21st Century GMP Compliant
• Science-based, risk-based, evidence-based, PAT intensive, closed cell processing and production
• Modernized from the ground up for cell therapy where cells are the product
OLD GMPs IMPEDE CELL THERAPY PROGRESS
Quality recognizes that legacy GMPs still dominant from the pill industry (cGMP) might be good enough to manufacture substrate cells for biologics manufacturing, but not therapeutic cells as the drug product.
- Live potent cells as product cannot be terminally sterilized, but legacy GMPs seem to depend on this.
- The phenotypic and genotypic integrity of the cell product cannot be compromised, but legacy GMPs allow this.
- New complex multistep production processes will need to incrementally and continuously improve over time, but legacy GMPs prohibit this.
- Massively parallel patient-specific batch production and distributed manufacturing will be necessary, but legacy GMPs inhibit this.
21st Century GMPs exclusively enable the development of clinical grade cells-as-product. The Platform is 21st Century GMP compliant now.
| OLD GMPs Legacy Mentality | NEW GMPs Modern Mentality |
|---|---|
| Absolute/dogmatic | Risk-based |
| Tradition/belief/superstition/opinion | Science-based/ evidence-based |
| Test 3 runs, then never change (never improve) | PAT > continuous improvement |
| QbT | QbD |
| Open | Closed |
| Cells not isolated from humans and room air | Cells isolated from humans and room air |
| Part-time cell optimization | Full-time cell optimization |
| Always bioburden (CFUs below threshold) | No bioburden (No CFUs) |
| Indiscriminate comprehensive decon/wash | Risk-based, evidence-based decon/wash |
| etc. | etc. |
WHY MODERNIZATION IS NECESSARY
Quality is what regulatory compliance is all about. Legitimate cell therapy developers understand regulatory is your friend. Despite the legacy GMP naysayers who assume anything new and unconventional won’t pass regulatory scrutiny for one lame legacy GMP reason or another, the reality is different. Regulatory agencies want science-based modernization, understand the composite risk comparison between open and closed, and are comfortable with a closed system designed for cells-as-product … despite our unconventional approach. The Platform gives you regulatory comfort despite the skeptics now.
| SCIENCE | cGMP |
|---|---|
| Cells have multiple physiologic critical process parameters (temperature, humidity/osmolarity, pH/carbon dioxide, oxygen/ROS) that have to be optimized full time during incubation AND all processing to maximize probability of product with reliable, reproducible, robust, phenotypic integrity (potency). | Old conventional open incubators, open hoods, open cleanrooms and isolators not good enough. |
| Open culture vessels require high humidity during incubation. Processing areas are best if extremely dry to mitigate risk of microbial growth. Certain process steps need different specific humidity and temperature levels. Temperature and humidity control requires enclosure material with insulation value to avoid condensation and minimize energy consumption. | Old conventional materials of stainless steel and glass not good enough. |
| Must simultaneously protect cell product from people and protect people from product due to biohazard potential of virus and vectors used to genetically engineer cells and infectious pathogens in cells sourced from diseased patients. | Old conventional positive pressure to protect product and negative pressure to protect people are not good enough. |
| Cell production processes are complex and vary widely. | Old conventional monolithic isolators are not good enough. |
| CO2, O2, RH, and temperature control make ventilation with air disruptive to process control and costly. | Old conventional ventilation with air is not good enough. |
MODERNIZATION IS ACCEPTABLE
All regulatory agencies recognize importance of and promote advancing and improving manufacturing technology.
FDA: “…we recognize that it may not be possible to follow each recommendation… Therefore, we recommend that you include your justification for adopting additional controls or alternative approaches to the recommendations in this guidance in the records…”. FDA Guidance “CGMP for Phase 1 Investigational Drugs” July 2008
EMA: “It is recognized that there are acceptable methods, other than those described in the Guide, which are capable of achieving the principles of Quality Assurance. The Guide is not intended to place any restraint upon the development of any new concepts or new technologies which have been validated and which provide a level of Quality Assurance at least equivalent to those set out in this Guide.” EU GMP Eudralex Vol 4 Preface p. 3
PIC/S : “…this document reflected current state of the art. It is not intended to be a barrier to technical innovation or the pursuit of excellence.” PI 014-3, p.3, sec.4.2. “The advice in this Recommendation is not mandatory for industry. However, industry should consider these recommendations as appropriate.” PI 014-3, p. 3, sec. 4.3
SCIENCE-BASED DESIGN REQUIREMENTS FOR XVIVO SYSTEM MODEL X2 (Xvivo GMP System®)
| MODERNIZATION | CYTOCENTRIC ISOLATOR |
|---|---|
| PROCESS AGNOSTIC | YES |
| OPTIMIZED CELL ENVIRONMENT | YES |
| MAXIMAL & OPEN P.A.T. | YES |
| PROTECT CELLS | YES |
| PROTECT PEOPLE | YES |
SCIENCE-BASED DESIGN REQUIREMENTS FOR XVIVO SYSTEM MODEL X2
HOW DO THE GMP COMPLIANT CELL MANUFACTURING OPTIONS COMPARE?
| CYTOCENTRIC ISOLATOR | FUNCTIONALLY CLOSED | TRADITIONAL ISOLATOR | OPEN CLEANROOM | |
|---|---|---|---|---|
| PROTECT CELLS |  | | |  |
| PROCESS AGNOSTIC | |  | | |
| CELL OPTIMIZED | | | | |
| MAXIMAL P.A.T. | | | | |
| PROTECT PEOPLE | | | | |
HOW DO THE GMP COMPLIANT CELL MANUFACTURING OPTIONS COMPARE?
