Developing Safe and Effective Cell Therapies

Special Topic on Deep Interpretation of GMP Product Quality Scan the QR code to download this resource Topic 1 Controlling External Contaminants In the Produc�on of Cri�cal Materials for CGT Topic 2 Asep�c Protec�on Strategies for Cri�cal Material Produc�on in CGT P1 P5 Topic 5 Regulatory Compliance for Cri�cal Materials in CGT Topic 3 Quality Control System for Cri�cal Materials in CGT Topic 4 Global Supply Chain Security System for Cri�cal Materials in CGT P9 P17 P13 Cell and gene therapy is a revolu�onary treatment modality that u�lizes gene-engineered cells to combat cancer, leading a new driving force behind innova�ve medical treatments. Manufacturing cell therapies has been a significant obstacle due to the wide array of guidelines and safety requirements set by regulatory bodies across the globe. In par�cular, qualifica�on of both raw materials and suppliers is cri�cal to ensure development of a safe and effec�ve cell therapy. Herein, we discuss in-depth research about the global regula�ons and standards related to raw materials in the CGT industry, emphasizing on asep�c assurance, quality control, global supply chain, and customs declara�on requirements. The core of our products and quality management system stems from these regula�ons and standards, and is con�nuously monitored to ensure our products are compliant with new regula�ons. Learn more about what goes into GMP-grade raw materals and how our raw materials and support can help facilitate cell and gene therapy clinical manufacturing and applica�on declara�ons. Explore our GMP products Request free samples Topic 1: Controlling External Contaminants In the Produc�on of Cri�cal Materials for CGT The quality of materials and reagents u�lized in the produc�on process of Cell and Gene Therapy (CGT) plays a pivotal role in determining the ul�mate product quality and therapeu�c safety. This is par�cularly crucial in safeguarding against exogenous contamina�on, which encompasses inadvertent introduc�on of contaminants like bacteria, fungi, mycoplasma, and viruses into raw materials, cell substrates, and produc�on products Generally, sponsors should ensure appropriate quality control of materials and reagents to mi�gate unreasonable risks to subjects or pa�ents, such as implemen�ng steriliza�on or sterility tes�ng to ensure the absence of microbial and viral contaminants. Stringent quality control of raw materials used in CGT produc�on is a necessary measure to reduce the risk of exogenous factor contamina�on in CGT final products and ensure the safety and efficacy of CGT products. All these three regulatory documents men�oned the safety of raw materials and emphasized the importance of safety. Our GMP-grade products have been designed and developed with a comprehensive considera�on of safety, including the To ensure the safety of upcoming therapeu�cs, regulatory agencies across the globe have established relevant requirements regarding the safety of raw materials used in CGT produc�on. In par�cular, the FDA recommends the use of readily available and feasible materials and reagents of the highest quality for CGT produc�on. These materials and reagents are o�en labeled as "GMP-grade" or claimed for use in cell therapy produc�on. Key regulatory documents include: (1) The "Content and Review of Chemistry, Manufacturing, and Controls (CMC) Informa�on for Human Soma�c Cell Therapy Inves�ga�onal New Drug Applica�ons" issued by FDA in April 2008. (3) EP 5.2.12 "Raw Materials of Biological Origin for the Produc�on of Cell and Gene Therapy Medicinal Products". 1. The cell line used for produc�on is well-documented and traceable to ECACC as the source. 2. The produc�on host cells, HEK293, a�er domes�ca�on and establishment, undergo comprehensive tes�ng (26 items). 3. The engineered cells undergo further tes�ng a�er the construc�on of the cell bank. The tes�ng, conducted by a well-known domes�c third-party tes�ng organiza�on, includes sterility, mycoplasma, cell morphology, different indicator cell inocula�on methods in vitro, retrovirus and exogenous virus detec�on, among others. 4. The upstream cell culture stage uses a chemically defined medium (CDM) as a well-defined culture medium. All materials used in the upstream produc�on process are serum-free (SF) and animal-origin-free (AOF). Cell recovery and amplifica�on are performed in a Class C clean area biosafety cabinet (BSC). The reactor produc�on stage u�lizes disposable closed systems and asep�c welding technology. Different stages of produc�on are separated to minimize the risk of contamina�on and cross-contamina�on. 5. During downstream purifica�on process design, virus removal/inac�va�on steps such as low pH treatment and nanofiltra�on are introduced. Viral removal process valida�on is also conducted (in progress) for cri�cal steps. The purifica�on process u�lizes project-specific separa�on columns and chromatographic media to avoid cross-contamina�on risks between different produc�on stages. The tes�ng is conducted by an interna�onally renowned third-party tes�ng organiza�on, in accordance with the following regula�ons: •ICH Q5 Part III: Cell Line Characteriza�on: viral tes�ng. •FDA's "Points to Consider in the Characteriza�on of Cell Lines Used to Produce Biologicals" (1993), specifically the "V. QUALITY CONTROL TESTING" sec�on. •FDA's "Characteriza�on and Qualifica�on of Cell Substrates and Other Biological Materials Used in the Produc�on of Viral Vaccines for Infec�ous Disease Indica�ons" (2010). (2) USP <1043> "Ancillary Materials for Cell, Gene, and Tissue-Engineered Products". Introduc�on 02 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com control of exogenous factor contamina�on throughout the en�re produc�on and quality control process. Here are the key aspects: 6. The formula�on produc�on is carried out in a strict Grade B+A produc�on environment. A�er sterilizing filtra�on, the semi-finished product is processed using fully automated equipment and a single-use sterile filling system. Opera�ons such as asep�c component assembly, filling, stoppering, automa�c infeed and ou�eed, and lyophiliza�on are performed in a B+A-grade clean environment (monitored using PMS con�nuous environmental monitoring system). A�er lyophiliza�on, vials are sealed in a Grade C+A environment. The finished products undergo manual inspec�on, labeling, and other opera�ons before being released a�er passing the quality inspec�on. 7. Strict asep�c process valida�on includes regular confirma�on of asep�c process control, including the use of asep�c nutrient media and/or product subs�tutes in APS (media simula�on containers). APS evaluates all asep�c opera�ons conducted from steriliza�on and cleaning of process materials to container sealing. Various known asep�c opera�ons and interven�ons under normal produc�on and worst-case condi�ons are considered. 8. Raw materials and packaging materials used for produc�on are selected from pharmaceu�cal-grade raw materials. For materials used in GMP product produc�on, they undergo joint evalua�on and classifica�on by research, produc�on, and quality teams. Key materials comply with the requirements of relevant regula�ons and pharmacopoeias, and their quality standards are established through cri�cal characteriza�on analysis. The material management process is as follows: The following regula�ons provide guidance on viral safety: •Viral Safety Evalua�on of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. 1999. Interna�onal Conference on Harmoniza�on（ICH）Q5A（R1）. •Guideline on Virus Safety Evalua�on of Biotechnological Inves�ga�onal Medicinal Products. EMEA /CHMP / BWP / 398498 / 2005. European Medicines Agency (EMA). 2009. •Viral Safety Evalua�on of Biotechnology Products Derived from Cell Lines of Human or Animal. USP General Chapters: <1050>. - Reference regula�on: •EU GMP Annex 1. 03 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com 9. Our GMP-grade products are not only produced under a pharmaceu�cal-grade manufacturing plant but are also designed and controlled under relevant domes�c and interna�onal CGT regula�ons. Taking the GMP-grade IL-15 as an example, our final product quality control release includes the followings: ACROBiosystems strictly controls poten�al exogenous factors throughout the en�re process of development, produc�on, quality tes�ng, and quality system, ensuring the safety of our products. We are commi�ed to developing high-quality reagents for clinical use in cell and gene therapy and combining drug produc�on standards with stricter quality management and release tes�ng standards to provide customers with be�ersafer GMP grade products! GMP Product Quality In-Depth Interpreta�on Special Series Trailer is Here! •Controlling external contaminants in the produc�on of cri�cal materials for cell and gene therapies. •Asep�c Protec�on Strategies for Cri�cal Material Produc�on for CGT •Quality Control System for Cri�cal Materials in CGT •Global Supply Chain Security System for Cri�cal Materials in CGT •How to Be�er Meet Regulatory Requirements of the United States for Cri�cal Materials in CGT •... •SDS-PAGE>95% •Endotoxin level less than 10 EU/mg •Residual Host Cell DNA content less than 0.02ng/μg •Residual Host Cell Protein content less than 0.5ng/ug •Biological ac�vity >0.8 x 107 IU/mg (Reference the WHO Human IL-15 (NIBSC code: 90/530) as standard) •Microbial tes�ng •Mycoplasma tes�ng •In vitro virus assay •Batch-to-batch consistency •Comprehensive stability data support (accelerated, freeze-thaw, long-term, shipping stability verifica�on) 04 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com >>> If a Supplier Survey or Quality Statement is required, please contact us. quality@acrobiosystems.com Scan the QR to explore our products and request free samples! Request a Custom Protein Topic 2: Asep�c Protec�on Strategies for Cri�cal Material Produc�on in CGT Given the asep�c nature of cell therapy product produc�on, it is impera�ve that the raw materials used in the process be sterile. The failure to ensure sterility represent a cri�cal setback in cell therapy product manufacturing, leading to the inability to deliver drugs that meet quality requirements to pa�ents in a �mely manner. Hence, sterility stand out as is a pivotal quality a�ribute for raw materials in the context of cell therapy. The asep�c control strategy employed during the raw material produc�on process assumes heightened signficance, especially for the produc�on processes of cytokines, an�bodies, and enzymes. These processes o�en entail non-terminal steriliza�on processes. Conduc�ng a thorough risk assessment is cri�cal to iden�fy poten�al sources of microbial contamina�on . The assessment should encompass a comprehensive examina�on of various factors, including, but not limited, to the facility, equipment, process design, material handling, personnel requirements, produc�on opera�ons, and environmental monitoring. Subsequently, it is essen�al to formulate targeted control measures to enhance both produc�on management and quality control. In this context, asep�c control strategies are subject to strigent standards set forth by various Good Manufacturing Prac�ce (GMP) regula�ons and guidelines across different countries. The industry consistently adheres to a set of commonly recognized GMP regula�ons and guidelines, encompassing: 1.European Union Good Manufacturing Prac�ce (EU GMP) Annex 1: Manufacture of Sterile Medicinal Products 2.United States FDA current Good Manufacturing Prac�ce (21 CFR Part 210, 211, 600) 3.FDA Guidance for Industry: Sterile Drug Products Produced by Asep�c Processing 4.PIC/S GMP Annex 1: Manufacture of Sterile Medicinal Products Regulatory Guide Requirements ACROBiosystems’ Asep�c Protec�on Strategies The cri�cal role of sterile raw materials in cell therapy Among them, the new version of Annex 1 of EU GMP, which was introduced on August 25, 2023, has the most stringent requirements for the produc�on of sterile products. The regula�on specifically covers ac�ve pharmaceu�cal ingredients, excipients, primary packaging materials, finished dosage forms, as well as various packaging sizes, produc�on processes, and technologies. Meanwhile, the regula�on provides general guidance on the overall design and control of facili�es, equipment, systems, and procedures used for the produc�on of all sterile products, following the principles of quality risk management (QRM). The aim is to ensure the absence of microorganisms, par�cles, and endotoxin/pyrogen contamina�on in the final product. The guidance emphasizes the overall assessment and contamina�on control from aspects such as facility, equipment, process, material, tes�ng, and environmental monitoring. ACROBiosystems ensures the compliance of its GMP-grade cell therapy products with the aforemen�oned regulatory and guidance standards. Employing an integrated approach, the company me�culously designs and incorporates asep�c control strategies for facili�es, equipment, materials, processes, and personnel. Con�nuous refinement and enhancement are integral to ACROBiosystems' commitment to quality assurance, facilitated by the systema�c applica�on of PDCA (Plan-Do-Check-Act) tools. 06 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com 1. Facili�es and Equipment The produc�on facility, u�li�es, and equipment adhere to strigent GMP regula�ons. Prior to ini�a�ng product produc�on, a comprehensive gap analysis and risk assessments are conducted for each facility and piece of equipment. Wri�en procedures are developed and strictly enforced, covering areas such as usage, cleaning, disinfec�on, and maintenance. These measures ensure that the management of these infrastructure is executed with precision, preven�ng any adverse impact on asep�c control. 2. Personnel Management Personnel engaged in produc�on and quality management ac�vi�es possess the requisiteeduca�onal background, training, and experience to uphod both the standard of produc�on and effec�ve control of contamina�on and cross-contamina�on.This commitment to personnel qualifica�on ensures a seamless and reliable execu�on of tasks cri�cal to maintaining the integrity of the produc�on process. 