Aseptic Process Simulation: Cell and Gene Therapy Manufacture

Sunday, October 1, 2023

Robert Dream- Managing Director, HDR Company

Aseptic process simulation (APS, AKA Media Fill) is a critical microbiological test carried out to assess the performance of an aseptic manufacturing procedure by replacing the pharmaceutical product with a sterile culture media. Aseptic manufacturing is a complex process used in the pharmaceutical industry. Good manufacturing practices (GMP) require pharmaceutical companies to regularly perform Aseptic process simulation tests to verify the microbiological state of their aseptic production process. The nutrient medium is selected based on the product quantity and the selectivity, clarity, concentration, and suitability of the medium for sterilization. The process simulation test should imitate, as closely as possible, the routine aseptic manufacturing process and include all critical subsequent manufacturing steps.

Aseptic process simulation test procedure/protocol
Culture media for aseptic process simulation tests
Incubation conditions for aseptic process simulation tests
Frequency of aseptic process simulation tests
Define aseptic boundary for cell and or tissue processing
Open versus closed processing system steps
Cryopreserved product versus fresh product
Process scale-up and scale-out
Aseptic process simulation study design considerations
A cell therapy aseptic process simulation protocol for validation of aseptic processing

Aseptic Process Simulation

Aseptic process simulation challenges the overall process with worst-case microbial contamination risks/conditions to evaluate aseptic process robustness and to comply with cGMP requirements.

It is a tool to evaluate the capability of aseptic processing activities, using microbiological growth-promoting media in place of the product. APS simulates the aseptic process from the product and component sterilization to the final sealing of the container. The media is made to contact all product contact surfaces of the equipment chain, container closure, critical environment, and process manipulations that the product itself will undergo. Media is then incubated and inspected for microbial growth. This information is used to assess the potential for product units to become contaminated during the aseptic processing operations

Purpose of Aseptic Process Simulation

To assess the capability of the aseptic process to produce sterile products repeatedly. Assess the contamination risk factors of the process and hence the state of control:

Assess vulnerability to microbial contamination.
Demonstrate that the aseptic operating practices and procedures are appropriate.
Evaluate the aseptic processing personnel practices
Qualify/requalify/disqualify personnel
Compliance with Good Manufacturing Practices and regulatory expectations

Environmental Control and Monitoring

The extent of environmental control depends on the manufacturing process and the working conditions: Less stringent when adopting automated closed manufacturing systems or environments (e.g., isolator). More stringent when performing manual open processing inside an ISO 5/Grade A Biological Safety Cabinets (BSC). Environmental monitoring (EM) should be performed during setup activities.

A routine EM program with established methods, frequencies, and sampling locations should be in place to demonstrate control over the environment. EM during APS should include non-viable air, viable air, viable surface, and viable personnel.

Cell and Gene Therapy Products – Unique Considerations

Highly product-specific manufacturing processes with inherent variability:

Allogeneic versus autologous therapies
Cryopreserved versus fresh final product
Centralized versus near-patient manufacturing

Final product consists of viable cells or cell-derived matrices and is not amenable to final sterilization/filtration. Aseptic techniques are often required throughout the manufacturing process. Full test results may not be available before the final release.

Cryopreserved Product Versus Fresh Product

Cryopreserved product

Generally, a long product shelf life, but may require additional processing steps
May facilitate distribution, but requires cold-chain shipping logistics
Final container closure suitability and integrity must be demonstrated after exposure to cryo-conditions (closure might get adulterated due to lower temperature effect on closure material)

Fresh product

Generally, a short product shelf-life
The final product may be sensitive to shipping conditions
Full test results may not be available before release
Demonstration of asepsis during product transportation (e.g., leak-proof) can be part of the validation strategy

Applicable Regulatory Requirements

Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (statutory cGMP). Title 21 Code of Federal Regulations. Parts 210s -211s – cGMP for Finished Pharmaceuticals. Parts 600 - 610s – Additional biological products standards.^5-8

Guidance; Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing, Current Good Manufacturing Practice (September 2004).¹

EU EudraLex GMP Guide Part IV section, 9.5.2 - Aseptic processing validation. Describes in general terms some considerations for APS, referred to as ‘aseptic processing validation’. This supports reduced processing times for closed processes such as incubation, and the use of segmentation, it may be acceptable to split the process into key stages and use of bracketing. Section 9.5.2 also appears to support the use of alternative approaches to operator participation in a full process APS for qualification purposes. The manufacturer is required to consider the relevance of the aseptic process simulation testing for the training of operators.⁹

