Implementation of Pharmaceutical Quality by Design in Wet Granulation

CHAPTER 21

Implementation of Pharmaceutical Quality by Design in Wet Granulation Xiang Yu, Lawrence X. Yu, Yue Teng, Dhaval K. Gaglani, Bhagwant D. Rege, Susan Rosencrance Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States

1 INTRODUCTION Decades ago, most pharmaceutical companies followed the “Pharmaceutical Quality by Testing” (QbT) regulatory framework to drug product. Under that system, the formulation was designed empirically and iteratively, the manufacturing processes were fixed, and product quality was achieved through a series of extensive and inefficient testing on raw materials, in-process intermediates, and final products. This situation remained unchanged until the publication of the FDA’s cGMPs for the 21st Century Initiative (FDA, 2004b) and process analytical technology (PAT) innovative framework (FDA, 2004a). Pharmaceutical Quality by Design (QbD) is a systematic, scientific, risk-based, and holistic approach to pharmaceutical development in which quality is built-in through product and process understanding and control. The principles of QbD were systemically described in the ICH Q8 (R2) guidance (Pharmaceutical Development). The Q8, Q9, and Q10 Questions and Answers and its appendix known as the Points to Consider document (FDA, 2011, 2012) also provided high-level directions for QbD implementation. In addition to this guidance and these documents, recent publications have further detailed the pharmaceutical QbD concept and objectives, and explained the QbD elements and implementation tools (Lionberger, Lee, Lee, Raw, & Yu, 2008; Yu, 2008; Yu et al., 2014, 2016). These regulatory efforts have achieved great success, with improved drug quality and process capability. QbD can be applied to all types of drug products, because the quality requirement of drug products, the management of manufacturing facilities, and the operation of manufacturing process are all on the same regulatory basis. This is especially true for drug products in solid dosage forms. No matter whether the manufacturing process is batch manufacturing or continuous manufacturing, the whole manufacturing process can be seamlessly assembled by individual but common unit operations such as blending, wet/dry granulation, compression, coating, etc. Therefore, successful implementation

Handbook of Pharmaceutical Wet Granulation https://doi.org/10.1016/B978-0-12-810460-6.00024-5

© 2019 Elsevier Inc. All rights reserved.

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of QbD in manufacturing process means a full understanding of each unit operation involved in the process, which also means using QbD tools to identify all critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs), and then developing corresponding control strategy. The FDA is the bridge between the United States’ public and the pharmaceutical industry. It is also the information warehouse for the pharmaceutical industry. The FDA approved and documented about 388 new drug applications (NDAs) and 2851 abbreviated new drug applications (ANDAs) in tablet and capsule dosage forms between 2006 and 2015 (FDA, 2016). Reviewing these approved drug product applications enables us to better evaluate the status of QbD implementation in drug product development by the pharmaceutical industry. Also, systematically utilizing the process data in these applications can also establish a knowledge base, which can help improve regulatory review quality and efficiency. This chapter documents our effort to develop a unit operation profile for systemically describing the general research pattern of a single unit operation under the QbD paradigm. On the basis of process information available from pharmaceutical industry, we created two unit operation profiles: one for high/low-shear wet granulation and the other for fluidized bed granulation. These unit operation profiles help quantify the importance of material attributes, process parameters, and process outputs in the profile, and summarize the behavior of wet granulation in the whole manufacturing process development and the utilization of QbD tools in wet granulation development. As an extension of “Understanding Pharmaceutical Quality by Design” (Yu et al., 2014), we hope this book chapter can enhance the prior knowledge of wet granulation development, and help regulatory agencies further enhance review efficiency and review quality.

2 FUNCTION AND POPULARITY OF WET GRANULATION Granulation is a typical unit operation of particle enlargement carried out by the pharmaceutical industry to produce pharmaceutical dosage forms like tablets and capsules for over 70 years (Parikh, 2009). The purpose of wet granulation can be, but is not limited to: • Enhance the uniformity of drug substance in the final dosage form • Increase the density of blend • Increase the flowability and compressibility of the powder mixture • Reduce the dust during manufacturing process • Alter the physical appearance or surface properties • Improve the wettability of a poorly soluble drug substance Generally, the wet granulation process commences after fully mixing the drug substance and other necessary intra-granular excipients to ensure the uniform distribution of each ingredient. The granule size used in pharmaceutical industry is usually controlled

Implementation of Pharmaceutical Quality by Design in Wet Granulation

between 0.2 mm and 4 mm, with narrow particle size distribution. Drying and milling are required before tablet compression or capsule filling (Parikh, 2009; Shanmugam, 2015). The pharmaceutical industry prefers direct compression/encapsulation over granulation. Wet granulation is to be considered next if the physical properties of final powder mixture cannot satisfy the requirement for direct compression or encapsulation. In order to understand how often pharmaceutical companies employ wet granulation in their manufacturing process to produce drug products in solid oral dosage forms, we conducted a survey by counting any type of wet granulation employed in the manufacturing processes from 98 approved new drug product applications (NDAs) and 128 approved abbreviated new drug product applications (ANDAs). Among these 226 applications, 73.9% of drug products are in tablet dosage form and the remaining 26.1% are in capsule dosage form. Among these, 46.7% of the tablets and 18.6% of the capsules employed at least one wet granulation step in the manufacturing process. The wet granulation process can be classified into three major types according to the shear force applied to the granulation materials: high-shear (HS) granulation, low-shear (LS) granulation, and fluidized bed (FB) granulation. The granulation mechanism of FB granulation is completely different from that of HS/LS granulation, while the strength of its shear force on the granule is between HS granulation and LS granulation. Fig. 1 shows a comparison of the popularity of three types of wet granulation used for tablet and capsule manufacturing. Clearly, HS granulation is the most popular wet granulation method in the pharmaceutical industry. About 69.2% of all tablet manufacturing processes with wet granulation and all capsule manufacturing processes with wet granulation employed HS granulation for wet granulation. The second most popular wet granulation technique is FB granulation, which was used among 24.4% of tablet

Fig. 1 Popularity of FB granulation, HS granulation, and LS granulation in manufacturing processes to produce drug products in tablet and capsule dosage forms.

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manufacturing processes. Because of its time-consuming nature and relatively higher difficulty in controlling the granule particle size, the LS granulation technique is much less popular than HS granulation and FB granulation, and only about 6.4% of tablet manufacturing processes still applied this technique. The HS granulation offers several advantages over FB and LS granulation, which make it the most popular wet granulation method in pharmaceutical industry. These advantages include short granulation time, use of less granulation fluid, and easy determination of granulation end point (Liu, Levin, & Sheskey, 2009). Of course, FB granulation would be of benefit if time/cost factors are not major considerations, or if a formulation has potential stability issues due to moisture exposure (Parikh & Jones, 2009). Although comparison of these three wet granulation methods has been well discussed in the literature, we notice that the selection of a specific wet granulation technique for the manufacturing process may not be fully science-based. In fact, in many situations, these three wet granulation methods can all produce granules with acceptable quality for the following downstream operations. At that time, previous R&D experience, facility availability from lab scale to final commercial scale, cost of wet granulation, and time required for wet granulation all become considerable factors for a pharmaceutical company to design and develop the manufacturing process. During the review of these applications, we did observe that some pharmaceutical companies switched from FB granulation to HS granulation even after completing the initial formulation development in order to save process cost. Meanwhile, we also observed some companies persisted in using LS granulation because of their prior knowledge of similar drug products and the availability of LS granulation facilities for research and manufacturing.

