Guidance
PET Drug Products – Current Good Manufacturing Practice (CGMP)
(PDF copy
of this document)
DRAFT GUIDANCE
This guidance document
is being distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 60 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to Dockets Management
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. All comments should be identified
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publishes in the Federal Register.
For questions regarding this draft document
contact Brenda Uratani, 301-827-8941.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2005
Compliance
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(Internet)
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2005
Compliance
Guidance
PET Drug Products –
Current Good Manufacturing Practice
(CGMP)
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the
title page of this guidance.
If you
plan to submit comments on this draft guidance, to expedite FDA
review of your comments, please:
- Clearly
explain each issue/concern and, when appropriate, include a
proposed revision and the rationale/justification for the proposed
change.
- Identify
specific comments by line number(s); use the PDF version of the
document, whenever possible.
This draft guidance is intended to help PET
drug producers better understand FDA’s thinking concerning
compliance with the proposed CGMP regulations. The guidance
addresses resources, procedures, and documentation for all PET drug
production facilities, academic and commercial. In some cases, the
guidance provides practical examples of methods or procedures that
PET production facilities could use to comply with the proposed CGMP
requirements. In developing this draft guidance, FDA has taken into
consideration relevant issues, concerns, and questions raised at the
public meetings held with professional associations, producers of
PET drug products, and other interested parties. A first draft
version of this guidance was issued in April 2002 in conjunction
with revised preliminary draft proposed regulations.
FDA's guidance documents, including this
guidance, should not be viewed as establishing legally enforceable
responsibilities. Instead, guidances describe the Agency's current
thinking on a topic and should be viewed only as recommendations.
The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
Section 121(c)(1)(A) of the Food and Drug
Administration Modernization Act of 1997 (the Modernization Act)
directed the Food and Drug Administration (FDA) to establish current
good manufacturing practice (CGMP) requirements for positron
emission tomography (PET) drugs. Concurrently with the issuance of
this draft guidance, FDA is proposing such requirements under 21 CFR
Part 212. In 1999, FDA published a preliminary draft of the
proposed PET CGMP regulations.
The FDA received comments on the preliminary draft proposed
regulations at a public meeting on the subject on September 28,
1999. The FDA made changes in the working draft in response to the
public comments. In 2002, a revised preliminary draft of the CGMP
regulations
was published in conjunction with a first draft of this guidance.
The FDA received comments on the preliminary proposed rule and the
draft guidance at a public meeting on May 21, 2002, and in writing
after the meeting and has taken all comments into consideration in
revising the proposed rule and this draft of the guidance. This
second version of the draft guidance provides more details for
discussion purposes on acceptable approaches to complying with the
proposed regulations should they be published in final form.
As directed by Congress in the Modernization
Act, to help in developing the proposed regulation and this draft
guidance, we closely examined the operations of many PET drug
producers, including not-for-profit institutions and commercial
manufacturers. Since the Modernization Act became law, significant
changes have occurred in PET drug production in the United States.
The number of PET production facilities has increased, as has the
number of facilities where PET scans are performed. The business of
PET drug production has changed as well. Historically, PET drug
products were produced by academicians and researchers at PET
production facilities located in universities and similar
not-for-profit institutions. An academically oriented PET
production facility usually produces small amounts (a few doses per
day) of a few PET drug products for on-site patient use and a larger
variety of PET drug products for clinical investigation and academic
research.
An increasing number of PET production
facilities are now operated by for-profit corporate entities that
contract with academic and medical institutions (many of which have
not-for-profit status) to manage the production of PET drugs at
those institutions. Most of these PET drug products are
administered on site, although often there is some distribution to
other local or regional hospitals. In addition, a growing number of
independent PET production facilities are not affiliated with any
university or hospital. These for-profit, often contractually
managed, and independently operated PET production facilities
distribute PET drug products to significantly greater numbers of
patients, sometimes hundreds of miles from the production site.
Our review of PET drug production has lead to
the conclusion that a PET drug producer’s status as either a
not-for-profit or for-profit entity has little bearing on the
quality of PET drugs that it produces and distributes for
administration to patients, or on the methods, facilities, and
controls that a PET production facility needs to ensure product
quality. Instead, production and CGMP differences among PET drug
producers are primarily a function of the size, scope, and
complexity of their production operations. We have also found that
implementing certain production standards and controls can ensure
the production of quality PET drugs, regardless of differences among
the various PET production facilities. The Agency believes that the
welfare of a patient undergoing a PET scan should not depend on
where a particular PET drug was manufactured.
The proposed regulations on CGMP requirements
contain what we believe are the minimum standards for quality
production of PET drugs at all types of PET production facilities.
We have designed the CGMP regulations to be sufficiently flexible to
accommodate not-for-profit, academically oriented institutions as
well as commercial producers.
The proposed
regulations also incorporate principles from the United States
Pharmacopeia (USP) general chapter on PET drug compounding. The USP
contains standards that are of significant regulatory importance for
PET drugs. Currently, under section 501(a)(2)(C) of the Federal
Food, Drug, and Cosmetic Act (the Act), a compounded PET drug is
adulterated unless it is produced in compliance with USP compounding
standards and official monographs for PET drugs. Section 121(b) of
the Modernization Act added this provision as a safety net during
the time it takes the Agency to develop the final regulations.
Under section 121(b) however, section 501(a)(2)(C) of the Act will
expire 2 years after the date on which we establish approval
procedures and CGMP requirements for PET drugs. At that time,
compliance with the final version of the regulation will be
required. Nevertheless, the USP general chapter on PET drug
compounding largely reflects the consensus views of the PET
community and FDA on how to properly produce PET drug products.
Consequently, we believe it is appropriate to incorporate many of
the principles and concepts in the USP general chapter into the
proposed CGMP requirements.
Proposed
§ 212.5(b) specifies the CGMP requirements for investigational,
research, and approved PET drugs. Proposed § 212.5(b)(1) states
that the regulations in part 212 apply to all PET drug products for
human use, other than research and investigational PET drug
products. We believe that it is appropriate to have less detailed
CGMP requirements for investigational and research PET drugs to
allow more flexibility during the development of these drugs. We
also recognize that many investigational PET drugs may not have
commercial potential. Therefore, proposed § 212.5(b)(2) states that
the regulations in part 212 do not apply to investigational PET
drugs for human use produced under an investigational new drug
application in accordance with part 312 and research PET drugs that
are produced with the approval of a Radioactive Drug Research
Committee (RDRC) in accordance with § 361.1.
Instead,
proposed § 212.5(b)(2) states that, for investigational and research
PET drugs, the requirement under the Act to follow CGMP is met by
producing drugs in accordance with Chapter <823> of the 26th edition
of the USP (2003). Chapter <823> sets forth requirements for PET
drug production, including control of components, materials, and
supplies; verification of procedures; stability testing and
expiration dating; quality control; and sterilization and sterility
assurance. Because most PET drug producers are very familiar with
the requirements in Chapter <823>, adopting the Chapter <823>
provisions as the CGMP requirements for investigational and research
PET drugs should greatly facilitate producers’ compliance with those
requirements. Although the provisions in Chapter <823>, including
those on documentation, are generally less specific and explicit
than the requirements in proposed part 212, we believe that they are
adequate to ensure that investigational and research PET drugs are
produced safely under appropriate conditions, consistent with
section 501(a)(2)(B) of the Act.
Although we
propose that USP Chapter <823>, rather than part 212, would
constitute the minimum CGMP requirements for investigational and
research PET drugs, FDA would retain the authority to inspect
facilities where investigational and research PET drugs are produced
to verify compliance with Chapter <823>. However, as with
inspection of investigational studies of non-PET drugs, we generally
would conduct inspections of facilities that produce investigational
or research PET drugs only on a for-cause basis (i.e., when we
become aware of a potential safety concern related to the production
of an investigational or research drug).
PET drugs,
other than investigational and research PET drugs, would have to
meet the requirements of proposed part 212. PET drug products that
would have to be marketed under an approved new drug application (NDA)
or an approved abbreviated new drug application (ANDA) would have to
be produced in accordance with proposed part 212.
