June 4, 2002

Dockets Management Branch (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Rockville, MD 20852

Submitted electronically to:
[fdadockets@oc.fda.gov](http://www.fda.gov/dockets/ecomments)

Re: \[Docket No. 99N-4063\] Current Good Manufacturing Practice for
Positron Emission Tomography Drug Products; Preliminary Draft Proposed
Rule

Attention: Dr. Brenda Uritani, CDER

The stakeholders in PET radiopharmaceutical production at Syncor
International Corporation have reviewed the preliminary proposed rule
for current good manufacturing practices for positron emission
tomography (PET) drug products that was published in the April 1, 2002
issue of the *Federal Register.* We offer the following comments and
suggestions regarding this document to you and members of the Agency's
PET Steering Committee. These comments are being submitted
electronically as directed in the "Comments" section of the *Federal
Register* announcement.

Syncor International is a leader in PET products provided to the
healthcare system. We currently have ten PET radiopharmaceutical
production sites in this country, operating as Syncor Advanced Isotopes,
LLC, a wholly owned subsidiary of Syncor International Corporation. The
comments that follow have been submitted by the following Syncor
stakeholders:

Katherine Seifert, Executive Director of Quality and Regulatory for
Syncor International

Janice Brownlee, Program Director, FDA/Quality Systems for Syncor
International

Dennis Eshima, Director of Technical Operations, Syncor Advanced
Isotopes, LLC

Charles Parraga, Regional Supervisor, Syncor Advanced Isotopes, LLC

Dao Pho, Regional Supervisor, Syncor Advanced Isotopes, LLC

Tony Tascione, Regional Supervisor, Syncor Advanced Isotopes, LLC

Most of these individuals, as well as other Syncor stakeholders, also
attended the Public Meeting held on May 21, 2002.

In general, we find the Proposed Rule to be responsible in its
requirements for production of PET drug products and their special
considerations. However, we have identified within the Proposed Rule the
following issues that we believe should be further modified or clarified
to best serve the PET industry and the caregivers/patients it serves:

**Note:** We believe there should be a Scope section that defines the
applicability of these rules and whether or not such PET drugs are
covered by these rules if they are for research use under an
FDA-accepted IND application or in accordance with 21 CFR 361.1
provisions(RDRC).

**212.1**

-   The definition for "active pharmaceutical ingredient" includes
    reference to pharmacological activity, which is inappropriate to
    discussions of PET drugs, and therefore should be deleted from this
    definition. We would suggest that "complaint" be defined to provide
    clarification and assist in compliance with section 212.100. We
    would suggest the following definition: "Any written, electronic or
    oral communication that alleges the PET drug product failed to meet
    its specifications regarding identity, quality, strength, purity or
    effectiveness for its intended purpose".

-   We would suggest that a definition for "in-process materials" be
    provided since this term is used in several places in the rule and
    it is not clear what this means in the context of PET drug
    production.

-   The definition of "master production and control record" might be
    clearer if it was described as a compilation of documents rather
    than "records". It might also be helpful to go on and explain that
    completion of a copy of the master documents during actual
    production creates the batch production record.

-   The definition of a "receiving facility" should include a nuclear
    pharmacy since they could accept a PET drug in a finished dosage
    form.

-   The definition of "strength" should be defined as the concentration
    of the API at time of calibration, not initial assay, to be in line
    with the production requirements of other radiopharmaceuticals.

-   The definition of "validation" says it is the establishment of a
    documented "program". However, the FDA's 1987 guidance document on
    process validation for drugs and devices, and the Global
    Harmonization draft issued by the FDA in 1998 both refer to
    documented evidence rather than a program. 21CFR Part 820.3 also
    defines validation as meaning "confirmation by examination and
    provision of objective evidence that the particular requirements for
    a specific intended use can be consistently fulfilled". The
    establishment of a program, in and of itself, may not offer any
    assurance of consistency in the quality of the product. To aid
    understanding and application of validation principles, it might be
    helpful if the definitions in these various FDA- supported documents
    were as consistent as possible.

-   The definition of "verification" should include the phrase
    "confirmation by objective evidence" in line with the discussion
    above on validation.

-   .

**212.2 (a)** This section again includes references to distribution
activities that are inconsistent. The first sentence in this section
includes distribution as part of cGMP's and the following sentence says
these regulations only apply to manufacturing or production activities.
It would be helpful if this could be clarified as to what aspects of
distribution, if any beyond the original consignee, are the
manufacturer's responsibility and then be applied consistently
throughout the regulation.

**212.20(c)** The last sentence implies that all specifications,
methods, processes or procedures have been validated, and therefore
should be evaluated to determine the need for revalidation following
changes. We believe this should read, " The unit also must assess the
need for revalidation after there has been a change in a validated
method or process that could affect product specifications or
procedures."

