Developing Safe and Effective Cell Therapies
eBook
Last Updated: June 19, 2024
(+ more)
Published: May 21, 2024
Credit: iStock
Cell and gene therapies are leading a new driving force behind innovative medical treatments for diseases such as cancer.
However, manufacturing such products comes with challenges, due to the wide array of guidelines and safety requirements set by regulatory bodies across the globe. In particular, the qualification of raw materials and suppliers is critical to ensure development of safe and effective cell therapies.
Download this eBook to learn more about:
- Safeguarding against exogenous contamination
- The critical role of sterile raw materials in cell therapy
- Maintaining material supply chains
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
Brought to you by
Download the eBook for FREE Now!
Information you provide will be shared with the sponsors for this content. Technology Networks or its sponsors may contact you to offer you content or products based on your interest in this topic. You may opt-out at any time.