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Questions and Answers on
Current Good Manufacturing Practices,
Good Guidance Practices, Level 2 Guidance
Equipment
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Many leading analytical balance manufacturers
provide built-in "auto calibration" features in their balances. Are
such auto-calibration procedures acceptable instead of external
performance checks? If not, then what should the schedule for
calibration be?
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Is there a list of CDER-approved drug manufacturing
equipment?
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Can Total Organic Carbon (TOC) be an acceptable
method for detecting residues of contaminants in evaluating cleaning
effectiveness? (updated
5/18/2005)
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A firm has multiple media
fill failures. They conducted their media fills using TSB prepared
by filtration through 0.2F
m-sterilizing filter. Investigation did not show any obvious
causes. What could be the source of contamination?
1. Many leading analytical balance
manufacturers provide built-in "auto calibration" features in their
balances. Are such auto-calibration procedures acceptable instead
of external performance checks? If not, then what should the
schedule for calibration be?
The auto-calibration
feature of a balance may not be relied upon to the exclusion of an
external performance check (211.68). For a scale with a built-in
auto-calibrator, we recommend that external performance checks be
performed on a periodic basis, but less frequently as compared to a
scale without this feature. The frequency of performance checks
depends on the frequency of use of the scale and the criticality and
tolerance of the process or analytical step. Note that all batches
of a product manufactured between two successive verifications would
be affected should the check of the auto-calibrator reveal a
problem. Additionally, the calibration of an auto-calibrator should
be periodically verified--a common frequency is once a year--using
National Institute of Standards and Technology (NIST)-traceable
standards or NIST-accredited standards in use in other countries.
References:
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21 CFR
211.68: Automatic, mechanical, and electronic equipment
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21 CFR
211.160(b)(4): General requirements (Lab Controls)
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USP
Chapter <41> Weights and Balances
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See
also: ASTM standard E 617: Standard Specification for Laboratory
Weights and Precision Mass Standards (this standard is incorporated
into the USP by reference; other widely recognized standards may be
acceptable)
Contact for further
information:
Mike
Gavini, CDER
gavinim@cder.fda.gov
2. Is there a list of approved drug
manufacturing equipment?
No. The CGMP regulations
neither approve nor prohibit specific equipment for use in
manufacturing of pharmaceutical products (with the exception of
asbestos and fiber-releasing filters, see 211.72). We do not
maintain a list of approved equipment. Firms are afforded the
flexibility to select equipment that best satisfies their particular
needs and that is capable of meeting the relevant CGMP requirements.
Each firm is responsible for selecting all equipment used in their
manufacturing process to produce quality product in accordance with
CGMP. They are also responsible for selecting the appropriate
intended use for the equipment's operation, and are free to modify
standard equipment designs to best suit their process and that are
compatible with the product under process.
The CGMPs require that
equipment be of appropriate design to facilitate operations for its
intended use and for cleaning and maintenance (see 211.63 and 211.67)
and, that any equipment surface in contact with components, in-process
materials, or drug products not be reactive, additive, or absorptive
so as to "alter the safety, identity, strength, quality, or purity of
the drug product beyond the official or other established
requirements" (see 211.65).
References:
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21 CFR
211.63: Equipment design, size, and location
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21 CFR
211.65: Equipment construction
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21 CFR
211.67: Equipment cleaning and maintenance
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21 CFR
211.68: Automatic, mechanical, and electronic equipment
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21 CFR
211.72: Filters
Contact for further
information:
Anthony Charity, CDER
charitya@cder.fda.gov
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3. Can Total Organic Carbon
(TOC) be an acceptable method for detecting residues of contaminants
in evaluating cleaning effectiveness?
Yes. Since the publication
of the inspection guide on cleaning validation in 1993, a number of
studies have been published to demonstrate the adequacy of TOC in
measuring contaminant residues.
TOC or TC can be an
acceptable method for monitoring residues routinely and for cleaning
validation. In order for TOC to be functionally suitable, it should
first be established that a substantial amount of the contaminating
material(s) is organic and contains carbon that can be oxidized under
TOC test conditions. This is an important exercise because some
organic compounds cannot be reliably detected using TOC.
