|
Questions and Answers on Current Good Manufacturing Practices,
Good Guidance Practices, Level 2 Guidance
Production and Process Controls
-
Do
the CGMPs require a firm to retain the equipment status
identification labels with the batch record or other file?
Assuming each major piece of equipment has a unique "Cleaning
and Use Log" that is adequately retained, is it acceptable to
discard these 'quick reference' equipment labels?
-
Can
containers, closures, and packaging materials be sampled for
receipt examination in the warehouse?
-
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?
-
Some
products, such as transdermal patches, are made using
manufacturing processes with higher in-process material reject
rates than for other products and processes. Is this okay?
-
Do CGMPs require three
successful process validation batches before a new active
pharmaceutical ingredient (API) or a finished drug product is
released for distribution?
-
Is it generally acceptable from a cGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying their facility?
-
In 2004, FDA issued a guidance entitled “PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” that encouraged industry to modernize manufacturing through enhancements in process control. How can I implement PAT (Process Analytical Technology)?
-
How do I contact CDER's Process Analytical Technology Team?
-
How do I contact CBER's Process Analytical Technology Team?
1. Do
the CGMPs require a firm to retain the equipment status
identification labels with the batch record or other file?
Assuming each major piece of equipment has a unique "Cleaning
and Use Log" that is adequately retained, is it acceptable to
discard these 'quick reference' equipment labels?
The CGMP regulations for
finished pharmaceuticals require the retention of cleaning and use
logs for non-dedicated equipment, but no similar requirement exists
for retaining what are intended to be "quick reference" or temporary
status labels. Examples of these kinds of status labels include
"mixing lot ###"; "clean, ready for use as of d/M/y"; "not clean." We
see no value in the retention of such labels in addition to the
required equipment log or batch record documentation. The labels
serve a valuable, temporary purpose of positively identifying the
current status of equipment and the material under process. Any
status label should be correct, legible, readily visible, and
associated with the correct piece of equipment. The information on
the temporary status label should correspond with the information
recorded in the equipment cleaning and use log, or the previous batch
record for non-dedicated equipment.
Labels are merely one way
to display temporary status information about a piece of equipment.
It is considered acceptable practice to display temporary equipment
status information on dry-erase boards or chalkboards. And it would
be appropriate for an FDA investigator to verify that the information
on a temporary status label is consistent with the log.
References:
Contact for further
information:
Brian
Hasselbalch, CDER
brian.hasselbalch@fda.hhs.gov
Back to Top
2. Can
containers, closures, and packaging materials be sampled for receipt
examination in the warehouse?
Yes. Generally, we believe
that sampling in a typical drug manufacturing facility warehouse would
not represent a risk to the container/closure or affect the integrity
of the sample results. But whether the act of collecting a sample in
the warehouse violates the CGMPs requirement that containers "be
opened, sampled, and sealed in a manner designed to prevent
contamination of their contents..." will depend on the purported
quality characteristics of the material under sample and the warehouse
environment. For container/closures purporting to be sterile or
depyrogenated, sampling should be under conditions equivalent to the
purported quality of the material: a warehouse environment would not
suffice (see 211.94 and 211.113(b)). This is to preserve the fitness
for use of the remaining container/closures as well as ensure sample
integrity, if they are to be examined for microbial contamination. At
a minimum, any sampling should be performed in a manner to limit
exposure to the environment during and after the time samples are
removed (i.e., wiping outside surfaces, limiting time that the
original package is open, and properly resealing original package).
Well-written and followed procedures are the critical elements.
Note that the CGMPs at
211.84 permit a manufacturer to release for use a shipment of
containers/closures based on the supplier's certificate of analysis
and a visual identification of the containers/closures. Once a
supplier's reliability has been established by validation of their
test results, a manufacturer could perform the visual examination
entirely in the warehouse.
References:
-
21 CFR
211.84: Testing and approval or rejection of components, drug
product containers, and closures
-
21 CFR
211.94: Drug product containers and closures
-
21 CFR
211.113(b): Control of microbiological contamination
-
21 CFR
211.122: Materials examination and usage criteria
Contact for further
information:
Anthony Charity, CDER
anthrony.charity@fda.hhs.gov
3. 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:
-
21 CFR
211.113: Control of microbiological contamination
-
21 CFR
211.72: Filters
-
21 CFR
211.84(d)(6): Testing and approval or rejection of components, drug
product container, and closures
-
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.
