10 Continuous Oral Solid Dose
Processing
Michael Rooney
CONTENTS
Overview of Continuous Granulation
Continuous Granulation versus Batch Processing
Batch Processing and Continuous Processing Facility Layouts
Design Details and Compliance Considerations
Equipment and Utility Requirements
Scaling of Continuous Processing
Cost Savings during the Development Stage
Special Discussion: Portable Granulation Suite
INTRODUCTION
Oral dose delivery of active pharmaceutical ingredients (APIs) is the oldest, simplest, and most common means for delivering a drug into the human body. An oral solid dose (OSD) product is defined as any solid pharmaceutical product ingested by mouth to be absorbed in the gastrointestinal (GI) tract. With the advent of modern clinical methods and achievements in scientific research and development (R&D), the delivery method of OSD products has become as critical as the API itself. How to deliver the APIs to specific target zones without losing their efficacy is at the heart of the OSD industry.
The first oral delivery systems were simple mixtures of ingredients that were compressed into a pill for ease of swallowing. This process, which involves mixing ingredients and then milling the mixture to reduce all particles to a consistent size, is called direct compression; the milling operation is continuous, whereby material is fed to a mill and processed particles are collected from the discharge of the equipment. While direct compression is the simplest and most cost-effective process, it has performance limitations. Dry granulation was developed to increase the amount of API per dose, known as drug loading, and to aid in manufacturing. Dry granulation increases the density of the mixture with a roller compactor, which, like a mill, is a continuous process.
Dry granulation was an improvement, but to meet product performance demands, wet granulation was developed. Wet granulation requires multiple steps. These three processes have been used for years to make most OSD products consumed worldwide (Figure 10.1).
Despite the various options available to a modern product formulator, OSD facilities predominantly use batch processing. Even though both direct compression and dry granulation are based on continuous processing, the facility layouts are based on batch manufacturing. Facility layouts and process flows are impacted by the individual process steps, quality testing, and indirect requirements, such as market demand. The critical product attributes associated with OSD products are particle size, concentration, and moisture content, all of which impact product efficacy, dissolution, GI track targeting, and onset of action. The OSD facilities also include many stopping points in the process where the quality of the product is evaluated. Downstream operations are dependent on the testing results of intermediate steps, and subsequent additions might require adjustments based on data from previous steps in the process.
Recently, continuous processing, using direct compression, dry granulation, and wet granulation, has been suggested for OSD manufacturing; thus, the individual processing steps would occur without incremental steps. Quality testing would still occur, but with data resulting in real-time control of the critical process attributes. This chapter explores continuous processing and its impact on quality, facilities, operations, equipment, and the future of the OSD business [1]. It addresses the developments in the industry that are responsible for the change. This chapter justifies the use of continuous granulation, identifies the risks, and provides the development necessary to support these changes. After reading this chapter, readers should have a good understanding of the benefits of continuous processing.
EXECUTIVE SUMMARY
Continuous processing, a cost-effective method for manufacturing certain pharmaceutical products, feeds raw materials into an integrated system and a finished dosage comes out, with no stops at the end of each step. Critical quality parameters are measured in-line, and process attributes are adjusted automatically by the control system to keep the process within specifications. Batch processing is typically scheduled to correspond to operating shifts, while continuous processing typically operates 24 h a day.
Continuous processing is not new. The food industry has been using vertical, gravity-fed processing trains for years. In a typical commercial food facility that handles dry powders for products, such as Jell-O (R) and cake mixes, the process starts many stories up in the facility and ends on the ground floor in the high-speed packaging line. There are no queuing steps or holding for testing. The food industry perfected vertical continuous granulation years ago to reduce operating costs. The challenges and design considerations associated with any continuous process are the same.
FIGURE 10.1 (a) Direct compression, (b) dry granulation, and (c) wet granulation.
Critical quality attributes must be monitored in-line, and correction algorithms to adjust the process automatically must be developed and validated in real time.
Product demand must be high to justify such costly technology. Not all pharmaceutical products have the market pull to justify the complexity and cost of a continuous granulation process.
When a problem appears in the continuous process flow, it must be determined how much of the process has to be quarantined and how to get the process back into steady state.
Development data must support an understanding of continuous processing in real time.
Capital costs for continuous processing equipment are high.
Vertical integration of any continuous solid processing is recommended, so the facility arrangement must be able to accommodate the height to maximize the benefits.
