Michael Avraam, Global Product Manager, ChargePoint Technology10.10.18
Use of high potency active pharmaceutical ingredients (HPAPIs) is increasing as pharmaceutical companies focus on developing more effective, better targeted medicines.
This growing interest is increasing demand for the specialist handling and containment systems needed to ensure such products can be manufactured in a manner that complies with employee safety regulations.
In addition, the trend has prompted manufacturers to search for faster, less labor intensive ways of verifying the efficacy of their containment systems.
As a result, the interpretation of containment verification data has become a major focus for internal teams at drug companies and contract manufacturing organizations (CMOs).
This article will outline some of the cutting edge handling and containment technologies being used to ensure the safety of pharmaceutical employees who work with HPAPIs. It will also outline validation and interpretation best practices industry leaders use to make sure their containment efforts are effective.
HPAPI industry surge
Demand for medicines that target and treat diseases more effectively and with fewer side effects has prompted many pharmaceutical manufacturers to invest in the development of HPAPI-based medicines.
Analysis by Transparency Market Research suggests by the end of 2024 the cancer segment of the HPAPI market, the largest HPAPI segment by far, will be worth close to $100 billion in value, expanding at a CAGR of 6.5%.
The term HPAPI is complicated. All active pharmaceutical ingredients have pharmacologic potency and each can be categorized on continuum of potency from low, to moderate and on to potent and highly potent.
Substances categorized as potent or highly potent must be handled in accordance with strict criteria designed to protect people using them in pharmaceutical manufacture. Generally, HPAPIs are classified as being occupational exposure band 5 (OEB 5), which means staff who work with them must be exposed to less than 1µg/m³ within a working day. Limiting exposure to such a low level necessitates effective containment technologies.
Containment tech in demand
The use of isolators, restricted access barrier systems (RABS) and split butterfly valves (SBVs) that separate drug products from operators has grown significantly in recent years.
Part of the reason for this is closed transfer technologies like the SBV limit manual intervention and reduce the risk of cross contamination. They also limit the presence of airborne dust particulates.
Containment in the manufacturing environment
Establishing effective containment systems in a pharmaceutical manufacturing environment is a considerable challenge because human intervention is present at almost every stage of manufacturing processes.
It is therefore vitally important that containment solutions should not hinder operability or reduce productivity.
Containment technologies such as SBVs have been developed to improve containment for processes where there is a risk of airborne exposure, including during all powder transfer stages.
These valves, when integrated with isolators or other containment technologies, allow for material to be transferred without the risk of it escaping.
Validation and assessment
Once the desired handling and containment systems have been selected it is very important they are tested for efficacy. The best approach is to use a best practices checklist to make this assessment to prevent anything being overlooked.
The International Society for Pharmaceutical Engineering’s (ISPE) SMEPAC (Standardized Measurement of Equipment Particulate Airborne Concentration) guideline is widely used. It outlines validation methodologies for a broad range of technologies and processing equipment, all of which are focused on assessing how well the system in question contains particulate matter. Specifically, it provides methodologies manufacturers can use to derive performance data that is invaluable for risk assessments.
The SMEPAC guideline is just that, a guideline rather than a set of strict requirements. Nevertheless, it provides companies with a means of benchmarking their containment capabilities and provides a way of identifying potential risks.
However, it is important to understand that the instructions and test methods set out in the guideline are conducted under controlled conditions in the laboratory. Effort must be made to understand how data generated during validation relates to real-world manufacturing.
Data interpretation considerations
The second phase of any containment technology validation process is data assessment and interpretation. Like all similar guidelines, the testing protocols set out in the SMEPAC document allow for a degree of inconsistency.
For example, manufacturers often look at containment performance data and use it to qualify the selection of the required containment technology for their production process. However, it is important that variability in the testing methods for each type of technology is taken into consideration before any decisions are made.
It is also important that validation testing takes the impact of operator intervention into consideration to ensure the containment device, some of which can be reliant on operator technique to achieve performance, is tested accordingly.
