In addition to the Compliance Program Guidance
Manual (CPGM) for API manufacturers, which we presented in our GMP
News of 16 March 2006, the FDA has in the meantime published a revised
version of this document type for biologics. It is intended as a guideline
for FDA inspectors.
The Compliance Program Guidance Manual, Chapter - 45 Biological Drug
Products is a must-read for everyone whose company is exporting biologics
to the USA. It covers both APIs and finished drug products. The product
group of biologics, which lies within the sphere of responsibility of the
Center for Biologics Evaluation and Research (CBER), has to comply not
only with the "usual" GMP requirements from 21 Code of Federal
Regulations (CFR), Parts 210 and 211, and Section 501 (a)(2)(B) of the
Food, Drug, and Cosmetic Act, but also with 21 CFR 600-680.
Owing to these comprehensive requirements and the complexity of
biologic products as well as of their manufacturing processes, the FDA
established the Team Biologics for inspections as far back as 1997. It is
supported by the Office of Regulatory Affairs (ORA) and by CBER.
The particularities of biologics are also reflected by the
above-mentioned CPGM. Since - apart from these particularities - the
document is based on FDA's systems-based approach to inspections, in the following
we will give only some examples for additional requirements.
The inspectors' attention is, e.g., drawn to starting materials of
animal origin. Testing of these materials has to be in compliance with 21
CFR 600.11 and the specifications in the marketing dossier.
The inspectors have to have a close look at the batch release records
and to verify that the raw data are within the limits of the data sent to
CBER. This is particularly important against the background that CBER can
require samples and batch records of every batch of product at any time
and decide itself about the release of the batch in question [21 CFR 610.0(a)].
Another specialty of biologics are Biologic Product
Deviations (BPDs). Here, the inspectors have the task of checking whether
all deviations have been reported to CBER. Special emphasis is placed on
the information flow between the manufacturer and a possible contract
manufacturer [21 CFR 600.14(a)].
Furthermore, they have to verify if side effects were reported
completely and within the set time limits to CBER [21 CFR 600.80].
The attachments to the Compliance Program Guidance Manual include
concise descriptions of the product groups and their manufacturing
processes for which CBER is competent, e.g. plasma fractionators,
vaccines, recombinant products, allergenics.
Our recommendation:
All those who are involved in the quality assurance of biologics should
read this document. It provides a very good overview of CBER's current
thinking and requirements.
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