The increasing complexity of New Chemical Entities (NCEs) entering the drug pipeline has fuelled demand for hazardous chemistry techniques which can provide a more efficient route to molecules.
Used to form the basis of synthetic manufacturing processes and access certain functionality within a molecule, these chemistries are helping Active Pharmaceutical Ingredient (API) developers and manufacturers to gain a competitive edge. This is because being able to safely carry out these chemistries at commercial scale provides more options for developing new and more efficient processes.
Hazardous chemistry can offer many benefits to manufacturers including potentially cleaner chemistry, with fewer or no side reactions, or a reduction in the number of synthetic steps. The approach potentially consumes less material, provides easier purification and produces less waste. Additionally, it can generate higher yields of targeted compounds, ultimately leading to a more sustainable environmental footprint for the product.
Ensuring product quality while minimizing the potential environmental impact of hazardous chemistry requires careful consideration, assessment, and planning with expert input.
The Shift towards Hazardous Chemistry
Increased focus on the advantages that hazardous chemistry techniques can bring has led development scientists to explore chemical routes involving simple but energetic molecules. This includes molecules such as ethylene and propylene oxide, diazomethane, epichlorohydrin, hydrazine and hydroxylamine. It has also placed added attention on chemistry involving nitrated species, for example nitroethane and aromatic nitrates, as well as precious metal powder catalysts or pyrophoric catalysts.
While some processes are hazardous due to the energetic nature of a reagent, some reagents that are considered to be innately stable and easy to handle may also react very energetically under certain conditions. Highly toxic reagents also require additional measures and evaluation, such as increased containment or modelling of toxic gas concentrations in the event of unintended release.
The growing trend towards the use of hazardous chemistry has created a need for procedures which allow the potential impact of operating these processes to be reviewed, as well as a careful assessment of the risks involved to be carried out. Assessments need to be conducted and measures put in place to both minimize the risk of injury to personnel and mitigate risks relating to product quality and the impact on the environment as a result of manufacturing.
Health and Safety Executive (HSE) and Regulatory Considerations
Every chemical step introduced into a manufacturing process should be understood and designed with safety in mind.
As the risks associated with hazardous chemistry become more prevalent, higher standards are being enforced. This is achieved through the introduction of stringent regulations to protect both the health of those working in the industry and the reputations of developers and manufacturers.
Where Major Accidents Hazards (MAHs) are found, manufacturers must be able to demonstrate that a plant or process can operate safely and in accordance with any nationally recognized guidance. If an MAH is associated with the use of certain materials, manufacturers must justify to the authorities why the selected route is still the most appropriate for the desired molecular transformation. An appropriate justification will need to take into consideration the environmental impact and the hazardous nature of the materials used. The outcomes of the hazard evaluation may also be used to demonstrate to the authorities why alternative routes may present greater risks.
Hazard Evaluation: Best Practice Approach
There are several risks associated with any manufacturing process and, as the name suggests, when dealing with hazardous chemistry processes. Therefore, identifying, analyzing and planning to prevent and respond to these potential unique reaction hazards is a necessity.
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There are a number of ways in which potential risks can be identified, however every process must be run through a reaction calorimeter. This test identifies potentially dangerous heat and gas outputs caused by reactions. These reaction outputs are then used to define the relevant control strategies for material and reactor cooling additions.
For example:
- A vent sizing package (VSP) can be used to assess gas generating reactions and identify emergency venting requirements during scale up, including emergency cooling and venting requirements, as well as emergency shutdown systems and response procedures.
- Taking samples of the reaction mixture throughout the testing process; then assessing the sample using differential scanning calorimetry (DSC), allows processes to be screened for thermal activity and decomposition temperatures.
- Accelerating rate calorimetry (ARC) can be conducted to identify potential thermal onset temperatures for runaway reactions and subsequent pressure rises.
- Minimum Ignition Energy (MIE) identification, 20 liter sphere tests for dust explosion classification and electrostatic charge relaxation identification.
