Dr. Edina Pallagi is the QbD pioneer of Hungary. The University of Szeged team recently published,
“New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach”
For a complimentary PDF access, download the QbD case study by Sept. 5
The one-sentence takeaway is:
By identifying the critical process parameters, the practical development was more effective, with reduced development time and efforts.
The paper covers:
- QbD methodology the researchers applied
- Formulation of dry powder inhalation – API and excipients
- QTPP, CQA and CPPs identified for pulmonary use along with target, justification and explanation
- Characterization test methods
- Knowledge Space development
- QbD software used
Here is the abstract:
“The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs).
According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent.
The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper.
Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations.
These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.”
The case study followed the QbD methodology:
Requirements for Pharmaceuticals for Human Use (ICH). These are the ICH Q8 (R2), ICH Q9 and ICH Q10 guidelines (EMEA/CHMP, 2009; EMA/CHMP, 2014a, 2014b). Steps described of QbD based development in pharmaceutical technology include the following:
- Definition of Target Product Profile (TPP) and its quality indicators (Quality Target Product Profile, QTPP). This usually comprises therapeutic requirements and other quality demands (eg. dissolution profile, stability aspects, etc.) (EMEA/CHMP, 2009).
- Identification of Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) which have critical influence on the desired final product quality. CQAs are generally associated with the drug substance, the excipients, the in-process materials or the drug product. CPPs are those process parameters which have an impact on the CQAs. The selection of the CQAs and the CPPs should be based on previous scientific experience and knowledge from relevant literature sources (Yu et al., 2014).
- RA is a systematic process of organizing information to support a risk decision (EMA/CHMP, 2014a) and is the key activity of the QbD based methodology. RA can be both initial and final, and it may be refined afterwards. RA results help to avoid profitless efforts in later phases of the development process.
The entire QbD methodology, including its steps and elements, is presented below:
DPIs have special formulation and regulatory aspects and their design is a highly complex task. The powder formula and the administration manner should be designed parallel, therefore DPIs are defined as combined products.
A regulatory and QbD based DPI product development process has several parameters that need special attention and critical thinking (EMA, 1998, 2006; FDA, 1994, 1998).
Usually these include the following: (1) Drug substance specifications (e.g. particle size, particle size distribution, shape, crystallinity etc.). (2) Moisture and temperature sensitivity aspects to avoid aggregation. (3) Specifications of the excipients (e.g., lactose). (4) Packaging (delivery device) for uniform dosing and for assuring the fine particle mass.
Below is the table of selected QTPPs, CQAs and CPPs of a specified formula for pulmonary use, their target, justification and explanation.
|Therapeutic indication||Anti-inﬂammatory (in cystic ﬁbrosis)||Anti-inﬂammatory treatment is essential in pulmonary diseases. Meloxicam is a well-known NSAID with anti- inﬂammatory effect. It can be used in monotherapy and in combinations. Its pulmonary use is not associated with aspirin-like hypersensitivity reactivity.||Therapeutic indication is a suggested QTPP by the ICH Q8.|
|Target patient population||Adults||The main target group for NSAIDs. Extensive literature data support the safe use of meloxicam in adults.||Therapeutic indication is a suggested QTPP by the ICH Q8.|
|Route of administration||Pulmonary administration||A newly investigated route of administration to avoid the disadvantages of oral therapy. Lungs have a relatively large and highly vascularized surface area, thus pulmonary administration is preferred in pulmonary diseases.||The route of administration has to be evaluated as a QTPP according to the ICH Q8 guideline.|
|Site of activity||Local effect||Local administration has several advantages in pulmonary diseases. It contributes to dose reduction and effectivity, and also offers the possibility of accelerated therapeutic effect.||It is critically related to the quality, safety and efﬁcacy of the medicinal product. Being a QTPP is a therapeutic requirement.|
|Dosage form||Dry powder for pulmonary use||Dry powders with optimal particle size allow better adsorption to the pulmonal mucosa, and thus inﬂuence the effectivity of the product.||Dosage form is a suggested QTPP by the ICH Q8 and is an administrational requirement|
|Dissolution proﬁle||Accelerated release, improved dissolution rate||Immediate effect is usually a critical expectation for locally administered pulmonary medicines. It is inﬂuenced by the solubility properties of the active pharmaceutical ingredient (API), the mucosal adsorption of the inhaled powder and wettability.||As dissolution affects bioavailability and pharmacokinetics, it is critically related to the quality, safety and efﬁcacy of the medicinal product. Being a QTPP is a therapeutic requirement.|
|Excipients (quality proﬁle)||Particle size, morphology, hydrophilic character and stability of DPI||• β-D-Mannitol (MA) is a hydrophilic excipient, characterized by high water-solubility, low toxicity, low hygroscopic proﬁle and signiﬁcant stability.
