In month of
December-2023, the FDA publish a guidance for Industry on “Reformulating drug
product that contain Carbomers Manufactured with Benzene”. This guidance was
published in accordance with 21CFR 10.115 (Good Guidance Practices) section (g)
(2) for immediate implement. As per 21 CFR 10.115 (g) (2), FDA is allowed to
publish any Level 1 guidance document before taking any comments from public.
However as per 21 CFR 10.115 (g) (3), public comment can be considered after
issuance of guidance copy.
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FDA define the
purpose for publish this guidance to providing recommendation for applicants
and manufacturer on what test to be performed and, how documentation to be done
and submitted to FDA to support the reformulation of drug product that use
Carbomer manufactured with benzene.
As Benzene is known
human carcinogenic in nature and it impacts on human health. However, FDA
identified as the United State Pharmacopoeia- National Formulary (USP-NF)
allowed to manufacturing of some of Carbomer e.g. Carbomer 934, Carbomer 934P,
Carbomer 940, Carbomer 941 and Carbomer 1342 with high Benzene level as 5000
ppm.
As per ICH Q3
guidance and USP general chapter <467> “Residual Solvent” it is defined that Benzene is Class 1 solvent.
The Class 1 solvents should be avoided and it was recommended to do not use in
manufacturing of drug substance, excipients, and drug products. As per Class 1
solvent grade, the limit of Benzene is defined as NMT 2ppm. There are several
grade of Carbomer are being manufactured by using benzene as a solvent however,
other alternative of Carbomer are also being manufactured without using the
Benzene as solvent.
FDA identified
that in same USP-NF, the Carbomer Homopolymer, Carbomer Copolymer, and Carbomer
Interpolymer monographs covers to manufacture the Carbomer without Benzene and
limit the Benzene as NMT 2 ppm. Hence to avoid any confusion and by considering
the patient safety, FDA recommended to USP to remove the Carbomer 934, Carbomer
934P, Carbomer 940, Carbomer 941 and Carbomer 1342 monograph from USP-NF
compendium. Hence it is clear that the issuance of this guidance will give
clarity to those manufacturers who manufacture the Carbomer by using Benzene as
solvent.
Recommendation and Requirements of FDA: FDA vision is clear for patient safety and by
considering the patient safety; FDA gives the reference of section 501
(a)(2)(b) of the FD&C Act (21 U.S.C 351 (a)(2)(B), which states that the
drug will considered as adulterated (impure) , which is not manufactured,
processed, packed or held in conformity with CGMP to assure that the drugs
meets the requirements for safety, quality and purity characteristic. The clear instruction of FDA to manufacturer
to should not use the benzene in manufacturing of drug product, excipients, or
drug substances because of their unacceptable toxicity.
The guidance ICH
Q3C and USP General Chapter <467> provide guidance in limited case to use
the benzene with tolerance limit. Specially, such cases if it is necessary to
use benzene in manufacturing of the essential drug product, then level should
be restricted as per recommendation of ICH Q3C guidance and USP general chapter
<467> unless otherwise justified.
FDA recommended
to manufacturer to use an alternative grade of Carbomer that is manufactured
without use of Benzene and having similar chemical composition and physical
property (e.g. viscosity, rheology). It is suggested by FDA to manufacturer that
when switching form benzene containing Carbomer to non-benzene containing grade
of Carbomer, then perform the evaluation by considering the chemistry,
manufacturing, and controls; in vivo release or dissolution testing, and in
vivo bioequivalence documentation. FDA also recommended to performing study on
different dosage form i.e. Semisolid dosage form, immediate release solid oral
dosage form, Modified release solid oral dosage forms, oral suspensions
according to their respective study guidance.
FDA suggested giving electronic comments if any to https://www.regulations.gov. and submit written comments to the Dockets
Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
Reference: Guidance for Industry Reformulating drug product that contain Carbomers
Manufactured with Benzene.
Abhishek Singh is the author of Pharma technical support. He is pharmaceutical professionals, having experience of more than 12 years in Quality.