Minimum QbD, Enhanced QbD, and R&D QbD – How Are They Different?

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I know what you are thinking. “We have no resources for implementing a full QbD. What is the minimum requirement to call our development process a QbD?” This article addresses that question. But it also provides a roadmap to enhance the “minimum QbD” over a period of time.

Ildikó Csóka, Edina Pallagi, Tamás L.Paál at the University of Szeged in Hungary published a new article:  Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes

Free Access link till August 31st from ScienceDirect.

Previously, the Szeged team published:

• QbD Application in Pharmaceutical Development for Nano Formulation
• QbD for Dry Powder Inhalation Formulation (Combination Product)

This article focuses on:

• Extended ICH Q8 (R2) Quality by Design (QbD) model

• QbD pathway for answering the challenges of drug R&D and industrial production

• Implementing an extended QbD in the pharmaceutical preformulation study design

• R&D QbD model based on the inputs of regulatory agencies, patient-feedback, manufacturing and social responsibility.

• Extended QbD chart for harmonized co-creation between patient, industry and regulatory agency.

The figure below visually summarizes the message of the article.

Abstract:

“Here, we propose the extension of the quality-by-design (QbD) concept to also fit the early development phases of pharmaceuticals by adding elements that are currently widely applied, but not yet included in the QbD model in a structured way. These are the introduction of a ‘zero’ preformulation phase (i.e., selection of drug substance, possible dosage forms and administration routes based on the evaluated therapeutic need); building in stakeholders’ (industry, patient, and regulatory) requirements into the quality target product profile (QTTP); and the use of modern quality management tools during the composition and process design phase [collecting critical quality attributes (CQAs) and selection of CPPs) for (still laboratory-scale) design space (DS) development. Moreover, during industrial scale-up, CQAs (as well as critical process parameters; CPPs) can be changed; however, we recommend that the existing QbD elements are reconsidered and updated after this phase.”

Here are some of the highlighted takeaways:

The ‘minimum QbD approach’ consists of:

1. Defining QTPP and the summary of the main product characteristics, based on the stakeholders’ expectations.
2. Determining CQAs: This is essential, because they have the most influence on the final product quality and performance characteristics (affecting also safety and efficacy), and need to be controlled.
3. Outlining the manufacturing process and the corresponding in-process control strategy.

The ‘enhanced QbD approach’ shows more active steps in the development stage:

1. a risk assessment (RA),
2. a Design Space development phase before the definition of the control strategy,
3. continuous quality improvement shown in lifecycle management. Quality risk management and pharmaceutical quality system approaches are published in ICH guidelines (Q9 and Q10). Application of the QbD approach in marketing authorization procedures is both preferred and highly recommended.

This ‘enhanced QbD’ methodology has the advantage of facilitating a deeper understanding of the material attributes and process parameters affecting the final quality of the targeted product. It also brings a holistic and risk-based structured way of thinking into industrial manufacturing procedures.

The ‘enhanced QbD approach’ is used to cover the early phases of pharmaceutical research activities, resulting in the time- and cost-effective transfer from the research phase to market approval and scale up manufacturing by using already existing tools for a risk-based approach,

Below diagram shows the ‘enhanced QbD’ workflow with the new activities highlighted in red.

Figure 1. Quality-by-design (QbD) for the R&D stage.

The preformulation Drug Substance Selection refers to the stage where a company consider the how biopharmaceuticals can target ‘unmet therapeutic needs.’ Here one considers all the possibilities including the administration route–dosage form–drug substance triangle. These initial steps can be labelled as the ‘Zero design phase’ within the R&D process.

This approach, complemented with a possible benefit and risk assessment, has been successfully used previously. For example, Pallagi et al. used this approach during the early development phase of the formulation of nanosized meloxicam powder gel for intranasal administration.

• QbD Application in Pharmaceutical Development for Nano Formulation

The approach also appeared to be used successfully in the development of meloxicam-containing dry powder for inhalation comprising also a process map on the production of a co-micronized (microcomposite) system.

• QbD for Dry Powder Inhalation Formulation (Combination Product)

The cause-effect diagram and Pareto charts from Lean QbD also helped in CQA and CPP selection during the early development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride.

Furthermore, Kovács et al. used this early QbD approach successfully in the formulation development of multiple emulsions for topical use.

Figure 2. Interrelations, decisions in the zero phase (a) and the implementation of stakeholders’ expectations (b).

When developing the QTPPs, it is important to consider the various stakeholders who define the acceptance criteria. Evaluation of these inputs forms the second important part of this new R&D QbD approach. This broader definition the target product profile include the following.

• Patient expectations, experience, and adherence regarding a given therapy, administration route, or dosage form should be considered as QTPP.
• Regulatory requirements (i.e. the consequences of the type of the submission) should be considered at the early phase of development..
• For products already in the market, information such as therapeutic indication, drug substance type and concentration, dosage form, etc. For a generic submission, the: CQAs of the reference product should be strictly reproduced.
• Manufacturing factors such as cost and scale-up difficulties,
• Finally, relatively new aspect in pharmaceuticals is social responsibility; namely, favoring the different ‘green technologies and avoiding toxic and hazardous materials during processing.

After defining the QTPP in a broad sense, determining the (critical) quality attributes (QAs) forms the next step, followed by the selection of the (critical) material attributes (MAs). These form an integral part of the composition and process design phase together with the determination of the CPPs (critical process parameters).

Criticality is determined using risk assessment. To collect these influencing and relating factors, several modern quality management tools can be used, including Ishikawa diagrams for evaluating cause–effect relations or the setting up of a decision tree that helps the route selection during the development process, as well as Pareto analysis, which helps identify causes of more frequent problems. This is the third ‘expansion’ of the classical QbD method.

The last improvement to the classical QbD approach comes after the Design Space development phase. Generally, it is the multidimensional combination and interaction of input variables (i.e., material attributes) and process parameters that have been demonstrated to provide an assurance of quality (i.e., the ‘space’ where CQAs are met given variations in CPPs). This is determined both on a laboratory scale and in the manufacturing environment. However, CPPs (and sometimes MAs) often, and almost inevitably, change during scale-up and/or during the commercial manufacturing environment. Thus, we recommended reconsidering and updating the existing QbD plan after this phase. This is the fourth expansion and indicated by Box (d) in Fig. 2. Naturally, reconsideration of CQAs and CPPs are part of the product lifecycle management and continuous improvement, which are integral to the QbD approach. The biggest changes in these parameters are to be expected during scale-up from laboratory to pilot manufacturing scale.

Summary:

The laboratory-scale development phase of pharmaceuticals, where the QbD approach should be followed are missing some important elements. Adding necessary elements into the enhanced QbD model could create an ‘R&D QbD’ that is better for the early development phase of pharmaceutical formulations.

Suggested elements are:

• Assessment of unmet therapeutic needs,
• The choice of drug substance type in correlation with the administration route and dosage form (preformulation study design),
• Building in stakeholder expectations,
• Use of modern risk assessment tools during the experimental (composition) design,
• Updating risk assessment and design space after manufacturing scale-up

Here’s the full article,

Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes