Journal:A systematic framework for data management and integration in a continuous pharmaceutical manufacturing processing line

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Full article title A systematic framework for data management and integration in a continuous pharmaceutical manufacturing processing line
Journal Process
Author(s) Cao, Huiyi; Mushnoori, Srinivas; Higgins, Barry; Kollipara, Chandrasekhar; Fernier, Adam;
Hausner, Douglas; Jha, Shantenu; Singh, Ravendra; Ierapetritou, Marianthi; Ramachandran, Rohit
Author affiliation(s) Rutgers University, Johnson & Johnson, Janssen Research & Development
Primary contact Email: rohit dot r at rutgers dot edu; Tel.: +1-848-445-6278
Year published 2018
Volume and issue 6(5)
Page(s) 53
DOI 10.3390/pr6050053
ISSN 2227-9717
Distribution license Creative Commons Attribution 4.0 International
Website http://www.mdpi.com/2227-9717/6/5/53/htm
Download http://www.mdpi.com/2227-9717/6/5/53/pdf (PDF)

Abstract

As the pharmaceutical industry seeks more efficient methods for the production of higher value therapeutics, the associated data analysis, data visualization, and predictive modeling require dependable data origination, management, transfer, and integration. As a result, the management and integration of data in a consistent, organized, and reliable manner is a big challenge for the pharmaceutical industry. In this work, an ontological information infrastructure is developed to integrate data within manufacturing plants and analytical laboratories. The ANSI/ISA-88 batch control standard has been adapted in this study to deliver a well-defined data structure that will improve the data communication inside the system architecture for continuous processing. All the detailed information of the lab-based experiment and process manufacturing—including equipment, samples, and parameters—are documented in the recipe. This recipe model is implemented into a process control system (PCS), data historian, and electronic laboratory notebook (ELN). Data existing in the recipe can be eventually exported from this system to cloud storage, which could provide a reliable and consistent data source for data visualization, data analysis, or process modeling.

Keywords: data management, continuous pharmaceutical manufacturing, ISA-88, recipe, OSI Process Information (PI)

Introduction

For decades, the pharmaceutical industry has been dominated by a batch-based manufacturing process. This traditional method can lead to increased inefficiency and delay in time-to-market of product, as well as the possibility of errors and defects. Continuous manufacturing in contrast, is a newer technology in pharmaceutical manufacturing that can enable faster, cleaner, and more economical production. The U.S. Food and Drug Administration (FDA) has recognized the advancement of this manufacturing mode and has been encouraging its development as part of the FDA's "quality by design" (QbD) paradigm.[1] The application of process analytical technology (PAT) and control systems is a very useful effort to gain improved science-based process understanding.[2] One of the advantages of the continuous pharmaceutical manufacturing process is that it provides the ability to monitor and rectify data/product in real time. Therefore, it has been considered a data rich manufacturing process. However, in the face of the enormous amount of data generated from a continuous process, a sophisticated data management system is required for the integration of analytical tools to the control systems, as well as the off-line measurement systems.

In order to represent, manage, and analyze a large amount of complex information, an ontological informatics infrastructure will be necessary for process and product development in the pharmaceutical industry.[3] The ANSI/ISA-88 batch control standard[4][5][6] is an international standard addressing batch process control, which has already been implemented in other industries for years. Therefore, adapting this industrial standard into pharmaceutical manufacturing could provide a design philosophy for describing equipment, material, personnel, and reference models.[7][8] This recipe-based execution could work as a hierarchical data structure for the assembly of data from the control system, process analytical technology (PAT) tools, and off-line measurement devices. The combination of the ANSI/ISA-88 recipe model and the data warehouse informatics strategy[9] leads to the “recipe data warehouse” strategy.[10] This strategy could provide the possibility of data management across multiple execution systems, as well as the ability for data analysis and visualization.

Applying the “recipe data warehouse” strategy to continuous pharmaceutical manufacturing provides a possible approach to handle the data produced via analytical experimentation and process recipe execution. Not only the data itself but also the context of the data can be well-captured and saved for documentation and reporting. However, unlike batch operations, continuous manufacturing is a complicated process containing a series of interconnected unit operations with multiple execution layers. Therefore, it is quite challenging to integrate data across the whole system while maintaining an accurate representation of the complex manufacturing processes.

In addition to data collection and integration of the continuous manufacturing plant, the highly variable and unpredictable properties of raw materials are necessary to capture and store in a database because they could have an impact on the quality of the product.[11] These properties of relevance to continuous manufacturing are measured via many different analytical methods, including FT4 powder characterization[12], particle size analysis[13], and the Washburn technique.[14] The establishment of a raw material property database could be achieved by the “recipe data warehouse” strategy. Nevertheless, compared to the computer-aided manufacturing used in the production process, the degree of automation would vary significantly in different analytical platforms. Therefore, an easily accessible recipe management system would be highly desirable in characterization laboratories.