3. Material Management Raw and auxiliary materials used in produc�on are preferably sourced as pharmaceu�cal-grade materials, including packaging materials. Stringent supplier management prac�ces are implemented through processes such as qualifica�on collec�on, on-site audits, etc.Quality control strategies are thoughfully formulated based on comprehensive risk assessment, par�culary in the realm of microbiological control, ensuring the integrity of the materials used in the produc�on process. 4. Produc�on Process and Quality Control Produc�on Environment Solu�ons and Process Gases Single-Use Consumables Raw Material Prepara�on: ISO Class C and A Drug Product Produc�on: ISO Class B and A Dynamic environment monitoring 0.1μm / 0.22μm sterilizing filtra�on Drug product produc�on with secondary sterilizing filtra�on Integrity tes�ng before and a�er filter use Process Control Equipment Control Cleaning processes and cleaning confirma�on for reusable equipment Disinfectant efficacy verifica�on Microbial limits control for raw materials Sterility tes�ng of products complies with USP Cleaning and Disinfec�on Quality Control Asep�c connec�ons Bacterial endotoxin control Asep�c process simula�on filling Gamma irradia�on steriliza�on Integrity check before use Upstream Cell Cul�va�on: In the cell culture produc�on phases, strict regula�on govern personnel gowning and behavior requirements to minimize contamina�on risks from opera�ons. Cell recovery and flask expansion stages are conducted in a Class C clean area as the background environment.Open opera�ons are performed in a Class A biosafety cabinet under laminar protec�on withdynamic environmental monitoring occuring simultaneously. Key points for asep�c control in the produc�on process include: 07 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com To ensure asep�c condi�ons, reactor expansion and perfusion culture stages incorporate disposable closed systems, employing sterile welding technology for process like inocula�on, feeding, and other processes to effec�vely avoid microbial contamina�on. During the cell culture stage, materials used undergo rigorous endotoxin control and are only used a�er passing stringent quality release criteria. The prepara�on of culture media and solu�ons adheres to the pharmacopoeial requirements for injec�on water. A�er prepara�on, the solu�ons are sterilized by passing through 0.1μm/0.22μm filters, and the integrity of the filters is tested. Simultaneously, sterility tes�ng is performed, and solu�ons can be proceed to cell culture produc�on only if both tests yield sa�sfactory results. Gases used in the process, such as carbon dioxide, oxygen, and compressed air, maintainhigh-purity or food-grade standards. Process gases connected to the reactor undergo effec�ve steriliza�on by passing through a 0.22μm filter. Disposable consumables, including reac�on bags and storage bags, undergosteriliza�on by radia�on to ensure sterility, ensuring that materials in direct contact with the liquid remain uncontaminated by microorganisms. Deep filtra�on membranes used for clarifica�on filtra�on are for single use. Before use, membrane packages are rinsed with injec�on water to remove impuri�es contained in the membrane packages. Following clarifica�on filtra�on, the liquid undergo a second filtra�on through a 0.22μm filter to effec�vely reduce microbial load before entering downstream purifica�on processes. Prior to transi�oning to downstream purifica�on, the harvested clarified liquid undergoes endotoxin tes�ng to ensure the intermediate product meets the process requirements. 08 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Topic 3: Quality Control System for Cri�cal Materials in CGT In recent years, the biopharmaceu�cal industry has witnessed a remarkable growth, with cell and gene therapy emerging as a pivotal sector amidst the con�nuous technological advancements. As biologics capture a larger share of next-genera�on medicine, ensuring these biological medicines are safe has become the utmost priority. This brings further scru�ny not only to the final cell and gene therapy, but also to the raw materials used during manufacturing and produc�on. This has been further underscored by the FDA emphasizing the use of ‘the highest quality’ materials suitable. Similarly, the Interna�onal Pharmaceu�cal Regulatory Plan Cell Therapy Working Group dra�ed a delibera�ve document dissemina�ng their perspec�ve on using high quality raw materials in manufacturing and licensed human CGT products. With regulatory bodies emphasizing the use of ‘high quality’ raw materials, what does this mean for cell therapy manufacturers? Evalua�ng raw material safety is defined through various contaminant controls and detec�on strategies to limit any residues that could cause harm or affect the final therapeu�c. This includes sterility tests, evalua�ons of contaminants such as endotoxins, mycoplasma, residual host cell DNA, and residual host cell proteins. • USP <71> Sterility Tests Ensuring the sterility of final cell and gene therapies is tricky. Since the final therapeu�c is cells, there is no easy method such as sterile filtra�on, autoclaving, etc. Thus, manufacturers must be very careful throughout the manufacturing process to ensure sterility of the final product. This applies to the raw materials used as well, requiring manufacturers to evaluate suppliers stringently. As such, raw materials suppliers for GMP-grade manufacturers including ourselves, are expected to control cytokines and other growth factors stringently, incorpora�ng automa�c fill-finish in B+A cleanrooms, online environmental monitors, and USP-compliant sterility tests. Thus, evalua�ng for sterility of raw materials is the primary methodology to ensuring sterility of the final therapeu�c. For more informa�on, read our Special Topic on Deep Interpreta�on of GMP Product Quality – Topic 2. • USP <85> Endotoxin Tests Endotoxins are toxins present in bacterial cells that are released a�er cell disintegra�on which can some�mes lead to diseases such as botulism. Maintaining a low endotoxin level in biologics is essen�al for ensuring pa�ent safety and preven�ng endotoxin-related diseases. Several methods are acceptable: qualita�ve gel clot and chromogenic LAL-based methods. In short, cell therapy manufacturers must do their due diligence in ensuring the quality of their raw materials, whether it comes from a supplier or developed in-house. Evalua�ons on quality control methods and standards for relevant raw materials including cytokines and other growth factors, are a necessary step within an inves�ga�onal new drug (IND) applica�on before proceeding with clinical research. These methods and standards are derived from several sources. Pharmacopeial methods, derived from organiza�ons such as USP or the European Directorate for the Quality of Medicines & Healthcare (EDQM) are standardized approaches that establish a fundamental requirement for produc�on and release. Non-pharmacopeial methods, such as the Interna�onal Conference on Harmoniza�on (ICH) documents, are supplemental analy�cal approaches tailored towards evalua�ng specific characteris�cs of a product and its manufacturing process. Many commercial products are currently marketed to follow these standards, commonly labeled ‘GMP-grade’ or Raw Material Safety Ensuring Quality in Cri�cal Raw Materials Introduc�on ‘cGMP-grade’. However, products that comply with the stated standards are o�en self-regulated. As such, responsibility s�ll falls upon cell therapy manufacturers to perform due diligence, which can make it difficult to find a trustworthy supplier. Herein, we highlight the three main aspects of a GMP-grade raw material quality control system that are cri�cal towards mee�ng IND requirements and successfully moving into the clinical phase. 