PET is a medical imaging modality that requires
the use of a unique type of radiopharmaceutical drug. A PET drug
exhibits spontaneous disintegration of unstable nuclei by the
emission of positrons (b+).
PET drugs are used to provide dual photon positron emission
tomographic images. The radionuclide is generally produced by a
particle accelerator (e.g., a cyclotron) and has a short half life.
Currently, a batch, or lot, of a PET drug typically consists of one
multiple-dose vial containing the PET drug product in a sterile
solution. A sample from the vial, which is representative of all
doses to be administered, is tested to verify that the batch or the
lot conforms to all established specifications.
A PET drug product is typically administered to
patients within a few minutes to a few hours following preparation.
Because of the short half life of the radionuclide and the mode of
production, PET drug products have unique storage, shipping, and
handling concerns. Under Section 121 of the Modernization Act, PET
producers must comply with the standards in the USP General Chapter
<823> Radiopharmaceuticals for Positron Emission
Tomography-Compounding, until FDA establishes approval
procedures and CGMPs for PET drug products.
Current good manufacturing practice (CGMP)
is a minimum standard that ensures that a drug meets the
requirements of safety and has the identity strength, quality, and
purity characteristics it is represented to possess. The Agency is
proposing CGMP regulations that would require manufacturers of PET
drugs to follow certain CGMP requirements. CGMP is demonstrated
through written documentation of procedures and practices. The
documents and practices may be similar or identical to documents and
practices requested by other oversight bodies (e.g., Nuclear
Regulatory Commission and state and local agencies). Documents
produced for others, where appropriate, can be used to provide the
documentation of compliance with CGMP requirements. However,
because of institutional, local, or state differences, some of these
documents may not have sufficient overlap to address the issues in
this guidance. Therefore, to ensure uniformity for all patients and
human subjects, where overlap does not exist, we recommend that PET
producers develop supplemental documentation.
FDA regulates the production of PET drug
products. Section 121 of the Modernization Act directs FDA to
establish appropriate approval procedures for PET drugs pursuant to
section 505 of the Act as well as appropriate CGMP requirements. In
the course of developing these approval procedures and CGMP
requirements, a question has been raised concerning how to
distinguish PET drug production from the practice of pharmacy
(regulation of which FDA has traditionally deferred to State and
local authorities).
FDA has determined that the production
of a PET drug product includes all operations to the point of final
release of a finished dosage form, and these activities would be
subject to CGMP. A PET drug product may be released to a hospital,
institution, imaging facility, nuclear pharmacy (e.g., pharmacy bulk
packages for use in accordance to USP <1> Injections), or
other entity or part of an entity. After a finally released PET
drug product is received by the receiving facility, FDA generally
regards subsequent dispensing of a patient-specific dose and use of
the drug product to be part of the practice of medicine and
pharmacy. FDA generally will defer to State and local authorities
concerning regulation of these activities. In general, a routine
FDA inspection to ensure compliance with CGMP would focus on
activities up to and including the point of final release of a PET
drug product.
In the following sections, the draft guidance
introduces each section by identifying the relevant requirements
from the proposed regulations. The section then provides more
detailed current thinking. Certain CGMP requirements in the
proposed regulations are self-explanatory and have not been further
clarified in this guidance.
Proposed 21 CFR
212.10 would require a PET production facility to have a sufficient
number of personnel with the necessary education, background,
training, and experience to enable them to perform their assigned
functions correctly. Each center also would have to provide
adequate resources, including equipment and facilities, to enable
their personnel to perform their functions.
The following section of the guidance addresses
personnel. Guidance on resources (facilities and equipment) is
provided in Section VI.
We recommend that
staffing levels correspond to the size and complexity of the
operation of the PET production facility and enable a PET production
facility to satisfactorily complete all intended tasks in a timely
manner before administration of a finished PET drug to humans. We
recommend that the responsibilities and assigned duties of all staff
be clearly identified in written policies.
For a PET production facility that typically
produces one or two batches of a product daily, it may be adequate
to employ one or two persons to accomplish all production and
quality control functions. We recommend the PET facility
demonstrate that the production and quality control functions can be
consistently accomplished in a timely and appropriate manner before
administration of a drug to humans. One individual can be
designated to perform the production as well as quality control
functions, provided he or she is highly qualified in the performance
of all such functions (i.e., has a degree, documented training, and
significant experience in the technical area).
Under current CGMP regulations in 21 CFR Part
211, FDA normally requires second-person checks at various stages of
production as well as test verification. In a PET production
facility with only one person assigned to perform production and
quality control tasks, it is recommended that that person recheck
his or her own work. Self-checks involve the confirmation of the
operator’s own action and would be documented. Examples of
self-check activities include reviewing batch records (e.g., review
the batch record to ensure that all finished-product test results
are within the acceptance criteria) before release of the drug
product for distribution and verifying calculations in analytical
tests.
At a PET production facility that produces
multiple PET drugs, we recommend the staffing level be adequate to
perform all quality assurance functions and to prevent mix-ups and
cross contamination.
As mentioned above, each person performing an
activity or a function in the production and quality control of a
PET drug product would have to have the appropriate education,
training, and experience related to that function and should be
trained in CGMP relevant to their assigned tasks. We recommend that
PET production facilities have adequate ongoing programs or plans in
place for training employees in new procedures and operations and in
the areas where deficiencies have occurred.
We recommend PET production facilities maintain
an updated file (e.g., curriculum vitae, copies of degree
certificates, certificate of training) for each employee.
Proposed 21 CFR 212.20 would require PET
production facilities to have a quality assurance function. Under
the proposed regulations, the following activities are defined as
the responsibilities of the quality assurance function:
·
Oversee production operations to ensure that PET drug
products have adequately defined identity, strength, quality, and
purity
·
Examine and approve or reject components, containers,
closures, in-process materials, packaging materials, and labeling
used in the production of PET drug products to ensure that all these
meet their current specifications
·
Examine any procedure affecting production, testing,
and specifications
·
Review production records for accuracy and
completeness
·
Ensure that all errors are investigated and corrective
action is taken
The quality assurance function in a PET
production facility typically consists of execution and oversight
activities.
We recommend that the execution of quality
assurance functions include the following:
·
Examine and evaluate each lot of incoming material
before use to ensure that the material meets its established
specifications
·
Review the production batch records and laboratory
control records for accuracy, completeness, and conformance to
established specifications before authorizing the final release or
rejection of a batch or lot PET drug product
We recommend that the oversight of quality
assurance functions include the following:
·
Approve procedures, specifications, process, and
methods
·
Ensure that personnel are properly trained and
qualified, as appropriate
·
Ensure that PET drugs have adequately defined
identity, strength, quality and purity
·
Investigate errors and ensure that appropriate
corrective action is taken to prevent their recurrence
·
Conduct periodic audits to monitor compliance with
established procedures and practices
For PET production facilities currently
producing one or two PET drugs, employees located at the facility
can perform both the daily execution and oversight functions.
On the other hand, a commercial PET firm
managing multiple production facilities may choose to have an entity
located outside the PET production facility help to achieve the
objective of manufacturing oversight and more efficient management.
For example, a corporate quality assurance/quality control
department, or consultants, can provide oversight.
Proposed 21 CFR 212.30(a) would require that a
PET production facility have adequate facilities to ensure the
orderly handling of materials and equipment, the prevention of
mix-ups, and the prevention of contamination of equipment or product
by substances, personnel, or environmental conditions.
Proposed 21 CFR 212.30(b) and (c) would require
that all equipment that would reasonably be expected to adversely
affect the strength, quality, or purity of a PET drug, or give
erroneous or invalid test results when improperly used or
maintained, is clean, suitable for its intended purposes, properly
installed, maintained, and capable of repeatedly producing valid
results. Equipment would have to be constructed so that surfaces
that contact components, in-process materials, or drug products are
not reactive, additive, or absorptive so as to alter the quality of
the PET drug product.