3 QbD AND UNIT OPERATION PROFILES FOR WET GRANULATION 3.1 From Product to Unit Operation As shown in Fig. 2, the entirety of drug product development based on pharmaceutical QbD is composed of six typical elements (Yu et al., 2014): 1. A quality target profile (QTPP) that identifies critical quality attributes (CQAs) of the drug product. 2. Product design and understanding including the identification of critical material attributes (CMAs) based on risk assessment, prior knowledge, first principles, and design of experiments (DOEs). 3. Process design and understanding including the identification of critical process parameters (CPPs) and a thorough understanding of scale-up principles, which link CMAs and CPPs to CQAs. 4. A control strategy that includes specifications for the drug substance(s), excipient(s), and drug product, as well as controls for each step of manufacturing process. 5. Process capability and product lifecycle management including continual improvement.

Implementation of Pharmaceutical Quality by Design in Wet Granulation

Fig. 2 Typical elements of Pharmaceutical QbD for product development.

These QbD elements are designed to help pharmaceutical companies identify characteristics that are critical to consumers, translate them into drug product CQAs, and establish the relationship between formulation/manufacturing variables and CQAs in order to reproducibly deliver the therapeutic promised in the label to the patients (Yu, 2008). When the development target is narrowed down to a specific step of manufacturing process, such as wet granulation, the elements of QbD can be rationally simplified to: (1) Identification of CQAs of wet granulation from the list of granulation outputs; (2) Product and process design & understanding of wet granulation; and (3) Control strategy of wet granulation. In order to better understand the research pattern of single unit operation, we propose to create a profile for each of these common pharmaceutical unit operations. The unit operation profile can be understood as: (1) A data structure in-line with QbD to store material and process information during unit operation development, which includes drug substance(s) and the corresponding physical, chemical, and biological properties, excipients and their physical/ chemical properties, process parameters, process outputs, equipment type and specific equipment model, etc.; (2) A data set of unit operations with information extracted from scientific documents and standardized, following the same data structure; and (3) A combination of statistical analysis and summary of collected data set.

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The feasibility of creating profiles to describe the general wet granulation development is based on three considerations: (1) Majority of recently approved drug product applications have followed QbD paradigm. (2) Drug products in solid dosage forms have similar QTPP and product CQAs. Therefore, the CQAs of wet granulation are also similar. (3) For the same type of wet granulation, the equipment made by different manufacturers can be operated in a similar manner and can execute the same function. Due to different granulation mechanisms and operation procedures, we created two independent profiles for high/low-shear (HS/LS) wet granulation and fluidized bed (FB) wet granulation. We manually collected all the information on wet granulation from previously approved applications to prepare the data set to create a HS/LS granulation profile and a FB granulation profile. The information includes the granulation procedure, process outputs, material attributes involved in process development, all reported process parameters, and QbD tools (PAT, risk assessment, and DOE). Limited by our time and labor resources, 70 applications in total were carefully reviewed and processed to prepare the data sets for HS/LS granulation and FB granulation. After aligning the operation procedures of wet granulation from different drug product applications, associated process parameters were further grouped, standardized, and analyzed. In this section, we only describe the operation procedures of HS/LS granulation and FB granulation. Details of quality characterization of granules, material attributes, process parameters, and application of QbD tools in wet granulation development (risk assessment, DOEs, and PAT) summarized from these unit operation profiles will be introduced in the following sections.

3.2 Process Operation Procedure in HS/LS Granulation Profile The created HS/LS granulation profile consists of five operation procedures, which are Preparation, Pre-mixing, Granulation I, Granulation II (optional), and Massing (Fig. 3). 1. Preparation: The granulator is cleaned and examined before any granulation operation. Granulation fluid is prepared by following the established protocol. All other intragranular material should be pre-processed (e.g., micronization of drug substance, screening of intragranular components), and accurately weighed.

Fig. 3 The unit operation profile of HS/LS granulation.

Implementation of Pharmaceutical Quality by Design in Wet Granulation

2. Pre-mixing: In this stage, the intra-granular components are transferred into the HS/ LS granulator. During this stage, the impeller is turned on and chopper is normally turned off. 3. Granulation I: After pre-mixing, the granulation fluid is pumped or sprayed into granulator. At the same time, both impeller and chopper (if available) are turned on, and appropriate impeller speed and chopper speed need to be adjusted. 4. Granulation II (optional): After completing the spraying of granulation fluid, extra granulation fluid or water may be further sprayed onto the top of granule mixture. In order to decrease number of process parameters to be studied during granulation, the process parameters (including impeller speed, chopper speed, and spray speed) of Granulation II are normally kept the same as that of Granulation I. The step of Granulation II is not necessary for most of HS/LS granulation operations. It may be employed for one of the following considerations: • Use a small amount of water to rinse the container after completing the spray of granulation fluid I. • Spray the granulation fluid with the new granulation fluid of Granulation II. • Continue the granulation, so that the reading of the impeller torque or power consumption matches the pre-determined granulation profile. 5. Wet massing: The alternative name for wet massing is kneading. The purpose of wet massing is to further unify the liquid distribution and densify the granules. Both the impeller and chopper are normally set to “on,” and the setting of these parameters usually is kept the same as the previous granulation step. The common input variables including material attributes and process parameters of these five steps of HS/LS granulation that are frequently studied and reported in drug product applications are listed in Table 1.

Table 1 The common input variables of HS/LS granulation Pre-mixing

Type of granulator

Impeller Impeller (tip) speed (tip) speed Chopper speed Pre-mixing Amount of Amount of time liquid I liquid II Spray rate/time

Batch size and volume fill ratio Spray system Drug substance properties

Granulation I

Granulation II (optional)

Preparation

Method of binder addition Jacket/product temperature Type, amount and grade of intra- Power consumption/torque granular excipient

Massing

Massing time

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3.3 Process Operation Procedure in FB Granulation Profile One advantage of FB granulation is that wet granules can be dried in the same equipment directly following the granulation operation. Many process scientists consider FB granulation, and FB drying as a completely integrated unit operation. But keeping in-line with HS/LS granulation, here the drying procedure is not included in our current profile of FB granulation. The general procedure of FB granulation is given in Fig. 4, which includes Preparation, Pre-heating, and Granulation three steps. 1. Preparation: Similar to HS/LS granulation, this step includes preparing and checking fluidized bed equipment, preparing granulation fluid, and preparing the dry powder mixture. 2. Pre-heating: the powder mixture is transferred into fluidized bed. By blowing hot air through the bottom of fluidized bed, the mixture is further mixed and fully fluidized, and the whole bed is heated to the intended temperature (normally the product temperature during granulation). 3. Granulation: Within this stage, granulation fluid is continuously sprayed onto the top of the powder mixture to form wet granules. The common input variables including material attributes and process parameters of these three steps of FB granulation that are frequently studied and reported in drug product applications are listed in Table 2.