10 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com • USP <63> Mycoplasma Tests Mycoplasma is a common contaminant in cell and �ssue cultures that results in the altera�on of cellular growth and phenotype. Tes�ng for mycoplasma is cri�cal in ensuring reliability in biologics and its raw materials. When evalua�ng mycoplasma, the gold standard remains as the culturing method, monitoring for growth of typical mycoplasma colonies on solid media. Other validated methodologies include the use of fluorescent dyes to highlight characteris�c par�culates or filamentous pa�erns on the cell surface. Although nucleic acid amplifica�on techniques or enzyme ac�vity-based methods can also be used, suitable valida�on and comparisons between methodologies to cell culture must also be addressed. • USP <509, 1132> Residual Host Cell DNA and Proteins Host cell DNA and protein are other factors that must also be controlled to acceptable levels to avoid any safety risks. Foreign DNA and protein are suscep�ble to causing immunogenic and oncogenic reac�ons that could cause more harm. Ensuring that these impuri�es are removed in any raw materials and subsequent manufacturing processes is crucial to pa�ent safety. Of course, as with any tes�ng or analy�cal method, valida�on is necessary to ensure that the tests used are accurate. The USP documents referenced above provide assay protocols and clear criteria for evalua�ng tests that are standardized across biologic materials. However, when it comes to material-specific assessments such as bioac�vity, analy�cal methods must first be validated, most commonly following ICH Q2 (Revision 1), �tled “Valida�on of Analy�cal Procedures Text and Methodology”. Depending on the type of assay to be validated, certain characteris�cs are generally assessed, as listed in Table 2. This includes specificity, accuracy, precision, detec�on limit, quan�ta�on limit, linearity, and range. For example, to determine cytokine concentra�on, we establish different assay methods, such as US-Spectrophotometric assay and the Lowry method. Each of these methods are fully validated in accordance with USP and ICH Q2 guidelines. To further validate the UV-spectrophotometric assay, a secondary confirmatory method, the Lowry method, was used. As a mature, well-established methodology, the Lowry method provides a solid founda�on for comparison. Thus, direct comparisons of the quan�ta�ve result of six different spiked samples ensure the accuracy and reliability of a UV method, shown in Table 4. Analy�cal Method Valida�on for Quality Table 1. Endotoxin Sample Curve Evaluation Table 2. Validation Characteristics for Consideration Theore�cal value Detected value Recovery rate 50 EU/ml 55.04 EU/ml 113.0% 5 EU/ml 5.96 EU/ml 104.7% 0.5 EU/ml 0.6 EU/ml 108.5% 0.05 EU/ml 0.06 EU/ml 108.0% Table 3. Validation of UV-Spectrophotometric Assay Method Valida�on Accuracy Repeatability Result Recovery Rate: 96% RSD：0.05% Criteria Recovery Rate: 90%-108% RSD≤3% Conclusion Pass Pass Robustness RSD：0.04% RSD≤3% Pass Linearity R2：0.99925 R2>0.999 Pass Range 0.0452-0.452 mg/ml 0.0452-0.452 mg/ml Pass Intermediate Precision RSD：0.48% RSD≤3% Pass Table 4. Secondary Confirmation Assay – Lowry Method Method Valida�on Lowry 461 ug/ml 476 ug/ml UV Method 436 ug/ml 436 ug/ml Conclusion 472 ug/ml 436 ug/ml 468 ug/ml 436 ug/ml 461 ug/ml 435 ug/ml Quan�ta�ve Result 465 ug/ml 436 ug/ml Pass However, if there are any inconsistent or conflic�ng results, the gel clot result is deemed authorita�ve. Internally, we u�lize a LAL method calibrated against USP Reference Standard endotoxin calibrants to ensure accuracy with sample results shown in Table 1. Subsequently, to ensure endotoxin tes�ng method is valid, preparatory tes�ng as outlined in USP <85> was performed, with an acceptable endotoxin recovery rate defined as being within the range of 50 to 200%. 11 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Wrapping-up GMP-grade Quality Control Systems Quality control evaluations generally opt for more mature and sensitive that meets specified requirements. Due to the potential limitations in analytical methods, it is advisable to consider utilizing simultaneous complementary methods to comprehensively evaluate not only raw materials, but also the final therapeutic. The analytical methods themselves also need to undergo rigorous validation. A well-established, stringent, and professional quality control system can be what makes-or-breaks any therapeutic approval process and should reference pharmacopeia standards such as USP. Thus, the international perspective on pharmaceutical quality management has evolved from drug quality controlled through inspection" to "drug quality is achieved through process control in production" and finally to, "drug quality is produced through good design (Quality by Design, QbD)." Embracing this QbD philosophy implies establishing a correlation between product quality attributes and clinical safety and efficacy, necessitating the creation of a comprehensive quality control system throughout the entire process and product lifecycle management. As such, it is through this mindset that ACROBiosystems continuously refines our GMP quality management system to help provide reliable support when it comes to raw materials for cell and gene therapies. GMP-grade Product Stability and Consistency Produc�on Bulk Recons�tuted Finished Product Accelerated √ √ Long-term (real �me) Freeze-thaw Cycle Simulated Shipping Finished Product (powder) √ √ √ √ √ √ Method Valida�on Parameter Rela�ve Accuracy Result Bias：1.1% Slope：1.01 Criteria Conclusion Pass Specificity Difference % (buffer): 8.8% Difference % (buffer) ≤ ±10% Pass Linearity Correla�on Coefficient: 0.97 Correla�on Coefficient ≥ 0.95 Pass Potency Range 0.0452-0.452 mg/ml Range of product efficacy standards (64% -156%) Pass Intermediate Precision GCV*：11.2% (GCV)* ≤ 20% Pass Table 6. Stability Assessment Parameters A B Using the same analy�cal method valida�on framework, this includes other assays such as cell ac�vity. For example, our TNF-α assay includes accuracy, intermediate precision, linearity, and range. However, the criteria differ due to the purpose of the assay. Table 5 Example of TNF-α Cell activity validation *GCV is calculated as the anti-log of the standard deviation. GCV = anti-log(SD) Figure 1. (A) Accelerated and (B) real-time stability evaluations of finished product (powder). Bias within ±12% range & Slope of regression equa�on between 0.80 and 1.25 Stability tes�ng is the basis of evalua�ng a product’s shelf-life. As such, this