The design of the
PET drug production facility should promote orderly operations
during the production process and protect the product from
contamination originating from personnel and surrounding areas. To
achieve this, a facility should contain adequate work areas suitable
for the intended tasks (e.g., area for analytical testing, aseptic
manipulation, chemical production, radiochemical production, and
component storage) and to allow completion of all production-related
tasks in an orderly manner. Potential sources of contamination
include particulate matter and chemical and microbiological
materials.
Phases of production
with the potential for microbiological contamination should be
performed under environmental conditions that minimize the
possibility of such contamination (e.g., in a laminar airflow
workbench (LAFW), or barrier isolator system).
The placement of
equipment and materials should be carefully evaluated to promote
efficient operation and eliminate errors, mix-ups, and
cross-contamination. All equipment used in production (e.g.,
particle accelerator, synthesis units, or other specialized
equipment) should be appropriately located and housed (e.g., with
shielding) so that all the work areas during the normal course of
production are easily accessible.
We recommend that
related work areas be organized and proximally located so as to
promote efficient operation and eliminate the potential for errors
in the production and control operations. Access to work areas,
production and testing equipment, components, containers and
closures, and the PET drug products, should be restricted to
authorized personnel.
In most PET
production facilities, the same area or room can be used for
multiple purposes. For example, the production (e.g., radiochemical
synthesis), laboratory operation (e.g., release testing), and
storage of approved components, including containers and closures,
can be located in the same room. Components that are approved for
use as well as those that are under quarantine can be stored in the
same area or on a different shelf in a cabinet, provided each lot is
properly labeled as to its status and contents and organized in a
manner that avoids mix-up or unintended use. Rejected components,
containers and closures, and other materials should be kept separate
from quarantined or approved materials.
As the complexity in
a PET production facility increases (production of multiple PET drug
products), it is important to develop the appropriate level of
control required to prevent mix-ups and contamination). Separate and
well-defined areas or rooms may be warranted for each independent
function of the operation, such as production, testing, and storage
of components. It is also important to consider what impact a
greater number of personnel and activities could have on the aseptic
processing portion of the process.
An aseptic work area
should be suitable for the assembly of the aseptic components
required for the preparation of a sterile PET drug product. We
recommend that air quality in the aseptic processing area be
controlled to limit the presence of microorganisms and particulate
matter. Critical activities in the production and testing of a PET
drug product that expose the PET drug product or the sterile surface
of the container/closure system to the environment should be
conducted within an aseptic workstation (e.g., a LAFW or barrier
isolator). Examples of such activities include the aseptic assembly
of sterile components (syringe, needle, filter and vial) for sterile
filtration of the PET drug product, and sterility testing of the
finished PET drug product. We recommend that the following
precautions be taken to help maintain the appropriate air quality of
the aseptic workstation:
·
The aseptic workstation is sanitized before each
operation.
·
Items within a laminar airflow aseptic workstation are
kept to a minimum and not interrupt the airflow.
·
Operators wear clean lab coats and sanitized gloves
when conducting an aseptic manipulation within the aseptic
workstation.
·
Gloved hands are frequently sanitized or changed when
working in the aseptic workstation. Gloves are examined for damage
(tears or holes) and replaced if they are compromised.
·
The surface of nonsterile items (e.g., test tube rack,
and the overwrap for sterile syringes, and filters) are sanitized
and wiped with an appropriate disinfectant (e.g., sterile 70 percent
isopropyl alcohol) before being placed in the aseptic workstation.
We recommend that
conditions in the room where aseptic manipulations are conducted not
present a challenge to the operating capability of the aseptic
workstation. For example, the room should not be carpeted nor have
overhanging pipes or hanging light fixtures. All areas of the
production and processing room should be easily accessible for
cleaning. Surfaces of the walls, floors, and ceilings in the
aseptic work areas should be easily cleaned. Cleaning should be
performed frequently to ensure consistent control of the
environmental quality. In addition, the aseptic processing area
(e.g., LAFW) should be situated in the section of the room with the
lowest traffic and lowest activity. Cartons and boxes should not be
stored or opened in the production area to minimize ingress of dust
and particulate into the aseptic work area.
Equipment used in the
production, processing, or packaging of a PET drug product would
have to be appropriate for the performance of its intended function
and not contaminate the product. We recommend that each piece of
equipment be suitably located to facilitate its use, cleaning, and
maintenance. We also recommend that each PET production facility
establish and follow written procedures that address the following
issues, where applicable:
·
Assignment of responsibility and frequency for
cleaning and maintenance of equipment
·
Description of cleaning and maintenance procedures in
sufficient detail to include disassembly and reassembly of equipment
·
Protection of clean equipment from contamination prior
to use
·
Inspection of equipment and calibration, if indicated,
prior to use
We recommend that
each PET production facility select suitable cleaning agents and
cleaning techniques and ensure that their cleaning operations not
contaminate the drug product.
We recommend that
newly installed equipment be qualified before first use to verify
that it was installed correctly and is capable of operating as
intended. Normally, the equipment vendor verifies that the equipment
is installed correctly (installation qualification (IQ)) and
operates according to specifications (operational qualification (OQ)).
Before the equipment is used for production, personnel in the PET
production facility should verify that the equipment, when operated
under actual production parameters or selected method, produces
consistent results within established specifications (performance
qualification (PQ)).
We recommend
developing a preventive maintenance schedule with sufficient
frequency to ensure the correct performance of the equipment. Where
needed, calibration should be performed prior to the use of the
equipment for the intended task. We recommend facilities follow
calibration checks recommended by equipment vendors unless the PET
production facility has determined that more frequent calibrations
are appropriate. Major repairs or upgrades in equipment may warrant
requalification. We recommend not using malfunctioning or
incorrectly operating equipment until repairs or corrective action
have been made and the equipment has been found to operate
correctly. All qualification, calibration, and maintenance
activities should be properly documented, including the date of such
performance and who performed them.
FDA recognizes that,
after they become subject to the requirements of the final CGMP
regulations, a number of PET production facilities may continue to
use existing equipment. If they do, PET production
facilities would have to make sure that the existing equipment is
working properly and is being maintained and calibrated according to
written procedures.
We recommend that PET production
facilities establish procedures to check the correct functioning of
the equipment that is developed in-house. Representative equipment
is discussed below to illustrate how it might be controlled in a PET
production facility.
a. Automated radiochemical synthesis apparatus
The apparatus enables
the PET production facility to carry out the production process
reliably and reproducibly. The provisions contained in the USP
General Chapter <1015> Automated Radiochemical Synthesis
Apparatus can help ensure proper functioning of a synthesis
apparatus.
Prior to the
production of a PET drug product each day, we recommend that the
operator should conduct a performance check to ensure the following:
·
The synthesis apparatus has been cleaned/flushed
according to the established procedures.
·
All appropriate tubing, reaction vessels, purification
columns or cartridges, and other materials have been replaced and
connected as required.
·
The monitoring and or recording devices (e.g.,
temperature, pressure, flow rate) are functioning properly.
·
When the process is under microprocessor control, the
operator ensures that the system is functioning and recording
correctly and that the correct program and operational parameters
are used.
b. Aseptic Workstation
The aseptic workstation should
provide an appropriate environment for aseptic procedures. Examples
of workstations include a laminar air flow workbench (LAFW) or
barrier isolator system. We recommend that an integrity test be
conducted at installation (including after each change of the
high-efficiency particulate air (HEPA) filter) to ensure proper
performance. We recommend that certification (integrity testing of
the HEPA filter) of the aseptic workstation be performed when the
unit is initially installed and at least every 6 months thereafter
to ensure the desired air quality. More frequent testing may be
appropriate if air quality is found to be unacceptable, for example,
as part of an investigation into a finding of sterility failure in a
PET drug, or if leakage or decrease in optimal airflow is found.