PROCESS ANALYTIC TECHNOLOGY (PAT)
Quality recognizes that the more one knows about the critical process parameters during each and every step of every production run, the better. All environmental quality parameters such as temperature, humidity, pressure, particles, and vapors should be monitored and controlled to mitigate risk. All critical cell parameters such as temperature, humidity, oxygen, and carbon dioxide should be monitored and controlled at optimums. Any additional specific process analytic technology should be able to be incorporated as well. The Platform does this now.
System Security:
– User password protection and administrator tools
– Safety protocols, logout and lockout options
Audit Trails:
– Time-stamped event log, recorded and stored
– Changes are recorded with “old” and “new” values
Records:
– All date files, graphs, etc are automatically and securely stored on hard drive
BATCH RECORDS
Quality recognizes that each batch, no matter how many, no matter where produced, must have a complete end-to-end secure batch record of all critical cell process parameters and all critical environmental parameters. The Platform does this now.
GLOBAL QUALITY ASSURANCE
SEE & RECORD
Every parameter, every batch, every location – worldwide.
VALIDATION GUARANTEED
Quality recognizes that validation of new, and reconfigured, and relocated production capacity regardless of scale or location must be 100% reliable and fast (within days). The Platform does this now.
Validation – FAT, SAT, IQ, OQ, PQ
COMPLIANT FACILITY OPTIONS
Quality should never be compromised by the type or purpose of the host facility, and compliance should be within reach of every type of legitimate cell therapy developer and practitioner, regardless of their budget, their application, or their institutional affiliation. The Platform does this now.
REGULATORY GUIDANCES FOR ISOLATORS IN ASEPTIC DRUG/CELL PRODUCTION
• FDA Sterile Drug Products Produced by Aseptic Processing cGMP, Appendix 1, Sept. 2004. • FDA Pharmaceutical cGMPs for 21st Century – a Risk Based Approach, Sept. 2004.
• ISO Cleanrooms and associated controlled environments Part 7: Separative Devices, 14644- 7:2004(E).
• PIC/S Isolators Used for Aseptic Processing and Sterility Testing, PI 014-3, Sept. 2007.
• EMA Manufacture of Sterile Medicinal Products, Eudralex, Annex 1, vol.4, 2008.
• USP-NF Pharmaceutical Compounding – Sterile USP-NF Pharmaceutical Compounding – Sterile Preparations. Chapter 797, 2004.
• etc.
CYTOCENTRIC ISOLATOR IN ISO 8 CLEANROOM
FDA, EMA, ISO, PICS COMPLIANT
CYTOCENTRIC ISOLATOR IN FREESTANDING HARDWALL OR SOFTWALL CLEANZONE
FDA, EMA, ISO, PICS COMPLIANT
SOFTWALL CLEANZONE (ISO 8)
FDA approved – located in surgical suite next to patients.
ISO 8 TENT, 100% RECIRCULATING, WITH PLASTIC STRIPS
CYTOCENTRIC ISOLATOR IN ISO 8 ROOM – NOT A CLEANROOM
FDA, EMA, ISO, PICS COMPLIANT
• No Anteroom
• No coved corners
• No walls or ceilings designed for washing
• etc.
CYTOCENTRIC ISOLATOR IN UNCLASSIFIED SPACE
USP, EUDRALEX COMPLIANT
EudraLex
The Rules Governing Medicinal Products in the European Union
Volume 4
Good Manufacturing Practice
“In exceptional circumstances and provided that it is duly justified (e.g. manufacturing of the ATMP takes place in the operating theatre and it is not possible to move the production to an outside clean room because the time between the donation and administration of the product is very short and the patient is also in the operating theatre waiting for administration of the ATMP), closed systems may be placed in a controlled but non-classified environment. The conditions of the operating theatre where the manufacturing activity takes place should be adequate and sufficient to ensure the quality and safety of the product. It is stressed that this is only acceptable in exceptional cases and that the product should not be exposed at any moment to the environment (e.g. supporting data from leak testing and pressure check of the equipment). Additionally, it should be demonstrated that the expected clinical benefit for the patient outweighs the risks linked to the absence of a classified background.”
CYTOCENTRIC ISOLATOR IN ISO 6/ISO 7 CLEANROOM SUITE
FDA, EMA, ISO, PICS COMPLIANT (OVER-COMPLIANT?)
FUNCTIONALLY CLOSED IN CYTOCENTRIC ISOLATOR
FDA, EMA, ISO, PICS COMPLIANT (OVER-COMPLIANT?)
CYTOCENTRIC ISOLATOR SYNERGY
| CYTOCENTRIC ISOLATOR | OPEN CLEANROOM + CYTOCENTRIC ISOLATOR | FUNCTIONALLY CLOSED + CYTOCENTRIC ISOLATOR | TRADITIONAL ISOLATOR + CYTOCENTRIC ISOLATOR | |
|---|---|---|---|---|
| PROTECT CELLS | | |  | |
| PROCESS AGNOSTIC | | | | |
| CELL OPTIMIZED | | | | |
| MAXIMAL P.A.T. | | | | |
| PROTECT PEOPLE | | | | |
CYTOCENTRIC ISOLATOR SYNERGY