tes�ng is a cri�cal component throughout the en�re drug development, clinical, market launch, and post-market monitoriza�on in quality research processes purposes. This means stability tes�ng must be conducted based on the unique quali�es and characteris�cs of the product. Addi�onally, performing stability studies systema�cally ensures minimal lot-to-lot varia�on, while also providing clear instruc�ons for storage upon delivery. To evaluate stability and consistency within a viable �meframe, the accelerated stability tes�ng method, based on the Arrhenius equa�on, is a widely recognized strategy, and numerous studies in recent years have demonstrated its applicability and accuracy. Both the 2002 document "EN13640 In Vitro Diagnos�c Medical Devices Stability Tes�ng" published by the European Commi�ee for Standardiza�on and the 2009 document "EP25A Evalua�on of Stability of In Vitro Diagnos�c Reagents" released by the Clinical and Laboratory Standards Ins�tute (CLSI) recommend the use of this method for determining the stability of in vitro diagnos�c reagents. Varying stability assessment parameters are shown in Table 6. 12 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Topic 4: Global Supply Chain Security System for Cri�cal Materials in CGT In the ever-evolving landscape of biopharmaceu�cal industry, cell and gene therapy (CGT) emerges as a highly compelling and rapidly advancing field of medicine. At the forefront of these breakthroughs includes autologous and allogeneic cell therapies, personalized treatments involving a pa�ent's own cells or donor cells for a select popula�on. Nevertheless, a challenge facing the CGT industry lies in ensuring a secure and reliable supply chain for cri�cal Good Manufacturing Prac�ce (GMP)-grade raw and ancillary materials for CGT manufacturing. This ar�cle explores cri�cal aspects of maintaining a material supply chains, including supply chain management, warehouse inventory management, transporta�on logis�cs, and adherence to interna�onal trade compliance. ACROBiosystems' Comprehensive Management System: To streamline opera�ons, we established an Order and Material Product Management System (OA-CRM-ERP-WMS-WCS). This system includes features such as business opportunity management, automated order conversion audits, unique iden�fica�on for material products, GMP product classifica�on, and end-to-end product lifecycle tracking. By leveraging barcodes, QR codes, and RFID labels, we ensure complete lifecycle traceability and management to guarantee our customers a consistent and stable supply of high-quality GMP raw materials. 1.Supply Chain Management When considering GMP-grade raw materials for CGT manufacturing, it is cri�cal to ask whether a supplier can stably supply the raw material needs throughout clinical trials and into commercializa�on. As the success of a CGT heavily relies on the quality and consistency of these ancillary materials, making the choice of a supplier a crucial decision. One main point to consider when evalua�ng a supplier is their supply chain management for GMP-grade raw materials, including robust supply agreements, stringent supplier management prac�ces, and transparent communica�on with suppliers. First and foremost, robust supply agreements are essen�al to ensure the availability of high-quality GMP-grade ancillary materials. These agreements should outline quality standards, delivery schedules, and con�ngency plans to mi�gate poten�al supply chain disrup�ons. For instance, securing large size batches reserved for one customer and valida�ng a second supplier can further secure the supply chain and final product stability, especially when scaling up from clinical trials to large-scale commercial manufacturing. Secondly, stringent supplier management prac�ces are cri�cal to guarantee the quality and consistency of GMP-grade ancillary materials. This involves thorough qualifica�on collec�on, on-site Introduc�on audits, and the establishment of a GMP-grade quality management system to ensure compliance with interna�onal standards and regulatory guidelines. Transparent communica�on with suppliers is another vital aspect of supply chain management for GMP-grade ancillary materials. Establishing a defined communica�ons lead and issue escala�on pathway for key suppliers can ensure that both par�es are aligned on key priori�es and poten�al challenges. Regular business review mee�ngs with key suppliers can further enhance transparency and collabora�on, ul�mately strengthening the supply chain. 2. Warehousing and Inventory Management In the intricate landscape of GMP-grade ancillary materials for CGT manufacturing, the pivotal role of warehousing and inventory management cannot be overstated. These func�ons are crucial for ensuring the safe storage, precise distribu�on, and efficient turnover of materials and products, ul�mately mi�ga�ng the risk of supply chain disrup�ons. Given the hypersensi�ve and vulnerable nature of GMP-grade materials, warehouses must adhere to stringent audits. These audits encompass controls over cri�cal factors such as temperatures, humidity, cleanliness, expira�on, turnover rates, and �mely shipment processes. The emphasis on precise inventory management with full lifecycle traceability becomes the founda�on to guarantee the safety and quality of raw materials. 14 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Robust Inventory Management Regular inventory checks and quality inspec�ons, aligned with internal control and audit standards, are integral to our approach. The inventory management system incorporates safety stock alerts and an AI-driven Material Requirements Planning (MRP) mechanism for �mely procurement, ensuring a consistent supply in the face of unforeseen circumstances and market fluctua�ons. Optimizing Warehousing Efficiency We con�nually op�mize warehousing layout design based on customer needs and future plans. Digitaliza�on, automa�on, and intelligent transforma�on enhance efficiency and space u�liza�on. Adhering to GMP requirements, storage areas are strategically divided, and materials are classified to prevent cross-contamina�on, ensuring a secure and high-quality storage environment. Global Warehousing Presence To maintain delivery of our products to customers globally, establishing warehouses and logis�c centers are cri�cal. We maintain three different centers in the United States, EU and China, ensuring product delivery to our customers as fast as possible. •North American Interna�onal Logis�cs Center: Opera�onal for over 10 years on the East Coast, this center is ISO9001 and ISO13485 cer�fied, with a finished product warehouse capacity exceeding 500,000 units. •European Logis�cs Center: Serving over 90% of European customers, this center aims for ISO9001 and ISO13485 cer�fica�ons by 2024, enhancing the speed of services. •Beijing Logis�cs Center: Opera�onal for over 13 years and holds ISO9001 and ISO13485 cer�fica�ons. This center in China oversees global warehousing logis�cs, implemen�ng automated low-temperature storage management with a capacity of up to 1.5 million units. 