Bringing in biologics
The success of the CMC pilot for conventional drugs has prompted CDER to launch a similar initiative for biotechnology submissions.
FDA announced the program in July 2008, calling for manufacturers to voluntarily submit CMC information in an Expanded Change
Protocol (ECP) that describes the implementation of QbD and risk-management approaches for large molecules. OPS's Office of
Biotechnology Products (OBP) is managing the pilot, which accepts original NDAs and biologic license applications as well
The stated aims of the OBP pilot are to define clinically relevant attributes for complex products and link these approaches
to the manufacturing process. Although many QbD principles apply equally to small molecules and to biologics, assessing relevant
attributes is "a much greater challenge for complex pharmaceuticals," states FDA (1). Manufacturers have used comparability
protocols to describe the specific tests and acceptance criteria that can ensure that a single manufacturing change will not
produce negative effects. ECPs will describe QbD approaches and critical quality attributes as applied more broadly to multiple
unit operations. As with drugs, QbD approaches for biologics aim to reduce process variability and to produce consistent therapies
that meet quality attributes related to the product's efficacy and safety. This task is more difficult for biotechnology products
because they are hard to characterize, and their manufacturing processes are more complex and variable.
Through the OBP pilot, FDA hopes to learn more about ways to link product performance characteristics and quality attributes
to clinically relevant measures. The program is limited to 10 supplements and five original applications, preferably products
that have been overseen by OBP through the product-development and testing process and that have benefited from early discussions
between the manufacturer and FDA reviewers about development issues. Several manufacturers have indicated interest in participating
and may submit applications and supplements for pilot review during the next two years.
That information should help the regulators implement a QbD, risk-based approach for complex products and to develop guidance
for industry. As with the CMC pilot for drugs, manufacturers that adopt quality and risk-based approaches may gain leeway
to make manufacturing-process changes without submitting postapproval manufacturing supplements.
Modifying early studies
Another FDA effort to establish appropriate oversight of drug manufacturing and quality-control methods involves modifying
certain requirements for producing test therapies used in Phase I clinical trials. As part of its campaign to encourage innovative
drug development, FDA proposed a new policy two years ago to exempt investigational drugs for early studies from certain GMP
regulations. The agency withdrew that proposal, however, in the face of objections that the change could jeopardize the health
and safety of participants in clinical trials. Since then, FDA has reviewed those comments and devised a new, more clearly
articulated final rule.
The new policy, which took effect in September 2008, explains more clearly that FDA is modifying only manufacturing requirements
that are not relevant for producing materials for early clinical trials (2). The agency has not changed policies designed
to ensure drug quality during studies of large numbers of patients or during commercial production. Instead, the rule drops
the requirement of a fully validated manufacturing process (including rotation of stock for drug-product containers) for products
made for use in Phase I trials and the requirement for separate packaging and production areas.
The main beneficiaries of the policy are expected to be research laboratories and clinics that conduct investigatorinitiated
studies. Some biotechnology companies might find the new policy helpful in producing small quantities of costly therapies
because the rule applies to vaccines, recombinant biopharmaceuticals, in vivo diagnostics, blood products, and gene therapies.
But most drug and biotechnology manufacturers that enter Phase I studies with the expectation of moving on to Phase II and
III trials are expected to meet GMP standards even when producing initial clinical supplies. Pharmaceutical companies want
to ensure that all procedures are in place for future scale-up to larger trials—where test products must meet GMP requirements
—and for eventual commercial production. Moreover, study sponsors want to avoid questions about the validity of data from
a Phase I study that result from complaints that the test drug was not produced by a well-controlled, reproducible process.
In general, FDA leaves it to manufacturers to determine whether it makes sense in their particular case to produce Phase I
drugs without fully complying with Part 211 regulations. Even manufacturers that decide to drop certain irrelevant manufacturing
procedures are still responsible for ensuring the quality and safety of their investigational drugs. And FDA emphasizes that
it always retains the right to halt a clinical trial if it finds that a test drug fails to meet quality standards.
To avoid such problems, FDA also issued a companion guidance with recommendations for establishing appropriate quality-control
procedures for meeting GMP requirements for clinical supplies. The guidance emphasizes that manufacturers of test products
should have well-defined written procedures, an adequately controlled manufacturing system, and accurate records from product
testing and manufacture. Anyone producing even small quantities of a drug should conduct a comprehensive and systematic evaluation
of the manufacturing setting (i.e., equipment, process, personnel, and materials) to identify and eliminate potential hazards.
Small-scale operations may do this efficiently by using disposable equipment and prepackaged materials that reduce the chances
of contamination. Using contract or shared manufacturing facilities and testing laboratories also may be helpful.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, email@example.com
1 FDA, "Submission of Quality Information for Biotechnology Products in the Office of Biotechnology Products; Notice of Pilot
Program," Fed. Regist.
73 (128), 37973 (July 2, 2008).
2. FDA, "Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials," Fed. Regist.
73 (136), 40453–40462 (July 15, 2008).