TOC use may be justified
for direct surface sample testing as well as indirect (rinse water)
sample testing. In either case, because TOC does not identify or
distinguish among different compounds containing oxidizable carbon,
any detected carbon is to be attributed to the target compound(s) for
comparing with the established limit. Thus, a firm should limit
'background' carbon (i.e., carbon from sources other than the
contaminant being removed) as much as possible. If TOC samples are
being held for long periods of time before analysis, a firm should
verify the impact of sample holding time on accuracy and limit of
quantitation.
References:
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21 CFR 211.67: Equipment cleaning and maintenance.
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21 CFR 211.160(b): General requirements (Laboratory
Controls)
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USP 643 Total Organic Carbon
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Guide to Inspections of Cleaning Validation, 1993
Contact for further information:
Abi
D'Sa, CDER
dsaa@cder.fda.gov
Brian
Hasselbalch, CDER
hasselbalchb@cder.fda.gov
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4.
A firm has multiple media
fill failures. They conducted their media fills using TSB (tryptic soy broth) prepared by filtration through 0.2
micron sterilizing filter. Investigation did not show any obvious
causes. What could be the source of contamination?
A firm recently had
multiple media fill failures. The media fill runs, simulating the
filling process during production, were conducted inside an isolator.
The firm used TSB (non-sterile bulk powder) from a commercial source,
and prepared the sterile solution by filtering through a 0.2 micron sterilizing filter. An investigation was launched to trace the
source of contamination. The investigation was not successful in
isolating or recovering the contaminating organism using conventional
microbiological techniques, including the use of selective (e.g.,
blood agar) and nonselective (e.g., TSB and tryptic soy agar) media,
and examination under a microscope. The contaminant was eventually
identified to be Acholeplasma laidlawii by using 16S rRNA gene
sequence. The firm subsequently conducted studies to confirm the
presence of Acholeplasma laidlawii in the lot of TSB used.
Therefore, it was not a contaminant from the process, but from the
media source.
Acholeplasma laidlawii
belongs to an
order of mycoplasma. Mycoplasma contain only a cell membrane and have
no cell wall. They are not susceptible to beta-lactams and do not take up Gram stain. Individual organisms are
pleomorphic (assume various shape from cocci to rods to filaments),
varying in size from 0.2 to 0.3 microns or smaller. It has been shown that Acholeplasma laidlawii is
capable of penetrating a 0.2 micron filter, but is retained by a 0.1
micron filter (see Sundaram, et al.). Acholeplasma laidlawii is
known to be associated with animal-derived material, and
microbiological media is often from animal sources. Environmental
monitoring of mycoplasma requires selective media (PPLO broth or
agar).
Resolution:
For now, this firm has
decided to filter prepared TSB, for use in media fills, through a 0.1
micron filter (note: we do not expect or require firms to routinely
use 0.1 micron filters for media preparation). In the future, the firm will use
sterile, irradiated TSB when it becomes available from a commercial
supplier. (Firm's autoclave is too small to permit processing of TSB
for media fills, so this was not a viable option.) The firm will
continue monitoring for mycoplasma and has revalidated their cleaning
procedure to verify its removal. In this case, a thorough
investigation by the firm led to a determination of the cause of the
failure and an appropriate corrective action.
References:
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21 CFR
211.113: Control of microbiological contamination
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21 CFR
211.72: Filters
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21 CFR
211.84(d)(6): Testing and approval or rejection of components, drug
product container, and closures
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Sundaram,
S., Eisenhuth, J., Howard, G., Brandwein, H. Application of membrane
filtration for removal of diminutive bioburden organisms in
pharmaceutical products and processes. PDA J. Pharm. Sci.
Technol. 1999 Jul-Aug; 53(4): 186-201.
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Kong, F.,
James, G., Gordon, S., Zekynski, A., Gilbert, G.L. Species-specific
PCR for identification of common contaminant mollicutes in cell
culture. Appl. Environ. Microbiol. 2001 Jul; 67(7): 3195-200.
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Murray,
P., Baron, E., Pfaller, M., Tenover, F., Yolken, R. Manual of
Clinical Microbiology ASM Press, Sixth Edition.
Contact for further
information:
Brenda Uratani, CDER
uratanib@cder.fda.gov
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cGMP
Date created: August 4, 2004,
updated May 18, 2005 |
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