EU Eudralex GMP Guide Annex 1, Sections 9.32–9.49 - Aseptic process simulation (APS). Primarily focused on filling operations but includes sterile active substances. General requirements for process APS and qualification of personnel included. 9.39 states manual processes require qualifying three times for operators and twice per year thereafter with a batch size that mimics routine manufacturing.¹¹

ISO 18362 Manufacture of cell-based health care products - Control of microbial risks during processing, acknowledges the fact that not all starting material may no longer be sterile or sterilized when ATMPs are processed. To reflect on this, the concept of extrinsic versus intrinsic contamination is introduced. To challenge the aseptic processing capabilities of such starting material and processes, the simulation exercise is split in two parts. One part is the conventional APS test. This part will focus and challenge the process capability in preventing contamination from extrinsic sources (classic re-contamination challenge), while the other part is a process confirmation study to challenge potential intrinsic contamination sources. Depending on the starting material going into the process, one of the two or both types of studies might be required. For process simulation studies for process including non-sterile starting material, sterile surrogate needs to be used. For process confirmation studies, necessary for non-sterile starting material, the studies are to be done with the original material. With the selection of media for APS studies, ISO 18362 goes beyond conventional microbiological challenges. The media selected may need to include growth support for prokaryotic and eukaryotic cells. The simulation studies need to be designed on the basis of a related challenge rationale.¹⁰

ISO 13408–1; Primarily focused on healthcare products that are intended to be sterile, but sterilization of final product is not possible; therefore, aseptic processing is required to control all possible sources of contamination to maintain sterility of biological product or systems. ISO 13408 provides general requirements and guidance on processes, programs and procedures for the development, validation and routine control of the manufacturing for aseptically processed healthcare products.¹²

PDA Technical Reports, TR 22 addresses process capability assessment for aseptic formulation and filling activities. TR 28 addresses process simulations for sterile bulk pharmaceutical chemicals. General APS guidance beyond regulations, TR 22 covers more current APS expectations compared to TR 28.^13-14

Aseptic Processing

Aseptic Processing - “Handling sterile materials in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels”.¹³ Critical elements to successful aseptic processing:

Personnel performance (gowning and aseptic techniques)
Environmental quality and control
Validated cleaning and sterilization of container/closures, equipment, utensils, and product-contact surfaces

Where Does the Process Start and Where Does it End?

Define aseptic boundaries for the manufacturing process. Initial aseptic cell/tissue harvest? Transport to bedside? Know your process – aseptic processing begins when you need to maintain sterility from that point forward and ends when the container closure system containing the final product is closed. APS should be performed for aseptically produced vectors, biological matrices, or cell culture media which are not amenable to terminal sterilization/filtration.

Manual/Open Aseptic Processing

Detailed step-by-step instructions should be in place for consistent, repeatable manual operations. All open manipulations, any direct/indirect (e.g., fluid path) operator, equipment contact with the product should be simulated as closely as possible. Include representative or worst-case operations, conditions, and interventions to challenge routine manufacturing operations. Glove/ sleeve change requirements should be based on operation risk assessments and a simple “change as necessary” may not be sufficient. Equipment and material layout during processing should be as defined as possible to avoid crowding and interference with airflow and minimize clutter. When tissue is used to obtain cells, a suitable tissue surrogate based on attributes and availability may be used to facilitate process simulation. Duration of process simulation may be shorter duration than your process based on risk assessments to ensure the shortened time will be representative of the actual duration in terms of interventions and shift changes.

Automated/Closed Aseptic Processing

Closed processing using closed aseptic transfer technology. Less stringent environmental requirements (ISO 7/8) and reduced human interventions. Validation of closed systems and process steps – functionally “closed”:

Demonstrate integrity of closed production and aseptic interfaces between the unit systems throughout lifecycle of use and under full range of operating conditions
Recommend performing APS as part of the initial validation of closed systems

Aseptic Process Scale-Up/Scale-Out

Does the quality system have the capacity to support process scale-up/ scale-out for the manufacturing process: where are the bottle-necks?