• Polyvinylpyrrolidone K-25 (PVP) is a stabilizing agent
• Polyvinyl alcohol 3–88 (PVA) is a microﬁne coating material.
• L-Leucine (LEU) is an amino acid that can be well co-spray dried with certain active compounds to modify the drug’s aerolization behaviour.
|ICH Q8 suggests that the excipients are reckoned as CQAs. Excipient are critically related to the dissolution and quality proﬁle of the ﬁnal product.|
|Particle size/ speciﬁc surface area (SSA)||Microsize product of 2– 5 µm;||Microsize dimension has the optimal speciﬁc surface area and optimal administration properties for pulmonary use.||Particle size is critically related to pulmonary administration and to the local and/or systemic therapeutic effect. It is related to safety, efﬁcacy and quality.|
|Appearance||Microcomposite||The microcomposite nature can affect wettability and local adsorption of the product, thus it can inﬂuence local irritation and/or local toxicity properties. Microcomposites can improve stability and may allow for an easier application.||Appearance inﬂuences the application properties, thus even the patient’s compliance. It also inﬂuences the characteristics of the local effect.|
|Dissolution||Accelerated dissolution (100% of drug in approx. 10 min)||Dissolution proﬁle highly affects the therapeutic effect. Accelerated drug release results in an immediate local effect. It is inﬂuenced by the modiﬁcation of the SSA, wettability and solubility.||Critically related to efﬁcacy of poorly water-soluble drugs.|
|Irritation/ toxicity||Non-irritative and non- toxic||Low toxicity and non-irritation is essential in case of application to the pulmonary mucosa.||Critically related to efﬁcacy and safety.|
|Stability (physical)||No physical modiﬁcation||The structure should be physically stable. There is no modiﬁcation in structure, no aggregation, etc.||Critically related to efﬁcacy, safety and quality.|
|Wettability||Hydrophilic character||It could be advantageous in terms of drug dissolution and pulmonary adsorption.||Critically related to efﬁcacy.|
|Structure (cryst./ amorph.)||Crystalline||Crystalline structure is associated with long-term stability||Critically related to efﬁcacy, safety and quality.|
|Solubility||Water soluble||Better water solubility can improve the bioavailability of the drug/product.||Critically related to efﬁcacy and safety.|
|Composition (Co-spray drying)||Micronized size, stabilized structure using additives.||Additives contribute to reaching the desired and predefined quality of the final co-spray dried product.
Shape forming(s), stabilizing agent(s), coating agent(s) and aerolization modifier(s) are usually applied.
|Critically related to the final product’s quality.|
|To reach the micronized state of the sample||Pressure influences the process of micronization across the cavitation process. It has to be selected so as to produce an optimal microsuspension of the API and the additives (1000–1500 bar).||Critically related to quality.|
|Inlet temperature (Co-spray drying)||Optimum drying efficiency for comicronized products||Inlet temperature has to be selected so as to produce the desired co-spray dried, co-micronized final product (100–130°C).||Critically related to quality.|
|Outlet temperature (Co-spray drying)||Optimum drying efficiency for comicronized products||Outlet temperature has to be selected so as to allow an optimal drying of the desired co-spray dried, co-micronized product (70–80°C).||Critically related to the quality of the final product.|
|Feed rate (Co-spray drying)||Optimum feeding frequency for the ﬁnal product’s quality properties||Feeding rate has a critical inﬂuence on the formation of co- micronized particles.||Critically related to the quality of the ﬁnal product.|
|Number of cycles (High pressure homogenization)||To reach the micronized state of the sample||The number of cycles inﬂuences the process of micronization. It has to be selected so as to produce a microsuspension of the API and the additives (5–15 cycles).||Critically related to quality.|
|RPM (High shear mixing)||To reach the optimal disintegration and wetting characteristics||The optimal rotation frequency of the mixer is critical to prepare a homogenous pre-suspension of the API and the additives (15000–24000 rpm).||Critically related to quality.|
|Time (High shear mixing)||Until reaching the optimal disintegration and wetting characteristics||Mixing time is critical to prepare a homogenous pre- suspension of the API and the additives (5–15 min).||Critically related to quality.|
QbD Risk Assessment
The initial Risk Assessment was performed using Lean QbD Software (QbDWorks LLC., Fremont. CA, USA, qbdworks.com). According to the design of the software, the connections between QTPPs, CQAs and CPPs are thoroughly evaluated.
The interdependence between QTPPs and CQAs, as well as between CQAs and CPPs was structured and evaluated one by one, then rated on a three-level scale. This scale reflects the impact of the parameters’ interaction on the product as high (H), medium (M) or low (L).
Determining the probability of risk occurrence was necessary for the analysis, and thus it was performed using the Acquisition Risk Management protocol (Engert and Lansdowne, 1999). For the probability rating, a 0–10 scale was used where the values were assigned to a similar H/M/L ranking structure by the software.
