Heidi Hagen, Chief Strategy Officer and Co-founder, Vineti01.28.20
In pharmaceutical manufacturing, Chain of Identity and Chain of Custody may not be new, but in advanced therapy manufacturing, they take on a whole new significance. Why? Because in personalized therapies, a person is a key part of the process.
With any pharmaceutical product, a key aspect of regulatory compliance is generating and maintaining a complete record of the lot genealogy, which includes the Chain of Identity (COI) and Chain of Custody (COC). This is true for cell therapies, gene therapies, and personalized cancer vaccines as well, and due to the unique and complex nature of these products, the requirements are even more stringent and detailed.
This commentary presents an overview of COI and COC, what lot genealogy looks like in traditional pharmaceuticals, and then highlights the major differences for personalized therapies.
What are COI and COC?
Here are definitions commonly used in the industry:
Chain of Identity (COI): The permanent and transparent association of a donor’s unique identifiers to their tissue or cells (raw material), and the resulting drug product, for the entire process from order through manufacturing to treatment and post-treatment monitoring. For example, an autologous donor’s patient number should be linked to their unique donation number and manufacturing batch number as part of the COI.
Chain of Custody (COC): The permanent capture of data related to who handled the collection and/or product, what actions were performed, and the location/date/time of the actions from the start of tissue/cell collection through product administration.
The core COI is the overarching record for an individual patient or donor and is used as a foundation to 1) link all of an individual’s collections and product journeys to them, AND 2) link together (associate) all the key data for an individual collection and product journey, clearly demonstrating a complete COI and COC.
The COI record has multiple links and layers, and sometimes applies to multiple doses or treatments. But it always ties back to the same patient or donor.
What is lot genealogy and how is it different in personalized therapies?
Lot genealogy is a fundamental regulatory requirement for all pharmaceuticals and a cornerstone for ensuring patient safety. It is simply a record of all the materials, processes, testing, and outputs of a pharmaceutical product. This record demonstrates GMP compliance, process control, and product quality.
For a traditional pharmaceutical product, lot genealogy is typically done on a large batch basis (or by “lot”) and is relatively straightforward. At a high level, it looks like this:
All the pieces of lot genealogy remain in place for personalized therapies, and the underlying principle is the same. As stated by the EMA in guidance related to Advanced Therapy Medicinal Products (ATMPs), “The records should enable the entire history of a batch to be traced.”1 But there are some significant differences, especially the addition of a stand-alone COI for each patient, and the emphasis on traceability of the live human cells.
COI and COC of the human cells are the “backbone” of patient safety in advanced therapies. The EMA’s advanced therapy guidance document further states: “Compliance with GMP is an essential part of the pharmaceutical quality system. In particular...it should be ensured that: adequate systems are implemented to ensure traceability of the ATMPs and of their starting and critical raw materials...The manufacturer should ensure that the following data is retained for a minimum of 30 years...Donation identification code received from the tissue establishment/blood establishment...and internal code (or other identification system) that is generated by the manufacturer to unequivocally identify the tissues/cells used as starting materials throughout the entire manufacturing process up to the point of batch release...”2
There are three reasons for this:
Cell therapies use live human cells as a key raw material, and manufacturing batch sizes are typically quite small—in autologous cell therapies, and some allogeneic cell therapies, there is one complete batch per donor/patient. These are major differences from traditional drug products.
Unlike traditional raw materials, the live human cells are not standardized or well characterized. There can be wide variability in cells from patient to patient, especially in populations of patients with serious, advanced health conditions such as late-stage cancer. It is important to capture and track key pieces of data related to this raw material, not only to ensure that patients are ultimately treated with the right product, but also to ensure drug product quality, regulatory compliance, and accurate health and outcomes information. Again, the EMA is quite clear on this point as well when they state, “Good documentation is an essential part of the quality system and is a key element of GMP. The main objective of the system of documentation utilized must be to establish control, monitor and record all activities which directly or indirectly may affect the quality of the medicinal products. Records required to ensure traceability should also be kept.”3
The live cells used in personalized therapies differ from traditional raw materials in another significant way. In other situations, human cells or tissues are not typically collected under GMP conditions, and the process for including them in the batch of drug product is more complex. Cell or tissue collection is typically done at a research hospital, outpatient clinic, or blood collection facility. These organizations have high quality standards, but not the same as the rigor of GMP. Providing these organizations with the tools, procedures, and training to comply with GMP, and to properly track COI and COC, is an important aspect of ensuring a successful and compliant product journey each and every time.
Additionally, once the cells are procured, there are typically special storage and transportation steps to ensure cell viability and to move them from the point of collection to the manufacturing facility. This must all be performed and tracked meticulously using GMP standards to ensure a complete COI, COC, and overall lot genealogy.