Scalability by size/volume (scale-up)
Have the aseptic connections changed?
Has the mass transfer frequency increased?
APS may be required along with PPQ and media hold studies
Scalability by adding parallel processing culture systems (scale-out)
Simulation to demonstrate capacity is dependent on the risks of cross-contamination (e.g., facility design, HVAC coverage)
Define and test at maximum capacity

APS requirements and strategies during process scale-up/scale-out will be highly dependent on process-specific, facility-specific risk assessments.

Connecting OT and IT in Process Applications

Connecting operational technology (OT) with information technology (IT) in process applications offers many distinct advantages for processing plants. While technology has made the task easier, there are still challenges to consider. The following several best practices can save plant operators a lot of headaches down the road.

It is best practice for connecting OT and IT system integration software for real-time data communications and the interplay of OT and IT in modern plants.

The more important one is timely access to information. If you isolate IT and OT networks, you end up with communications between them being human-mediated. This means slow communications and incomplete information that’s prone to errors. There’s a real advantage to getting that information directly from OT into IT, and from IT back into OT. Obviously, for production planning, resource management, safety monitoring analytics, and fault prediction, not everybody needs real-time data, but there’s a big advantage to not having to wait until the end of a shift or the end of the day to gain production insights.

One of the rules of communicating between IT and OT is that the OT network should never have a direct Internet connection. This means you must route data through IT to get to some of the up-and-coming services such as artificial intelligence (AI) systems^15,16 that are cloud-based, or centralized monitoring where there are multiple, geographically diverse locations, centralized reporting, and aggregation of data from different sources. All these need a mechanism to get data out to those processing locations, but you don’t want that to be a direct connection out of OT.

This issue stands in the way when companies deal with the need to share data with third parties. They’ve got suppliers or customers, who want access to the real-time information coming off their processes, either for just-in-time supply or for insight into what the process is doing. Customers want to know what to expect. But they need a transmission path that isn’t exposed to the risks associated with the Internet.

There are three items that could be classified as availability, security and reliability. Availability is effectively the ability to provide data when it’s required in a form its consumers can use. This means designing networks that can deliver the data and choosing protocols that deliver it in a usable form.

The protocol you choose will affect the network topology. Or, if you have a certain network topology in mind, that’s going to limit the protocols you can choose. If you want a cloud service, it may expect a direct connection from OT into the cloud, which is not desirable and will impact security.

Security and availability are inversely correlated. The more available you want to make your data, the less secure it’s going to be and vice versa. So, you must adjust your availability requirements according to your security needs. When we look at something like industrial protocols, typically they’re not designed with the goal of sharing data across networks. They’re typically client/server designs, which are inappropriate when the server is in the protected network. You don’t want to reach into the OT network to collect data from a server. You are going to end up with a mix of protocols depending on the leg of the journey your data is taking. So, all the way from the PLC or DCS right up to a cloud or an analysis system, you may need different protocols for each segment of the path the data traverses.

Then there’s a reliability issue—preserving data during disconnections. If you lose a network connection or you have a hardware failure, you want to preserve as much data as you can during that time. That typically means you want to have store-and-forward capability for data, so you can deal with a network loss. Redundancy is required, so you should have multiple data paths. If one path goes down, the other is available.

Once again, the choice of protocol determines how much redundancy or what sort of store-and-forward you can offer/afford. That again, limits the protocol choices. If you rely on a particular vendor’s redundancy solution, e.g., it may limit your security capabilities or your network topology.

IT and OT should treat one another as hostile. It doesn’t mean there’s hostility between the two teams. People can get along well, but the networks shouldn’t. There shouldn’t be an opportunity for one network to compromise another due to an entry point between them. They should be entirely distinct from one another. No program should be able to connect from one network to the other.

To achieve this, you’ll have to set up a mechanism that stands between the two networks. A network with a neutral territory zone for safety and security is a common approach. Some people say, ‘We only open one port.’ This has been said many times, and it really misses the point. It’s not firewall ports that are attacked during an attempted compromise on a network. It’s the software that runs on that port. It doesn’t matter who you are or what your development team is like, there is always an exploit. The only way to protect yourself from exploitation through an open firewall port is not to have an open firewall port.