3. Transporta�on Logis�cs Interna�onal transporta�on logis�cs serve as the crucial link connec�ng various facets within the raw material supply chain. Given the sensi�vity of GMP-grade raw materials, environmental factors such as temperature, humidity, and vibra�ons during transporta�on can exert irreversible impacts on their quality, thereby escala�ng logis�cs costs and complexity. Therefore, establishing a reliable transporta�on logis�cs system is of utmost importance. A stable logis�cs system ensures the �mely and secure delivery of GMP-grade raw materials, enhancing the efficiency and reliability of the CGT manufacturing supply chain. In light of this, we have strategically partnered with globally renowned and highly reliable logis�cs suppliers. These logis�cs partners bring extensive experience in the biopharmaceu�cal industry and possess a specialized understanding nature of GMP-grade raw material. They offer secure and reliable transporta�on services across different temperature ranges, ensuring compliance with industry regula�ons and traceability, aligning with the transporta�on specifica�ons for cri�cal GMP materials. To our Americas and Europe customers, more than 90% of deliveries are accomplished within three days. Globally, 97% of shipments are in transit within three working days. Furthermore, a temperature monitoring system is implemented throughout the transporta�on process, enabling con�nuous monitoring and tracking. This system detects anomalies promptly, allowing for immediate ac�ons to ensure temperature control remains within acceptable ranges, safeguarding the safety and integrity of the raw materials during transporta�on. In addi�on, we have a thoroughly developed plan encompassing transporta�on and route planning, ensuring the �mely delivery of GMP grade raw materials for customers. Tailoring packaging materials and containers based on the unique characteris�cs of different materials and des�na�on requirements, the company selects the op�mal transporta�on mode, including air and land transporta�on. Transporta�on �mes are though�ully arranged to minimize both the �me and risk associated with raw material transporta�on. 15 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com 4. Interna�onal Trade Compliance Managing the interna�onal movement of cri�cal raw materials is a crucial aspect of supply chain management in the global therapeu�c technology landscape of CGT. Yet, naviga�ng interna�onal trade remains challenging due to diverse regulatory landscapes and trade policies across countries and regions. Dis�nct regula�ons and tax policies for CGT products vary, poten�ally restric�ng certain imports or exports. This introduces extra compliance costs and �me delays for biopharma. A strategic approach to evalua�ng and managing interna�onal import and export opera�ons is essen�al to minimize risks, enhance efficiency, and ensure a stable supply of key GMP-grade raw materials. A fundamental understanding of the import-export regula�ons and tax policies in the target market is the key to successful interna�onal trade. 5. summary This ar�cle focuses on how ACROBiosystems addresses the increasing demand for high-quality materials in CGT manufacturing. It highlights key elements of their global supply chain system, emphasizing robust management of GMP grade products. The company employs stringent supplier agreements, transparent communica�on, and advanced warehousing through its Comprehensive Management System. This system includes features like end-to-end product tracking and efficient inventory management to meet the growing needs of CGT manufacturing. Our strategic approach extends to global warehousing, transporta�on partnerships, and a commitment to interna�onal trade compliance, posi�oning them as a proac�ve contributor to the evolving field of CGT. Regula�on (EU) 2021/821 of the European Parliament and of the Council of 20 May 2021 se�ng up a Union regime for the control of exports, brokering, technical assistance, transit and transfer of dual-use items (recast) (EU)1143/2014；(EU)2017/160; (EC)428/2009; (EC)3285/94; (EC)519/94; (EEC) 2603/69; (EEC)2913/92 NO. Regula�ons/Legisla�on Name/Regulatory Body Issuing Organiza�on 1 CBP, U.S. Customs and Border Protec�on US 2 EAR, Export Administra�on Regula�ons US 3 CCL, Commerce Control List US 4 USDA, U.S. Department of Agriculture US 5 APHIS, Animal and Plant Health Inspec�on Service US 6 FDA, Food and Drug Administra�on US 7 CCP; GPSD; EC; EFTA EU 9 New Legisla�ve Framework (NLF / 2008) EU 10 EU 8 EU Table 1: List of Relevant International Regulations We are unwavering in our commitment to con�nuous learning, understanding, and adherence to per�nent interna�onal trade laws, regula�ons, and standards. Our emphasis is on ensuring the compliance of its import and export opera�ons. This involves familiarizing itself with the import-export specifica�ons and procedures of the targeted market, establishing robust document management, and filing systems to minimize poten�al legal risks. Internally, we have nurtured stable partnerships within its supply chain network, encompassing suppliers, agents, and service providers. These enduring and posi�ve collabora�ons guarantee the stability and reliability of the supply chain. Regular assessments of exis�ng service providers are conducted to ensure their capability to consistently deliver high-quality services. In addi�on, when required, new service providers are carefully evaluated based on their qualifica�ons, reputa�on, and professional competence, par�cularly in handling unforeseen emergencies. We also places significant emphasis on informa�on sharing and adop�ng localized business prac�ces. By maintaining close �es with relevant departments, partners, and local governments, ACROBiosystems advocates for specialized, localized services. This proac�ve approach enables them to stay abreast of changes and trends in interna�onal trade policies promptly, facilita�ng �mely adjustments and informed decision-making in their business opera�ons. The overarching goal is not only to navigate the complexi�es of interna�onal trade but to do so in strict compliance with internal laws and regula�ons, ensuring a seamless and lawful global opera�on. 16 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Topic 5: Regulatory Compliance for Cri�cal Materials in CGT Introduc�on Compliance Requirements for GMP ancillary materials in CGT Manufacturing 2.USP〈1043〉《细胞、基因和组织工程产品的辅助材料》 Cell and Gene Therapy (CGT) made its entrance as a poten�al treatment for blood-based cancers through the FDA’s accelerated approval process. Despite its introduc�on as the next-genera�on of biologic-based treatments, these pioneering medicines have been quickly reined in by the dynamic landscape of regulatory guidelines that are designed to ensure pa�ent safety. Guiding principles sent from regulatory agencies in the United States and Europe have been published to regulate various facets of this rapidly growing field. Within this intricate regulatory framework, securing Inves�ga�onal New Drug (IND) approval for CGT products can be a challenge. Something that is overlooked when it comes to obtaining IND approval is ensuring that the raw materials u�lized are manufactured under the necessary quality controls behind the raw materials used. When it comes to our Good Manufacturing Prac�ce (GMP) products, we performed extensive research on the global regula�ons and standards pertaining to raw or ancillary materials before produc�on. This means from product incep�on to commercializa�on, considera�on of regulatory requirements have been incorporated into the material design. Therefore, our ancillary materials meet the highest GMP standards mandated by regulatory bodies across the globe. So which regulatory requirements did we consider for our GMP-grade products? Across industry, GMP-grade products are expected to adhere to the following pharmacopeia documents, governing different aspects of raw materials. 