pharmaceutical manufacturing evolves from an art form
to a science-based process, the Food and Drug Administration
is eyeing opportunities to translate better information
about product quality into more risk-based regulatory
review and inspection policies. The over-ridingS goal
is to apply a "quality by design" approach
to pharmaceutical manufacturing to achieve the "desired
state" of product quality and performance, explains
Ajaz Hussain, deputy director of the Office of Pharmaceutical
Science (OPS) in FDA's Center for Drug Evaluation and
Research (CDER). At the July meeting of FDA's Manufacturing
Subcommittee of the Advisory Committee on Pharmaceutical
Science, Hussain and others outlined a number of steps
FDA is taking to encourage more rational pharmaceutical
development and manufacturing systems.
If a manufacturer can demonstrate a good understanding
of key product attributes (e.g., stability, bioavailability)
and provide evidence that it can control critical variables
and detect product deviations, regulatory authorities
will be able to review applications in one review cycle,
permit improvements in a manufacturing process without
prior approval, and implement a risk-based inspection
process, explains Pfizer Vice-President John Berridge.
To achieve this ideal situation, FDA is taking steps
to re-engineer its chemistry, manufacturing, and controls
(CMC) review process in new drug applications (NDAs)
and abbreviated NDAs (ANDAs) for generic drugs. Prime
goals are to curb multiple review cycles, reduce application
resubmissions, and reduce oversight of most postapproval
changes. At the same time, FDA is working with other
regulatory authorities and manufacturers to reach agreement
on new standards for submitting drug quality information
in the common technical document (CTD) developed by
the International Conference on Harmonization (ICH).
Streamlining CMC reviews
The current CMC review system is resource-intensive,
imposes unnecessary regulatory burdens on industry,
and discourages manufacturers from making improvements
such as those achieved through process analytical technologies
(PAT) in approved products, observed Moheb Nasr, director
of CDER's Office of New Drug Chemistry (ONDC) in OPS.
He cited a number of factors for this unfortunate state:
* ONDC reviewers evaluate all CMC information, regardless
of its importance or the reviewer's expertise.
* Applications closely follow FDA and ICH guidances,
even if a different manufacturing approach is more logical.
* ONDC does not examine manufacturing process information
in detail because the current system leaves that task
to FDA's field force.
* FDA and manufacturers seek tight product specifications
determined by limited data to ensure consistency in
a manufacturing process; this often leads to recalls
and drug shortages.
* Manufacturers frequently submit late and voluminous
CMC amendments, which delay reviews.
* NDAs seldom include critical information about pharmaceutical
development which is necessary for a risk-based assessment
of the product.
* CMC information in applications varies widely because
many applicants fail to consult with FDA before filing
an NDA, and fail to follow agency recommendations when
These factors delay application approvals and discourage
manufacturers from improving systems, adding to the
cost of already expensive new drug products. A recent
study found that manufacturing problems are responsible
for delaying first-cycle NDA reviews of many new molecular
entities. And with its workload rising, CDER is eager
to eliminate unnecessary and redundant activities. This
past year, ONDC reviewed 159 NDAs, 342 commercial investigational
new drug applications (INDs), 1745 supplements, and
more than 1000 annual reports.
A risk-based CMC review system, which is being developed
first for conventional drugs, will focus on the relevance
to safety and efficacy of critical quality attributes
such as chemistry, formulation, manufacturing processes,
dosage form, and product performance, Nasr explains.
Interdisciplinary teams of chemists, pharmacists, engineers,
and others using modern statistical methods to evaluate
information in pharmaceutical development reports (PDRs)
and a quality overall summary (QOS) will conduct reviews.
The new approach aims to achieve more consistency among
chemistry review teams and improve FDA's ability to
oversee new technologies, combination products, and
novel dosage forms.
FDA is implementing this more streamlined review approach
first for CMC sections of resubmitted NDAs. Under a
pilot study, a senior CMC reviewer will conduct a quick
(14-day) preliminary assessment of a resubmission, order
a copy of any referenced drug master file, and develop
an "assessment protocol" for reaching approval.
This information then will go to a primary reviewer
who will perform an in-depth assessment and seek to
resolve CMC issues quickly.
ONDC also is exploring ways to down-regulate or eliminate
those CMC supplements unlikely to adversely affect the
quality, purity, or stability of a drug product. A more
efficient supplement review process would encourage
continuous post-marketing product improvement by manufacturers
and also free up ONDC resources for NDA reviews, Nasr
comments. A related initiative is to encourage manufacturers
to submit comparability protocols (CPs) in NDAs to link
the current CMC policy to this new quality assessment
approach. CPs also can facilitate continuous improvement
by reducing the need to file manufacturing supplements
when a firm wants to change a manufacturing process
or product attribute.
Speeding up generics
Similar initiatives are being adopted by CDER's Office
of Generic Drugs (OGD), which continues to struggle
with an increasing number of ANDAs and supplements.
OGD expects to receive nearly 600 ANDAs and more than
3500 supplements this year, noted OGD director Gary
Buehler at the advisory committee meeting. On average,
OGD takes 18 months to approve an ANDA because all applications
must sit in a never-diminishing queue, with no preference
allowed for very complete or very simple submissions
that could be processed quickly. ANDA approvals also
are delayed by legal disputes and lawsuits, which appear
to be intensifying (see sidebar, "Generic drug
Buehler would like more authority to identify applications
suitable for quick review treatment and to review groups
of applications for the same product. But because Congress
must authorize such a change in the "first-in,
first-reviewed" generic drug approval process,
Buehler is trying to streamline the ANDA review system
One initiative is to encourage manufacturers to calculate
product specifications more carefully, which would reduce
the time OGD staff must spend negotiating tighter limits.
An OGD study found that 40% of all deficiencies in first
cycle reviews relate to overly loose specifications,
Buehler notes. He urges manufacturers to determine specifications
on the basis of knowledge of the manufacturing process
and critical product attributes and to provide a clear
rationale for how specifications are selected.
This process, Buehler believes, will lead to more one-cycle
reviews in initial applications and permit expedited
handling of later supplements. Basing reviews on knowledge
of the product and which manufacturing changes will
make a difference represents "a fundamental change
in thinking," Buehler says. The benefits for manufacturers
are greater flexibility to improve manufacturing processes,
more ease in making post-manufacturing changes, and
fewer problems in plant inspections. Buehler is urging
generics makers to demonstrate their expertise in drug
product manufacturing by incorporating advances in pharmaceutical
science and manufacturing technologies to improve product
quality and reduce risk. Such an approach, he comments,
will help generics makers challenge any perception that
generic drugs are lower in quality than innovator products.
In addition to streamlining its own CMC review process
and data requirements, FDA is looking to gain international
agreement on risk-based quality standards through the
ICH. In the past year, regulators in the European Union
(EU), Japan, and the United States agreed to develop
new guidance encouraging manufacturers to provide information
that reflects a better understanding of critical product
and manufacturing design and process factors. The aim
is to encourage risk-based approaches to manufacturing
oversight and continuous improvement strategies in all