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IJCRR - 14(18), September, 2022

Pages: 21-28

Date of Publication: 24-Sep-2022


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Identification and Mitigation of Risks using Quality Risk Assessment Tools for Formulation Development of Pazopanib HCl Extrudates by using HME Technique: A Systematic QbD Approach

Author: Amit Gupta, Rashmi Dahima

Category: Healthcare

Abstract:Introduction: Pharmaceutical development ensures to design a valued product and robust manufacturing process to consistently deliver intended performance. It is necessary to recognize that quality cannot be tested into drug products but it should be built in during formulation design and development. Pazopanib HCl is a protein kinase inhibitor molecule approved by USFDA and European agencies for the treatment of renal cell carcinoma (RCC) patients and other renal malignancies, but it has very poor aqueous solubility and drug release. Therefore, it is essential need to improve the solubility and in vitro dissolution characteristics. Objective/Aim: The main objective of this study was to prepare stable Pazopanib HCl extrudates (PZP-Ex) by using the Quality by Design (QbD) approach. Method: Pazopanib HCl extrudates (PZP-Ex) was manufactured using hot melt extrusion technique. Initially, the quality target product profile (QTPP) and critical quality attributes (CQAs) were identified, and then risk assessment was done using a heat map and failure mode and effect analysis (FMEA) approach. A full factorial design (FFD) was used to study the impact of two continuous variables i.e., level of polymer, milling speed and one categorical (milling screen type) factor on particle size distribution (PSD), disintegration time and dissolution of extrudates. Results: The significance (p) value for studied response variables i.e., percent retention on 40 mesh ASTM sieve (420 µ), disintegration time and percent drug release in 15 min were 0.006, 0.0243 and 0.0355 respectively from the actual by a predicted plot which signifies that the model is significant. The polymer-to-drug ratio has a significant impact on drug release and disintegration time of extrudates. Conclusion: Pazopanib HCl extrudates were successfully prepared by HME technique. Critical formulation and process parameters such as polymer to drug ratio, milling screen size and milling speed were optimized using FFD.

Keywords: CQAs, FMEA, Heatmap, QbD, QTPP, Risk management

Full Text:

Introduction

In the 21st century, “Risk Management Principles” are most commonly and effectively employed in various areas of business operations such as finance, safety, public health including biological and pharmaceutical research domain.1 The main objective of pharmaceutical development is to design a quality product and its manufacturing process to deliver consistently the intended performance of the drug product.2

In past decade, the traditional quality by testing (QbT) approach was used to ensure the quality of drug products by checking it against the regulatory specifications.3 Quality by design (QbD) is described in ICH Q8, Q9 and Q10 guidance documents. QbD principles promote systematic, scientific knowledge-based development for continuous improvement of pharmaceutical drug products. The product or process knowledge, risk assessment and its management, quality management system (QMS) along with the use of process analytical technology (PAT) are tools for successful product development.4 Now a days, pharmaceutical industries are more focusing to develop and integrate the quality systems within organizations practices; hence, quality risk management is a valuable and main component of an effective quality system.5

Pazopanib HCl is a potent tyrosine kinase inhibitor that inhibits angiogenesis through the VEGFR receptor and blocks tumor growth. This drug molecule has been used in the treatment of renal cell carcinoma and other malignancies. It is a poorly water soluble and highly permeable class II drug of Biopharmaceutics Classification System (BCS). The recommended maximum daily dose of Pazopanib HCl is up to 800 mg, administered as 4 tablets of 200 mg strength.6 The goal of this study was to identify, ranking and mitigation of process associated risksto the drug product critical quality attributes(CQAs) during the development of Pazopanib HCl HME extrudates using QbD elements and risk management tools.7

It is hypothesized that HME polymer physicochemical properties will have a major impact on the qualities of drug extrudates, since the HME polymer is major component. The aim of the present study was to optimize polymer to drug ratio to get maximum miscibility and obtain a Pazopanib HCl extrudates (PZP-Ex) with faster disintegration time and drug release. The critical process parameters (CPPs) such as milling screen size and milling speed during extrudate preparation and its impact on extrudates PSD, disintegration, and dissolution time were also studied.

Commonly used material such as Affinisol HPMCas HME polymer and poloxamer 188 as plasticizer were used in current study. The outcomes from this study may provide a way forward to other researchers in developing HME extrudates with better compressibility and desired attributes, such as faster disintegration time and dissolution.