We recommend that a
qualified operator change the prefilters in the aseptic workstation
periodically in accordance with written procedures and preventive
maintenance schedules. Some laminar flow hoods are equipped with
easily readable static pressure gauges that indicate when the
pressure builds up behind the filter because of the clogging of the
filter. We recommend that the filter be changed when clogging is
detected.
We recommend laminar
airflow velocities be monitored periodically at the work surface as
well as at the HEPA filter face to ensure adequate uniformity of
flow throughout the critical area. We recommend that operators be
trained on the importance of minimizing objects and equipment within
the critical area so laminar airflow is not disrupted. We recommend
that microbiological monitoring (e.g., using settle plate) in the
LAFW be conducted during sterility testing and critical aseptic
manipulation.
c. Electronic or analytical weight balance
d. Dry-heat ovens
If glassware and
heat-stable materials are depyrogenated and sterilized on-site, we
recommend that the PET production facility demonstrate and document
that the depyrogenation cycle will achieve at least a 3-log
reduction of an endotoxin challenge, as measured by a bacterial
endotoxins test. A suitable challenge study usually involves random
placement of endotoxin indicators in a representative oven load of
materials. Suitable endotoxin indicators include glass vials that
contain 1,000 to 10,000 Endotoxin Units.
e. High performance liquid chromatograph (HPLC)
When an HPLC is used
for purification of a PET drug, we recommend the operator ensure
that the system is working properly and there is no bleeding of
unintended materials (e.g., column material) into the mobile phase.
f. Temperature recording device
We recommend that the
temperature and humidity (where appropriate) of the dry heat oven,
refrigerator, freezer, and incubator be recorded on each workday
when in use. Automated recording devices are recommended for ease
of documentation and for recording any deviations.
We recommend that PET
production facility have the appropriate equipment to adequately
perform each quality control function that it intends to perform.
Representative quality control equipment can include:
a. Gas chromatograph (GC)
Prior to each day of
its use, the analyst should make sure that the GC system is
functioning correctly by conducting system suitability testing. At
least one injection of the standard preparation (reference standard
or internal standard) should be done before the injection of test
samples (see USP General Chapter <621> Chromatography).
b. High
performance liquid chromatograph (HPLC)
We recommend that the HPLC system have detectors suitable for
the intended purpose and be of sufficient sensitivity. Prior to
each day of its use, the analyst should make sure that the HPLC
system is functioning correctly by conducting system suitability
testing (see USP General Chapter <621> Chromatography and FDA
reviewer guidance, Reviewer Guidance Validation of
Chromatographic Methods (November 1994). At least one injection
of the standard preparation (reference standard or internal
standard) should be done before the injection of test samples.
c. Dose calibrator
We recommend a dose calibrator be used to measure the radioactivity of PET
drug products. Accuracy and linearity should be assessed at
installation and at appropriate intervals thereafter. The
instrument should be calibrated in accordance with nationally
recognized standards or the manufacturer's instructions. System
suitability testing should include a constancy check with a suitable
high-energy radionuclide standard source.
d. Radiochromatogram scanner
We recommend that a
radiochromatogram scanner (or equivalent equipment that provides a
radiochromatogram) be used to measure radioactivity distribution in
the developed thin layer chromatography plate (e.g., instant
thin-layer chromatography (ITLC), paper or plate). The scanner
should have sufficient sensitivity and spatial resolution for the
intended discriminatory and quantitative objective. Manufacturer
recommended checks and maintenance should be performed on the
radiochromatogram scanner (see USP General Chapter <821>
Radioactivity).
e. Multichannel analyzer (MCA)
A multichannel
spectrometer coupled to a calibrated sodium iodide scintillation
detector (or preferably with the higher resolution germanium lithium
compensated, Ge (Li) detector) can be useful to determine
radionuclidic purity and to identify the radionuclide. The overall
system should have sufficient sensitivity and resolution for the
intended purpose (see USP General Chapter <821> Radioactivity).
Adequate calibration using National Institute of Standards and
Technology (NIST) traceable standards and preventive maintenance
should be performed at intervals specified in a written procedure
and as recommended by the equipment manufacturer. More frequent
intervals should be used if problems in the operation of the MCA are
encountered.
Proposed 21 CFR 212.40(a) and (b) would require
PET production facilities to establish, maintain, and follow written
procedures for the control of components, containers, and closures.
There would have to be appropriate written specifications for
components, containers, and closures.
Proposed 21 CFR 212.40(c) would establish the
minimum standards for controlling components, containers, and
closures from receipt to consumption.
Proposed 21 CFR 212.40(d) would require that
components, containers, and closures be handled and stored in a
manner that prevents contamination, mix-ups, and deterioration.
Proposed 21 CFR 212.40(e) would require that
PET production facilities keep a record of each shipment of each lot
of components, containers, and closures that they receive.
The written procedures would have to specify
how each material (components, containers, and closures) will be
selected and controlled in PET production facilities. Procedures
should cover the life cycle of a material, from time of receipt to
ultimate consumption. The process for procurement and use of
materials should include the following elements, where applicable:
We recommend only
qualified vendors be used. A vendor is qualified when there is
evidence to support its ability to supply a material that
consistently meets all quality specifications. We also recommend
that PET production facilities ask the vendor to report any major
changes in the manufacture of an item. It is preferable to have
more than one qualified vendor for a component. A vendor should be
replaced if there is an indication that it is supplying
unsatisfactory materials.
We recommend that each lot of material
be checked upon receipt to determine that the order was filled
correctly and arrived in good condition. Each lot should be logged
in and assigned a new identification code number. The code number
would be used in the disposition of that lot. Sufficient
information should be documented to enable the PET production
facility to have full traceability of each lot. We recommend that,
before release for use, incoming materials be segregated and placed
under quarantine and labeled as Quarantined. A lot can then
be inspected, sampled, and tested, if applicable.
Analytical results in the certificate
of analysis (COA) for each lot of incoming material should be
inspected against the PET production facility's current
specification sheet to ensure that acceptance criteria are met.
Where appropriate, certain components described below (see
Acceptance Testing) can be tested to confirm their identity before
they are accepted and released for use in the production of a PET
drug product.
Materials that meet a PET production
facility’s specifications can be approved and released for use.
Such release should be recorded and the examination and testing data
maintained. It may be helpful to have a component logbook to record
information such as receipt date, quantity of the shipment,
supplier's name, lot number, expiration date, results of any testing
performed, and person responsible for release.
Approved materials can be labeled Approved with an
identifying code number, storage conditions, and expiration date.
We recommend that materials be stored under the proper storage
conditions and in an area designated for approved materials. If a
lot is rejected, we recommend it be labeled Rejected,
segregated, properly disposed of, and each of these actions be
documented.
We recommend that items be stored under
the conditions recommended by the vendor (e.g., temperature and
humidity). Moisture sensitive materials should be stored in
desiccated devices in sealed containers. There should be an
expiration date for each item. We recommend that PET production
facilities have a policy that guides the expiration dating of items,
by category. Vendor assigned expiration dates could be used unless
the in-house date is sooner.
a. Reagents,
solvents, gases, purification columns, and other auxiliary materials
We recommend that PET
production facilities have procedures in place to ensure that only
materials meeting applicable specifications from approved reliable
sources are used. The COA and container label for each lot of each
shipment of incoming materials should be examined to ensure that all
specifications are met.
b.
Components that yield an active pharmaceutical ingredient
(API) and inactive ingredients
Under
proposed § 212.40(c)(1)(i), for the production of PET drugs where
finished-product testing ensures that the correct components have
been used (e.g., production of F18 FDG) PET producers may rely on
the certificate of analysis (COA) from the suppliers. Analytical
results in the COA for each lot of component would have to be
examined and compared against the PET production facility's current
specifications to ensure that acceptance criteria are met. We
recommend that PET producers have scientific rationale and
supporting data to justify why identity testing is not needed.
Under
proposed § 212.40(c)(1)(ii), for the production of a PET drug where
the finished-product testing does not ensure that the correct
components have been used, identity testing would have to be
performed. When specific identity tests exist, we recommend that
they be used.
