glaucoma) and Region – Global Analysis and Forecast to 2025.Converged Markets. 2018. Web.
- Global High Potency Active Pharmaceutical Ingredient (HPAPI) Market: Rising Incidence of Cancer to Boost the Market, says TMR.Transparency Market Research. Aug. 2017. Web.
- High Potency Active Pharmaceutical Ingredients (APIs) Market Analysis by Product (Synthetic, Biotech), Manufacturer (In-house, Outsourced), Drug Type, Therapeutic Application (Oncology, Hormonal, Glaucoma, Others), and Segment.
- Accessed from https://www.epmmagazine.com/opinion/highly-potent-discussing-the-growing-need-for-high-potency-h/ on 24-JAN-2020.
- Accessed from: https://bioprocessintl.com/manufacturing/facility-design-engineering/containment-of-high-potency-products-in-a-gmp-environment-302814/ on 24-JAN-2020.
- Accessed from: https://www.scientistlive.com/content/advances-high-containment-technologies on 25-JAN-2020.
- Access from: https://www.manufacturingchemist.com/news/article_page/Aseptic_and_high_potency_manufacture_in_one_solution/95307 on 25-JAN-2020.
- Accessed from: https://www.gea.com/en/products/ on 25-JAN-2020.