In its comments on the preliminary draft regulations on CGMP
for PET drug products that FDA issued in September 1999, the PET community
focused on five major concerns. These were: (1) requirements for
not-for-profit institutions vs. commercial manufacturers, (2) identity and
sample testing of PET drug components, (3) reserve samples, (4) release of
product after equipment breakdown, and (5) methods validation. FDA
addresses some of these issues in the preliminary draft proposed rule (PDPR)
on PET drug CGMP; other issues are addressed in FDA’s draft guidance on
CGMP for PET drugs. Notices of the availability of the PDPR and the draft
guidance were published in the Federal Register on April 1, 2002.
Following is a summary of FDA’s response to these issues
raised by the PET community:
· Relevant differences
between not-for-profit institutions and commercial manufacturers:
Section 121 of the Food and Drug Administration
Modernization Act directs FDA to take due account of any relevant
differences between not-for-profit institutions and commercial
manufacturers in developing approval procedures and CGMP for PET drugs.
The PET community noted that this issue was not specifically addressed in
the preliminary draft regulations.
The draft guidance notes that we closely examined the
operations of many PET drug producers, including not-for-profit
institutions and commercial manufacturers. We reached the conclusion that
a PET center’s status as a not-for-profit or for-profit entity does not
have a significant bearing on the quality of drugs that it produces or the
methods, facilities, and controls it needs to ensure product quality.
Instead, production and CGMP differences are a function of the size,
scope, and complexity of a PET center’s operations. The draft guidance
states that we have designed the CGMP regulations to be sufficiently
flexible to accommodate not-for-profit, academically oriented institutions
that make PET drug products for their own patients and research use as
well as larger commercial producers that serve a greater number of
patients in a broader region. For many aspects of CGMP, the draft guidance
makes different recommendations depending on the size, scope, and
complexity of a PET center’s operations.
· Identity testing and
sample testing:
The preliminary draft regulations stated that an identity
test must be conducted on each lot of PET drug components, containers, and
closures. They also stated that a representative sample of each lot of
component, container, and closure must be tested for conformity to its
written specifications. However, a report of analysis from the supplier
could be accepted provided the PET center established the reliability of
the supplier’s test results, performed at least one specific identity
test on each lot of components, and conducted at least a visual
identification of each lot of containers or closures. The PET community
expressed concerns about certain aspects of these requirements.
The PDPR clarifies when identity testing must be conducted
on a lot of a PET drug component. Rather than having to conduct an
identity test on each lot of all components, a PET center would only have
to test each lot of a component that yields an active pharmaceutical
ingredient and each lot of an inactive ingredient (the PDPR would not
require identity testing of reagents and solvents). If the PET center uses
as an inactive ingredient a product that is marketed as a finished drug
product intended for intravenous administration, the PET center would not
have to perform a specific identity test on that ingredient. Regarding
sample testing to ensure conformity with specifications, the PDPR deletes
the requirements (when relying on a supplier’s report) to also perform a
specific identity test on each lot of component and conduct a visual
identification of each lot of containers and closures.
· Reserve samples:
The preliminary draft regulations contained a requirement
to keep a reserve sample from each batch of a PET drug product for thirty
days. The PET community opposed this requirement, noting that sometimes a
batch contains only one vial and a patient may require the entire batch.
The PDPR deletes the requirement to keep a reserve sample
from each batch.
· Release of product after
equipment breakdown:
The preliminary draft regulations stated that a PET center
must conduct laboratory testing to confirm that each PET drug meets the
acceptance criteria before release of the drug product. The PET community
stated that it would like to be able to release a PET drug product when a
PET center was unable to complete a particular analytical test due to a
temporary equipment breakdown.
In the PDPR, we state that we are considering whether to
include a provision that would permit final release of a PET drug product
even though the PET center could not complete a required finished-product
test because of equipment failure. However, because we do not want to
create an exception that would expose patients to unnecessary risks for
the sake of convenience, we believe that such a release would only be
appropriate under certain conditions. To help determine whether the
proposed exemption is appropriate, we are asking for comments on issues
relating to equipment failure.
· Methods validation:
The preliminary draft regulations stated that the
processing of each PET drug must be validated according to established
procedures. The PET community suggested that retrospective, repeated
end-product validation is appropriate for the validation of many of the
methods used in producing well-established PET drugs.
The draft guidance basically agrees. It states that for a
PET center that has an established history of PET drug production,
validation of a PET drug can be conducted retrospectively, provided that
the current process is supported by adequate accumulated data to support a
conclusion that the process is normally sufficiently capable of
yielding batches meeting predetermined specifications.