The live cells used in personalized therapies differ from traditional raw materials in another significant way. In other situations, human cells or tissues are not typically collected under GMP conditions, and the process for including them in the batch of drug product is more complex. Cell or tissue collection is typically done at a research hospital, outpatient clinic, or blood collection facility. These organizations have high quality standards, but not the same rigor as GMP. Providing these organizations with the tools, procedures, and training to comply with GMP, and to properly track COI and COC, is an important aspect of ensuring a successful and compliant product journey each and every time. Additionally, once the cells are procured, there are typically special storage and transportation steps to ensure cell viability and to move them from the point of collection to the manufacturing facility. This must all be performed and tracked meticulously using GMP standards to ensure a complete COI, COC, and overall lot genealogy.
All records of any products started in a cell therapy process, even if they are not finished or administered, must have a complete COI. The EMA has clearly articulated the requirement for a completely linked COI: “A system that enables the bidirectional tracking of cells/tissues contained in ATMPs from the point of donation through manufacturing, to the delivery of the finished product to the recipient should be created.”4 The FDA, which has also been evaluating regulatory requirements for advanced therapies, is preparing to release a new set of guidances later this year.
The window of traceability can be much longer for a cell therapy than for a traditional pill as well. The COI becomes part of the health system once the drug product is administered to the patient. They have received modified human cells and this must be monitored and traceable for the patient’s lifetime.
Conclusion
COI and COC are simply an expansion of the traditional lot genealogy concept to adapt to the biological complexity of personalized therapies. The COI and COC for a personalized therapy must be captured in a single record relating to a specific donor or patient and it must demonstrate a safe and compliant product journey. Each product journey is different—it happened under different conditions, was handled by different people, and had its own dedicated processing steps and test results. Regardless, the standard for lot genealogy remains the same, which is to demonstrate GMP compliance, process control, and product quality—and protect the safety of each and every patient.
References
Heidi Hagen is the chief strategy officer and a co-founder of Vineti. Over the course of her career, she has overseen the operations and delivery for more than 100,000 doses of cell therapy. If you’d like to learn more about how Vineti’s software platform supports scalable COI and COC for cell and gene therapies, visit http://vineti.com.
With any pharmaceutical product, a key aspect of regulatory compliance is generating and maintaining a complete record of the lot genealogy, which includes the Chain of Identity (COI) and Chain of Custody (COC). This is true for cell therapies, gene therapies, and personalized cancer vaccines as well, and due to the unique and complex nature of these products, the requirements are even more stringent and detailed.
This commentary presents an overview of COI and COC, what lot genealogy looks like in traditional pharmaceuticals, and then highlights the major differences for personalized therapies.
What are COI and COC?
Here are definitions commonly used in the industry:
Chain of Identity (COI): The permanent and transparent association of a donor’s unique identifiers to their tissue or cells (raw material), and the resulting drug product, for the entire process from order through manufacturing to treatment and post-treatment monitoring. For example, an autologous donor’s patient number should be linked to their unique donation number and manufacturing batch number as part of the COI.
Chain of Custody (COC): The permanent capture of data related to who handled the collection and/or product, what actions were performed, and the location/date/time of the actions from the start of tissue/cell collection through product administration.
The core COI is the overarching record for an individual patient or donor and is used as a foundation to 1) link all of an individual’s collections and product journeys to them, AND 2) link together (associate) all the key data for an individual collection and product journey, clearly demonstrating a complete COI and COC.
The COI record has multiple links and layers, and sometimes applies to multiple doses or treatments. But it always ties back to the same patient or donor.
What is lot genealogy and how is it different in personalized therapies?
Lot genealogy is a fundamental regulatory requirement for all pharmaceuticals and a cornerstone for ensuring patient safety. It is simply a record of all the materials, processes, testing, and outputs of a pharmaceutical product. This record demonstrates GMP compliance, process control, and product quality.
For a traditional pharmaceutical product, lot genealogy is typically done on a large batch basis (or by “lot”) and is relatively straightforward. At a high level, it looks like this:
- Raw materials are procured in bulk from GMP suppliers;
- Ingredients added to a batch are recorded throughout the process;
- Activities performed by personnel are recorded in the batch record; and
- A certificate of analysis is generated to show that the product meets pre-defined specifications.
All the pieces of lot genealogy remain in place for personalized therapies, and the underlying principle is the same. As stated by the EMA in guidance related to Advanced Therapy Medicinal Products (ATMPs), “The records should enable the entire history of a batch to be traced.”1 But there are some significant differences, especially the addition of a stand-alone COI for each patient, and the emphasis on traceability of the live human cells.