Also, it is vital to keep in mind that all containment technologies used for a particular HPAPI-based pharmaceutical manufacturing process must be validated to ensure the performance of the system as a whole. Each step where there is potential exposure must be validated and the subject of a detailed risk assessment.
The final stage of the validation process should also include the development of a preventative maintenance program based on areas of potential risk that are identified during the assessment phase. The idea is to look at the condition of each containment device and develop a maintenance plan that helps to safeguard the reliability of the containment solution.
Integration and monitoring
As illustrated above, validating containment technologies in a manufacturing environment where HPAPIs are used can be complex and very time consuming.
One approach used to streamline this process is to select containment technologies with capacity for both continuous operational monitoring and the ability to communicate with other systems in place on the manufacturing line.
A continuous flow of equipment operational data can shorten the time taken for revalidation of an existing line or indeed to develop a validation plan for new lines using duplicate technologies. This data can also provide insight into the wear and tear of equipment and therefore, when combined with containment testing results, allows users to secure a safe operating period or usage cycles for the valve before they begin to experience compromised performance. With this kind of monitoring, preventative maintenance can take place on a different level than before.
A continuous monitoring approach is also a good fit for the ‘industry 4.0’ paradigm, which is based on the idea that Wi-Fi enabled components able to transmit data cut maintenance costs and allow problems to be quickly identified.
Conclusion
There are a huge range of factors a pharmaceutical firm must consider when working with HPAPIs. Containment is the most important consideration from a manufacturing standpoint as preventing these highly pharmacologically active substances injuring employees is critical.
However, as stated above, it is also important the correct containment technologies and handling procedures are put in place and that all of these are validated in accordance with appropriated guidelines. Likewise, it is vital operations continue to be monitored for containment deviations after the process has been established and new wireless monitoring technology is set to make a real impact in terms of providing important operational performance data.
Michael Avraam is the global product manager at ChargePoint Technology for the PharmaSafe range of products. He is responsible for the development and evolution of ChargePoint’s split butterfly valve technology, including containment performance testing as well as developing new products and technologies.
This growing interest is increasing demand for the specialist handling and containment systems needed to ensure such products can be manufactured in a manner that complies with employee safety regulations.
In addition, the trend has prompted manufacturers to search for faster, less labor intensive ways of verifying the efficacy of their containment systems.
As a result, the interpretation of containment verification data has become a major focus for internal teams at drug companies and contract manufacturing organizations (CMOs).
This article will outline some of the cutting edge handling and containment technologies being used to ensure the safety of pharmaceutical employees who work with HPAPIs. It will also outline validation and interpretation best practices industry leaders use to make sure their containment efforts are effective.
HPAPI industry surge
Demand for medicines that target and treat diseases more effectively and with fewer side effects has prompted many pharmaceutical manufacturers to invest in the development of HPAPI-based medicines.
Analysis by Transparency Market Research suggests by the end of 2024 the cancer segment of the HPAPI market, the largest HPAPI segment by far, will be worth close to $100 billion in value, expanding at a CAGR of 6.5%.
The term HPAPI is complicated. All active pharmaceutical ingredients have pharmacologic potency and each can be categorized on continuum of potency from low, to moderate and on to potent and highly potent.
Substances categorized as potent or highly potent must be handled in accordance with strict criteria designed to protect people using them in pharmaceutical manufacture. Generally, HPAPIs are classified as being occupational exposure band 5 (OEB 5), which means staff who work with them must be exposed to less than 1µg/m³ within a working day. Limiting exposure to such a low level necessitates effective containment technologies.
Containment tech in demand
The use of isolators, restricted access barrier systems (RABS) and split butterfly valves (SBVs) that separate drug products from operators has grown significantly in recent years.
Part of the reason for this is closed transfer technologies like the SBV limit manual intervention and reduce the risk of cross contamination. They also limit the presence of airborne dust particulates.
