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Die amerikanische Food & Drug Administration (FDA) hat am 4. Dezember 2007
Änderungen zum cGMP Guide (21 CFR 210/211) veröffentlicht. Wir hatten bereits in
unserer
News vom 22. Oktober 2007 über die geplanten Maßnahmen berichtet, auf die
auch Fred Blumenschein von der Behörde anlässlich der von der Universität
Heideberg, der ECA und der European QP Association organisierten 2nd European
GMP Conference Ende Juni 2007 in Heidelberg eingegangen ist.
Mit der Ankündigung der neuen Texte hat die FDA auch die so genannte "proposed
rule" aus dem Jahr 1996 zurückgezogen. Diese "proposed rule" hatte wesentliche
Änderungen des cGMP Guides beinhaltet. Eine Arbeitsgruppe der FDA hat jedoch
festgestellt, dass diese geplanten Änderungen nicht mehr mit dem neuen
risikobasierenden Ansatz der FDA in Einklang stehen.
Mit den Änderungen will die FDA einerseits bestimmte Vorgaben konkretisieren und
andererseits in einem schrittweisen (incremental) Ansatz eine Modernisierung der
cGMP erreichen. Der geänderte cGMP Guide soll dann im Einklang mit der
Initiative cGMP für das 21. Jahrhundert stehen.
Eine Änderung betrifft beispielsweise den Bereich "Aseptic Processing". Hier hat
die FDA mit der Guidance for Industry: "Sterile Drug Products Produced by
Aseptic Processing" ein Dokument publiziert, welches nach einer Analyse der GMP
Harmonisation Analysis Working Group entstanden ist. Gegenstand der Analyse war
auch ein Vergleich mit dem EU GMP Guide. Nunmehr hat die FDA notwendige
Konkretisierungen im cGMP Guide vorgenommen. Die neuen Texte sind nicht
überraschend, denn sie beinhalten im Wesentlichen Anforderungen, die bereits
viele Jahre Interpretation der FDA gewesen sind. Allerdings ist nun aber auch
der rechtliche Rahmen geschaffen worden.
Die nachfolgend aufgeführten Änderungen treten am 17. April 2008 in Kraft.
Kommentare können bis zum 19. Februar 2008 übermittelt werden. Wenn keine
wesentlichen Kommentare eingehen, die gegen eine Umsetzung der neuen Inhalte
sprechen, wird am 18. März 2008 eine Ankündigung im Federal Register erfolgen,
welche den o.g. Inkraftsetzungstermin bestätigen wird.
Sie finden nachfolgend die neuen Texte:
PART 210-CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING,
PACKING, OR HOLDING OF DRUGS; GENERAL
■ 1. The authority citation for 21 CFR part 210 continues to read as follows;
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262,
263a, 264.
■ 2. Section 210.3 is amended by revising paragraph (b)(6) to read as follows:
§ 210.3 Definitions.
(b) * * *
(6) Nonfiber releasing filter means any filter, which after appropriate
pretreatment such as washing or flushing, will not release fibers into the
component or drug product that is being filtered. * * * * *
PART 211-CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS
■ 3. The authority citation for 21 CFR part 211 continues to read as follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C. 216, 262,
263a, 264.
■ 4. Section 211.48 is amended by revising paragraph (a) to read as follows:
§ 211.48 Plumbing.
(a)
Water supplied by the plumbing system of the facility must be safe for human
consumption. This water shall be supplied under continuous positive pressure in
a plumbing system free of defects that could contribute contamination to any
drug product.
* * * *
■ 5. Section 211.67 is amended by revising paragraph (a) to read as follows:
§ 211.67 Equipment cleaning and maintenance.
(a)
Equipment and utensils shall be cleaned, maintained, and sanitized and/ or
sterilized at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.
* * * *
■ 6. Section 211.68 is amended by adding paragraph (c) to read as follows:
§ 211.68 Automatic, mechanical, and electronic equipment.
* * * *
(c)
Such automated equipment used for performance of operations addressed by §§
211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the
requirements included in those sections for the performance of an operation by
one person and checking by another person if such equipment is used in
conformity with this section and one person verifies that the operations
addressed in those sections are performed accurately by such equipment.
■ 7. Section 211.72 is revised to read as follows:
§ 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing, or packing of
injectable drug products intended for human use shall not release fibers into
such products. Fiber-releasing filters may not be used in the manufacture,
processing, or packing of these injectable drug products unless it is not
possible to manufacture such drug products without the use of such filters. If
use of a fiber-releasing filter is necessary, an additional nonfiber-releasing
filter of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing
conditions so dictate) shall subsequently be used to reduce the content of
particles in the injectable drug product.
■ 8. Section 211.82 is amended by revising paragraph (b) to read as follows:
§ 211.82 Receipt and storage of untested components, drug product containers,
and closures.
* * * *
(b)
Components, drug product containers, and closures shall be stored under
quarantine until they have been tested or examined, whichever is appropriate,
and released. Storage within the area shall conform to the requirements of §
211.80.
■ 9. Section 211.84 is amended by revising paragraphs (c)(1), (d)(3), and (d)(6)
to read as follows:
§ 211.84 Testing and approval or rejection of components, drug product
containers, and closures.