**212.20(d)** The last sentence in this section implies that a full
investigation is necessary whenever there is an error or nonconformance.
In most quality system discussions regarding nonconformances, including
21CFR 820.90, it is stated that an evaluation should be done of
nonconformances and deviations to determine the need for an
investigation. The root cause may be readily evident or the error may be
quite minor. Usually it is recommended that the amount of investigation
be commensurate with the degree of risk involved in the nonconformance
or deviation, so that those situations which potentially present the
highest probability of occurrence and/ or severity of effect are not
compromised because an equal amount of time is spent on more detectable
and less consequential ones. We would like to suggest that the wording
in this section be consistent with other FDA regulations and state
that..." the quality control unit must ensure that the errors or
failures have been evaluated to determine the need for an investigation,
that investigations are fully conducted when necessary, and that
corrective actions have been taken."

**212.40 ( c ) (1)** The first line implies that the most specific
identity test is to be used when it is available. However, the "specific
" test may be impractical in actual application due to the cost of the
equipment or the time it takes to do that test compared to the risk
involved. If you have verified the validity of the supplier's
Certificate of Analysis, and the risk of the misidentity of the
component has been considered, a variety of methods for assuring
identity should be allowed, including those that may be less specific.
The most "specific" tests may really only be needed for those components
where the misidentity of the component would otherwise not be detectable
during processing or finished product testing, and its effect is
considered potentially adverse. Perhaps this should state, "You must
conduct identity testing, *using appropriate methods*, on each lot..."
and leave it up to the facilities to determine what is appropriate given
their supplier confidence, the components used, their production
processes and PET drug product.

**212.40(e)** This section should end with the phrase, "when
appropriate" because not all components, containers and closures will
have an expiration date.

**212.50(b)(2)** We are not exactly sure what is required by this
section, and ask that it be clarified.

212.50(b)(5) We believe that the last sentence in this section should
read, "Reasonable variations are permitted in the amount of component
necessary if they are *specified* in the master production and control
record". Many methods and amounts for manufacture were established years
ago and the justification for how those ranges were determined may not
be known today but have been verified through use. If the acceptable
range is specified in the master record, that means it has been reviewed
and approved prior to implementation.

**212.50(b)(6)** We do not agree that there should be such a requirement
on yield, as it is not indicative of product quality for PET drug
products. If a PET Center wishes to monitor yield as an indicator of
process performance, need for preventive maintenance or as an economic
issue should be at their discretion, not be required. Yields for other
drug products must be monitored because you cannot realistically test
every capsule or bottle to determine if it received the correct amount
of ingredients. You rely in those settings on process validation and
testing of samples, and then use the comparison of theoretical yield to
actual yield as a means of determining that at least in theory each
product got the amount of ingredient it is purported to have. In the
case of a PET drug you get one bottle at the end and its concentration
and activity must meet specification in order for it to be released.
Whether that bottle contains as much volume as you had hoped or not does
not affect the quality of the resulting product.

212.50( c )(9) The batch record should at least reference evaluations or
investigations done, but in some programs the actual record and results
may be kept separately, i.e. in a nonconformance investigation file
etc.. Therefore, we suggest line 9 say "Indication of any deviations,
evaluations or investigations relative to the batch", to allow the
actual reports and results to be stored elsewhere if desired.

212.50(f) The FDA's Quality System Regulation, specifically 21CFR
820.75, states "Where the results of a process cannot be fully verified
by subsequent inspection and test, the process shall be validated with a
high degree of assurance and approved according to established
procedures". While we realize those regulations were written with
medical devices in mind, the applicable principles for process
validation are the same. The Global Harmonization Task Force Draft
Process Validation Guidance of 1998 also supports the concept of
"special processes" needing validation as being those that cannot
otherwise be fully verified. Therefore it may not be necessary for the
entire process used for the production of a PET drug to be validated,
because at least some aspects may be able to be fully verified through
subsequent test or inspection, every batch is tested, and because there
is only one product container at the end of the production from which
the testing material is drawn. We would recommend, in order to reflect
current approaches to validation, that this section start, " Where the
results of a PET drug production process cannot be fully verified
through subsequent inspection and test, that process must be
validated....".

212.60(b) This heading should probably be Specifications and Standards
since not all components, containers and closures have established
standards. This is also how it is described in Part 212.60(g). In
addition, it should say " sampling, *inspection* and testing procedures"
since some containers are only visually inspected. And the last line
should say, "... drug products conform to appropriate *specifications
or* standards,..." to account for those things that do not have a
published standard.

212.60(d) The last sentence says all solutions used for testing must be
labeled with identity, composition and expiration date. We believe the
identification will either provide sufficient traceability to a
procedure that describes the composition, or include the composition in
its name. Also, the composition may not easily fit on the label.
Therefore, the requirement for composition to be on the label seems
redundant and unnecessary.

212.60(f) This section just needs to have the phrase "as appropriate"
added after the word equipment. There are some pieces of equipment that
do not require calibration and others that do not require maintenance
etc.

