FDA Promotes QbD for Biotech Therapies - New pilot supports manufacturers that establish quality systems to manage product risk. - BioPharm International


FDA Promotes QbD for Biotech Therapies
New pilot supports manufacturers that establish quality systems to manage product risk.

BioPharm International
Volume 21, Issue 10


An important payoff for manufacturers that adopt QbD may be more lenient requirements governing postapproval manufacturing changes. The FDA is developing guidance that will spell out opportunities for reduced oversight of certain low-risk CMC changes. The plan is to propose some 40 categories of changes that could be downgraded to allow manufacturers to report such actions in annual reports, instead of having to file CBE (changes being effected) or CBE-30 (changes being effected in 30 days) supplemental applications. Some actions that may not need agency review involve changes to:

  • Components and composition involving a switch to a new non-functional coating material previously approved by the FDA for other products.
  • Manufacturing processes, such as installing new equipment of similar design to what's being replaced, or adding a duplicative process as part of scale-up, with no changes in parameters.
  • Site changes for testing laboratories and packaging of oral solids, but not for most biotech products.
  • Specifications related to an additional in-process test or tightening of existing acceptance criteria.
  • Container–closure systems for nonsterile drug substances or a switch to a new glass supplier for the same type of product.
  • Stability protocols that reduce test frequency or shorten an expiry date, provided there is no stability failure.

Such anticipated postapproval manufacturing changes may be spelled out in a CMC postapproval management plan currently under development by the FDA. The plan would reflect the company's understanding of process and product, and provide a scientific basis for managing change.


Another FDA effort to establish more appropriate oversight of drug manufacturing and quality control programs involves modifying some rules for producing supplies for Phase 1 clinical trails. The FDA issued a revised policy two years ago, but withdrew that proposal because of objections that the change could jeopardize the health and safety of study participants. Since then, the FDA has revised its policy to explain more clearly its rationale for modifying certain CMC requirements for producing very small quantities of a test therapy (Federal Register, Vol. 73, no. 136, July 15, 2008, p. 40453–62). The new rule drops the need for a fully validated manufacturing process for products made for use in Phase 1 trials; for rotation of stock for drug product containers; and for separate packaging and production areas.

The main beneficiaries of the policy should be research laboratories and clinics involved in investigator initiated studies. Small biotech companies that are developing vaccines, recombinant therapies, in vivo diagnostics, blood products, or gene therapies also might find the new rule helpful for simplifying the production of small quantities of costly biologics for early trials.

However, most established pharmaceutical and biotech manufacturers are expected to continue to meet GMP standards even for early clinical supplies to ensure that all procedures are in place for future scale-up to larger trials and for eventual commercial production. Those biotech companies that decide to drop irrelevant manufacturing procedures, moreover, still have to ensure the quality and safety of their investigational drugs. The FDA emphasizes that it retains the right to halt a clinical trial if it finds that a test drug fails to meet quality standards.

To avoid such problems, the FDA also issued a companion guidance with recommendations for establishing 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. The guidance points out that anyone producing a drug, even if just for early human testing, should conduct a comprehensive evaluation of the manufacturing setting to identify and eliminate potential hazards. Small-scale operations may do this more efficiently by using disposable equipment and prepackaged materials that can reduce the risk of contamination.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,

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