COI and COC of the human cells are the “backbone” of patient safety in advanced therapies. The EMA’s advanced therapy guidance document further states: “Compliance with GMP is an essential part of the pharmaceutical quality system. In particular...it should be ensured that: adequate systems are implemented to ensure traceability of the ATMPs and of their starting and critical raw materials...The manufacturer should ensure that the following data is retained for a minimum of 30 years...Donation identification code received from the tissue establishment/blood establishment...and internal code (or other identification system) that is generated by the manufacturer to unequivocally identify the tissues/cells used as starting materials throughout the entire manufacturing process up to the point of batch release...”2
There are three reasons for this:
- Adding live human cells to a product significantly increases the variability of raw materials;
- It is critical that patients are treated with the drug product containing the cells or formulation meant specifically for them, whether it’s their own cells (autologous therapies) or donor cells (allogeneic therapies with some matching), to avoid safety consequences such as product rejection or anaphylactic shock; and
- The complexity of the process exponentially increases because of how the cells are procured and transported, the careful handling and processing required, and the potential for multiple batches and/or doses per patient. Each product journey is fundamentally different and unique.
Cell therapies use live human cells as a key raw material, and manufacturing batch sizes are typically quite small—in autologous cell therapies, and some allogeneic cell therapies, there is one complete batch per donor/patient. These are major differences from traditional drug products.
Unlike traditional raw materials, the live human cells are not standardized or well characterized. There can be wide variability in cells from patient to patient, especially in populations of patients with serious, advanced health conditions such as late-stage cancer. It is important to capture and track key pieces of data related to this raw material, not only to ensure that patients are ultimately treated with the right product, but also to ensure drug product quality, regulatory compliance, and accurate health and outcomes information. Again, the EMA is quite clear on this point as well when they state, “Good documentation is an essential part of the quality system and is a key element of GMP. The main objective of the system of documentation utilized must be to establish control, monitor and record all activities which directly or indirectly may affect the quality of the medicinal products. Records required to ensure traceability should also be kept.”3
The live cells used in personalized therapies differ from traditional raw materials in another significant way. In other situations, human cells or tissues are not typically collected under GMP conditions, and the process for including them in the batch of drug product is more complex. Cell or tissue collection is typically done at a research hospital, outpatient clinic, or blood collection facility. These organizations have high quality standards, but not the same as the rigor of GMP. Providing these organizations with the tools, procedures, and training to comply with GMP, and to properly track COI and COC, is an important aspect of ensuring a successful and compliant product journey each and every time.
Additionally, once the cells are procured, there are typically special storage and transportation steps to ensure cell viability and to move them from the point of collection to the manufacturing facility. This must all be performed and tracked meticulously using GMP standards to ensure a complete COI, COC, and overall lot genealogy.
The live cells used in personalized therapies differ from traditional raw materials in another significant way. In other situations, human cells or tissues are not typically collected under GMP conditions, and the process for including them in the batch of drug product is more complex. Cell or tissue collection is typically done at a research hospital, outpatient clinic, or blood collection facility. These organizations have high quality standards, but not the same rigor as GMP. Providing these organizations with the tools, procedures, and training to comply with GMP, and to properly track COI and COC, is an important aspect of ensuring a successful and compliant product journey each and every time. Additionally, once the cells are procured, there are typically special storage and transportation steps to ensure cell viability and to move them from the point of collection to the manufacturing facility. This must all be performed and tracked meticulously using GMP standards to ensure a complete COI, COC, and overall lot genealogy.
All records of any products started in a cell therapy process, even if they are not finished or administered, must have a complete COI. The EMA has clearly articulated the requirement for a completely linked COI: “A system that enables the bidirectional tracking of cells/tissues contained in ATMPs from the point of donation through manufacturing, to the delivery of the finished product to the recipient should be created.”4 The FDA, which has also been evaluating regulatory requirements for advanced therapies, is preparing to release a new set of guidances later this year.
The window of traceability can be much longer for a cell therapy than for a traditional pill as well. The COI becomes part of the health system once the drug product is administered to the patient. They have received modified human cells and this must be monitored and traceable for the patient’s lifetime.
Conclusion
COI and COC are simply an expansion of the traditional lot genealogy concept to adapt to the biological complexity of personalized therapies. The COI and COC for a personalized therapy must be captured in a single record relating to a specific donor or patient and it must demonstrate a safe and compliant product journey. Each product journey is different—it happened under different conditions, was handled by different people, and had its own dedicated processing steps and test results. Regardless, the standard for lot genealogy remains the same, which is to demonstrate GMP compliance, process control, and product quality—and protect the safety of each and every patient.
References
- European Commission, 2017. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Section 6.3, Sub-section 6.26, P. 33). Brussels, Belgium. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf
- European Commission, 2017. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Section 1.2, Sub-section 1.24 viii, P. 7; Section 6.6, Sub-section 6.37 i, P. 36). Brussels, Belgium. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf
- European Commission, 2017. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Section 6.1, Sub-section 6.10, P. 30). Brussels, Belgium. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf
- European Commission, 2017. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Section 6.6, Sub-section 6.35, P. 36). Brussels, Belgium. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf
Heidi Hagen is the chief strategy officer and a co-founder of Vineti. Over the course of her career, she has overseen the operations and delivery for more than 100,000 doses of cell therapy. If you’d like to learn more about how Vineti’s software platform supports scalable COI and COC for cell and gene therapies, visit http://vineti.com.
