Quality by Design for Generic Drugs

The authors relay the outcome of a two-day workshop that brought together regulators and generic-drug industry representatives.
Oct 02, 2009
Volume 33, Issue 10

The US Food and Drug Administration's Office of Generic Drugs (OGD) and the Generic Pharmaceutical Association (GPhA) held a two-day workshop in June 2009 in Maryland, on pharmaceutical quality by design (QbD) for generic-drug products. The purpose of the workshop was for scientists from FDA and the generic-drug industry to discuss QbD for generic drugs in the context of the International Conference on Harmonization Q8(R1) Pharmaceutical Development and its Annex (1). The specific objectives of this workshop were to identify gaps in the understanding of QbD between FDA and industry and to build a common understanding of certain key aspects of QbD, including:

  • The quality target product profile (QTPP) and critical quality attributes (CQAs)
  • Drug substance and excipient properties
  • Formulation design and development
  • Manufacturing process design and development
  • Identification of critical process parameters (CPPs) and critical material attributes (CMAs)
  • Risk assessment and design space
  • Scale-up and control strategy.

This article summarizes the outcome of the workshop and identifies issues that require further clarification and discussion.

Quality target product profile and critical quality attributes

QTPP. The QTPP is a prospective summary of the quality characteristics of a drug product that will ideally be achieved to ensure the desired quality, taking into account the safety and efficacy of the drug product. According to ICH Q8(R1), it:

"Could include the intended use in a clinical setting, route of administration, dosage form, delivery systems, dosage strength(s), container-closure system, therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed, and drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product" (1).

Before the publication of ICH Q8(R1), the QTPP was called the target product quality profile (TPQP) (2, 3).

Two key questions about the QTPP came up during the workshop: should the QTPP be assessed qualitatively or quantitatively and should the QTPP be expected to change during the course of pharmaceutical development? Some participants thought that some elements of the QTPP should have quantitative targets. At the meeting, there was criticism of the value of QTPP because it restates obvious aspects of product quality. Generic-drug manufacturers are currently using QTPP concepts under different names such as development goals or design constraints.

Many of the QTPP elements such as dosage form, strength, route of administration, identity, assay, and content uniformity are expected to be constant during development because there are regulatory requirements that these elements be the same as the reference listed drug or meet compendial standards. Other QTPP elements such as dissolution may change based on knowledge gained during development.

The QTPP is different from the product specification because the QTPP may include elements such as a container–closure system and information about pharmacokinetics and bioequivalence that are not part of a product specification. The specification may include tests not found in the QTPP. Tablet hardness, for example, may be included in the specification for process monitoring but may not be included in the QTPP. In general, the QTPP should only include patient-relevant product-performance elements.

CQAs. Identification of CQAs is the next step after developing a QTPP in drug-product development. A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs should only include product attributes that have the potential to be altered by changes to process parameters or formulation variables during pharmaceutical development and that are directly related to the safety and efficacy of a drug product. For example, assay, content uniformity, dissolution, and impurities are common CQAs for an immediate-release tablet product. The QTPP may include other quality attributes of a drug product such as strength and dosage form. These attributes are not considered to be CQAs because they will not change during the pharmaceutical development process even though they are essential elements of a marketable product.

To facilitate communication, the term CQA is reserved for attributes of the drug product. The term CMA is used for attributes of drug substance, excipient, and in-process materials. During the workshop, FDA and industry scientists agreed that generic-drug manufacturers should define the QTPP and CQAs before starting development work and share this information with FDA as a part of pharmaceutical development. If the QTPP or CQAs change during development, the change(s) should be indicated in the product-development report.

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