April 20, 2014

Quality by Design—Bridging the Gap between Concept and Implementation

The drive to embed quality-by-design (QbD) principles into the pharmaceutical regulatory framework of the European Union has reached a key point 10 years after the European Medicines Agency (EMA) first backed QbD concepts. A relatively small number of marketing approval applications made in Europe have supporting QbD data, with EMA conceding that application dossiers with QbD information are far from becoming a standard approach. Nonetheless, the pharmaceutical industry has been internally adopting the QbD concepts laid down in the guidelines of the International Conference on Harmonization (ICH) covering pharmaceutical development (Q8), quality risk management (Q9), pharmaceutical quality systems (Q10), and the development and manufacture of drug substances (Q11) (1-4).

The international pharmaceutical companies in particular have benefited from applying QbD principles to their manufacturing operations. These companies have seen increased production efficiencies and yields as a result, with fewer off-specification outputs and a decrease in production recalls. Some of the leading pharmaceutical companies have been pace setters in including QbD data in authorization dossiers for approval of new medicines. Most pharmaceutical manufactures, however, have been reluctant to tie their marketing-authorization applications to this higher standard of quality management.

The need of global regulatory alignment
QbD is now at a “critical step” between regulatory support for its concepts and a much deeper implantation of its principles, Georges France, external relations head of quality at Novartis, noted at a joint quality-by-design workshop of EMA and Parenteral Drug Association (PDA) in London in late January 2014. According to France, the next step involves a streamlined system of regulatory review of QbD applications that needs to be extended to a “global regulatory alignment.”

The workshop, which included participants from FDA and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), revealed that there are, however, a number of big hurdles to widespread adoption of QbD despite considerable progress in its acceptance by the industry in recent years. One of the speakers at the meeting, Christine Moore, acting director of FDA’s Office of New Drug Quality Assessment (ONDQA), summarized the main concerns as being the classifying of criticality, levels of details required in process descriptions and in risk assessments, design-space verification, and changes to non-critical process parameters (non-CPPs).

Other major issues emerging at the conference, which focused on six case studies of QbD submissions evaluated by EMA, included real-time release testing (RTRT), application of QbD to continuous manufacture and biopharmaceutical production, dealing with post-approval changes to QbD processes, and the need for international harmonization of assessment methods. Regulators at the meeting complained that one big difficulty comes from the differences in terminology as well as the definitions used by pharmaceutical companies in their submissions, or during consultations on QbD matters.

“We have dealt with doubts about the terminology of terms by asking companies to verify what they mean before we review submissions,” commented one regulator speaking from the floor. “But the use of different definitions by companies for the same terms is something that should be sorted out between regulators.”

Some differences in terminology appear to have stemmed from companies adopting QbD concepts internally to gain greater operational efficiencies but in the absence of making QbD submissions with marketing-authorization applications, some of these companies have lost touch with the terminology in the ICH QbD guidelines.

Lessons from a QbD dossier
In a QbD dossier drawn up by GlaxoSmithKline (GSK), which was the subject of a case study presented at the meeting, the company used terms created before the ICH guidelines were finalized. As a result, “ICH terminology was not always followed, which in some situations, made it difficult to follow the information in the dossier in relation to guideline requirements,” said Gorm Herlev Joergensen, head of pharmabiotech, Danish Health and Medicines Authority, and Theodora Kourti, senior technical director, GSK, who jointly presented the case study (5). With some aspects of QbD, the ICH guidelines do not provide definitions. Non-CPPs, for example, are not defined in the guidelines.


Tags: QbD, EMA, Europe, regulatory