The inactive
ingredients in PET drugs usually consist of a diluent, a stabilizer,
and/or a preservative. Under proposed § 212.40(c)(1)(ii), if a
product that is marketed as a finished drug product intended for
intravenous administration is used as an inactive ingredient, it
would not be necessary to perform a specific identity test for that
ingredient. Proposed § 212.40(c)(1)(ii) also states that if an
inactive ingredient (e.g., 0.9 percent sodium chloride solution) was
prepared on site, an identity test on the components used to make
the inactive ingredient would have to be performed before it was
released for use.
c.
Commercially available ready-to-use sterile, pyrogen-free, sealed
container/closure systems for injections, syringes, transfer sets,
and filters used in aseptic process
We recommend
that PET production facilities use reliable sources for these items.
Most PET production facilities use sterile and depyrogenated
containers (sealed vials with stoppers and crimps) that are
commercially available (510K product). Under proposed §
212.40(c)(2), a visual identification of each lot of containers and
closures would have to be conducted. We recommend that a COA
showing conformance with the established specifications be obtained
before accepting a lot of the container/closure system. We
recommend that the container/closure system be properly stored under
appropriate environmental conditions (e.g., correct temperature,
humidity, and sterility).
If the
sterilization and depyrogenation of the container/closure are
performed on site, we recommend that the efficacy of each process be
demonstrated. We recommend that established procedures be shown to
be reproducible and used in such cases.
When a lot of material
has met all acceptance criteria, the material can be labeled
Approved. Under proposed § 212.40(d), approved materials would
have to be handled and stored in a manner that prevents degradation
or contamination. Unacceptable materials should be promptly
rejected, identified, and segregated to prevent their use prior to
appropriate disposal.
Under proposed §
212.40(e), records would have to be kept for each shipment of each
lot of components, containers, and closures that the PET production
facility receives, including results of any testing performed.
Proposed 21 CFR 212.50 would require adequate
production and process controls to ensure consistent production of a
PET drug product that meets the applicable standards for identity,
strength, quality, and purity. Under proposed § 212.50(a), PET
production facilities would be required to have written production
and process control procedures to ensure and document that all key
process parameters are controlled and that any deviations from the
procedures are justified.
Proposed § 212.50(b) would require PET
production facilities to have master production and control records
that document all steps in the PET drug production process.
Proposed § 212.50(b) also specifies what would be required in the
master production and control records.
Proposed § 212.50(c) would require that a batch
production record be generated from the master production record
template for each new batch of a PET drug product. Each batch of a
PET drug product would have to be uniquely identified, and its batch
record would have to include each major production step, weights,
and identification codes of components used, dates of production
steps, identification of major equipment, testing results,
labeling, initials or signatures of persons performing or checking
each significant step in the operation, and results of any
investigations conducted.
Proposed §
212.50(f) would require that when the results of the production of
an entire batch of a PET drug product are not fully verified through
finished-product testing or when only the initial sub-batch in a
series is tested, the PET drug producer would have to demonstrate
that the process for producing the PET drug product is reproducible
and is capable of producing a drug product that meets the
predetermined acceptance criteria. Process verification activities
and results would have to be documented. Documentation would have
to include the date and signature of the individual(s) performing
the verification, the monitoring and control methods and data, and
the major equipment qualified.
Master production and control records are the
principal documents describing how a product is made. The master
production record serves as a template for all batch records,
documenting how each batch will be produced. The designated
individual should approve the master production and control records,
or any changes to them, before they are implemented.
We recommend that the master production and
control records present logical, chronological step-by-step
instructions that document how the PET drug is to be produced.
Production should be discussed under headings, where applicable,
such as accelerator operation, radiochemical synthesis, purification
steps, and formulation of the finished product. We recommend the
entire production process be pre-established and fully described in
the master production and control record. The SOP in performing a
specific step can be referenced. The master production and control
records would include specifications for each critical step.
Critical steps include the process step, process condition, or other
relevant parameters that are controlled within predetermined
criteria to ensure that the API meets its specification. Under
proposed § 212.50(b), the master production and control records
should include the following:
·
The name and strength of the PET drug product in MBq/ml
or mCi/ml (strength should be measured at a calibration time
immediately after production)
·
If applicable, the name and radioactivity or other
measurement of each API as well as any inactive ingredient (e.g.,
diluent, stabilizer, or preservative) per batch or per unit of
weight or measure of the drug product and a statement of the total
radioactivity or measurement of any dosage unit
·
A complete list of components designated by names and
codes (component code) sufficiently specific to indicate any special
quality characteristic
·
Identification of all major equipment used in
production of the drug product
·
An accurate statement of the weight or measurement of
each component (e.g., batch formula). In the process of producing
FDG F 18, for example, multiple components are weighed or measured
by volume. The radioactive component should be recorded in terms of
radioactivity units.
·
A statement of the action limit on radiochemical yield
(i.e., the minimum percentage of yield beyond which investigation
and corrective action would be required)
·
Complete instructions (or references) for production,
control, and testing of the PET drug. The synthesis of certain PET
drugs, such as FDG F 18, involves multiple steps including drying,
exposure to organic solvents, heating, pH adjustments, passage
through purification media, and sterilizing filtration. We
recommend there be a description of all in-process steps and their
controls so that the operator can confirm that all steps are
completed within specified conditions, where feasible. Controls for
movement of liquids or gases should also be provided. For automated
radiochemical synthesis equipment, it may be sufficient to reference
the equipment manufacturer’s manual that contains a full description
of the automated production steps and controls.
·
A description of the PET drug product containers,
closures, and packaging materials, including a specimen or copy of
each label and all other labeling.
Proposed § 212.1 defines a batch of a PET drug
product as a specific quantity of PET drug product intended to have
uniform character and quality. In the case of FDG F 18, a batch
normally consists of the PET drug product produced in a single
synthesis and purification operation. For ammonia N 13, a batch
normally consists of multiple sub-batches having uniform character
and quality, that are produced according to a single preparation
order during one succession of multiple irradiation using a
synthesis and/or purification operation.
Proposed § 212.50(c) would require the use of a
batch record to document the production and testing of each batch.
The batch records provide complete traceability and accountability
for production and control of each batch. We recommend that
information in the batch record (paper, or electronic copy)
accurately reflect the information contained in the master
production and control records. The control records may be
cross-referenced and not be included as part of the batch record.
The batch record is therefore a simplified version of the master
production and control records that should contain the information
needed for a documented history of the batch produced, including:
·
Documentation of the execution of each critical
production step (e.g., timed events occurred within specifications,
heating steps occurred at the specified temperature, and ingredients
were properly transferred into the reaction vessel) where feasible,
taking radiation exposure concern into consideration. For automated
radiochemical synthesis unit, the printout at the end of synthesis
documenting the execution of the production steps and controls could
be used for the chemical synthesis portion of the batch record.
·
A compilation of tests and printouts that led to
acceptance of the final product.
Under proposed § 212.50(c), information
specific to batch production and control records would include the
following:
·
Name and strength of the PET drug product
·
Unique identifier or number for each batch (an
identifier or number also can be provided for each sub-batch
produced)
·
The name and radioactivity or other measure of each
active pharmaceutical ingredient and each inactive ingredient per
batch or per unit of radioactivity or other measurement of the drug
product;
·
Date and time of production steps
·
Identification of major pieces of equipment where
identical equipment in the facility can be used
·
Actual weights (or measures) and identification codes
of components used
·
Labeling (a description of the finished drug product
container label and the outer container label should be included)
·
Initials or signatures of the person(s) performing and
checking each significant step of the operation
·
Results of any investigations conducted (this should
include documentation of any deviations and follow-up
investigations). Reference to the deviation and investigation
reports can be indicated if stored separately.