Materials and Methods

Materials

Pazopanib HCl active pharmaceutical ingredient was gifted from Sun Pharmaceutical Industries Ltd., Gurgaon, India. The cellulosic polymer Affinisol HPMC HME 15LV was donated by Dupont (Nutrition and Biosciences, USA). Other ingredients such as Poloxamer 188 were obtained from BASF Corporation (Mumbai, India). All other chemicals and solvents used in this study were of analytical grade.

Methods

QbD elements and risk assessment procedure

The main component of product development by QbD are quality target product profile (QTPP), critical quality attributes (CQAs),design of experiments (DoE), risk assessment and control strategy.8 Control strategy is generally defined based on the scientific knowledge gained during product development and experimentation, which establish the relationship between formulation and process variables that must be controlled to develop high quality product.9,10 Quality risk assessment process is utilized for identification, analysis, evaluation and mitigation of risks related to intermediate in process quality assurance (IPQA) and during production check quality assurance.11 A general process flow for quality risk assessment (QRA) are described in figure1.

Preparation of Pazopanib HCl HME Extrudates (PZP-Ex)

The Pazopanib HCl extrudates (PZP-Ex) was manufactured as per below mentioned formula in Table 1. Initially Affinisol HPMC 15 LV polymer, poloxamer 188 and pazopanib HCl drug were mixed in rapid mixer granulator for 5 minutes at slow impeller speed. Then prepared premix was extruded using a hot melt extruder instrument. Hot melt extrusion were carried out using co-rotating twin-screw extruder (Thermo-scientific) fitted with various screws containing kneading elements at 30° and 60 ° orientation. The feed rate of the premix material and the screw speed were kept constant at 2 g/min and 100 rpm respectively. The barrel temperature was kept as (100/180/180/180/180 °C) for different trials. The extrudates were kept at room temperature prior to milling operation. A Quadro Comil (Fitzpatrick) was operated at defined speed with forward knives fitted with suitable size screen to mill the extrudates. The 16 # ASTM (1204 µm) to 20 # ASTM (850 µm) powder fraction was collected and further used for disintegration and dissolution testing.

Heat map

In heat map, the level of risk (low/medium/high) is assigned through colour. Risk coding is based on prior scientific knowledge including experimental outcomes and justification is provided for assigned risk in each cell considering severity. The green colour has been coded for low risk, yellow for medium risk and red for high risk.12

Failure mode and effect analysis (FMEA)

FMEA is an exhaustive technique thatcan help us to determine the potential failure modes and its causes, potential failure effects, severity rank of the failure effect, occurrence rank of the failure, current detection mode and its failure rate. Hence, risk assigned in heat map and FMEA shall be mitigated based on the scientific rationale and through execution of experiments.13 Refer below tables for risk level, RPN range, colour criteria and scoring criteria for failure mode and risk analysis (Table 2, 3).

 

Experimental trials

DoE approach was employed for systematic optimization of formulation and process variables during Pazopanib HCl extrudates (PZP-Ex) preparation. A full factorial design (FFD) was selected with three factors and two levels (low and high) as shown in Table 4.  The polymer-to-drug ratio and milling speed are continuous variables and evaluated at the ratio of 0.5:1 to 2:1 and 1200 -2400 rpm respectively. Whereas, milling screen size is a categorical factor and studied the impact of 40G and 50G milling screens on granule characteristics, disintegration time and percent drug release.

Results

QbD elements and risk assessment procedure

Based on the clinical and pharmacokinetic characteristics as well as the physicochemical characteristics requirements, QTPP and CQAs elements were defined to guide the development of Pazopanib HCl extrudates by HME technique (Table 5).

 

Preparation of pazopanib HCl HME Extrudates (PZP-Ex)

Pazopanib HCl extrudates were manufactured using hot melt extrusion technique, which are having unit operations such as sifting, mixing, extrusion and milling. Process map are described in below figure (figure 2).

Heat map

Heat map is a systematic approach employed to understand and prioritize the risk elements. In order to evaluate the impact of each variable on DPCQAs, risk coding is done.

In heat map (Table 6), variable location, parameter location and drug product CQAs is listed in the header row. For each variable, the cell is filled with designated colour for the assigned risk and justification updated. The justification is provided based on the severity.

Failure mode and effect analysis (FMEA)

Failure mode and effects analysis is a structured and systematic process to identify potential possible failures in drug product. Initial FMEA for manufacturing process of pazopanib HCl extrudates are summarized in Table 7.

 

Experimental trials

Based on the initial risk assessment for formulation components, experimental trials were conducted to evaluate the risk of processing steps. The experimental trial matrix and trial outcomes are depicted in table 8. All statistical analysis has been carried out using JMP Software (by SAS, version 16).

The particle size distribution of extrudates was carried out using a sieve shaker and percent retention on 40 mesh sieve size was calculated. The 16 # ASTM (1204 µm) to 20 # ASTM (850 µm) extrudates fraction was collected and further used for disintegration and dissolution testing. The disintegration time is also an important in-process material attribute and were carried out in water (n=6) at 37±20C with a sinker using disintegration test apparatus.A disintegration test of 16-20 # fraction extrudates material was carried out by holding the material in 40# stainless steel sinker. The percent drug release at 15 min time point in pH 6.8 phosphate buffer, 900 ml, type I (basket)was carried out and samples were analyzed using the validated HPLC method.

Statistical Outcomes of Experimental Trials                       

The DoE trials with responses were analyzed in JMP software (version 16.0) through “fit Model” approach. Based on the ANOVA and regression analysis, p value and R square value were observed from the “Actual predicted plot” for each response and recorded in table 9.

The sorted parameters (Table 10) and prediction profiler (Figure 3) indicated the impact of polymer-to-drug ratio level, milling screen and milling speed and its interaction terms on extrudates characteristics such as particle size distribution, disintegration time and dissolution. The sorted parameters for each term are summarized below:

Impact of polymer to drug ratio: Based on the sorted parameters and prediction profiler (figure 3) it can be concluded that polymer level has significant impact on studied responses and p value was found < 0.05. At optimum polymer to drug ratio (1:1), model predicted the % retention on 40#, DT and dissolution at 15 mins about 38.1%, 99 secs (1 min 39 secs) and 81.3% respectively.

Impact of milling screen size: Based on the p value from the sorted parameter results as shown above in the table 10, milling screen size has significant impact on all the studied responses. As per the prediction profiler, 40G screen size has obtained the finer granules in comparison to the 50G obtained granules.

Impact of milling speed: Based on the sorted parameters it can be concluded that milling speed has no significant impact on studied responses and p value was found > 0.05. However, from prediction profiler it was observed that% drug release decreased by decreasing the milling rpm. This might be due to slight less fine formation at lower milling speed.

Failure mode and effect analysis (FMEA)-Updated:

FMEA was updated based on DoE optimization studies results and risk was reduced to low from high or medium risk.

Discussion

In 2007, Food and Drug Administration (FDA) published guidance on defining a target product profile (TPP). The TPP provides a written statement of the overall intent of drug development program.14 QTPP and CQAs were discussed initially to design and development of Pazopanib HCl extrudates (PZP-Ex). Process map was defined for preparation of extrudates using HME technique. Initially risk was identified for the formula and process variables using risk assessment tools i.e., heat map and FMEA. The assigned risk for each unit operations were mitigated for medium and high risks process steps based on the scientific knowledge gained during the product development and through experimental trials.

In the present study, full factorial design was used for the optimization of formula and process variables and total of 10 experimental trials were executed. The DoE trials with responses were analysed in JMP software (version 16.0) through “fit Model” approach. The p-value signifies whether the model is significant or not. The p value was observed less than 0.05 for all the studied response variables i.e., percent retention on 40 # ASTM sieve, disintegration time and percent drug release in 15 min hence model was significant.

The sorted parameters and p-value are summarized for the study's responses (Table 10). The % dissolution was directly proportional to the polymer level and this might be due to the fact that a higher polymer-to-drug ratio will convert the crystalline drug into an amorphous solid dispersion state. Milling screen size may impact on extrudates granulometry due to aperture size differences between 40G and 50G mesh. 40G screen has small apertures in comparison to 50G screen.  Disintegration time is likely to be impacted by the ratio of coarse to fine granules, hence 40G obtained granules show faster disintegration and percent drug release. 

Conclusion

In this study, the impact of input variables on studied responses for prepared Pazopanib HCl extrudates by HME technique were successfully optimized. The Pazopanib HCl API was embedded in Affinisol HPMC polymer along with using Poloxamer 188 as a plasticizer. The main goal to carry out risk assessment for Pazopanib HCl extrudates are to reduce the process variations, probability failure rate and manufacturing process defects, thereby obtaining robust unit operations and enhancing manufacturing efficiencies. The polymer-to-drug ratio has a significant impact on drug release and disintegration time of extrudates. The key elements of pharmaceutical QbD were included i.e., QTPP, process design and understanding, CQAs, prior scientific knowledge, risk elements (Heat map and FMEA), DoE screening, and control strategy. Based on the DoE screening study, critical process parameters such as polymer-to-drug ratio, milling screen size and milling speed were optimized and proposed as 2:1, 40G and 1800 rpm respectively.

Acknowledgment: Authors are thankful to BASF, India and Dupont for providing excipients as gift sample. The authors are also grateful to authors/publishers of referenced articles, books and journals.

Source of funding: Nil

Conflict of interest: We declare that we do not have any conflict of interest.

Authors’ Contribution:

Gupta A conceptualized the research work. Also performed experimentation and analysis.

Dahima R performed the statistical data interpretation and contributed to the manuscript writing. 

Abbreviations: ANOVA: analysis of variance; BCS: biopharmaceutics classification system; CPPs: critical process parameters; CQAs: critical quality attributes;  DoE: design of experiments; DPCQA: during production check quality assurance; FDA: food and drug administration; FFD: full factorial design; FMEA: failure mode and effect analysis; HME: hot melt extrusion HPLC: high-performance liquid chromatography; ICH: international council for harmonization of technical requirements for pharmaceuticals for human use;  IPQA: in-process quality assurance; NSAID: non-steroidal anti-inflammatory drug; PAT: process analytical technology; Pazopanib HCl Extrudates: PZP-Ex; QbD: Quality by design; QbT: quality by testing; QRA: quality risk assessment; QTPP: quality target product profile;  TPP: target product profile

References:

1. USFDA Guidance for industry: Q9 quality risk management. Centre for drug evaluation and research; Center for biologics evaluation and research, food and drug administration 2006;1:3- 21.

2. ICH harmonized tripartite guideline. Quality risk management Q9. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use 2005; 1:3-19.

3. Dahima R, Gupta A, Rathore D. Quality by Design (QbD) approach for formulation development of hydralazine hydrochloride tablets. J Chem Pharm Res 2016;8(5):336-41.

4. European medicines agency. Guideline on real-time release testing. Committee for Medicinal Products for Human Use 2010; 1:3-7.

5. Das A, Kadwey P, Mishra JK, Moorkoth S. Quality risk management (QRM) in the pharmaceutical industry: tools and methodology. Int J Pharm Quality Assur 2014;5(3);13-21.

6. Abd-Elbary A, Tadros MI, Alaa-Eldin AA. Development and in vitro/in vivo evaluation of Pazopanib HCl controlled porosity osmotic pump tablets. AAPS Pharm SciTech 2011;12(2):485-95.

7. Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res 2008;25(10):781-91.

8. Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS Pharm SciTech. 2016;17(1):20-42.

9. Kannissery P, Tahir MA, Charoo NA, Ansari SH, Ali J. Pharmaceutical product development: A quality by design approach. Int J Pharm Investig 2016;6(3):129-38.

10. Lionberger RA, Lee SL, Lee LM, Raw A, Yu LX. Quality by design: Concepts for ANDAs. AAPS J 2008;10(2):268-76.

11. Lotlikar MV. Quality risk management in the pharmaceutical industry: A review. International Journal of Pharm Tech Research 2014;6(3):908-14.

12. USFDA. Draft guidance for industry and review staff. Target product profile-a strategic development process tool. Centre for drug evaluation and research; Centre for biologics evaluation and research, food and drug administration 2007;1:2-13.

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14. Fahmy R, Kona R, Dandu R, Xie W, Claycamp G Hoag SW. Quality by design I: application of failure mode effect analysis (FMEA) and Plackett–Burman design of experiments in the identification of “main factors” in the formulation and process design space for roller-compacted ciprofloxacin hyhydrochloride immediate-release tablets. AAPS Pharm SciTech 2012;13(4):1243-254.

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A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09

List of Awardees

A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award


A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award


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International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal

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