“Closed system.” The term itself seems pretty simple. But the definition of a closed system and its implementation and impact on biomanufacturing has been anything but simple.
The journey for implementation of closed systems is over 20 years old. Early mention of closed systems came in January 2000, with the draft issue of ICH Q7.[i] From that point in time, other Industry guidance documents began to define and support process/system closure as a primary means of risk mitigation in order to meet the baseline requirement of protecting the product as defined in current good manufacturing practice.[ii]
There are currently three recognized definitions of a closed system identified by global regulatory agencies, each having very similar language and focus on product protection. The definitions from EU Annex 1[iii], EU Annex 2[iv], and the PIC/s Annex 2A[v] all focus on product protection where the product is not exposed to the immediate room environment during manufacturing. This is where our journey will start.
[i] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients,” section 4.12, January 2000.
[ii] Title 21 – FDA, Chapter 1, Subchapter C, part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, subpart F, 211.113
[iii] European Commission, Annex I, Manufacture of Sterile Medicinal Products, Glossary, August 2022.
[iv] European Commission, Annex II, Maintenance Annex, volume 4, Glossary, June 2018.
[v] Pharmaceutical Inspection Convention, Guide to Good Manufacturing Practice for Medicinal Products, combined glossary, February 2022
Protect the Product
What is a closed system? “A system in which the product is not exposed to the surrounding environment.” – Annex 1.
Regulatory agencies across the globe focus on three aspects of manufacturing; safety, efficacy, and quality. There is no exception to this fact. And the first attribute always mentioned is safety; safety of the product to the Patient.
Regulatory agencies also understand that any Industry guidance can only be so prescriptive in defining expectations and requirements. Recent guidance documents put an increased focus on the principles of risk management. Formal risk assessments (RA) with associated risk mitigation practices are considered a mandatory basis for CGMP compliance. A Contamination Control Strategy (CCS) has become an essential design-basis document to assure the appropriate design of the facility, equipment, systems, and associated processes to mitigate and control the risks of contamination and cross-contamination. The RAs and CCS help define what is appropriate and required to meet regulatory expectations, including but not limited to, open/closed processes. Protect the product.
We know that Biopharmaceutical Manufacturing unit operations are carried out in either an open or closed process. Process Closure is critical for all biopharmaceutical products that are potentially adulterated via outside incursions of contamination. So, the simple intent of a closed process is to manage outside access to contaminants and preserve product quality. Keep the Patient safe.
In order to protect anything, you must know what you are protecting it from. To achieve product protection during manufacturing operations, it is important to understand the potential sources of contamination that could contribute to the breach of integrity of the API. A summary list of potential sources of contamination in a typical bioprocessing environment is:
- Raw materials used as components in the manufacturing process
- In-process materials such as buffers
- Consumables, single use bags, tubing, and filters
- Utility services, Air, WFI, O2, CO2, and N2
- The actual manufacturing environment can be a contributor:
- Personnel within the manufacturing suite
- PPE such as gowns that are shedding, shoes, or other items
- Equipment such as motors, fans, and compressors are all generators of particulates and aerosols,
- Process equipment that is inappropriately cleaned and sanitized between operations
The basic premise of biomanufacturing is this; a system is either open or closed. While there may be varying conditions during process operations, equipment is either open or it is closed. If it is closed, the product is at a much lower risk of being contaminated from any contaminants present in the manufacturing environment.
The layers of protection needed to protect a product, process and ultimately the Patient from contaminants present in the production environment are a key element of process and facility design. (Figure A)[i]
[i] “Why a Closed Processing Playbook?” J. Odum and M. Pelletier, ISPE webinar, April 2021.
Defining Closure Boundaries
Process closure requires the identification of boundaries that describe the biomanufacturing unit operations and facility attributes that protect the product. (Figure B)
Figure B
The primary system barrier (Process Zone), is controlled in in a closed system, where the detection of leaks and control of contamination to the system is provided. Product protection within the Process Zone requires control of the introduction of components such as unfiltered air, gasses, liquids, and operator contamination. The primary barrier is the layer of protection closest to the product that surrounds and controls the process.
The secondary system barrier provides the process boundary that provides support to closing the Process Zone. The secondary barrier surrounds the primary barrier and is also controlled in order to mitigate contamination risk from the external environment. (Figure C)
Closing the System
Closing a biomanufacturing system should focus on treating each process unit operation as a unique closed system. Each unit operation should “run” as a closed system. Each unit operation should be broken down into sub-closed systems.
In this situation, a closed system can be broken down into three basic parts:
- The equipment assembly
Examples: bioreactor, vessel, filtration system, chromatography systems, etc. - The streams in and out from the system
Examples: compress air, exhaust, media and buffers, etc. - Connections and disconnections to the system
Examples: valve, double-block, valve-ring, single use connectors and dis-connectors, etc.
The goal is to demonstrate risk mitigation for each component/part in order to ensure that the system operates in a closed manner. A typical closed system schematic would be shown in Figure E[i]. Proof of closure would be via a Closure Analysis Risk Assessment (CLARA).
[i] ibid
Figure E
When to Close
The priority in process closure should begin with open aseptic operations. This would include operations such as cell bank preparation, inoculum preparation, some weigh and dispense operations, and sampling. The analysis must also include all connections that pose a risk for contamination, as defined in the executed CLARA.