Regulatory requirements defined by the Food and Drug Administration (FDA) are very strict regarding the approval of drugs and manufacturing facilities to ensure the safety of the patient. A thorough understanding of regulations, validation, and quality systems is necessary to develop any compliant manufacturing operation.
The pharmaceutical industry was reluctant to implement continuous processing because of the lack of adequate process automation tools. Process automation technology (PAT) is the ability to measure critical process attributes in-line and then control the parameters that affect these attributes in real time. The standards to meet FDA regulations for a pharmaceutical manufacturing operation are significantly higher than those of a food production line; for example, the FDA requires that the amount of an API per dose must be within 10%. The dissolution of the finished product in the GI tract has to be repeatable. These are specific requirements that guarantee that our drug industry is safe and provides a consistent product. In cake mix processing, for example, if there is 15% more of one ingredient than necessary, the result may not be satisfactory to the customer, but the consumer’s health is not compromised. The pharmaceutical industry has traditionally manufactured with a batch format with quality checks and quarantine steps between each process step to ensure quality and minimize losses. Wet granulation further necessitated the practice of batch processing (Figure 10.2).
PAT is the most significant technological advancement in the evolution of continuous granulation. Continuous processing can reduce labor costs, necessary facility space, quality assurance (QA) testing, purified water use, waste, and yield loss, all while providing tremendous scaling capabilities. Continuous granulation requires a high initial capital cost for equipment, but less capital for facilities. Depreciation of equipment and facilities is typically 15 and 25 years, respectively, so the offset of capital between equipment and facility is not equal.
The amount of historical and developmental data required to use PAT for control of a commercial process cannot be underestimated. If a commercial process is monitored in real time, the controller needs a validated developmental database to evaluate the performance. Without a real-time baseline, the PAT monitoring system cannot effectively control the commercial process. This presents a significant challenge if the application for continuous granulation and in-line PAT is for an existing commercial batch process. New benchmark data are required to retrofit the process, which would require a significant investment.
Continuous granulation is best applied to pharmaceutical products that meet the following three criteria: (1) Product demand should be large enough to justify the extra capital expense. (2) Developmental data should be available due to scale-up and clinical development. (3) A facility must allow for vertical integration to maximize the integration of the continuous processing equipment.
Table 10.1 compares a 25 kg/h continuous granulation train with a traditional batch process. Assuming the continuous process operates 24 h a day, the basis of this analysis is 600 kg/batch.
These data show a significant reduction in operating costs for continuous processing, but the numbers are also based on a product demand of 1 billion tablets a year for each process train, which requires an appropriate business plan to support the investment.
Continuous granulation can have an impact on more than just manufacturing commercial products. Continuous granulation is based on a feed rate and time. When developing a new pharmaceutical product, one must scale the process up to prove the process is viable and repeatable and supply product to various clinical trials. As the product development progresses, the volume and equipment for a new product progress with it. In the case of a batch process, the product development sequence must find bigger and bigger batch equipment until the product is approved and then commercialized. During this development phase, the scientists conduct countless experiments to optimize product performance. With a continuous process, the design of experiments (DOE) is simpler and less costly in labor and API materials because the only parameter to change during development is time. The equipment is the same for development as it is for commercial use. This approach can reduce the need for new expensive APIs and labor to run many experiments on equivalent batch equipment trains. The money saved in development and commercial manufacturing of a product forms a very compelling reason to dive into the use of continuous granulation technology [2].
FIGURE 10.2 Process flow diagrams. IBC, intermediate bulk container; PAT, process automation technology; QC, quality control.
TABLE 10.1
Batch Processing versus Continuous Processing
Continuous granulation is not the answer for all products, but given certain criteria, it can result in significant efficiencies and improve business performance. The assumption that all products can be processed in batch or continuous processing is not realistic. Significant testing is required to develop and validate products during development to confirm that the technology is capable, controllable, and repeatable.
OVERVIEW OF CONTINUOUS GRANULATION
BATCH PROCESSING
Most OSD products are manufactured using direct compression, dry granulation, or wet granulation. Most of the unit operations are the same; for example, milling and blending are used in all three operations. Each unit operation in batch processing includes unload and reload steps, which result in yield and time losses that are additive throughout the entire process. If the product is hazardous and requires containment, then each unload and reload operation requires additional containment equipment, which reduces yield and adds operating costs, which significantly increases capital costs.