As the output of the RA evaluation, Pareto diagrams (Scott and Marshall, 2009) were generated showing the ranked parameters according to their potential impact on product quality.
Knowledge Space Development
As described before, the targeted profile in this study was an anti-inflammatory microcomposite formula for pulmonary use with local and immediate effect. The initial step of this QbD and Risk Assessment based work was developing an Ishikawa diagram (Ishikawa, 1968) (fishbone-diagram).
It includes all the parameters which may have any effect on the final quality of the DPI product. This was constructed according to the relevant international guidelines (EMA, 1998, 2006; FDA, 1994, 1998) and current scientific literature (Fig. 2).
The next part of knowledge space development was constructing the process map for the selected production method, which is presented in Fig. 3.
In Lean QbD software, this looks like:
After defining the QTPP and selecting CQAs and CPPs, Risk Assessment was performed for our QbD-based product design and development. A 3-point scale estimation was used, and each QTPP factor was ranked as H, M or L (Fig. 4). The initial Risk Assessment was performed using the Lean QbD Software.
Interdependence rating (Fig. 4) was first performed for the CQAs and QTPPs and then for the CQAs and CPPs at the same three-level scale.
These interactions, together with the estimated occurrence rating of the CPPs are shown in Fig. 4.
This science and practical knowledge based and software supported risk estimation produced a precise impact score or severity score for each influencing parameter.
These severity scores for each CQA and CPP are presented in Pareto charts in Fig. 5. The Pareto principle (also known as the “80/20 rule”) states that, for many events, roughly 80% of the effects come from 20% of the causes. In this case this 20% of influencing factors require the 80% of focused efforts during the drug development process. The charts presented in Fig. 5 graphically show the differences among the influencing properties of each parameter, and thus make a priority list.
Amongst the CQAs shown in Fig. 5(A), particle size (or the specific surface area) of the API has the highest impact on the desired quality of the final product. It is followed by pulmonary irritation or toxicity properties, wettability and solubility. These three factors have the same influencing effect with the same severity score, while the effect of the API size is 1.69 times higher than that. The quality profile of the excipients also exerts a relatively high impact, but it is 1.96 times lower than the effect of API size. The API’s structure exerts the lowest effect on the final product’s quality, as shown by an impact score 5.5 times lower than that of the API size.
Part B of Fig. 5 represents that it is the composition used for co- spray drying that has the highest impact among the CPPs on the final product. The impact or severity score of the composition is 2.08 times higher than that of the following item, i.e. the pressure used in the high pressure homogenization phase. Similarly, it is 2.13 times higher than the impact of inlet and outlet temperatures and feed rate of the co-spray drying process. Notably, there is a 5.5 times difference between the critical process factor with the highest effect (composition) and those with the lowest effect (RPM and the length of high shear mixing) on the final product’s properties.
Based on the results of this software-based RA we could identify those factors which need the highest attention when designing the composition, and selecting materials, excipients etc. during the actual drug development in practice. This means that the specified factors need the highest focus during both the experimental design and the practical work.
Based on the QbD prediction our objective was to check how experimental studies correlate with the outcome of the RA and the specified critical factors.
This study illustrates that the regulatory science based QbD approach can be adapted in the early stage of the development of an anti-inflammatory microcomposite formula for pulmonary application. Meloxicam was chosen as a model active agent and a mannitol-based co-spray dried DPI system was produced as a model dosage form according to the QbD methodology and Risk Assessment thinking.
After primary knowledge space development and determination of QTPPs, CQAs and CPPs, Risk Assessment revealed those factors which have the highest influence on the final product’s quality. The actual experimental microcomposite formulation was based on the preliminary parameter ranking and priority classification.
Focusing on the critical parameters identified, the practical development was more effective, with reduced development time and efforts.
Characteristics of the developed end-product were in correlation with the predictions, and all data were thoroughly confirmed by the relevant results of the in vitro investigations.
The formulated microcomposites represent a novel option for the anti-inflammatory treatment of pulmonary fibrosis and other inflammatory pulmonary diseases, either in monotherapy or in combination treatment. The innovative production technology and product appear to be of great potential in pulmonary drug delivery.
Moreover, this QbD-guided modern research methodology is demonstrated to be suitable for the early development of such innovative formulations like DPIs, and allows for a risk and regulatory based, modern and effective product development.
The article is summarized as:
- Formulation was for a dry powder inhalation systems (DPIs), a mannitol based co-spray dried formula as the dosage form with meloxicam as the active agent
- Used Quality-by-Design approach including identification of QTPP, CQA, CPP and linked them using QbD risk assessment
- Compared the QbD based theoretical prediction and the results of the experimental development
- Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations.
For a complimentary PDF access, download the QbD case study by Sept. 5