1.USP <1043> Ancillary Materials for Cell, Gene and Tissue-Engineered Products USP 1043 classifies ancillary materials (AM) into four �ers based on their significance in Cell and Gene Therapy (CGT) processes and risk assessment. Essen�al documenta�on, including Drug Master Files (DMF), Cer�ficates of Analysis (CoA), and assurances that AM with animal or human-derived materials has been purified, tested, and is free of external exogenous factors are highlighted. As such, most cytokines for cell culture addi�ves fall into Tier 2 where regula�ons play a crucial role in guaranteeing the traceability, quality, and safety of ancillary materials, emphasizing transparency and reliability in CGT manufacturing processes. 2.IPRP (International Pharmaceutical Regulators Programme) “General Considerations for Raw Materials Used in the Production of Human Cell and Gene Therapy Products” Establishing a Quality Management System The IPRP report, in Sec�on 3.1, mandates CGT manufacturers to ins�tute a robust quality management system, encompassing raw material cer�fica�on programs. This encompasses essen�al facts such as supplier approval, execu�on of quality agreements, provision of CoA, and submission of suppor�ng documents. As such, responsibility falls upon the CGT manufacturer to perform due diligence when it comes to finding raw materials supplier. This means inspec�ng the adherence of raw material storage requirements, stability control, and the effec�ve management of expira�on dates by both supplier and manufacturer. Ensuring Transparency of Origin and Traceability Sec�on 3.3 underscores the significance of origin and traceability considera�ons. Raw materials must be accompanied by per�nent documents, including Cer�ficates of Origin (COO), facilita�ng traceability and iden�fica�on of the origin of materials or components used in the produc�on process. When u�lizing materials from human or animal sources, CGT product manufacturers are advised to selec�vely opt for materials with accessible source informa�on. This may necessitate establishing 18 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Due to the complex interchange between supplier and manufacturer, we are dedicated to streamlining this process. We offer tailored solu�ons to assist and support our valued customers in naviga�ng these requirements seamlessly. Our commitment to staying on top of industry regula�ons ensures that we can provide the necessary support to facilitate a smooth and compliant produc�on process. Having thoroughly examined key guidelines established by regulatory bodies, we are able to effec�vely support our customers regulatory filing requirements in both the United States and the EU. Here are a few ways in which we can be a valuable partner in naviga�ng the regulatory landscape for CGT produc�on. a.Comprehensive Regulatory Support Documents: At the forefront of our capabili�es is the careful compila�on of Regulatory Support Files (RSF), aligning seamlessly with interna�onal regula�ons and specific customer or official requirements. These documents me�culously outline the indispensable qualifica�ons required for GMP-grade materials in CGT produc�on, custom-tailored to meet the diverse needs of customers across various developmental stages. 4.ISO 20399:2022 (E) “Biotechnology — Ancillary materials present during the production of cellular therapeutic products and gene therapy products” The Interna�onal Organiza�on for Standardiza�on introduced ISO 20399:2022(E), offering a comprehensive framework that describes the roles of AM suppliers and users in the produc�on of CGT products. 3.European Pharmacopeia 5.2.12 “Raw materials for the production of cell-based and gene therapy medicinal products” This pharmacopeia document outlines the stringent requirements for raw materials of biological origin employed in the produc�on of CGT products across their lifecycle within the EU region. Specifically, in Sec�on 3.2 addressing produc�on, key considera�ons include the impera�ve for produc�on within an appropriate quality management system and facility, incorpora�ng a stringent asep�c produc�on process that considers the impact of addi�ves, notably an�bio�cs. General quality requirements for raw materials encompass a comprehensive set of criteria, covering iden�fica�on, purity, biological ac�vity, impuri�es (including residual host cell protein/DNA), microorganisms, virus contaminants, mycoplasmas, water purity, content, and biological ac�vity (specific ac�vity). These criteria collec�vely ensure the integrity and safety of raw materials throughout the produc�on process. A pivotal emphasis is placed on the sterility of raw materials, with a mandate that they are either produced as sterile or terminally sterilized under asep�c condi�ons unless explicitly specified otherwise. In cases where the raw material is not inherently sterile, a prerequisite is the knowledge and disclosure of the level of microbial contamina�on. This detailed approach to raw material specifica�ons aligns seamlessly with the overarching goal of ensuring the highest standards in quality and safety throughout the CGT manufacturing process. User and Supplier Responsibli�es for Ancillary Material Use-ISO 20399:2022(E)with ACROBiosystems's Solu�on Ac�vity AM Supplier AM User ACRO Solu�on Provide a CoA, CoO and SDS for the AM Provide documented evidence that the AM is safe with respect to source-relevant animal diseases (e.g. BSE/TSE) Prepare and submit a master file for AM, if applicable Assess the stability of the AM Systema�c research on the stability of research products Strict management of product changes, following procedures to ensure that product changes do not affect key quality a�ributes, ensuring safe and stable produc�on for users Report on the air�ghtness of the packaging system Complete documenta�on for AM products provided Tes�ng items and standards are established based on pharmacopeial drug requirements and actual applica�on scenarios, including iden�fica�on, purity, func�onality, virus contamina�on, and animal sourcing. Regulatory requirements are followed for the management of produc�on, quality, packaging, storage, and logis�cs to ensure stable produc�on processes and product quality, maintain safety stock, and ensure supply security. Customiza�on of GMP products according to customer requirements Open to supplier qualifica�on