Fig. 4 The unit operation profile of FB granulation. Table 2 The list of common input variables of FB granulation, aligned with preparation, pre-heating, and granulation (Fig. 4) Preparation Pre-heating Granulation

Type of fluidized bed Batch size and volume fill ratio Spray system Process filter system Drug substance properties Method of binder addition Type, amount and grade of intra-granular excipient

Pre-heat inlet air temperature and preheat time

Amount of granulation fluid Spray rate/time Atomization air pressure Atomization air flow Inlet air temperature Inlet air volume Inlet dew point Product (bed) temperature Exhaust air temperature

Shake time/interval

Implementation of Pharmaceutical Quality by Design in Wet Granulation

4 QUALITY CHARACTERIZATIONS OF WET GRANULATION PRODUCT The main purpose of wet granulation is to increase the flowability and compactibility of powder mixture for tablet compression or encapsuling, or to increase the blend uniformity of the powder mixture due to the low dose of drug substance. However, because of the natural properties of wet granules (such as massy, sticky, and easy to agglomerate), it is difficult to directly and fully characterize the wet granules and then to choose appropriate outputs of wet granules to correlate with the CQAs of drug product. In such a case, process scientists prefer to consider the following downstream unit operations such as drying, dry milling, and/or blending/lubricating as an extension of wet granulation by fixing the process parameters of these following unit operations during the study of wet granulation. Alternatively, process scientists consider wet granulation plus these downstream unit operations to be a tightly integrated functional assembly to be studied together. Table 3 lists the outputs of wet granulation and the reported frequency of use of each output for tablet products and capsule products summarized from our HS/LS profile and FB profile. The report frequency indicates how often a variable (an output or a material attribute or a process parameter) of wet granulation was described in the drug product applications, which can be calculated by the number of applications that described the variable divided by the number of reviewed applications. This result shows that the majority of process scientists put the focus of granulation quality evaluation on the characterization of dried granules (usually after the step of dry milling). The top four outputs of granulation for capsule products are: 1. Particle size and size distribution (PSD) of dried granules (100%), 2. Capsule dissolution (87.78%), 3. Loss on drying (LOD) of dried granules (55.56%), and 4. Bulk density (55.56%). The top three outputs of granulation for tablet products include: 1. LOD of dried granules (78.26%), 2. Tablet dissolution (71.74%), and 3. Particle size and the size distribution of dried granules (60.87%). Clearly, directly measuring the impact of granule properties on at least one of product CQAs is a standard approach to evaluate the quality of granulation. It is important to point out that this table should not be directly considered a weight matrix of intermediate CQAs for wet granulation for two reasons. First, this table is summarized from two general profiles and the importance of specific quality requirement of some drug substance/product cannot be fully reflected in this table. For example, if the component in drug product formulation tends to degrade or transform morphology under high temperature/humidity environment, substance-related physical/chemical property should always be continuously monitored throughout the whole development process and should be considered a CQA if that variable qualifies the definition of CQA in ICH Q8(R2) guidance (FDA, 2009). Second, the risk evaluation of these outputs

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Table 3 The reported frequency of wet granulation outputs for both capsule products and tablet products Step Output Capsule (%) Tablet (%)

Wet granulation

After dryinga

After lubrication and/or final blending

After capsuling

After compression

API

a

Pre-mixing blend uniformity In-process LOD and final LOD of granules PSD of wet granules Compressibility Strength and content uniformity Sphericity Bulk density Tapped density Granule flow Appearance LOD/humidity Yield PSD of dry granules Impurity Compressibility Strength and content uniformity Bulk density Tapped density Granule flow Appearance LOD/humidity PSD of blend Capsule strength and content uniformity Capsule dissolution Tablet strength and content uniformity Tablet dissolution Tablet disintegration time Tablet hardness and tensile strength Tablet compression defect Tablet friability Tablet thickness Tablet weight API polymorphic form API impurity and degradation Residual solvents of dried granules

Usually the dry granules are sampled after both drying and milling.

22.22 0

13.04 10.7

0 22.22 11.11

2.17 8.7 15.22

11.11 55.56 44.44 22.22 0 55.56 11.11 100 22.22 0 11.11

0 34.78 32.61 13.04 4.35 78.26 4.35 60.87 17.39 17.39 30.43

0 0 0 0 0 33.33 33.33

21.74 19.57 28.26 4.35 4.35 34.78 0

87.78 0

0 65.65

0 0 0

71.74 45.65 47.83

0 0 0 0 11.11 22.22 0

8.7 15.22 13.04 21.74 0 10.87 2.17

Implementation of Pharmaceutical Quality by Design in Wet Granulation

should be always iteratively updated throughout the process development and the lifecycle of drug product. Consequently, the importance of these outputs evaluated by process scientists may also change.

5 PRODUCT DESIGN AND UNDERSTANDING OF WET GRANULATION As addressed in recent publication (Yu et al., 2014), the key elements of product design and understanding for wet granulation under QbD quality system include the following: • Identify physical, chemical, and biological attributes of drug substance(s) that could impact the performance of final product. • Identify and determine intragranular excipient type, grade, and amount. • Use risk assessment, prior knowledge, and experiments to understand drug-excipient interactions; and identify potentially high-risk material attributes. • Identify CMAs of both excipients and drug substance, and optimize the formulation. • Develop control strategy for CMAs of both drug substance and excipients that can have an effect on product CQAs. A sound understanding of properties of the drug substance(s) can be helpful in (1) rationally selecting excipients whose properties can compensate for the properties of the drug substance, and (2) developing a robust granulation process. Before any formulation and process development, the physical properties, chemical properties, and biological properties of drug substance and potential influence on granulation performance and final product quality should be considered (Table 4). Understanding the properties of drug substance(s) is the key for selecting appropriate intra-granular excipients. The input variables of drug substance usually include: • Drug load • Drug particle size • Drug addition method (dry addition or wet addition) Table 4 Physical properties, chemical properties, and biological properties of drug substance that should be considered during initial product design Biological Physical properties Chemical properties properties

Bulk/tapped density Particle size distribution Morphology (crystalline or amorphous) Solubility in different solvent Intrinsic dissolution rate Hygroscopicity Thermostability Melt point(s)

pKa Chemical stability in different environment Photolytic stability Oxidative stability

Partition coefficient Membrane permeability Bioavailability

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Pharmaceutical excipients, which are defined as the substances other than the active pharmaceutical ingredient, are intentionally included in all drug products in solid dosage forms and are essential to product performance. As the same situation to quality control drug product, both the manufacturing of excipient and using of the excipient in drug product are controlled under regulatory oversight. The USP and NF general chapter on excipients listed 48 functional categories of excipients used in pharmaceutical products (The United States Pharmacopeial Convention, 2016). Intragranular formulation usually contains 1 to 5 excipients. These mainly include diluent, disintegrant, wet binder, and sometimes sweetener, coloring agent, glidant, and antioxidant (if necessary). During process development and process validation, the major input variables of intra-granular excipients can be summarized as: • Type, level, and grade of wet binders. • Type, level, and grade of disintegrants, if needed. • Type, level, and grade of diluents, if needed. • Type, level, and grade of other intragranular excipients, if needed. • Binder addition method (dry addition, wet addition, or the combination of two methods). Because the formulation development is such a large topic, it deserves to be an independent chapter. Here, we only summarize some considerations of the formulation that may influence on the granulation performance and, therefore, the quality of drug product. Obviously, the binder is the pivotal excipient in intra-granular formulation. The USP-NF lists 72 different wet binders and other binders. Binders that are frequently used in tablets/capsules include hydroxypropyl cellulose (HPC), hypromellose (HPMC), providone (PVP), pregelatinized starch, and corn starch. These wet binders normally have multiple functions in the formulation. For example, corn starch and microcrystalline cellulose are more frequently considered as disintegrant and diluent, and lactose monohydrate is mainly considered as diluent in tablets and capsules (The United States Pharmacopeial Convention, 2016). Throughout our review study, over 70% of pharmaceutical companies still follow the classical “trial and error” strategy for formulation development. As a consequence, the whole formulation was considered a single variable in the manufacturing process development. Such a development practice does not really help evaluate the importance of formulation variables. It unintentionally undermines the interactions between material attributes and process parameters, and leads to a local optimization of drug product. For example, majority of applicants didn’t pay attention to the potential interaction of the particle size of drug substance, the grade/supplier of binder, and the ratio of intragranular binder vs. extra-granular binder with other process parameters on granulation quality. Another objective of formulation development of wet granulation is to determine the binder addition method. The binder addition method affects the granule properties and

Implementation of Pharmaceutical Quality by Design in Wet Granulation

thus the dissolution profile of drug product (Holm, Schaefer, & Larsen, 2001). The addition methods include dry addition (binder is mixed with other intra-granular components), wet addition (binder is dissolved in granulation fluid), and the combination method (binder is included in both intragranular mixture and granulation fluid). Usually, the method of binder addition is determined by the formulation scientist at the early stage of formulation development and will not be changed throughout the manufacturing process development. The reviewing result shows that about 49% of the applications chose dry addition method, 33% chose wet addition method, and the remaining 18% chose the combination of dry addition and wet addition. Finally, pharmaceutical developer should consider the following at the early stage of formulation development: 1. Unless sufficient toxicity data of new excipient can be provided to the agency to demonstrate its safety, the amount of excipient in the final formulation is not encouraged to exceed the safety limit listed in the FDA inactive ingredients database (https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm), which is based on the amount of excipient used in prior approved drug products. 2. Systematic drug-excipient compatibility studies should be performed prior to formulation optimization. Excipients can be a major variability source of drug quality. Performing drug-excipient compatibility studies at early stage of formulation development can help develop a robust formulation by maximizing the stability of a formulation and, hence, the shelf life of the final drug product. Also, identification of potential interactions between drug substance and excipients helps root cause analysis, if and when a stability problem occurs. 3. Risk assessment and DOEs as powerful research tools are highly recommended to be employed in formulation development, even if QbD paradigm is not planned in the product development.

6 PROCESS DESIGN AND UNDERSTANDING OF WET GRANULATION Process parameters are referred as the input operating parameters (e.g., speed and flow rate) or process state variables (e.g., temperature and pressure) of a process step or unit operation. Lawrence and other coauthors listed the typical material attributes, process parameters, and outputs of HS/LS granulation and FB granulation in their 2014 QbD paper (Yu et al., 2014), but the importance of these process parameters was not further evaluated and reported by the authors later. This is the initial driving force compelling us to prepare this book chapter. Here, based on the HS/LS granulation profile and FB granulation profile generated from recently approved drug product applications, we calculated the reported frequencies and risk factors of common process parameters, and characterized the research behavior of each process parameter at laboratory scale and pilot/submission batch scale. The submission batch is a drug product batch manufactured

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under GMP environment with its stability data to be submitted to regulatory agency for quality review. There is a mandatory requirement of batch size for the submission batches submitted by both NDA applicant and ANDA applicant.

6.1 Process Parameters for HS/LS Granulation The 13 process parameters of HS/LS granulations that are commonly studied by process scientists are listed in Fig. 5. Because process scientists usually choose to provide an agency with details about the process information, they think that is important for process understanding and development; the reported frequency of these process parameters may reflect the process scientists’ opinion about the importance of process parameters in HS/LS granulation. However, the current HS/LS granulation profile is a general unit operation profile without considering some special situations (e.g., temperature sensitivity of drug substance, dry addition method vs wet addition method). The reported frequency for some process parameters (e.g., jacket or product temperature, amount of granulation fluid II) may be potentially biased. Calculating the frequency of a process parameter considered to be critical process parameter (CPP) is an ideal way to represent the risk of that process parameter to the granulation process in general. But the judgment of a process parameter to be a CPP or not is greatly influenced by the setting of final operation range of that parameter in the proven operating space (Lionberger et al., 2008). Therefore, the risk factor of each

Fig. 5 Process parameters with report frequency and the ratio of high risk of the listed process parameters from HS/LS-granulation profile.

Implementation of Pharmaceutical Quality by Design in Wet Granulation

Fig. 6 Study frequencies of process parameters that were reported (with investigation range) at laboratory scale, pilot scale, and submission batches from HS/LS-granulation profile.

process parameter was calculated and provided in Fig. 5 in order to help process scientist better perform risk assessment in their own process development. The risk factor of a process parameter is defined as reported number of high risk divided by number of our reviewed applications, while the reported number of high risk is represented as the number of times that a process parameter was determined to be CPP in the application or that process parameter was statistically significant in DOE studies at any scale. To each of the listed process parameters in Fig. 5, process scientists may choose to either fix the process parameter to a specific value, or obtain an operation range of that parameter through a series of trials. In order to obtain the parameter research pattern from these process studies, we also calculate the rate at which the process parameter was studied and the range of investigation (Fig. 6). Any process parameter that was not reported in the application was considered to be a fixed variable and was not to be studied in the trials. The common process parameters for HS/LS granulation are discussed below, and the behavior of these process parameters at laboratory scale and pilot scale are summarized in Table 5. 6.1.1 Equipment Type About 79% of companies reported the type of HS/LS granulators used for process development and scale-up. For LS granulation, planetary mixer is the only type of low-shear granulator employed for LS granulation. For HS granulation, the high-shear granulators

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Table 5 The batch size ranges and representative high-shear granulator models for each range of batch size Batch size (kg) Example

0.2–2 3–6 9–40 40–125 >125

Diosna P1-6 PMA-1 Gral 150 VG400 VG600

can be classified into vertical high-shear granulator and horizontal high-shear granulator per the geometric position and orientation of the primary impeller. The impeller shaft of a vertical high-shear granulator rotates in the vertical plane, and the impeller is bladelike, while the impeller shaft of a horizontal high-shear granulator rotates in the horizontal plane. In our study, we observe that vertical (either top-driven or bottom-driven) high-shear granulator is more popular than the horizontal high-shear granulator, and two types of vertical high-shear granulators (top-driven and bottomdriven) are both frequently employed in high-shear granulation. FDA SUPAC Manufacturing Equipment Addendum (FDA, 2014) lists the major manufacturers of both low-shear and high-shear granulators. Different granulator types, or even granulators of the same granulator type but produced by different manufacturers, can definitely impact granulation quality attributes, such as the average particle size of granules (Bouwman, Visser, Eissens, Wesselingh, & Frijlink, 2004; Liu et al., 2009). Nonetheless, this equipment impact can be well compensated by adjusting the process parameters (e.g., the amount of granulation fluid, granulation impeller speed, massing time). Therefore, no applicant had even considered granulator type to be critical. 6.1.2 Batch Size and Volume Fill Ratio The FDA highly encourages the pharmaceutical industry to both provide batch sizes with batch identification numbers and to list specific equipment models used during process development in the application to facilitate the review and evaluation. Except for few applications with historical issues, most of pharmaceutical companies provided at least the size of submission batches to the agency. The normal ranges of batch size for HS granulation development are summarized in Table 5. During process development, the batch size of experimental trials at various scale levels are normally fixed, as to the volume fill ratio. Unlike batch size that is always reported in the drug product application explicitly, the volume fill ratios are able to be captured from only a few applications. Even though we consider the volume fill ratio is provided by pharmaceutical companies as long as batch size and equipment capacity are given in the application, the overall reported volume fill ratio only reached around 0.63. Normally, the volume fill ratio is controlled between 0.4 and 0.6, but this number can be

Implementation of Pharmaceutical Quality by Design in Wet Granulation

extended from 0.2 up to 0.8 in some special cases. Fig. 6 indicates that pharmaceutical companies prefer to fix the batch size and volume fill ratio for the regulatory consideration. 6.1.3 Amount of Granulation Fluid I (w/w) and Amount of Granulation Fluid II (w/w) The amount of granulation fluid should always be controlled within a narrow range because it is widely acknowledged to dictate the properties of the final granules. The amount of granulation fluid I and the amount of granulation fluid II are top 2 process parameters with the highest risk factor in Fig. 5. The amount of granulation fluid can be expressed as the weight of granulation fluid divided by the weight of dry intragranular powder mixture, by which this process parameter is converted to scale independent variable. Because the required amount of granulation fluid is also affected by other variables (e.g., formulation change during scale-up, geometry difference of two granulators, and change of impeller speed and massing time), process scientists may need to verify or optimize the amount of granulation fluid at each scale level. The initial investigation value of granulation fluid can be within the range of 10% (w/w) and 55% (w/w). 6.1.4 Solid Level of Granulation Fluid I The granulation fluid can be as simple as purified water (normally seen in wet granulation with dry binder addition method), but can also be as complex as a mixture of solvent, drug substance, binders, and other excipients (frequently seen in wet granulation with wet binder addition method or the combined binder addition method). In the latter case, solid level of granulation fluid becomes a process parameter and may need to be evaluated during process development. The overall report frequency is 0.16 as shown in Fig. 5. As discussed in previous section, the formulation was considered as a fixed input variable by majority of process scientists. Consequently, the solid level in granulation fluid can not only impact the viscosity of granulation fluid and the spray performance, but can also affect the amount of granulation fluid for wet granulation. Process scientists may optimize this parameter at small scale and fix the value after scaling up. The initial investigation value of solid level is normally selected between 2% to 20% and, theoretically, it is a scale-independent variable. 6.1.5 Pre-Mixing Impeller Speed and Pre-Mixing Time The pre-mixing stage is usually considered low risk. The pre-mixing impeller speed can be the intended impeller speed for granulation or lower speed, and the chopper of HS granulator is normally turned off. The typical pre-mixing time for initial investigation is chosen between 2 min and 20 min at various scales.

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6.1.6 Spray Rate and Spray Time Generally, the spray rate is chosen such that local over-wetting of the powder mass is not a concern. At the same time, the spray rate should be fast enough to accommodate the whole granulation process time. Therefore, the process scientists prefer to study and control the spray rate within a range rather than at a fixed value. The spray rate of granulation fluid is associated with the theory of granule growth. It can be as low as 2–10 g/[min
kg] and as high as >100 g/[min
kg]. The spray time is controlled typically between 2 min and 15 min at various scales. 6.1.7 Granulation Impeller Speed and Chopper Speed Because the mechanical energy is mainly delivered by rotating impeller, the impeller speed/tip speed is always studied by scientists (Bardin, Knight, & Seville, 2004; Chitu, Oulahna, & Hemati, 2011; Oulahna, Cordier, Galet, & Dodds, 2003). The general trend is that the faster the impeller speed, the larger the granules. Similar to the analysis result of spray rate, it is difficult to suggest a general investigation range for impeller speed. The initial setting of impeller speed in our observation can be as low as 40 rpm but as high as 800 rpm, by taking account of considerable factors such as the intended mechanical and dissolution properties of granules, specific granulator configuration, batch size, etc. The function of the chopper is to break down the wet lumps into granules. The rotation speed of the chopper may range from 0 rpm to 3600 rpm. Because the chopper speed of many HS granulators with large bowl capacity is not adjustable, it is usually a fixed value at pilot scale or commercial scale. 6.1.8 Wet Massing Time Wet massing affects the density of the granules and the granule size. Normally, the impeller speed and chopper speed are kept the same as granulation stage, the research focus on exploring appropriate wet massing time. A typical investigation range of wet massing time is selected within 6 min at various scales. 6.1.9 Power Consumption or Torque Power consumption and torque are electrical and mechanical characteristics of the impeller motor. Traditionally, monitoring power consumption or torque is the indirect measurement to determine the end point of wet granulation. The correlation between power consumption or impeller torque and granule/product properties has been extensively studied in the past 20 years (Achanta, Adusumilli, & James, 1997; Holm et al., 2001; Holm, Schaefer, & Kristensen, 1985; Kopcha, Roland, Bubb, & Vadino, 1992; Kornchankul, Parikh, & Sakr, 2001). However, in current practice, majority of the process scientists choose to use massing time or total processing time as the end point of granulation, but they may still monitor power consumption or torque as reference to prevent potential risk of over-granulation during process development.

Implementation of Pharmaceutical Quality by Design in Wet Granulation

6.1.10 Jacket or Product Temperature Only a few applications reported that the granulation temperature was controlled or monitored, but one fourth of the reports suggested the importance of this parameter. Generally speaking, the higher the granulation temperature, the larger or faster the granules grow. Impact of temperature should be considered if: (1) The drug substance or excipient is temperature sensitive. (2) Site transfer occurs between different climate zones during or after process development. (3) Multiple sub-batches may need to be executed continuously by using the same granulator. It should be noted that many process parameters such as spray nozzle position, nozzle type and configuration, nozzle angle, impeller diameter are not included in Fig. 5. It is not because these parameters are not important, but because these parameters are generally considered a fixed variable during process development. Based on our analysis of the reported frequency, risk factor, and parameter research behavior listed in Figs. 5 and 6, we suggest that the spray rate/time, the amount of granulation fluid I, massing time, and granulation impeller (tip) speed are top four process parameters that process scientists should pay attention to throughout wet granulation development. We are considering developing a scoring matrix that balances the reported frequency, risk factor, parameter research behavior, expert opinion, and other considerations to objectively evaluate the risk of process parameters on HS/LS in the future.

6.2 Process Parameters for FB Granulation Based on our unit operation profile of FB granulation, the process parameters of FB granulations that were frequently studied and reported by applicants are listed in Fig. 7. Also, the study frequency of process parameters listed in Fig. 7 are counted and given in Fig. 8. 6.2.1 Equipment Type The information of equipment type is clearly addressed in about 74% of reviewed applications. Theoretically, top spraying fluidized bed, bottom spraying fluidized bed, and tangential spraying fluidized bed are all capable for FB granulation. In practice, top spraying fluidized bed is the default choice for FB granulation due to equipment availability and prior knowledge of FB granulation with top spraying fluidized bed. 6.2.2 Batch Size and Volume Fill Ratio We can retrieve the batch size information from most of our reviewed applications and the ranges of batch size are summarized in Table 6. Similar to HS/LS granulation, we cannot retrieve the volume fill ratio information from majority of applications. But we may estimate the volume fill ratio as long as the batch size and equipment model are available in the application. Therefore, the adjusted overall reported frequency of

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Fig. 7 Process parameters with report rate and the importance ratio of the reported parameter summarized from FB-granulation profile.

Fig. 8 Study frequencies of process parameters that were reported with investigation range at laboratory scale, pilot scale, and submission batches from FB-granulation profile.

Implementation of Pharmaceutical Quality by Design in Wet Granulation

Table 6 The batch size ranges and representative FB granulator model for each range Batch size (kg) Example

0.4–1 1–5 10–20 30–80 >100

GPCG 1.1 Aeromatic S2 GPCG 5 GPCG 60 CPGC 120

volume fill ratio can reach 1. Like the unit operation profile of HS/LS granulation, process scientists prefer to fix the batch size to minimize the impact of volume fill ratio. Ken Yamamoto and Z. Hesse Shao provided two general equations to estimate the minimum and maximum batch size for top spraying FB granulation (Yamamoto & Shao, 2009) Smin ¼ V  0:5  BD Smax ¼ V  0:8  BD where S is the batch size in kilograms, V is the product bowl capacity in liters, and BD is the bulk density of finished granules in g/cm3. 6.2.3 Pre-Heat Temperature and Pre-Heat Time The fluidized bed should be heated to target temperature before the granulation step. Normally the pre-heat inlet air temp is the intended inlet air temperature for granulation. The pre-heat time is scale and equipment dependent, which may need to be monitored and recorded again after scale-up. 6.2.4 Amount of Granulation Fluid (w/w) Similar to HS/LS granulation, water is the first choice as solvent to prepare granulation fluid, and binders can be added by dry addition method, wet addition method, or a combined method. It is interesting to find out that process scientists had different research behaviors on HS/LS granulation development and FB granulation development regarding this process parameter. According to the FB granulation profile we prepared from our reviewed applications, the effect of granulation fluid on FB granulation was not frequently reported by process scientists (Fig. 7). At the same time, process scientists preferred to systematically study this process parameter at small scale and considered it a fixed variable at larger scales (Fig. 8). This is significantly different from the research behavior of this variable in HS/LS granulation profile, in which its reported frequency is over 0.8 and its study frequencies at both laboratory scale and pilot scale are all above 0.6. Moreover, because the granulation fluid for FB granulation needs to be atomized into tiny droplets, the viscosity or the solid content of the granulation liquid is limited.

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FB granulation may require more granulation fluid than HS/LS granulation. The initial investigation value of among of granulation fluid can be any value between 30% (w/w) and 90% (w/w), and, in some applications, this value may be extended to over 100%. 6.2.5 Inlet Air Condition The inlet air condition includes inlet air temperature, volume, and dew point. These three variables plus the spray rate are acknowledged as four key factors. Their interactions have a direct impact on nucleus formation and granule agglomeration, and, therefore, the properties of granulation product (Loh, Er, Chan, Liew, & Heng, 2011). Inlet air volume also controls the status of fluidized bed. Proper air volume should fully fluidize the bed without clogging the filters. Although inlet air temperature and inlet air dew point are scale independent variables and values of risk factor for these three process parameters are below 0.1, process scientists are used to continuously optimize them after scaling up to pilot scale and to commercial scale. The initial investigation range for inlet air temperature is usually selected within 40° C–90°C, and the range for inlet air dew point is normally selected within 5°C–15°C. The setting of inlet air volume is influenced by equipment manufacture, specific configuration of equipment, physical properties and batch size. Because the reported frequency for inlet air volume is only 0.58, ranges of inlet air volume for different ranges of batch size can only be roughly estimated, which is 10–300 cubic feet per minute (CFM) for batch sizes smaller than 20 kg and >300 CFM for batch sizes larger than 20 kg. 6.2.6 Spray Condition The importance of droplet size of granulation fluid at the spray zone and the amount of granulation fluid in controlling the granule formation and growth have been well acknowledged (Lipps & Sakr, 1994; Panda, Zank, & Martin, 2001; Rambali, Baert, & Massart, 2003). Among many variables such as spray rate, solution viscosity or granulation fluid concentration, atomization air pressure, atomization air flow, nozzle position, nozzle orifice size and nozzle type, spray rate and atomization air pressure are more frequently reported by the process scientists. The common investigation range of spray rate could be 1–80g/[min
kg
nozzle] for batch size 4.5 kg, and 0.8–5 g/[min
kg
nozzle] for batch size 10 kg. The initial investigation range of atomization air pressure could start from 0.5 to 4 bars at various scales. 6.2.7 Product Temperature and Exhaust Temperature Both product temperature and exhaust temperature are scale-independent process state variables mainly controlled by inlet air temperature, inlet air volume, and spray rate. Pharmaceutical companies may have different and unique process development/control strategies, such that either product temperature or exhaust temperature can be selected as

Implementation of Pharmaceutical Quality by Design in Wet Granulation

target for process control. The investigation ranges for these temperature parameters are usually selected within 25°C–60°C. Other important but not listed process parameters includes spray nozzle system (number of nozzle, position of nozzle, nozzle type, and orifice diameter) and process filter system (filter material, shaking time, and shaking interval). These variables are always pre-selected variables and would not be changed unless granulation failure happened during process development. Compared to HS/LS granulation, the process development pattern of FB granulation is much clearer. Amount of granulation fluid, spray rate and time, and inlet air volume are top three process parameters having high impact on CQAs of granules and final product. Inlet air condition is a set of process parameters that process scientists like to validate and optimize after scale-up from laboratory scale.

6.3 Scale-up Consideration By definition, process scale-up is the transfer of a controlled process from small scale to large scale. To a process scientist, successful scale-up means to maintain the properties of the granules at a similar level and produce a final drug product of consistent quality. To the regulatory agency, scale-up is an important component of risk management and is of interest to reviewers for evaluating whether a pharmaceutical company can still produce drug products of consistent quality after technique transfer or after scaling up to proposed commercial scale. In this review study, only a very limited number of applicants fully reported their scale-up procedure in the documents. Instead, many applicants chose to provide experimental information at intended commercial scale level to alleviate the regulatory concerns. The process control and scale-up strategies of HS/LS granulation process have been well developed (Faure, York, & Rowe, 2001). Under the premise that the spraying time was kept constant by increasing the spraying rate of granulation fluid, HS/LS granulation can be scaled up linearly by following: 1. Keep the relative swept volume constant, or 2. Keep the tip speed of the impeller constant, or 3. Keep certain dimensionless number (i.e., Froude number, spray flux) constant. Theoretically, keeping certain dimensionless numbers constant should be a better approach for HS/LS scale-up, and many granulator manufacturers are likely developing equipment based on certain similarity of dimensionless number (e.g., Froude number) rather than geometrical similarity (Horsthuis, Vanlaarhoven, Vanrooij, & Vromans, 1993). In practice, our review of applications indicates that keeping the impeller tip speed constant is currently the most popular approach for HS/LS process scale-up. We also observed a scale-up case by maintaining self-defined dimensionless number from small scale to large scale, but no scale-up case using the approach by keeping the swept volume constant. An ideal scenario of linear scale-up of HS/LS granulation process is that the

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granulators used for wet granulation at various scales are geometrically, kinematically, and dynamically similar. This is extremely difficult to achieve simultaneously. Additional experimental work may be required for some compensatory changes in amount of granulation fluid, impeller speed, or wet massing time to produce equivalent granules. DOE is highly encouraged for the purpose of process optimization and validation of design space after scale-up (Yu et al., 2014). On the other hand, keeping the droplet size and fluidized bed humidity consistent across different scales is widely acknowledged to be two universal and essential keys of FB granulation scale-up (Rambali et al., 2003). There are many theories and models help guide the scale-up of FB granulation (Glicksman, Hyre, & Woloshun, 1993; Horio, Nonaka, Sawa, & Muchi, 1986; Sanderson & Rhodes, 2003). In practice, the commonly used method is linear scale-up approach, which is quite straightforward. In an ideal situation, the following process parameters should be kept constant: • Fluidization velocity of the inlet air through the granulation system. • The ratio of granulation spray rate to drying capacity of inlet air volume. • Droplet size of the granulation fluid. The fluidization velocity can be estimated as the inlet air volume divided by the crosssectional area of the equipment. The drying capacity of inlet air volume is determined by the inlet air volume, inlet air temperature, and inlet air dew point (humidity) together. By keeping inlet air temperature and inlet air dew point constant, the drying capacity is in linear relationship with the inlet air volume. Droplet size of the granulation fluid is controlled by spray rate, specific nozzle type and nozzle configuration, atomization air pressure and air volume, and, of course, the formulation—especially if a formulation change can alter the physical properties of the granulation fluid. All process parameters related to spray system need to be pre-adjusted at each scale. Atomization air pressure may need to be further optimized at pilot scale and final commercial scale. Prior knowledge and experience still play significant roles in adjusting appropriate parameters for scale-up, but DOE is highly encouraged for process optimization and design space validation of FB granulation (Yu et al., 2014).

7 QbD TOOLS AND WET GRANULATION DEVELOPMENT As a tightly integrated part of QbD approach, the QbD tools include, but are not limited to, risk assessment, DOE, and PAT as shown in Fig. 2.

7.1 Risk Assessment The key objective of risk assessment in pharmaceutical development is to identify potentially high-risk API properties, formulation variables, and process variables that could impact the quality of final drug product, so that appropriate control strategy can be implemented to ensure CQAs are within the expectations. Risk assessment is also an iterative

Implementation of Pharmaceutical Quality by Design in Wet Granulation

process and occurs throughout the development. During the initial phase of risk assessment, prior knowledge serves as the primary basis for the development designation. Then, the outcome of experimental investigations provides the basis to further re-evaluate and correct the risk score of each variable. ICH Q9 (FDA, 2006) provides a non-exhaustive list of common risk assessment tools, which includes basic risk management facilitation methods; Failure Mode Effects Analysis (FMEA); Failure Mode, Effects, and Criticality Analysis (FMECA); Fault Tree Analysis (FTA); Hazard Analysis and Critical Control Points (HACCP); Hazard Operability Analysis (HAZOP); Hazard Operability Analysis (HAZOP); risk ranking and filtering; and supporting statistical tools. It might be appropriate to adapt these tools for risk assessment in specific area. The subject of risk assessment can be as large as a whole manufacturing process (Table 7), but can also be as small as single unit operation development (Fig. 9). Currently, simple and qualitative risk assessment approaches are still the preference by process scientists, but advanced tools are also frequently used by experienced scientists to gain a more comprehensive understanding of the risks involved. We observed that, compared with process scientists who only followed minimum requirement of risk assessment in ICH guidance, process scientists who used advanced tools (e.g., FMEA) were more likely to identify the significant interactions between material attributes and process parameters in wet granulation process development.

7.2 Design of Experiment Design of experiments (DOEs) is a structured and organized method to determine the relationship among factors that influence outputs of a process. The meaning of DOEs in QbD implementation has been well addressed in ICH Q8 guidance and other scientific publications (Huang et al., 2009; Lionberger et al., 2008; Yu, 2008; Yu et al., 2014). In QbD quality system, DOE should be used in both product and process development for product/process understanding and optimization. Table 7 Example of early risk assessment across unit operations of the drug product CQAs for a modified release (MR) tablet Unit operation Drug product CQAs

Dry mixing Granulation Drying Milling Blending Lubrication Compression Film coating

Appearance

Impurity

Assay

Content uniformity

Dissolution

Low Low Low Low Low Low High High

Low Low Low Low Low Low Low Low

Medium High Low Low Low Low High Low

Medium High Low Low Medium Low High Low

Medium High High Low Low Low High High

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Fig. 9 Example of fishbone diagram for HS/LS granulation.

With respect to DOE application in process development using wet granulation, currently our review results show that DOE was applied in approximately 50% of our reviewed HS granulation research and about 20% of LS granulation research. Because of the special status of wet granulation in the whole manufacturing process, about 30% of these DOE studies cover input variables and process parameters from more than one unit operation. The amount of granulation fluid, massing time, and impeller (tip) speed are three process parameters most commonly selected for DOE study. Among these DOE studies, 18% included material attributes such as the ratio of intra-granular binder against extra-granular binder, and the solid content of granulation fluid. On the other hand, DOE was used only for approximately 20% of FB granulation research. Compared to HS/LS granulation, implementation of DOE in FB granulation research is more challenging because inappropriate selection of process parameters and their operation ranges may result in process interruption and failure. The amount of granulation fluid and the spray rate are two process parameters most frequently selected in DOE study. Because inlet air temperature, inlet air volume, product temperature, and exhaust temperature are several parameters that directly control or indicate the physical status and humidity of the fluidized bed, it is reasonable to choose just one of these process parameters in the experimental design to avoid potential control failure. In order to maximally benefit from DOE, appropriate type of experiment design should be selected at different stage of process development. At the early stage of process development, depending on the amount of knowledge and prior experience of wet granulation, screening DOE is necessary to evaluate the risks and gain the knowledge from experiment. Screening DOE enables us to focus on the key variables that may

Implementation of Pharmaceutical Quality by Design in Wet Granulation

significantly impact a CQA when there are a large number of variables to evaluate. The representative types of screening DOE include full/fractional factorial design. Once sufficient knowledge is obtained from these studies, optimization DOE can be very useful to further understand the complex interactions and even quadratic effects of process variables and develop the design space on CPPs. The representative types of optimization DOE include central composite design and Box-Behnken design. Finally, according to QbD paradigm, the design space of the process can be directly derived from DOE studies. The established design space at small scale should be further verified after scaling up to pilot scale and to commercial scale.