212.60(g)(1) We do not understand why the time the sample was taken and
the time the sample was received are required, unless you are sending
the sample out to another lab for analysis and perhaps want to keep
track of how promptly the sample is tested. But, it would not seem
important to record the time a sample was taken on incoming material for
identity testing, for instance. Please modify this so that unnecessary
information is not required, or clarify the purpose

212.70(b) We believe this section should have certain exceptions- if you
are using an established USP test procedure that is specific to your
drug product or component, you should not have to re-establish its
accuracy, specificity and reproducibility. Only methods developed
in-house should require such validation. Established generic test
methods that are used during production of PET drugs, should be verified
to ensure they are suitable for that specific application.

212.70(c) In response to your question in the draft guidance on whether
or not some allowance should be made for conformance to specifications
when there is an equipment malfunction, we would urge you to add a
paragraph here to address that situation. Equipment does occasionally
malfunction and when that equipment is used in final release testing,
and you have no other alternatives in-house for determining conformance
to the specification, other arrangements need to be available. We would
suggest that if all other release criteria have been met, and the PET
center can demonstrate that historically their product has met the
missing criteria, that the product should be allowed to be released as
long as the missing test is performed as soon as possible, and if it is
possible, on a retained sample. The PET center must be prepared to
follow its nonconformance investigation procedures if the later testing
does not meet the specification, and act accordingly.

212.70(d) Note: Though not specifically required in the rule, the
preamble mentioned the need for notification of final release to the
receiving facilities. We believe this should be at the discretion of the
PET center how to handle this, but whatever method chosen must be
applied consistently. If the facility chooses to only notify when the
batch does NOT pass all criteria for final release, that should be
allowed since that is much more the exception and more apt to be done
conscientiously. Under such circumstances, confirmation of receipt of
the notification would have to be made as part of the nonconformance
investigation and the proper corrective action documented. If on the
other hand, the receiving facilities were to be notified for all
shipments to be told it is released or it is not, the notification might
not be noted as carefully and taken as seriously. The question will
ultimately be, "Is the method being used effective in preventing the
final release/distribution of nonconforming product and is it applied
consistently?"

212.70(e) With a 24 hour time limit for initiation of sterility testing,
PET product made on Friday, requires someone to come in on Saturday to
start the sterility testing, or risk higher exposure to radiation by
starting the test sooner, before they leave on Friday. If the
requirement was "on the next workday" the test could be initiated for
Friday's batch on Monday. The ultimate outcome would be the same- the
product is already in the patient in either case, and if the product is
not sterile, it will show up on the test and require the same
notifications. But the safety of the technician is heightened- they do
not have to come to the lab, possibly alone, on Saturday, and they do
not have to handle "hot" material on Friday. We would ask that some
allowance be made in this section to say "...must be started within 24
hours of sterile filtration, when practical, or on the next workday...."

This section also requires immediate notification of the receiving
facilities if product fails the sterility test. In our experience,
failed sterility tests, once investigated and repeated, have always been
found to be related to the technique, not nonsterility of the actual
product. Immediate notifications and recommendations under these
circumstances could be more detrimental than helpful. For other medical
products- drugs and devices- a reasonable amount of time (5-30 days) is
typically allowed for investigation and proper handling of reported
adverse events or malfunctions after distribution. Therefore, we would
ask that this section allow for immediate investigation and retest to
determine if the product is really nonsterile, before notification is
sent.

We would also like to request that the rule and guidance acknowledge
that the USP allows for one sterility test per production period. So PET
centers that are doing multiple runs of one product per day, should only
have to test one of those runs for sterility, but the run chosen should
be consistently applied.

212.80(a) and (e) We would suggest that the wording for these sections
be combined to avoid redundancy. In section (a), no one can always
"ensure" that the integrity of a product is maintained during shipping.
But the intention of this section to protect the product is addressed
again in section (e). The wording chosen in section (e) is more in line
with that used in other FDA regulations and reflects a more reasonable
and realistic approach. However, we would suggest the word "customary"
as used in 21CFR 820.130, rather than "established" to describe
conditions. Due to the short half-life of these products, none of them
are going outside a fairly local area, so what is "customary" better
reflects the conditions that each PET center must address for packaging,
labeling and shipping requirements. This section could be worded, "A PET
drug product must be suitably labeled and packaged to protect the
product from alteration, contamination or damage during the customary
conditions of handling and distribution."

212.90 (a) As discussed in the previous comment, the process of shipping
is not something that can be controlled by the PET center, though the
method of shipment and the container chosen can. Perhaps this section
should indicate "...that the *method* of shipping *should be chosen to
protect* the identity, purity, or quality of the PET drug product".

212.90(b)(4) We do not understand why the time you shipped is important
to note on the record- the requirement for the date we can understand.

212.110(a) We believe this section should start with the phrase, "All
records required by this rule must be maintained...." so that it is
clear which records are subject to retention requirements and FDA
inspection

Thank you for the opportunity to comment on the Preliminary Draft of
Part 212. If you would like to discuss any of these issues further,
please contact Kathy Seifert at 818-737-4514 or seifertk@syncor.com.