·
Results of testing
Batch records should include documentation that
each significant step in the production was accomplished. When
entries are made in batch records, an entry should be made directly
after performing the activity (in the order performed) and would
have to identify the person (signature or initials) making the
entry. Corrections to paper entries would be dated and signed or
initialed, leaving the original entry still readable. We recommend
that each batch record be reviewed and approved for final release
(signature/initials and date). For requirements and information on
electronic records and signatures, interested persons should refer
to Part 11 (21 CFR Part 11, Electronic Records; Electronic
Signatures) and the Agency guidance on the scope and application of
Part 11, Electronic Records; Electronic Signatures.
Most PET drug products are designed for
parenteral administration and are produced by aseptic processing.
The goal of aseptic processing is to make a product that is free of
microorganisms and toxic microbial byproducts, most notably
bacterial endotoxins. The use of aseptic technique and control of
microbiological impurities in components can eliminate microbial and
endotoxin contamination from PET drugs. Aseptic processing of PET
drugs should involve microbiological control over various types of
components, as discussed below.
Production processes
that are relatively free of water or have rigorous chemical
processes are unlikely to have microbial or endotoxin contaminants.
PET production facilities often use Water for Injection, USP
(WFI), an approved drug product. Using finished packaged WFI
eliminates the need for the PET production facility to verify,
maintain, and document a sterile water system.
Nonsterile water can
develop significant microbial growth in a matter of days. We
recommend that production processes that are water-intensive have
sufficient controls to avoid microbial growth and development of
biofilm (bacterial colonization). If nonsterile water is allowed to
stagnate in a container or tubing, biofilm will develop. To
minimize their contact with nonsterile water, it is recommended that
tubing and glassware be washed, rinsed, and promptly dried.
Glassware and
heat-resistant containers are relatively easy to keep free of
microbial growth and pyrogens because they can be appropriately
wrapped in foil and terminally sterilized by a suitable dry-heat
cycle (see Section VI). Control procedures for these items should
include prompt cleaning after use, rinsing with purified or WFI
water, wrapping in aluminum foil, and depyrogenation by a suitable
dry-heat oven cycle.
Transfer lines, which
are used for synthesis and transfer of solvents or products, are
usually made of durable plastic and are amenable to reuse. Prompt
cleaning with organic solvents after use, rinsing with WFI, flushing
with a volatile solvent, and drying with nitrogen are measures that
help to control microbial contamination. Organic solvents such as
ethanol and acetone are useful as a final rinse and are easily dried
from containers or lines.
For PET drugs with a
very short half life (e.g., ammonia N 13), sometimes a long fluid
line is used to deliver multiple batches of the product solution to
a remote area for further processing. We recommend that procedures
be established to ensure that these fluid lines are clean and free
of pyrogen contamination prior to each use.
Resin columns are a
potential source of microbes and pyrogens because they can be
contaminated with microorganisms. If available, the purchase of
low-microbial grade resin material may limit bioburden. Material
used for preparing resin columns should be suitably processed and
rinsed with a large amount of WFI to control contamination. The
prepared column should be appropriately flushed. Refrigerated
storage is helpful in controlling contamination. We recommend that
wet columns not be stored for a prolonged period of time.
The selection of a
reliable vendor and high-quality materials are effective ways to
limit the risk of microbiological contamination. Components that
support microbial growth during storage should be kept under
controlled conditions and periodically assessed for microbial
growth/ contamination.
Aseptic
processing in PET drug production normally consists of, but is not
limited to, (1) the aseptic assembly of the container/closure system
(syringe, needle, sterilizing filter and vial) and (2) sterile
filtration of the PET drug product. The ability of personnel to
perform aseptic processing can be assessed by conducting media
fills. Simulations of aseptic manipulations (e.g., the aseptic
assembly of the container system, vent connection, and sterile
filtration) can be carried out by substituting a bacterial growth
medium for the actual drug product. We recommend that an operator
complete three successful media fill runs to qualify as a new
operator. Each operator can be requalified annually by conducting
one media fill run. Only personnel trained in aseptic techniques
should conduct aseptic processing.
Even if care is taken
to minimize microbiological contamination during synthesis, a drug
is considered to be nonsterile until it is passed through a
sterilizing grade filter. Generally, PET production facilities can
use commercially available, presterilized filters to sterilize these
solutions, provided that the vendor has been shown to be reliable,
the filter is certified as compatible for the product, and it meets
acceptable specifications.
Integrity testing of
membrane filters should always be performed postfiltration. This is
to ensure that the filter has performed according to
specifications. Testing can be accomplished by performing the
bubble-point test to show that the integrity of the filter was not
compromised during or before use.
Environmental
monitoring is crucial to maintaining aseptic conditions. We
recommend that microbiological testing of aseptic
workstations be performed
during sterility testing and critical aseptic manipulation. Methods
can include using swabs or contact plates for surfaces and settling
plates or dynamic air samplers for air quality.
Proposed § 212.50(f)(1) states that for PET
drug production in which every batch undergoes full finished-product
testing to ensure the PET drug product meets all specifications
(e.g., F18 FDG), process verification is not required.
Proposed § 212.50(f)(2) would require that when
the results of the production of an entire batch of a PET drug
product are not fully verified through finished-product testing or
when only the initial sub-batch in a series is tested, the PET drug
producer would have to demonstrate that the process for producing
the PET drug product is reproducible and is capable of producing a
drug product that meets the predetermined acceptance criteria.
Process verification activities and results would have to be
documented. Documentation would have to include the date and
signature of the individual(s) performing the verification, the
monitoring and control methods and data, and the major equipment
qualified. The determination not to conduct process verification
should be supported by scientific rationale and data.
For a PET production
facility that has an established history of PET drug production, the
process verification can be accomplished using historical batch
records, provided that there is adequate accumulated data to support
a conclusion that the current process yields batches meeting
predetermined acceptance criteria. We recommend that a
comprehensive review of accumulated production, testing, and control
data be conducted according to a written protocol defining the
acceptable conditions. The accumulated data should verify that the
process used was consistent and should document all changes to and
failures of the process.
We recommend that new
processes or significant changes to existing processes be shown to
reliably produce PET drug products meeting the predetermined
acceptance criteria before any batches are distributed. This
verification should be conducted according to a written protocol and
generally include at least three consecutive acceptable production
runs.
Because PET drugs have
short half lives, a PET producer may decide to evaluate the
reliability of a new process or a significant change to an existing
process to produce a PET product, meeting the predetermined
acceptance criteria concurrently with the distribution
of the batch. Such a decision should be justified in writing,
subjected to quality control procedures, and performed according to
a written protocol. Under this situation, we recommend each batch be
processed in strict adherence to the written procedures, fully
tested (except sterility testing), and found to comply with all
procedural and quality test requirements prior to final release.
Synthesis of some PET
drugs can be executed under automated or computer control. We
recommend that the computer program be verified before first use to
demonstrate that it is suitable for its intended purposes and is
capable of producing results that meet the predetermined acceptance
criteria. We also recommend that subsequent changes or upgrades
made to the computer program be documented and the process
demonstrated to be capable of producing a PET drug product that
meets the predetermined acceptance criteria. PET production
facilities can rely on a certification by the software or system
vendor that the specified software was verified under its operating
conditions.
Proposed 21 CFR 212.60 would require the
establishment and implementation of procedures for testing
components, in-process materials, and finished PET drug products.
All necessary tests of materials and products would have to be
documented. Each laboratory would also be required to have
sampling and testing procedures designed to ensure that components,
drug product containers and closures, in-process materials, and PET
drug products conform to appropriate standards. Analytical methods
and test equipment would have to be suitable for their intended
uses. Reagents, solutions, and supplies used in testing procedures
would have to be adequately controlled. The preventive maintenance,
calibration, and procedures to make sure that the equipment is
functioning properly would have to be documented. A complete record
of all tests related to the production of a PET drug product would
have to be kept to ensure compliance with established specifications
and standards, including examinations and assays, as follows:
! A description
of the sample received for testing, including its source, the
quantity, the batch or lot number, the date (and time, if
appropriate) the sample was taken, and the date (and time, if
appropriate) the sample was received for testing.
·
A description of each method used in the testing of
the sample, a record of all calculations performed in connection
with each test, and a statement of the weight or measurement of the
sample used for each test.