-
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.
-
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
brenda.uratani@fda.hhs.gov
Back to Top
4. Some
products, such as transdermal patches, are made using manufacturing
processes with higher in-process material reject rates than for other
products and processes. Is this okay?
Maybe. It depends on the
cause and consistency of the reject rate. Many transdermal patch
manufacturing processes produce more waste (i.e., lower yield from
theoretical) than other pharmaceutical processes. This should not of
itself be a concern. The waste is usually due to the cumulative
effect of roll splicing, line start-ups and stoppages, roll-stock
changes, and perhaps higher rates of in-process sampling. This is
most pronounced for processes involving lamination of rolls of various
component layers. Roll-stock defects detected during adhesive coating
of the roll, for example, can often only be rejected from the roll
after final fabrication/lamination of the entire patch, which
contributes to the final process waste stream.
We expect that validated
and well-controlled processes will achieve fairly consistent waste
amounts batch-to-batch. Waste in excess of the normal operating rates
may need (see 211.192) to be evaluated to determine cause (e.g., due
to increase in sampling or higher than normal component defects... or
both) and the consequences on product quality assessed. We've seen a
small number of cases where unusually high intra-batch rejects/losses
were due to excessive component quality variability and poorly
developed processes.
References:
-
21 CFR
211.100: Written procedures; deviations
-
21 CFR
211.103: Calculation of yield
-
21 CFR
211.110: Sampling and testing of in-process materials and drug
products
-
21 CFR
211.192: Production record review
Contact for further
information:
Brian Hasselbalch, CDER
brian.hasselbalch@fda.hhs.gov
Back to Top
5. Do CGMPs
require three successful process validation batches before a new
active pharmaceutical ingredient (API) or a finished drug product is
released for distribution?
No.
Neither the CGMP regulations nor FDA policy specifies a minimum
number of batches to validate a manufacturing process. The current
industry guidance on APIs (see ICH Q7A for
APIs) also does not specify a specific number of batches for process
validation.
FDA recognizes that validating a
manufacturing process, or a change to a process, cannot be reduced to
so simplistic a formula as the completion of three successful full
scale batches. The agency acknowledges that the idea of three
validation batches has become prevalent, in part due to language in
its own guidance documents. However, FDA is now clarifying current
expectations on process validation.
The 1987 Guideline of General Principles of Process Validation is currently being revised to address this issue. The emphasis for
demonstrating validated processes is placed on the manufacturer’s
process design and development studies in addition to its
demonstration of reproducibility at scale, a goal that has always
been expected.
However, a minimum number of
conformance (a.k.a. validation) batches necessary to validate the
manufacturing processes is not specified. The manufacturer is
expected to have a sound rationale for its choices in this regard.
The agency encourages the use of science based approaches to process
validation.
In March 2004, FDA revised the
Compliance Policy Guide (CPG) (Sec. 490.100) on Process Validation Requirements for Drug Products and Active
Pharmaceutical Ingredients Subject to Pre-Market Approval.
The CPG describes the concept that, after having identified and
establishing control of all critical sources of variability,
conformance batches are prepared to demonstrate that under normal
conditions and operating parameters, the process results in the
production of acceptable product. Successful completion of the
initial conformance batches would normally be expected before
commercial distribution begins, but some possible exceptions are
described in the CPG. For example, although the CPG does not
specifically mention concurrent validation for an API in short supply,
the agency would consider the use of concurrent validation when it is
necessary to address a true short-supply situation, and if the
concurrent validation study conforms to the conditions identified in
the CPG (See paragraph 4. a-c).
The
conditions outlined in the CPG include expanded testing for each batch
intended to address a short-supply situation. Expanded testing,
conducted according to an established validation protocol could
provide added assurance that the batch
meets all established and appropriate criteria before the API is used
in the finished drug product. Additionally, confidence in the API
manufacturing process may be gained by enhanced sampling (larger
sample size representative of batch) and perhaps the testing of
additional attributes. Validated analytical methods are needed for
testing every batch, including validation batches. The agency would
also expect the manufacturer to use a validation protocol which
includes a review and final report after multiple batches are
completed, even though the earlier batches may have been distributed
or used in the finished drug product.