Concepts, Principles, and Regulatory Expectations

Number and Frequency of APS

The number and type of APS should be based on a Risk Assessment of the aseptic process and qualification/validation of a new facility or new production process. APS is performed after facility, process, equipment, facility decontamination, personnel training, room qualification, and EM program implementation is complete. APS is one of the last steps in the qualification/validation process. Typically, a minimum of three (3) APS are a regulatory expectation. Semi-annual APS are a regulatory expectation for a qualified line/ process. If there are major changes to the facility or aseptic process – perform a Risk Assessment to determine if APS is needed and how many.

Risk Assessment and Worst-Case Scenarios

Definition of Risk - a combination of a hazard and its likelihood of occurring and harming the patient. In aseptic processing, this is a loss of sterility assurance. Risk assessment can be used to determine the worst-case manufacturing scenarios using a holistic approach:

Operating conditions-including personnel
Interventions
Container closure – size and configuration
Line speed
Batch size

The Risk Assessment should be documented and used as the basis for the design of the APS study.

Study Design

An APS study program should incorporate the contamination risk factors that occur on a production line, and accurately assess the state of process control. APS studies should closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case activities and conditions that provide a challenge to aseptic operations. FDA recommends that the APS program address applicable issues such as:¹

Aseptic Compounding

The entire aseptic compounding process should be simulated including all aseptic additions. APS can be stand alone for the compounding step or integrated with filling.
Filling
Longest duration of run on an aseptic processing line.
Interventions – inherent (routine) and corrective (non-routine)
Aseptic assembly-line set up
Number of personnel – duration and activities, shift changes, breaks
Number of aseptic additions/transfers
Connections/disconnections
Processes such as Lyophilization
Line speed and configuration
Container closure types/systems
Inert gassing
Number of units filled
Frequency and number of runs

Documentation

Documentation of every step of the APS is very important. The documentation will serve as record of the rationale for APS design and its performance. Documentation should include step by step instructions of the performance of the APS, acceptance criteria, all results obtained, any deviation.

An aseptic simulation policy/procedure should be prepared which gives an overall comprehensive list of requirements and rationale for APS studies. The following documentation procedure is recommended.

Protocol

An approved APS protocol should be in place prior to starting the study. Information/instructions in the protocol should include at a minimum:

Responsible groups for execution, testing
Rationale for “worst case” scenarios
Identification of room, filling line, equipment, process flow.
Types of container closure to be used
Fill volume
Minimum number of units to be filled and rationale
Line speed(s)
Type of media to be used with rationale
Number and types of interventions
Number, identity and roles of personnel
Environmental monitoring to be performed
Accountability of units filled
Incubation conditions and durations
Inspection of units – pre-incubation, post incubation and intermediate
Acceptance criteria
Conditions of exclusion of vials from incubation (this should be rare)
Growth promotion
Conditions for invalidating/cancelling – decision making authority
Personnel training requirements
Details about batch record to be used
Documentation requirements for the final report

Batch Record

A detailed batch record (BR) written in the same format as the production BR with the same data recording and verification/sign off requirements should be in place.

An additional section detailing the step-by-step performance of the Interventions should be a part of this BR. All interventions performed (planned and unplanned) with details such as time, operators involved, duration, the identity of the tray filled, any line stoppages, sample units removed, should be clearly documented. All results should be a part of the batch record including:

Environmental and personnel monitoring results
Number of units filled, number of units incubated, full accountability
Number of units rejected pre-incubation with cause for rejection
Results of inspection – number of units positive for growth, tray identity, detailed investigation with root cause and corrective/ preventive actions
Growth promotion of media after incubation
Record of activities and occurrences during the APS
Any deviations/OOS
A Final Report which evaluates the entire aseptic process simulation and formulates a conclusion on the acceptability of the APS is required.
Quality unit oversight of the entire process including observation in real-time

Points to Consider for APS

Number of APS – for new line/process a minimum of three (3) APS are required. For ongoing requalification – minimum semi-annual. If different processes are performed on the same line, each process has to be re-evaluated semi-annually.

Container closure – if multiple sizes of containers of the same type and in same process are used, a bracketing approach (smallest-largest) may be used.

Filling speed-generally should be set at the production filling range. However, if higher or lower speeds present “worst case” conditions those may be used. For example, the bracketing approach of the highest speed with the smallest unit (operational challenge-PM generation) or the slowest speed with the largest vial (larger neck size – maximum exposure) may be used.

Fill volume- container need not be filled to full capacity. The amount of media should be sufficient to contact all container–closure surfaces when inverted and allow for the detection of microbial growth.

Media used – the most common medium used is Soybean Casein Digest Medium (SCDM). This medium is capable of supporting the growth of aerobic microorganisms commonly found in the clean room environment and personnel samples. If the process being validated is anaerobic then Fluid Thioglycolate Medium (FTM) may be used.

Inert gassing – Typically nitrogen or other inert gases are used to protect oxygen-sensitive products and also to provide positive pressure for transfer. For APS the nitrogen should be replaced by air using the same method of delivery and at the same steps.

Duration and Number of Units Filled

The duration should simulate the longest fill or be representative of routine operations. The duration should be sufficient to allow all interventions and process steps to be executed. Number of units filled during APS should be based on contamination risk and sufficient to simulate the process. Generally, 5,000-10,000 units are considered acceptable for average production runs.¹

For production batches less than 5,000 units, the APS batch should be equal to the production batch size.
For production batches of 5,000 to 10,000 units, the APS batch should be comparable in size (5,000-10,000 units).
For production batches >10,000 units, the APS batch should be > 10,000 units with several approaches to the batch size and filling process.

Interventions

Activities performed by personnel in proximity to the aseptic fill zone are called Interventions. Some of these are unavoidable and part of the process. However, Interventions in aseptic processes should be kept to a minimum. The Risk Assessment performed should be used to record and evaluate the contamination risk posed to the product due to each intervention.

Identification of Interventions- the type and frequency of each intervention must be identified. Hence a list of interventions with the frequency of occurrence is to be maintained and re-evaluated.
The interventions are grouped into two categories – inherent (routine) and corrective (non-routine).

Inherent (routine) Interventions

These are normal planned activities that occur during an aseptic filling process. Some examples are:

Equipment set up – aseptic assembly
Fill weight checks and adjustments
Recharging stoppers and other closures
Environmental Monitoring sampling
Shift changes, breaks, duration of personnel activity

Corrective (non-routine) Interventions

These are performed to correct an aseptic process during execution. They are not a part of the normal aseptic process but they are well defined and recognized as occurring on infrequent occasions.

Some examples:

Container breakage and picking up fallen units
Correcting stopper jams
Changing out filling needles or equipment
Pulling samples
Clearing rejected units
Maintenance work – line stoppage
Changing out of filters, tubing, and pumps

List and Process for Interventions

There should be an approved list of interventions. This list is to be re-evaluated at predetermined intervals or if any unusual events occur during production runs.

There should be established procedures that describe how to perform these interventions. Only personnel trained/qualified in the interventions should be permitted to perform them. During an APS these interventions should be incorporated to represent the type and frequency of each type on the approved list. During routine production operations, any interventions performed should be documented and frequency noted. If any unusual interventions are performed, they should be evaluated and a Risk Assessment performed as necessary. Based on the risk/evaluation they should be incorporated into the approved list of interventions for APS.

Process Qualification

Lyophilized Products – most are aseptically filled and then transferred to a pre-sterilized lyophilization chamber and subject to lyophilization. The process of loading the partially stoppered units into the lyophilizer, the lyophilization process, and the final unloading of the chamber must be captured during an APS. This can be done as follows:

Load /unload with shortened hold time and partial vacuum.
Simulated lyophilization- where the units are held under partial vacuum for the full duration of the cycle.
In both cases sterile air is used to vent the chamber instead of nitrogen.
APS is used to qualify and requalify the aseptic steps of the lyophilization process

Personnel Qualification

The requirements and the process for the qualification of personnel should be documented in a procedure and results documented and records maintained per each person.

Pre-requisite – all relevant training such as gowning qualification, clean room and aseptic behavior training, GMP training, and procedure training.

Initial Qualification- Personnel should participate in a successful APS in which they perform activities which they would normally perform. Periodic Qualification- Personnel should participate in a successful APS in which they perform activities which they would normally perform once per year at a minimum. Disqualification can occur if the personnel fail to participate in periodic qualification, fail gown certification repeatedly, or participate in a failed APS whose failure was directly attributed to their poor aseptic technique.

Pre-Incubation Inspection

After the completion of the filling and sealing process, the exact unit count is recorded and verified. The units are subject to pre[1]incubation inspection. The purpose is to remove all non-integral units which would have been removed during normal product inspection. Once again count of units proceeding for incubation is documented and verified.