7.3 Process Analytical Technology Process analytical technology (PAT) is defined by FDA as a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality (FDA, 2004a). As an essential part of QbD paradigm, PAT provides continuous monitoring of CPPs, CMAs, and/or CQAs in commercial manufacturing to examine the process condition and to ensure the process remains within an established design space. In order to successfully apply PAT to achieve advanced quality control of manufacturing process and final drug product, PAT should be initiated at the early stage of process development on every unit operation of high risk identified by risk assessment. However, our review of drug product applications shows that only very limited number of applicants have ever applied PAT in their process design and understanding. Several possible reasons that keep PAT absent from wet granulation process include, but are not limited to: • The acceptable quality range of granules is wide and the downstream process that includes one or two milling operations significantly decreases the risk of wet granulation. • Applicants prefer to adapt the quality control strategy of similar legacy products approved by FDA previously to avoid regulatory concerns caused by the application of new technology. • Majority of applicants are still used to traditional quality control strategy by tightly constraining both formulation variables and process parameters rather than following the QbD paradigm. However, such quality strategy does not necessarily eliminate the failures within the manufacturing facilities that may result in poor drug quality. There is a lot of literature reporting the successful implementation of PAT in both HS/LS granulation process and FB granulation process (Alcala, Blanco, Bautista, & Gonzalez, 2010; Awotwe-Otoo, Agarabi, & Khan, 2014; Halstensen, de Bakker, & Esbensen, 2006; Huang et al., 2010; Luukkonen et al., 2008; Matero et al., 2009, 2010; Rantanen, Lehtola, Ramet, Mannermaa, & Yliruusi, 1998; Rantanen, Wikstrom,

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Turner, & Taylor, 2005; Sandler, 2011; Watano, Numa, Miyanami, & Osako, 2001; Whitaker et al., 2000; Wikstrom, Marsac, & Taylor, 2005) at various scale levels. The common process analytical chemistry tools used for multivariate data collection include image analysis (Sandler, 2011; Watano et al., 2001), acoustic emission (Halstensen et al., 2006; Matero et al., 2009; Whitaker et al., 2000), near infrared spectroscopy (Alcala et al., 2010; Luukkonen et al., 2008; Rantanen et al., 1998, 2005), Raman spectroscopy (Wikstrom et al., 2005), and focused beam reflectance (Huang et al., 2010; Matero et al., 2010). The overall purpose of these PAT application researches is to quickly measure one or multiple outputs of granulation such as in-process granule moisture, particle size distribution, and/or drug substance polymorphic transformation during processing so that the process scientist can better master the status of the granulation process. The advantage of PAT application in wet granulation is obvious: (1) The end-point determined by PAT is more flexible than massing time, and also more accurate than power consumption or impeller torque (only for HS granulation). (2) As discussed by Lawrence Yu in his recent publication (Yu et al., 2014), PAT helps lift the control strategy from level 3 (relying on extensive end-product testing and tightly contained material attributes and process parameters) to level 2 (controlling with reduced end-product testing, flexible material attributes, and process parameters within the established design space) and even level 1 (automatic engineering control in real time). (3) It improves the process capability and makes the improvement possible. For example, the particle size distribution of granules and the content deviation can be further narrowed down, the process flow “granulation ! wet milling ! drying ! dry milling” may be simplified to “granulation ! drying ! dry milling” so that processing time and manufacturing expense can be saved with less GMP concerns at the same time. Current pharmaceutical industry is under the transition from batch manufacturing practice to continuous manufacturing practice (Lee et al., 2015). Continuous manufacturing is faster, more reliable, and efficient than traditional batch manufacturing. It also requires PAT system being used throughout the whole manufacturing process for quality control. In 2015 and 2016, both Vetex and Janssen have drug products using continuous manufacturing approved by FDA. Over the past decade, FDA had expended great effort on the regulation side to encourage application of new technology in the manufacturing process. It is continuously making its own effort to ensure that the application of regulatory policies reflects state of the art manufacturing technology and ensure a continuous supply of drugs for the US public (FDA, 2015).

8 SUMMARY Unit operation is the basic unit of pharmaceutical manufacturing process. QbD is a systematic and risk-based approach to pharmaceutical development, which has been widely

Implementation of Pharmaceutical Quality by Design in Wet Granulation

accepted by pharmaceutical industry for many years. By systematically collecting qualityand process-related information on wet granulation from recently approved drug product applications, we created a general profile for high-shear/low-shear (HS/LS) granulation and a general profile for fluidized bed (FB) granulation. Based on these unit operation profiles, we are able to quantify the reported frequencies of quality attributes of granulation products, list the consideration points of product design and product understanding related to wet granulation development, quantify the reported frequencies and risk factors of process parameters, and also pattern the research behaviors on these process parameters. Based on general profiles for HS/LS granulation and FB granulation, we suggest the spray rate/time, the amount of granulation fluid I, massing time, and granulation impeller (tip) speed for HS/LS granulation; and the amount of granulation fluid, spray rate and time, and inlet air volume for FB granulation are important process parameters that process scientists should pay attention to during wet granulation development. We hope this review work can help the pharmaceutical industry better prepare the development of wet granulation under QbD paradigm, and can help regulatory agency improve the review quality and consistency. This is our first effort to develop a profile for specific unit operation. Actually, many unit operations such as bin blending, milling, roll compaction, Wurster coating, and pan coating have been well studied, and have been employed in the manufacturing process for many years. Enriched process data accumulated at agency enable us to gradually develop general profiles for these common unit operations. Consequently, we also can derive a more dedicated unit operation profile targeting at a specific dosage form, a time period, drug substance, a similar formulation, or an excipient involved in the unit operation development, etc. Developing an in-house integrated unit operation profile system with quality scoring matrix in the future can be a powerful knowledge base for regulatory review, and help the regulatory agency gradually transition from qualitative CMC review to quantitative CMC review in the future.

REFERENCES Achanta, A. S., Adusumilli, P. S., & James, K. W. (1997). Endpoint determination and its relevance to physicochemical characteristics of solid dosage forms. Drug Development and Industrial Pharmacy, 23(6), 539–546. Alcala, M., Blanco, M., Bautista, M., & Gonzalez, J. M. (2010). On-line monitoring of a granulation process by NIR spectroscopy. Journal of Pharmaceutical Sciences, 99(1), 336–345. Awotwe-Otoo, D., Agarabi, C., & Khan, M. A. (2014). An integrated process analytical technology (PAT) approach to monitoring the effect of supercooling on lyophilization product and process parameters of model monoclonal antibody formulations. Journal of Pharmaceutical Sciences, 103(7), 2042–2052. Bardin, M., Knight, P. C., & Seville, J. P. K. (2004). On control of particle size distribution in granulation using high-shear mixers. Powder Technology, 140(3), 169–175. Bouwman, A. M., Visser, M. R., Eissens, A. C., Wesselingh, J. A., & Frijlink, H. W. (2004). The effect of vessel material on granules produced in a high-shear mixer. European Journal of Pharmaceutical Sciences, 23(2), 169–179. Chitu, T. M., Oulahna, D., & Hemati, M. (2011). Wet granulation in laboratory-scale high shear mixers: effect of chopper presence, design and impeller speed. Powder Technology, 206(1–2), 34–43.

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