With the current Industry focus on Cell Therapy (CT) manufacturing as an example, when to focus on closure for Autologous and Allogeneic manufacturing processes is represented in Figure F.
Figure F
The Impact of Closure on Facility Design
To provide an example of the significant impact that process closure can have on biomanufacturing design, the following case study will be presented. As background, the focus of the design effort was to create an aseptic controlled environment to manufacture autologous and allogeneic therapeutics for pre-clinical and human clinical use with a high level of sterility assurance. Some of the target goals were:
- Fast transfers of biological materials in various containers (cell culture flasks, conical tubes, cryovials, bags, etc.)
- Gene manipulation by viral transduction / electroporation
- Fast and ultra-rapid decontamination cycles
- Operator and patient safety
- Acceptance from cGMP regulatory authorities, US FDA and EU EMA, and other global agencies in the future
- Preference for Grade C cleanroom facility with Grade A closed system to reduce gowning and operational costs from planned Grade B/Biosafety cabinet approach
The original production suite implemented traditional manual-focused manufacturing operations within a designated Grade A Biosafety Cabinet (BSC), operational within a Grade B background environment. (Figure G). The unit operations consisted of initial Apheresis processing, thaw-wash-incubation operations, sorting/sampling, expansion/harvest, and cryopreservation.
Figure G
Performing an analysis of the unit operations as previously described, the key risk mitigation strategies were:
- Close the primary operations by moving operations out of the BSC and into a closed isolator system
- Reduce environmental classifications
- Optimize air handling unit design based on lower HVAC design criteria
- Reduce gowning requirements to correspond with new manufacturing approach
- Provide higher level Operator training on new equipment
- Optimize facility layout design in accordance with new area classification requirements
Based on these recommendations, the new manufacturing suite schematic layout is shown below. (Figure H)
Figure H
Key design attributes of the optimized design include:
- Grade C or Grade D Suites with Grade A closed systems to reduce gowning and operational costs from planned Grade B/BSC approach
- Improved operator and patient safety
- Higher probability of acceptance from cGMP regulatory authorities, US FDA and EU EMA, and other global agencies in the future
- Lower HVAC and operational costs
- Fewer classified spaces – easier to operate, maintain, and validate
- Maintenance shutdowns reduced
- Less solid waste handling
The summary of the risk mitigation effort was:
- Overall facility classified environment space reduced by 995 square feet
- The elimination of 4,475 square feet of Grade B classified space
- The elimination of multiple Grade B airlocks
- A reduction of air handling unit sizing of 35%
- An increase of $800,000 in equipment qualification/validation costs
- A decrease in overall facility qualification costs by $250,000
- A decrease in environmental monitoring costs projections by $1.5 million
This risk mitigation effort was also analyzed over a five-year projected ROI. The result is shown below in Figure I.
Figure I
Performance of a Pros/Cons review of the risk mitigation effort yielded the following analysis. For the baseline open manufacturing controls:
- Costs for Grade B space significantly higher
- Environmental monitoring
- Gowning
- Unidirectional airflow to create Grade A aseptic environment ONLY possible when used with FULL GOWNING in a Grade B environment
- Multi-step A/Ls required
- HEPA certification
- Construction
- BSC costs lower
- Equipment
- Qualification
- Current operational baseline
- Protocols
- SoPs
- Simple Controls
- Higher Life Cycle costs
When this is compared to the new closed process-driven layout design, we see:
- Initial capital TIC was 140% higher
- Equipment cost 215% higher
- Facility cost 45% lower
- Validation costs 220% higher
- Isolator Decontamination cycle validation
- Annual operating costs 47% lower
due to elimination of Grade B space - Simplification of Operations
- Facility Flows
- Gowning
- Operator Training
- Higher Sterility Assurance levels
- 10E6 vs. 10E3
Lower risk of Microbial Contamination
What did we Learn?
This risk-driven exercise around closed system implementation gave validity to the premise that, by “closing the system” a company can reduce facility costs through reductions in area environmental classifications, reducing annual operations costs, reducing overall space footprint, and simplifying day-to-day operations. This type of exercise also comes with challenges; moving away from the traditional operational philosophy of the Company, accepting a new paradigm approach to some manufacturing unit operations, increasing the needed skill set of Employees, and changing philosophy around risk mitigation.
But the numbers make a strong case for using process closure as a manufacturing risk mitigation strategy.
[i] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients,” section 4.12, January 2000.
[ii] Title 21 – FDA, Chapter 1, Subchapter C, part 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, subpart F, 211.113
[iii] European Commission, Annex I, Manufacture of Sterile Medicinal Products, Glossary, August 2022.
[iv] European Commission, Annex II, Maintenance Annex, volume 4, Glossary, June 2018.
[1] Pharmaceutical Inspection Convention, Guide to Good Manufacturing Practice for Medicinal Products, combined glossary, February 2022
[v] “Why a Closed Processing Playbook?” J. Odum and M. Pelletier, ISPE webinar, April 2021.
[vi] R. Burke, Hyde & Associates
[vii] J. Odum, “Designing Flexible Facilities for Development and Manufacturing”, The Bioprocessing Summit, August, 2018.
[viii] ibid