Some examples of units that may be removed are units with cracks, misaligned or missing stoppers, and poor crimps- units with compromised container closures. These would also be removed during a routine inspection of the product. No unit may be removed due to cosmetic defects. The number of units removed and the cause should be documented and verified.

Incubation Conditions

Incubation conditions should be suitable for the recovery of bioburden and environmental isolates. It should be in the range of 20-37°C. Incubation time should be no less than 14 days. A single incubation temperature for 14 days or two temperatures for seven days each may be used. If two incubation temperatures are used it is recommended to start incubation at the lower temperature. Prior to the start of incubation, all units should be inverted or manipulated so that the media comes into contact with all internal surfaces.

Post–Incubation Inspection

After completion of incubation, all APS units are inspected visually for the presence of microbial growth. Personnel trained to detect low/high levels and different types of microbial growth should perform the inspection. The count of units is performed and verified after inspection. If non-integral units are found an investigation should be performed as these should have been detected during pre-incubation inspection. All these activities should have the oversight of the Quality unit. Growth Promotion should be performed after the final inspection.

In addition to ATCC cultures, the most common environmental isolates should be used.

Acceptance Criteria

The target acceptance criteria for the APS study is zero contaminated units. Per FDA Guidance for Aseptic Processing.

When filling < 5000 units

One contaminated unit is cause for revalidation

When filling 5000 to 10,000 units

One contaminated unit – investigation and possible repeat aseptic process simulation
Two contaminated units- revalidation following an investigation

When filling > 10,000 units

One contaminated unit – investigation
Two contaminated units- revalidation following an investigation

Investigation of an APS Positive/Contamination

A thorough investigation should be performed and documented with root cause and corrective/preventive actions clearly identified. At a minimum, the investigation should include the following:

Species-level identification of the contaminant and comparison to EM/personnel isolates
Holistic look at all systems and engineering controls
Environmental trend and recovery review
Personnel activities and qualification
Sanitization process review
Review of batch records, sterilization processes, and any deviations
Tracing the location of the contaminant and correlating it to any interventions
Trend review of previous APS

References

FDA Guidance for Industry- “Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practices.” September 2004. Guidance for Industry (fda.gov)
PDA Technical Report No. 22 – “Process Simulation for Aseptically Filled Products.” 2011.
GUIDELINES, The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1 Manufacture of Sterile Medicinal Products; Brussels, 22.8.2022. 20220825_gmp-an1_en_0.pdf (gmp-compliance.org)
FDA GUIDANCE DOCUMENT, Aseptic process simulation s for Validation of Aseptic Preparations for Positron Emission Tomography, APRIL 2012, Aseptic process simulation s for Validation of Aseptic Preparations for Positron Emission Tomography | FDA
21 CFR Part 210, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part 210 -- Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
21 CFR Part 211, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part 211 -- Current Good Manufacturing Practice for Finished Pharmaceuticals
21 CFR Part 600-610s, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part 600 -- Biological Products: General
8. TITLE 21--FOOD AND DRUGS, CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER C - DRUGS: GENERAL, Section 501(a)(2) (B), Jun 07, 2023; CFR - Code of Federal Regulations Title 21 (fda.gov)
EudraLex GMP Part IV section, 9.5.2, 2017_11_22_guidelines_gmp_for_atmps_0.pdf (europa.eu).
ISO 18362:2016, Manufacture Of Cell-Based Health Care Products - Control Of Microbial Risks During Processing, first edition 2016-02-01; ISO 18362:2016 - Manufacture of cell[1]based health care products - Control of microbial risks during processing (ansi.org).
EU GMP, The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, 22.8.2022; 20220825_gmp-an1_en_0.pdf (europa.eu).
BS EN ISO 13408-1:2015, Aseptic processing of health care products General requirements; 2015-08-31; BS EN ISO 13408-1:2015 Aseptic processing of health care products General requirements (en-standard.eu).
PDA Technical Report No. 22, (TR 22) Revised December 2011 Process Simulation for Aseptically Filled Products.
PDA Technical Report No. 28 Revised September 2006, (TR 28) Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals.
Stuart Russell, Peter Norvig, Artificial Intelligence a Modern Approach, Fourth Edition, Pearson, 2022.
Johannes Ernesti, Peter Kaiser, Python 3 - the Comprehensive Guide; Rheinwerk Computing, 2022, Boston, MA.

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