References:
-
21 CFR 211.100: Written procedures; deviations
-
21 CFR 211.110: Sampling and testing of in-process materials and
drug products
-
CPG 490.100 Process Validation Requirements
for Drug Products and Active Pharmaceutical Ingredients Subject to
Pre-Market Approval.
-
ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients
Contact for further
information:
Grace McNally, grace.mcnally@fda.hhs.gov
Back to Top
6. Is it generally acceptable from a cGMP perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when qualifying their facility?
No. It is generally not acceptable from a current good manufacturing practice (“cGMP”) perspective for a manufacturer of sterile drug products produced by aseptic processing to rely solely on ISO 14644-1 Part 1: Classification of Air Cleanliness (“14644-1”) and ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (“14644-2”) when qualifying their facility. Rather, a manufacturer of sterile drug products produced by aseptic processing should use these ISO standards in combination with applicable FDA regulations, guidance and other relevant references to ensure a pharmaceutical facility is under an appropriate state of control. Consequently, appropriate measures augmenting ISO’s recommendations (e.g., with microbiological data) would likely be expected for a firm to meet or exceed CGMP in a pharmaceutical facility.
Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones (“Federal Standard 209E”). In November 2001, the U.S. General Services Administration canceled Federal Standard 209E.
While not FDA regulations or FDA guidance, the Agency believes 14644-1 and 14644-2 are useful in facilitating the international harmonization of industrial air classification for non-viable particle cleanliness in multiple industries (e.g., computer, aerospace, pharmaceutical). As such, FDA adopted these particle cleanliness ratings in the 2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. However, due to the unique aspects of producing sterile drug products by aseptic processing (e.g., microbiological issues) an aseptic processing manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying their facility.
References:
Author:
Stephen Mahoney (HFD-326)
Contact Information:
Division of Manufacturing and Product Quality (HFD-320): CGMP Subject Contacts.
Back to Top
7. In 2004, FDA issued a guidance entitled “PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” that encouraged industry to modernize manufacturing through enhancements in process control. How can I implement PAT (Process Analytical Technology)?
The objective of FDA's PAT program is to facilitate adoption of PAT. In our 2004 guidance, we discuss FDA's collaborative approach to promote industry uptake of new and beneficial technologies that modernize manufacturing operations and enhance process control. FDA recognizes that firms should be encouraged to promptly implement new systems that improve assurance of quality and process efficiency. Accordingly, our approach to PAT implementation is risk based, and includes multiple options:
1. PAT can be implemented under the facility's own quality system. CGMP inspections by the PAT Team or PAT certified Investigator can precede or follow PAT implementation.
2. As another quality system implementation option, FDA invites manufacturers to request a preoperational review of their PAT manufacturing facility and process by the PAT Team (see ORA Field Management Directive No.135).
3. A supplement (CBE, CBE-30 or PAS) can be submitted to the Agency prior to implementation, and, if necessary, an inspection can be performed by a PAT Team or PAT certified Investigator before implementation. This option should be used, for example, when an endproduct testing specification established in the application will be changed.
4. A comparability protocol can be submitted to the Agency outlining PAT research, validation and implementation strategies, and time lines. Following collaborative review of the general strategy outlined in the comparability protocol, the regulatory pathway can include implementation under the facility's own quality system, a pre-operational review, CGMP inspections (either before or after PAT implementation), a combination of these, or another flexible approach.
Manufacturers should evaluate and discuss with the Agency the most appropriate option for PAT implementation. For products regulated by the CDER, contact the Process Analytical Technology Team with any questions.
Back to Top
8. How do I contact CDER's Process Analytical Technology Team?
Manufacturers are encouraged to contact the team via email regarding any PAT questions at: PAT@cder.fda.gov
To contact our PAT Team via mail, please see the PAT Web page (under the section “Contact Us”) for our new mailing address at White Oak.
All correspondence should be identified clearly as "Process Analytical Technology" or "PAT."
Please also refer to the Web page to keep abreast of the latest information on PAT.
Back to Top
9 . How do I contact CBER's Process Analytical Technology Team?
Manufacturers should contact the appropriate review division in CBER to discuss applicability of PAT to CBER-regulated products.
References:
“PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance”
Contact Information:
 Back
to Top  Back to
cGMP
Date created: August 4, 2004,
updated November 12, 2008  |
|