·
A complete record of all data (including graphs,
charts, and spectra). For example, a print-out of the chromatogram
with the calculated amounts of each component analyzed by the test
·
A statement of results of the tests and their relation
to acceptance criteria
- The initials or signature of the analyst and
the date of the test
Under proposed
§ 212.60, a PET production facility would have to have written test
procedures that describe how to conduct each test of finished
products and, where applicable, of components and in-process
materials. Appropriate testing procedures would have to be
established to ensure that PET drug products conform to appropriate
standards, including established standards (e.g., relevant USP
monographs) of identity, strength, quality, and purity. Analytical
tests would have to be suitable for their intended purpose and have
sufficient sensitivity, specificity, and accuracy.
We recommend that any new analytical test
method be validated, through documented data, to show that it will
consistently yield results that accurately reflect the quality
characteristics of the product tested. The FDA and USP have
published information for determining the appropriate analytical
parameters (e.g., accuracy, precision, linearity, ruggedness) that
should be used to validate a new method (see ICH Q2A Text on
Validation of Analytical Procedures and USP General Chapter
<1225> Validation of Compendial Methods). On the other hand,
validation is not required for compendial methods.
If a USP analytical test method is used, a PET
producer should verify that the method works under the actual
conditions of use.
Most analyses use reference standards. We
recommend that PET production facilities establish the reference
standards identified in the analytical procedure or SOP. When a
primary reference standard is obtained from an officially recognized
source (e.g., USP), the material usually does not need further
testing if it is stored under conditions consistent with the
supplier’s recommendations. However, where an official standard is
not available or if a PET production facility establishes its own
reference standard, we recommend that data to fully confirm the
material’s identity and purity be established and documented.
Documentation such as reference spectra or other supporting data to
prove the identity and purity of the reference standard may be
available from the supplier.
Under proposed § 212.60(f), equipment would
have to be routinely calibrated and maintained according to the
established written procedures (see Section VI). We recommend that
PET production facilities verify that the equipment is in good
working condition at the time the samples are analyzed. We also
recommend that prior to each day of use of the HPLC and GC, a system
suitability test using reference standards be conducted to verify
that the resolution and reproducibility of the chromatographic
system are adequate for the analysis to be done.
We recommend that any reagent or solution
prepared on-site be adequately controlled (including temperature
control, if applicable) and properly labeled with respect to
identity, composition, and expiration date.
Raw test data (such as chromatograms, spectra,
and printouts) and any calculations performed can be documented and
become part of the batch production and control record. Records
should have information such as the source of the test material, a
description of the appearance of the material, the amount used, test
and acceptance criteria, and an entry for data and interpretation of
results. Laboratory controls should be followed and documented at
the time of performance. We recommend that deviation from written
procedures be documented and justified. Any out-of-specification
results obtained should be investigated and documented.
Proposed 21 CFR 212.61 would require the
establishment of a written stability testing program for each PET
drug product. This program would have to be used to establish
suitable storage conditions as well as expiration dates and times.
As with other drug products, PET drug molecules
are expected to remain stable during storage. Although PET drug
products have extremely short shelf lives, because of their short
half lives compared to other kinds of drug products, there are
stability concerns due to radiation-related radiolysis. Certain PET
drug products (e.g., F18 fluorodopa) can undergo very rapid chemical
changes. Therefore, appropriate parameters should be evaluated to
establish and document the stability of PET drug products under
proposed storage conditions. Examples of stability parameters
include radiochemical identity and purity (including levels of
radiochemical impurities), appearance, pH, stabilizer or
preservative effectiveness, and chemical purity. We recommend that
appropriate stability-indicating methods that can distinguish
degradation products and impurities be used. Stability testing of
the PET drug product should be performed at the highest radioactive
concentration, and the whole batch volume in the intended
container/closure should be stored. At least three production runs
of the final product should be studied for a time period equal to
the labeled shelf life of the PET drug product.
Although stability studies in support of an
expiration dating period would be needed for approval of a PET drug
product, subsequent changes to the expiration date could be made
without prior approval (changes would be noted in the annual report
for the drug product).
Proposed 21 CFR 212.70 would require that
specifications be established and met for each PET drug product
batch, including identity, strength, quality, purity, and, if
appropriate, sterility. The proposed regulation would require the
implementation of procedures to ensure that a product is not
released until appropriate laboratory testing is completed,
reviewed, and approved by an appropriate releasing authority.
Proposed 21 CFR 212.71 would require a PET
production facility to reject PET drug products that fail to meet
acceptance criteria. Procedures would have to be established to
identify and segregate the product. There would have to be
predetermined procedures for investigating the cause of the problem
and preparing a timely report on the occurrence, including a
description of the corrective action taken, where appropriate.
Methods of PET drug production may differ from
site to site. As a result, there may be specific impurities to
assess depending on the method of production, such as kryptofix in
FDG F 18. We recommend using approved NDA specifications, or the
IND accepted specifications. Under proposed § 212.70, PET
production facilities would have to ensure that each batch of PET
drug product meets its established acceptance criteria, except for
sterility (see subsection C below), before it is given final
release.
Sterility testing would have to be started
within 30 hours after the completion of PET drug production. If
the sample for sterility testing is held longer than indicated
(e.g., over the weekend), PET producers should demonstrate that the
longer period does not adversely affect the sample and the test
results obtained will be equivalent. The samples should be stored
appropriately (e.g., under refrigeration). Verification of
equivalent results can be accomplished by inoculation of USP
indicator organism(s) and demonstrate that there is little, if any,
loss in viability of the inoculated microorganism. The USP General
Chapter <71> Sterility Tests provides information about media
and incubation conditions.
We recommend that testing be conducted in a
controlled area such as a laminar airflow workbench (LAFW) with
clean-room apparel. Aseptic techniques should be used for sterility
testing. The greatest risk of false-positive results arises in the
sampling and transfer of the test aliquot from the vial to the
media. It may be convenient to apply direct inoculation into
commercial media. We recommend that the media be observed on days
3, 7, and 14 after inoculation, but it is prudent to observe the
media more often during the first week of incubation.
The USP Bacterial Endotoxins Test (BET)
(General Chapter <85>) should be performed for a sterile PET drug
that is intended for injection. The BET contains gel-clot and rapid
photometric methods for endotoxin measurement.
The product can be distributed under control
after a pharmacopeial bacterial endotoxin test is initiated.
However, the endotoxin results should meet the acceptance criteria
before administering the product to humans.
If the result of any bacterial endotoxin test
exceeds the acceptance limit, or if a sterility test is positive for
microbial growth, we recommend a complete investigation be conducted
immediately and documented. We recommend that corrective actions
based on the results of the investigations be implemented promptly.
We recommend the designated individual review
all laboratory testing and documentation from the batch record to
determine whether or not the PET drug product has met all acceptance
criteria. If the product has met acceptance criteria, the
designated individual with quality assurance function should sign
and date the release sections of the batch record and sign a release
for human administration.
In many cases, modifications to this standard
procedure for product release may be appropriate. For example,
transportation deadlines may justify a prerelease for distribution
before all elements of testing and review are finalized. Other than
sterility testing, all finished-product tests would have to be
completed or in progress at the time of shipment or distribution and
PET drug products can be released for distribution (but not
administration) while some tests are pending. Under proposed §
212.70, these tests would have to be completed prior to final
release for human administration. When it is determined that all
acceptance criteria have been met, the PET production facility
should then provide a notice of final release to the receiving
facility so that the dose may be given to the patient. We recommend
the establishment of effective procedures for immediate notification
of the receiving facility if there is evidence of an
out-of-specification result. Notification of the receiving facility
due to product failure should be documented.
PET drugs that have a very short half life
(e.g., ammonia N 13) can be produced in multiple sub-batches on the
same day. End product testing of the initial sub-batch can be
conducted, provided a sufficient number of sub-batches (beginning,
middle, and end) have been demonstrated to produce a product meeting
the predetermined acceptance criteria. For routine production in
this circumstance, the release of subsequent sub-batches can be
qualified if the initial sub-batch meets all acceptance criteria.
