Contains Nonbinding Recommendations
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CQAs may be used to specify key characteristics of the DS and DP including, but not
limited to, their specifications for a later phase clinical study or BLA. It may be crucial
to establish CQAs as early as possible particularly when you plan to make manufacturing
changes during product development because well-established CQAs are generally
necessary for demonstrating product comparability by analytical methods. For additional
information regarding establishing CQAs, please see FDA’s Guidance for Industry:
“Q8(R2) Pharmaceutical Development” (Ref. 6), and “Q11 Development and
Manufacture of Drug Substances” (Ref. 8). Information to support a CQA and results
from specific studies or published literature may be included in Module 3 of the CTD in
the “Manufacturing Process Development (3.2.S.2.6)” section or the “Pharmaceutical
Development (3.2.P.2)” section (see Ref. 1) depending on whether the attribute pertains
to a DS or a DP. Information may also be linked to the relevant nonclinical or clinical
sections of the application in the CTD.
B. Drug Substance and Drug Product
Your IND must contain a description of the DS (21 CFR 312.23(a)(7)(iv)(a)) and DP (21
CFR 312.23(a)(7)(iv)(b)), including the physical, chemical, or biological characteristics,
manufacturing controls, and testing information, to ensure the DS and DP meet
acceptable limits for identity, strength (potency), quality, and purity. A bulk DS means
the same as “active pharmaceutical ingredient” (21 CFR 207.3; see also 21 CFR 207.1),
which is further described as any substance that is intended for incorporation into a
finished DP and is intended to furnish pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the
structure or any function of the human body (21 CFR 207.1). An active ingredient is
defined as any component that is intended to furnish pharmacological activity or other
direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function in the human body of man or other animals. The term
includes those components that may undergo chemical change in the manufacture of the
DP and be present in the DP in a modified form intended to furnish the specified activity
or effect (21 CFR 210.3(b)(7)). For these products, it follows that a vector
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used to
transduce cells ex vivo and which furnishes a pharmacological activity for the treatment
of disease is a critical component. Without the vector, the resulting cell product would
not have the same pharmacological activity.
Similarly, a vector in its final formulation for administration of the genetic material is
generally considered a DP. A DP is defined as “a finished dosage form, for example,
tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not
necessarily, in association with inactive ingredients. The term also includes a finished
dosage form that does not contain an active ingredient but is intended to be used as a
placebo” (21 CFR 210.3(b)(4)). Additionally, a vector in its final formulation used for
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Where a “vector” is defined as a vehicle consisting of, or derived from, biological material that is designed to
deliver genetic material. Examples include plasmids, viruses, and bacteria that have been modified to transfer
genetic material. (Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for
Industry; January 2020, available at https://www.fda.gov/media/113768/download
).