* * * * *
(c)
** *
(1)
The containers of components selected shall be cleaned when necessary in a
manner to prevent introduction of contaminants into the component.
* * * * *
(d)
* * *
(3) Containers and closures shall be tested for conformity with all appropriate
written specifications. In lieu of such testing by the manufacturer, a
certificate of testing may be accepted from the supplier, provided that at least
a visual identification is conducted on such containers/closures by the
manufacturer and provided that the manufacturer establishes the reliability of
the supplier's test results through appropriate validation of the supplier's
test results at appropriate intervals.
* * * * *
(6) Each lot of a component, drug product container, or closure with potential
for microbiological contamination that is objectionable in view of its intended
use shall be subjected to microbiological tests before use.
* * * *
■ 10. Section 211.94 is amended by revising paragraph (c) to read as follows:
§ 211.94 Drug product containers and closures.
* * * * *
(c)
Drug product containers and closures shall be clean and, where indicated by the
nature of the drug, sterilized and processed to remove pyrogenic properties to
assure that they are suitable for their intended use. Such depyrogenation
processes shall be validated.
* * * *
■ 11. Section 211.101 is amended by revising paragraphs (c) and (d) to read as
follows:
§ 211.101 Charge-in of components.
*
* * * *
(c)
Weighing, measuring, or subdividing operations for components shall be
adequately supervised. Each container of component dispensed to manufacturing
shall be examined by a second person to assure that:
(1)
The component was released by the quality control unit;
(2)
The weight or measure is correct as stated in the batch production records;
(3)
The containers are properly identified. If the weighing, measuring, or
subdividing operations are performed by automated equipment under § 211.68, only
one person is needed to assure conditions of paragraphs (c)(1), (c)(2), and
(c)(3) of this section have been met.
(d)
Each component shall either be added to the batch by one person and verified by
a second person or, if the components are added by automated equipment under §
211.68, only verified by one person.
■ 12. Section 211.103 is revised to read as follows:
§ 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be determined at the
conclusion of each appropriate phase of manufacturing, processing, packaging, or
holding of the drug product. Such calculations shall either be performed by one
person and independently verified by a second person, or, if the yield is
calculated by automated equipment under § 211.68, be independently verified by
one person.
■ 13. Section 211.110 is amended by revising paragraph (a) introductory text and
by adding paragraph (a)(6) to read as follows:
§ 211.110 Sampling and testing of in-process materials and drug products.
(a)
To assure batch uniformity and integrity of drug products, written procedures
shall be established and followed that describe the in-process controls, and
tests, or examinations to be conducted on appropriate samples of in-process
materials of each batch. Such control procedures shall be established to monitor
the output and to validate the performance of those manufacturing processes that
may be responsible for causing variability in the characteristics of in-process
material and the drug product. Such control procedures shall include, but are
not limited to, the following, where appropriate:
*
* * * *
(6) Bioburden testing. * * * * *
■ 14. Section 211.113 is amended by revising paragraph (b) to read as follows:
§ 211.113 Control of microbiological contamination.
*
* * * *
Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include validation of all aseptic and
sterilization processes.
■ 15. Section 211.160 is amended by revising paragraph (b)(1) to read as
follows:
211.160 General requirements.
* * * * *
(b)
* * *
(1)
Determination of conformity to applicable written specifications for the
acceptance of each lot within each shipment of components, drug product
containers, closures, and labeling used in the manufacture, processing, packing,
or holding of drug products. The specifications shall include a description of
the sampling and testing procedures used. Samples shall be representative and
adequately identified. Such procedures shall also require appropriate retesting
of any component, drug product container, or closure that is subject to
deterioration.
* * * * *
■ 16. Section 211.182 is revised to read as follows:
§ 211.182 Equipment cleaning and use log.
A written record of major equipment cleaning, maintenance (except routine
maintenance such as lubrication and adjustments), and use shall be included in
individual equipment logs that show the date, time, product, and lot number of
each batch processed. If equipment is dedicated to manufacture of one product,
then individual equipment logs are not required, provided that lots or batches
of such product follow in numerical order and are manufactured in numerical
sequence. In cases where dedicated equipment is employed, the records of
cleaning, maintenance, and use shall be part of the batch record. The persons
performing and double-checking the cleaning and maintenance (or, if the cleaning
and maintenance is performed using automated equipment under § 211.68, only the
person verifying the cleaning and maintenance done by the automated equipment)
shall date and sign or initial the log indicating that the work was performed.
Entries in the log shall be in chronological order.
■ 17. Section 211.188 is amended by revising paragraph (b)(11) to read as
follows:
§ 211.188 Batch production and control records.
* * * * *
(b) * * *
(11) Identification of the persons performing and directly supervising or
checking each significant step in the operation, or if a significant step in the
operation is performed by automated equipment under § 211.68, the identification
of the person checking the significant step performed by the automated
equipment.
* * * *
Zusammengestellt von:
Oliver Schmidt
CONCEPT HEIDELBERG
Quelle: http://www.fda.gov/cber/rules/amendcgmp.pdf
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