In certain cases, testing each sub-batch for certain attributes
prior to release may be appropriate (e.g., for pH determination in
ammonia N-13 production method using Devarda’s alloy catalyst).
When one of the required finished product tests
cannot be completed due to a breakdown of the analytical equipment,
proposed 212.70 (f) establishes criteria under which PET producers
may still release the drug product for human use. If equipment is
properly maintained, breakdowns should be a rare occurrence. We
recommend that PET producers determine if the missing testing would
adversely affect the safety and effectiveness of the PET drug
product. Conditional release should be extremely infrequent. Only
products that meets all conditional release criteria would be able
to be released. Conditional release of a PET drug product would not
be permitted if a PET drug producer could not perform a
radiochemical identity/purity test on the active pharmaceutical
ingredient of a PET drug product. All activities of conditional
release would have to be documented.
Under proposed § 212.71(a), a batch of a PET
drug product that fails to meet established specifications would
have to be rejected, and procedures would have to be established to
identify and segregate the product. Proposed § 212.71(b) would
require that documentation of the investigation of a nonconforming
product include the results of the investigation and final
disposition of any rejected product.
Under proposed § 212.70 (d), a drug product can
be reprocessed if pre-established procedures (set forth in
production and process controls) are followed and the finished
product conforms to specifications before final release. When the
option for reprocessing is exercised, we recommend that the event be
documented and conditions described in a brief deviation report.
Examples of reprocessing could include a second passage through a
purification column to remove an impurity, or a second passage
through a filter if the original filter failed the integrity test.
Proposed 21 CFR 212.80 would require that:
- A PET drug product be suitably packaged and
labeled to protect the product from alteration, contamination, and
damage during the established conditions of storage, handling, and
shipping.
- Labels and packaging operations be
controlled to prevent labeling and product mix-ups.
- All information stated on each label be
contained in each batch production record.
Regardless of the scope of operation of a PET
production facility, we recommend that appropriate measures be taken
to handle labels in a way that prevents mix-ups with any other
labeling materials.
We recommend that PET drug products be labeled
with adequate, legible identifying information to prevent errors
during storage, shipment, and use.. Once an NDA or ANDA is approved
for a PET drug product, the label approved in the NDA must be used.
Prior to approval of the NDA or ANDA, the label should be approved
by persons responsible for quality assurance procedures. Labels can
be computer generated or handwritten.
Because of radiation exposure concern, it is a
common practice to prepare much of the labeling in advance. For
example, an empty product vial can be prelabeled with partial
information (e.g., product name, batch number, date) prior to
filtration of the radioactive product, and upon completion of QC
test, the outer shielded container can be labeled with the required
information (e.g., radioactivity). Alternatively, a string label
can be used to label the immediate container provided that there is
a way to associate the label with the vial if the label were to come
off. Different approaches can be used as long as the approach
ensures that the required information is available on the label. A
label identical to that affixed to the container shield can be
incorporated into the batch production record. A final check should
be made to verify that the correct and complete label has been
affixed to the container and the shield.
Proposed 21 CFR
212.90 would require the development of procedures to ensure that
the shipment will not adversely affect the product. PET production
facilities would have to maintain distribution records for PET drug
products.
PET drug products should be shipped in
accordance with labeled conditions (e.g., temperature) to ensure the
identity, purity, or quality of the drug product. For PET
production facilities distributing to outside clients or outside
pharmacies, information on the method of shipment and the contact
person at the final destination should be included. We recommend
that a system be put in place by which the chain of distribution of
each batch of PET drug product can be readily determined to permit
its recall if necessary. A recall should consist of notifying the
receiving facility, pharmacist, and the patient’s physician, if
known. When the receiving facility disposes of the recalled drug,
the PET drug producer can obtain a notification from the receiving
facility confirming the recalled drug has been disposed of and
describing the manner in which it was disposed.
When the PET production facility ships the
final released PET drug product supplied as a pharmacy bulk package
(USP<1> Injections) to a nuclear pharmacy for dispensing into
individual patient doses, FDA generally regards subsequent
distribution of the drug product as part of the practice of
pharmacy.
Proposed 21 CFR 212.100 would require that
procedures be developed and implemented for receipt and handling of
all complaints pertaining to a specific PET drug product, including
review by a designated individual to determine compliance with
specifications and to initiate an investigation into the problem. A
file for drug product complaints would have to be maintained. The
file would have to contain the name and strength of the PET drug
product, the batch number, the name of the complainant, the date the
complaint was received, the nature of the complaint, and the
response to the complaint. The file would also have to include the
findings of any investigation and followup. A PET drug product
implicated in a complaint could not be reprocessed and would have to
be destroyed in accordance with applicable Federal and State law.
We recommend that the designated individual be
responsible for collecting as much information as possible about the
drug and the nature of a complaint and for completing an
investigation of the matter as soon as possible. Corrective action
should be taken immediately if there is any reason to believe that
an adulterated drug was implicated in the complaint. Under proposed
§ 212.100(c), complaints would have to be maintained in a file
designated for that purpose. We recommend that complaint files be
easily retrievable for review and trending.
Proposed 21 CFR 212.110(a) would require that
all records be maintained at the PET production facility or another
location that is reasonably accessible to responsible officials of
the PET production facility and FDA investigators.
Proposed § 212.110(c) would require that all
records referenced in part 212 be kept for at least 1 year from the
date of final or conditional final release of a PET drug product.
The regulation would require that records be
stored at a PET production facility or another location that is
reasonably accessible. A reasonably accessible location is one that
would enable the PET production facility to make requested records
available to an FDA investigator in a reasonable period of time
during an inspection. The records would have to be legible and
stored in a manner that prevents their deterioration and/or loss.
We recommend that forms for collecting data be
kept to a minimum by designing multipurpose documents and
eliminating redundancy, where possible. It is prudent to have as
much of the required information within the batch production record
as possible. Records can be kept electronically.
Other records that would have to be kept
include information relating to the composition and quality of the
PET drug product and operation of the production processes, such as
laboratory records, out-of-specification results, master and batch
records, distribution records, and complaint files. Records
relevant to materials and PET drug products would have to be kept at
least 1 year from the date of final or conditional final release.
Verification reports should be kept as long as the systems are in
use.
FDA. Guide to Inspection of Computerized
Systems in Drug Processing. February 1983.
FDA. General Principles of Process
Validation. May 1987.
FDA. Sterile Drug Products Produced by
Aseptic Processing. June 1987.
FDA. Q2B Validation of Analytical
Procedures: Methodology. May 1977.
FDA. Q2A Text on Validation of Analytical
Procedures. March, 1995.
FDA. 21 CFR Part 11; Electronic Records;
Electronic Signatures. FR Notice 7/21/99 (64 FR 39146).
U.S. Pharmacopeia. <1> Injections. USP
26, NF 21, 2003.
U.S. Pharmacopeia. <71> Sterility Tests.
USP 26, NF 21, 2003.
U.S. Pharmacopeia. <85> Bacterial Endotoxins
Test. USP 26, NF 21, 2003.
U.S. Pharmacopeia. <621> Chromatography.
USP 26, NF 21, 2003.
U.S. Pharmacopeia. <821> Radioactivity.
USP 26, NF 21, 2003.
U.S. Pharmacopeia. <823>
Radiopharmaceuticals for Positron Emission Tomography-Compounding.
USP 26, NF 21, 2003.
U.S. Pharmacopeia. <1015> Automated
Radiochemical Synthesis Apparatus. USP 26, NF 21, 2003.
U.S. Pharmacopeia. <1225> Validation of
Compendial Methods. USP 26, NF 21, 2003.
The draft guidance for industry PET Drug Applications — Content and
Format for NDAs and ANDAs, which was issued in March 2000,
will be available soon in final. Also, a sample format for a
batch production and control record is available at
http://www.fda.gov/cder/regulatory/pet
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Date created: September 16, 2005 |