review, including wri�en audits, on-site or remote audits, etc. Detailed safety tes�ng reports are available (2nd level of RSF documenta�on) Assistance to customers in providing AM-related informa�on required for risk assessment. Assistance available for customers in developing quality control strategies, and provision of paid version quality inspec�on method documents (second-level RSF) Product development tailored to applica�on scenarios, along with the provision of preliminary applica�on scenario verifica�on data Collabora�on with customers to develop quality control strategies, and provision of higher level quality inspec�on method documents (second-level RSF) Tes�ng standards are established based on pharmacopeial drug requirements and actual applica�on scenarios, with reference to pharmacopeias and relevant regula�ons for method valida�on. Long-term monitoring of batch-to-batch differences to ensure stable and reliable produc�on processes with minimal varia�on. New batches of AM sent to protocol customers for trial use, feedback collec�on, and con�nuous op�miza�on of produc�on processes and product performance Inform the AM user of any changes that will very likely or with certainty impact the AM (e.g. under a quality agreement) Conduct characteriza�on tes�ng of the AM and prepare a specifica�ons document (e.g. iden�ty, purity, func�onality, viral contamina�on, animal origin) Execute a quality and supply agreement Provide user requirement specifica�ons to the AM supplier Conduct a risk-based AM supplier qualifica�on process, generally including ini�al screening, onsite audit, formalized approval, con�nuous monitoring/oversight Determine if biocompa�bility, biodistribu�on, cytotoxicity or adven��ous agent tes�ng is needed (or if tes�ng results are available from the AM supplier, if applicable) Conduct a risk assessment for the use of an AM, based on informa�on provided by the AM supplier, or in collabora�on with the AM supplier, e.g. failure modes and effects analysis Qualify the performance of the AM in the intended applica�on Establish similar assurances and plans for alterna�ve suppliers Confirm the CoA test result(s) cri�cal to the cell product (e.g. func�onal assay) Assess the effect of lot-to-lot varia�on of the AM on the final cell product Establish and implement a qualifica�on plan for the use of an AM Conduct an assessment of the AM container closure system DMF filing numbers: 037338/037569/039280 Animal origin free manufacturing process, comprehensive control of external contamina�on factors, and tes�ng for virus and other external contaminant pollu�on in the final product. Can provide a declara�on of absence of TSE/BSE √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ agreements with suppliers to provide materials sourced from specific regions, ensuring a transparent and traceable supply chain. Microbial Safety in Raw Material Production In addressing microbial safety concerns during raw material produc�on (Sec�on 4.2), the report highlights a key issue: most CGT products do not undergo terminal steriliza�on. This means rigorous sterile tes�ng of raw materials used in CGT product produc�on is impera�ve. Given the limita�ons of tradi�onal virus inac�va�on/removal procedures for CGT products, the report advocates for the use of validated methods for virus inac�va�on/removal steps when u�lizing biologically sourced raw materials. In cases where such procedures are imprac�cal, comprehensive tes�ng for the presence of relevant viruses in raw materials should be conducted, accompanied by a well-founded ra�onale for their u�liza�on. This mul�faceted approach ensures the robustness and safety of raw materials integral to the produc�on of innova�ve Cell and Gene Therapy products. 19 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Level 1 Documents: The Level One documents, focusing on product qualifica�ons, are provided free of charge to customers who have purchased GMP products. These documents, approximately 40-60 pages, are designed to serve the needs of customers in the research and pre-clinical stages. They act as essen�al proof of supplier qualifica�ons during the material screening phase. Level 2 Documents: Level Two documents are defined as unique quality and safety documents, comprising over 1000 pages. These documents are available for purchase and target customers entering the clinical phase. At this stage, customers require detailed informa�on on raw materials to support their clinical applica�ons or market authoriza�on. Level Two documents include thorough Standard Opera�ng Procedures (SOPs), analy�cal method valida�on reports, and contribute significantly to saving �me, costs, and manpower in material analysis development and valida�on. b.Comprehensive GMP Products with U.S. FDA Filing Support: We ac�vely support Drug Master File (DMF) filing, a comprehensive set of documents containing informa�on on product chemistry, manufacturing, and controls (CMC) informa�on. As the first company to secure FDA DMF filing for recombinant protein reagents, we con�nue that support across our GMP products and other recombinant proteins. The ar�cle delves deep into the intricate regulatory landscape of Cell and Gene Therapy (CGT) manufacturing, with a primary focus on ensuring compliance with the stringent regulatory requirements of both the US and EU. Understanding the supplier-manufacturing rela�onship and the necessary checks and balances behind manufacturing cell therapies can greatly streamline IND approval. This examina�on of key regulatory guidelines, encompassing USP, IPRP, European Pharmacopeia, and ISO, sheds light on the criteria governing ancillary materials while highligh�ng steps that we take help navigate the intricate regulatory landscapes of CGT produc�on, while catering to the diverse needs of customers across developmental stages. c.IND/New Drug Applica�on (NDA)/Biological License Applica�on (BLA) Stage Compliance Support: We also provide on-site support to customers throughout the IND/NDA/BLA filing process. This support encompasses addressing regulatory queries related to ancillary materials, ensuring that our customers have the correct documenta�on needed for their filings. 20 Tel: +1(800)810-0816 Web: www.acrobiosystems.com E-mail: order@acrobiosystems.com Resources eBook: Make the transition into GMP eBook: Solutions for lmmune Cell Therapy Development More information about Key Raw Materials for Cell and Gene Therapy: h�ps://www.acrobiosystems.com/A1751-Key-Raw-Materials-for-Cell-and-Gene-Therapy.html Request for Free Sample: h�ps://www.acrobiosystems.com/A1556-Free-sample-applica�on-of-GMP-IL-15.html#SRFGMPa Copyright Statement This material is copyrighted by the Company. All rights in this material are reserved by the Company. Unless otherwise indicated in writing, all material in this material is copyrighted by the Company. No part of this material may be copied, photocopied or reproduced in any form or redistributed to any other person or used in any other manner which infringes the Company's copyright without the prior written authorisation of the Company. Scan the QR code to download this resource