The objective of OSD processing is to create a specific mix of APIs and excipients that can be compressed or encapsulated in a way that produces repeatable results. Mixing technology is a challenge when working with many ingredients of various particles, sizes, and shapes. Particle sizing with milling equipment is a common step in OSD processing that results in particles of similar size and shape for a consistent blend. Roller compactor equipment is used to compress a powder mixture, influencing its density and increasing the API loading per unit volume. A wet granulation process adds moisture to bind particles together to increase the density for higher API loading. These various steps are used uniquely or in combination to obtain a repeatable product.
Due to the yield losses associated with the many steps of a batch process, maintaining the correct formulation throughout the process requires testing at each step. If the composition of an in-process batch is not monitored, the consistency of the mixture may not be repeatable as required by FDA regulations. Since the formulation of most OSD products requires progressive additions of materials during the process, quality checks are required after each unit operation and before the addition of materials. For example, a formulation might require the addition of sucrose late in the process in an amount based on the percentage of the total weight, which is critical to the performance of the product. If the yield loss varies between 10% and 20%, then the additional weight is based on the actual yield of each batch; thus, the batch is weighed and the added amount adjusted to match the critical percentage.
To ensure the consistency and quality of a product, the yield and mixture integrity is checked at each step in a batch process. Each quality test point includes sampling, testing, and release by quality control (QC). Thus, in addition to the unloading and reloading operations for each step, there is sampling and testing, which requires time between steps of a batch process. The results of the testing might determine a pass–fail result or weight adjustments for downstream material additions.
TECHNOLOGIES AND IMPROVEMENTS
In-process testing performed during a batch operation has traditionally been completed in a lab, either within the production area or in a separate lab building. A critical element of continuous processing is in-line and real-time data collection and analysis. The three most important process parameters are particle size, blend composition, and moisture content, with each parameter monitored, using size analyzers, near-infrared, and loss in drying, respectively. The instruments associated with measuring these parameters have significantly improved over the years to be capable of in-line testing in real time. These instruments are the basis of the OSD PAT program.
The next challenge is to impact the process with a conclusion from the data. Historically, operators made adjustments to the process based on test results. Over the past 10 years, there have been significant improvements in the analytical instrument and data collection industry that allow the equipment to adjust itself instead of requiring human intervention. Changes in the instruments have given them the ability to (1) measure the key process parameters in-line without disrupting the process, (2) evaluate the data against a standard that confirms that the present state is within a validated range, and (3) modify the inputs into the system before the actual values exceed alarm limits, known as correction algorithms.
The use of continuous processing was very limited until these three issues were resolved, which allowed the various process steps to be integrated into a continuous process equipment system. Equipment suppliers began to convert batch equipment to continuous equipment. The direct compression and dry granulation processing were already based on continuous processing: milling and roller compaction. Additionally, the dosage operations, such as tablet compression and encapsulation, were based on continuous processing.
The first step toward this development was the improvement in raw material feeders and in-line blending systems. Product raw material formulations do not come in equal parts; some of the excipients might have a 10:1 ratio between the largest and smallest raw material components. However, the feeding and mixing of each component must be consistent despite the various component ratios. Significant improvements have been made to allow accurate feeding of large variations in formulation. When engineers consider using continuous processing, they must know the formulation requirements and the limitations of each feed station so that the formulation matches the feeder capability and accuracy. The engineer must also consider potential conditioning steps that some material might require before the feeding process, such as sieving, screening, and de-lumping.
Improvements have also been made to the granulation and drying equipment systems used for wet granulation processing. New proprietary screw-type granulators can now complete the work of a high-shear granulator. These in-line continuous granulators can compress the powder, add moisture, and thoroughly mix multiple ingredients to specific process requirements, completing multiple steps of the process that previously required additional equipment. The discharge of this unit operation can now use PAT to check moisture and composition as the material leaves the twin-screw granulators. The signal is compared to the standard, and then the system makes adjustments to the feeders of raw material automatically (Figure 10.3).
The last step in the restructuring of a batch of a wet granulation process is the conversion of the typical batch drying fluid bed to a continuous product dryer. Suppliers have come up with two basic methods as of the writing of this chapter; cyclical segmented fixed volume and linear continuous flow fluid bed drying technique.
The rotary segmentation design converts a traditional batch-type, fluid-bed bowl and expansion chamber volume into small pie-shaped segments. Repeated processing of small segments of a typical fluid bed simulates continuous manufacturing.
The high-shear granulator feeder can feed all segments of the fluid bed, one segment at a time.
A rotating diverter system is used to divert the flow of material from the high-shear mixer to the various segments.
FIGURE 10.3 In-line shear granulator.
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