Application of Hazard Evaluation to Process Design
Due to the specialized nature of hazardous chemistry, well thought out integration of hazard evaluation, engineering, chemistry and analytical expertise are required, as well as knowledge of how the scale up process and larger volumes could impact operations and resulting safety requirements. To ensure an optimum process a multidisciplinary team, who are experts in their field, is required to review the process. This team should comprise of process engineers, hazard evaluation scientists, production and plant engineering, and development chemists.
The information gathered during the hazard evaluation will then be assessed by this team and the insight gained during this assessment can then be used to advise the design of the manufacturing plant.
Where MAHs are identified as having the potential to effect an individual’s safety or the environment, a more detailed risk assessment will then follow. This will include a Layer of Protection Analysis (LOPA) or a Quantified Risk Assessment (QRA). This then needs to be provided to the team working on the project in addition to the assessment and definition of the Safety Integrity Level (SIL) of any required instrumentation.
Where hazards are identified, the engineer may propose changes which aim to reduce the consequences of the hazard. However, this may require further investigation and approval by the chemist. Ultimately, the output of the safety review could mean additional investigation into the chemistry is necessary as it may need to be modified in order to be operated safety at scale, for example, it may be necessary to adopt a different order of operation or alternative reagents.
By putting in place a cross-disciplined team, chemists and engineers can work together to eliminate or reduce the consequences of identified hazards. This in turn helps to ensure more successful and safe outcomes for their manufacturing processes, as well as comprehensively ensure that the chosen process is suitable for scale up.
Future-Proofing
Testing processes prior to manufacture can significantly reduce the potential for hazards. Similarly, identifying hazards early in the development phase can bring considerable efficiencies to overall development programs. Post-validation or post registration, it is generally time consuming and expensive to change the established process. Early identification can also influence the choice of reagents and conditions to eliminate or, at least minimize, the consequences.
It is essential that commercial manufacture is taken into consideration from the outset. Processes also need to be safe and scalable to future-proof the supply of a product and ensure the processes are both viable and safe on a larger scale.
Advances in technologies, such as continuous processing, are helping to make hazardous chemistry more accessible. With such approaches, the risks associated with the processing of hazardous materials are reduced as a result of a decrease in the inventory of hazardous materials.
This type of manufacturing is beneficial for the right products as it is able to limit impact if failures allow materials to reach onset temperatures. Furthermore, it ensures hazardous by-products can be effectively quenched at low volumes. While the initial investment may be comparable to a new batch reactor, there are several risk reduction benefits to be gained, as well as cost savings linked to the maintenance of safety systems and in supporting regulatory audits.
Summary
Hazardous chemistry may present the most economically viable and environmentally responsible route to a particular molecule. It brings with it several advantages, including more direct and cost-effective processes that result in the production of better yields. However, it also brings new risks that must be managed with the support of dedicated chemistry and engineering expertise. Evaluations need to be undertaken to establish a complete understanding of all hazards associated with a process, with measures being put in place to eliminate or minimize the impact of these on both human safety and the environment.
Hazard evaluation is a highly specialized field meaning it is vital to put a highly competent team in place in order to ensure more successful and safe outcomes for manufacturing processes.
Many pharmaceutical manufacturers lack the necessary expertise in- house. Subsequently, they are turning to contract partners that can bring specialist knowledge and broad experience of manufacturing complex products. These providers are also highly experienced at putting the right teams in place to offer precise and efficient control of process conditions.
While finding the right manufacturing partner will require careful consideration and thorough evaluation of credentials and prior safety records, the need for strong hazard evaluations and health and safety protocols will continue to grow as more and more complex APIs enter development.
Author Biography
Sam Brogan, PhD, is Lab Project Manager of the R&D department at Sterling Pharma Solutions and is responsible for leading a team of development chemists and senior scientists working across several process development projects. Sam joined the Sterling team in 2012 as a development chemist and assumed responsibility as the technical lead for the introduction of several hazardous processes to plant. In her current role Sam works with her team to perform development work to gain process understanding and make the process cheaper, more efficient, more robust and support the transfer to manufacture.