Containment in the manufacturing environment
Establishing effective containment systems in a pharmaceutical manufacturing environment is a considerable challenge because human intervention is present at almost every stage of manufacturing processes.
It is therefore vitally important that containment solutions should not hinder operability or reduce productivity.
Containment technologies such as SBVs have been developed to improve containment for processes where there is a risk of airborne exposure, including during all powder transfer stages.
These valves, when integrated with isolators or other containment technologies, allow for material to be transferred without the risk of it escaping.
Validation and assessment
Once the desired handling and containment systems have been selected it is very important they are tested for efficacy. The best approach is to use a best practices checklist to make this assessment to prevent anything being overlooked.
The International Society for Pharmaceutical Engineering’s (ISPE) SMEPAC (Standardized Measurement of Equipment Particulate Airborne Concentration) guideline is widely used. It outlines validation methodologies for a broad range of technologies and processing equipment, all of which are focused on assessing how well the system in question contains particulate matter. Specifically, it provides methodologies manufacturers can use to derive performance data that is invaluable for risk assessments.
The SMEPAC guideline is just that, a guideline rather than a set of strict requirements. Nevertheless, it provides companies with a means of benchmarking their containment capabilities and provides a way of identifying potential risks.
However, it is important to understand that the instructions and test methods set out in the guideline are conducted under controlled conditions in the laboratory. Effort must be made to understand how data generated during validation relates to real-world manufacturing.
Data interpretation considerations
The second phase of any containment technology validation process is data assessment and interpretation. Like all similar guidelines, the testing protocols set out in the SMEPAC document allow for a degree of inconsistency.
For example, manufacturers often look at containment performance data and use it to qualify the selection of the required containment technology for their production process. However, it is important that variability in the testing methods for each type of technology is taken into consideration before any decisions are made.
It is also important that validation testing takes the impact of operator intervention into consideration to ensure the containment device, some of which can be reliant on operator technique to achieve performance, is tested accordingly.
Also, it is vital to keep in mind that all containment technologies used for a particular HPAPI-based pharmaceutical manufacturing process must be validated to ensure the performance of the system as a whole. Each step where there is potential exposure must be validated and the subject of a detailed risk assessment.
The final stage of the validation process should also include the development of a preventative maintenance program based on areas of potential risk that are identified during the assessment phase. The idea is to look at the condition of each containment device and develop a maintenance plan that helps to safeguard the reliability of the containment solution.
Integration and monitoring
As illustrated above, validating containment technologies in a manufacturing environment where HPAPIs are used can be complex and very time consuming.
One approach used to streamline this process is to select containment technologies with capacity for both continuous operational monitoring and the ability to communicate with other systems in place on the manufacturing line.
A continuous flow of equipment operational data can shorten the time taken for revalidation of an existing line or indeed to develop a validation plan for new lines using duplicate technologies. This data can also provide insight into the wear and tear of equipment and therefore, when combined with containment testing results, allows users to secure a safe operating period or usage cycles for the valve before they begin to experience compromised performance. With this kind of monitoring, preventative maintenance can take place on a different level than before.
A continuous monitoring approach is also a good fit for the ‘industry 4.0’ paradigm, which is based on the idea that Wi-Fi enabled components able to transmit data cut maintenance costs and allow problems to be quickly identified.
Conclusion
There are a huge range of factors a pharmaceutical firm must consider when working with HPAPIs. Containment is the most important consideration from a manufacturing standpoint as preventing these highly pharmacologically active substances injuring employees is critical.
However, as stated above, it is also important the correct containment technologies and handling procedures are put in place and that all of these are validated in accordance with appropriated guidelines. Likewise, it is vital operations continue to be monitored for containment deviations after the process has been established and new wireless monitoring technology is set to make a real impact in terms of providing important operational performance data.
Michael Avraam is the global product manager at ChargePoint Technology for the PharmaSafe range of products. He is responsible for the development and evolution of ChargePoint’s split butterfly valve technology, including containment performance testing as well as developing new products and technologies.
