Raw materials are a critical part of the manufacturing process for cell
therapy products. However, selecting and qualifying raw materials
can be challenging and confusing for cell therapy manufacturers. For
example, definitive regulations for raw materials have not yet been
developed, resulting in regulatory ambiguity for both cell therapy
manufacturers and raw material suppliers. Similarly, there is no single
"raw material-grade" manufacturing standard or any standardization
of compliance claims, such as ancillary-grade, clinical-grade, Good
Manufacturing Practice (GMP)-grade, and animal-component-free. For
reasons such as these, it can be difficult for cell therapy manufacturers
to determine the qualification regime required for a particular raw
material. In order to help clarify these issues, this technical bulletin
discusses the fundamentals of raw material qualification with reference
to a publication in the journal Cytotherapy.1
What are Raw Materials?
Raw materials are components, reagents, and materials used during
the manufacture of cell therapy, gene therapy, or tissue-engineered
products that are not intended to be part of the final product. Raw
materials include cell isolation reagents, culture and cryopreservation
media, and disposables such as plasticware and bioprocessing bags.
The term "raw materials" is not globally recognized by regulators and
nomenclature varies among regions (for example, raw materials are
called "ancillary materials" in North America).
Even though raw materials are not intended to be present in the
final product, they can still affect its safety, efficacy, and consistency.
Therefore, it is important for raw materials to be carefully scrutinized
in terms of their chemical and biological characteristics, as well as
their effects on the final cell therapy product.
What Type of Qualification Is Required for Raw Materials?
"Raw material qualification" refers to the process of establishing the
source, identity, purity, biological safety, and general suitability of a
given raw material. The specific qualification process required for a raw
material depends on many factors, including the type of raw material,
the type of cell or gene therapy product or tissue-engineered product
being manufactured, and the stage of manufacture in which the raw
material is used. Therefore, it is impossible to provide a "one-sizefits-all" qualification program suitable for every situation. Instead,
manufacturers must design their own qualification programs using a
risk-based approach and an understanding of applicable guidelines and
While there are still no specific and definitive regulations for raw
materials, chapter <1043> of the United States Pharmacopeia
(USP), provides guidelines for developing appropriate raw materials
qualification programs. Such programs should focus on five areas: (1)
identification, (2) selection and suitability for use in manufacturing,
(3) characterization, (4) vendor qualification, and (5) quality assurance
and control. For more information on each of these areas, consult USP
<1043>, Ancillary Materials for Cell-, Gene-, and Tissue-Engineered
The level of risk associated with a raw materials will affect the
qualification activities that are necessary. USP <1043> provides a
framework for classifying raw materials into four different tiers based
on risk. For a raw material in Tier 1 (low-risk, highly qualified), the
manufacturer may need to request a Regulatory Support File, obtain
certificates of analysis (CoA) and certificates of origin (CoO), assess
removal from the final product and the effects of lot-to-lot variability,
and conduct stability studies. For a raw material in Tier 4 (high-risk,
minimally qualified), the manufacturer would need to carry out all the
activities listed above, as well as more extensive qualification, such as
confirming critical CoA results, conducting adventitious agent testing,
and possibly working with the supplier to upgrade the raw material
manufacturing process to cGMP standards.
The outline above is only a very high-level overview of raw material
qualification. For more details, see USP <1043>, ISO/TS 20399-1, 2, 3,
Ph.Eur. General Chapter 5.2.12 and Solomon et al.1
What "Grade" of Raw Material is Required for Cell Therapy Manufacturing?
Contrary to widespread belief, globally there is no particular grade of raw
materials that is required for use in cell therapy manufacturing. However,
raw materials that are manufactured under robust quality management
systems and strictly controlled processes reduce the qualification burden
for a cell therapy manufacturer. For this reason, it can be preferable
to source raw materials that are manufactured under cGMP, or that
are themselves approved, cleared, or licensed therapeutic products or
Note, however, that even an approved therapeutic product used as a
raw material must be validated for applications outside of its intended
use. A manufacturer may not need to repeat tests that the raw material
supplier has already carried out in the course of material qualification,
but they will still need to evaluate its stability and performance in the
manufacturing process, as well as the impact of lot-to-lot variability on
the final product.
How Can Manufacturers and Raw Material Suppliers Work Together to Streamline Raw Material Qualification?
While raw material qualification is ultimately the responsibility of
the cell therapy manufacturer, it can be made much more efficient
through close partnership with the raw material supplier. Suppliers
can assist manufacturers in many ways, such as by providing robust
quality documentation, permitting audits of their facility, notifying
manufacturers of changes to a raw material before such changes take
effect, preparing and submitting a Regulatory Support File (RSF), and
providing increased levels of testing or custom formulations. Table 2 in
Solomon et al.1, summarized on the right, provides a clear overview of
the respective accountabilities of cell therapy manufacturers and raw
Manufacturers should establish strong working relationships with raw
suppliers at an early stage. With clear communication between the two
parties, it is often possible to anticipate and resolve issues or concerns
related to the use of a raw material. Table 3 in Solomon et al1 reviews
several case studies in which manufacturers and raw material suppliers
were able to work together to resolve quality or regulatory issues.
This document provides only a general overview of raw material
qualification. For a more in-depth discussion of these topics, see Solomon
et al.1, which reviews the current state of raw materials regulations from
a global perspective. Note, however, that it is critical for manufacturers
to familiarize themselves with USP <1043>, ISO/TS 20399-1, 2, 3, Ph.Eur.
General Chapter 5.2.12 and other applicable guidelines, preferably
engaging directly with regulatory authorities at an early stage in the
product development process.
User and Supplier Accountabilities for Raw Material Use
Performance in the intended application
Provide CoA, CoC, CoO for raw material
Verify country of origin to assure raw material is safe with respect to source-relevant animal diseases (e.g. BSE/TSE)
Conduct a risk assessment for use of raw material, based on information provided by supplier, or in collaboration with the supplier, for example, failure modes and effects analysis
Establish and implement qualification plan for raw material
Confirm CoA test results critical to the cell product (e.g. functional assay)
Characterization testing of raw material and set specifications (e.g. identity, purity, functionality, viral contraw materialination, animal origin, etc.)
Assess effect of lot-to-lot variation of raw material on the final cell product
Determine if biocompatibility, biodistribution, cytotoxicity or adventitious agent testing is needed (or testing results might be available from supplier, if applicable)
Assess presence of residual raw material in the final cell product
Assess stability of raw material
Qualify the supplier of the raw material (e.g. supplier audit)
Execute quality and supply agreement
Implement higher manufacturing standards, custom formulation or replacement of substandard components
Upgrade manufacturing process for raw material under cGMP compliance (i.e in some instances, there may be requirements for shared costs and risk)
Inform the user of any changes in the manufacturing process of the raw material or design/formulation of the raw material (e.g. under a quality agreement)
Prepare and submit a master file for raw materal, if applicable
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Solomon J et al. (2016) Current perspectives on the use of ancillary materials for the manufacture of cellular therapies. Cytotherapy 18(1): 1-12.
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Raw Material Qualification – A Fundamental Overview
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