Moreover, a cloud computing technology for data management and storage is adapted to deal with the massive amount of data generated from the continuous manufacturing process. While traditional computational infrastructures involve huge investments on dedicated equipment, cloud computing offers a virtual environment for users to store or share infinite packets of information by renting hardware and storage systems for a defined time period.[15] Because of its many advantages—including flexibility, security, and efficiency—cloud computing is suitable for data management in the pharmaceutical industry.[16]

Objectives

In this work, a big data strategy following the ANSI/ISA-88 batch control standard is applied for data management in continuous pharmaceutical manufacturing. The ontology of recipe modeling and the design philosophy of a recipe is elaborated. A data management strategy is proposed for data integration in both a continuous manufacturing processes and the analytical platforms used for raw material characterization. This strategy has been applied to a pilot direct compaction, continuous tablet manufacturing process to build up data flow from equipment to recipe database on the cloud. In the characterization of raw material and intermediate blend properties, experiment data is also captured and transferred via a web-based recipe management tool.

Materials and methods

Ontology

An ontology is an explicit specification of a conceptualization, where "conceptualization" refers to an abstract, simplified view of the world that we wish to represent for some purpose.[17] A more detailed definition of an ontology has been made where the ontology is described as a hierarchically structured set of terms for describing a domain that can be used as a skeletal foundation for a knowledge base.[18] Ontologies are created to support the sharing and reuse of formally represented knowledge among different computing systems, as well as human beings. They provide the shared and common domain structure for semantic integration of information sources. In this work, a conceptualization through the ANSI/ISA-88 standard shows the advantage of building up a general conceptualization in the pharmaceutical development and manufacturing domains.

Information technology has already developed the capabilities to support the implementation of such proposed informatics infrastructure. The language used in an ontology should be expressive, portable, and semantically defined, which is important for the future implementation and sharing of the ontology. The World Wide Web Consortium (W3C) has proposed several markup languages intended for web environment usage, and Extensive Markup Language (XML) is one of them.[19] XML is a metalanguage that defines a set of rules for encoding documents in a format which is both human readable and machine readable. The design of XML focuses on what data is and how to describe data. XML data is known as self-defining and self-describing, which means that the structure of the data is embedded with the data. There is no need to build the structure before storing the data when it arrives. The most basic building block of an XML document is an element, which has a beginning and ending tag. Since nested elements are supported in XML, it has the capability to embed hierarchical structures. Element names describe the content of the element, while the structure describes the relationship between the elements.

As an XML Schema defines the structure of XML documents, an XML document can be validated according to the corresponding XML Schema. XML Schema language is also referred to as XML Schema definition (XSD), which defines the constraints on the content and structure of documents of that type.[20]

Recipe model

In ANSI/ISA-88, a recipe is defined as the minimum set of information that uniquely identifies the production requirements for a particular product.[4] However, there will still be a significant amount and different types of necessary information, which is required to describe products and to make products. Holding all the information in one recipe would be complicated and cumbersome for human beings. As a result, four types of the recipe are defined in ANSI/ISA-88 to focus on different levels and accurate information.

Recipe types

Table 1 shows the four recipe types, as defined in ANSI/ISA-88, and their relationship. The different recipe types are shown together with an example from the pharmaceutical industry in Figure 1.

Table 1. ANSI/ISA-88 recipe types
Type Definition
General A type of recipe that defines raw materials and site independent processing requirements
Site A type of recipe that usually derived from the general recipe to meet specific conditions or constraints of the site manufacturing the product
Master A type of recipe that contains the information of an individual product and depends on equipment situation
Control A type of recipe that defines the manufacturing process a single batch of product


Fig1 CaoProcess2018 6-5.png

Figure 1. ANSI/ISA-88 recipe model

Process model

The ANSI/ISA-88 standard defines a process model that has four levels, including process, process stages, process operations, and process actions. The structure of this process model is shown in Figure 2. As shown in the figure, the higher level consists an ordered set of the lower levels. The information of equipment, parameter, and material can be included in the attributes of the process actions.


Fig2 CaoProcess2018 6-5.png

Figure 2. ANSI/ISA-88 process model

It is important to note that the reference model and guideline recommended in the ANSI/ISA-88 standard are not to be strictly normative. This feature provides the sufficient level of flexibility to represent the current manufacturing process according to the ANSI/ISA-88 standard, as well as the opportunity to expand the reference model to suit unusual manufacturing.[21] In this case, the ANSI/ISA-88 recipe model is extended to continuous manufacturing, instead of the batch manufacturing process, to provide a hierarchical structure for data management and integration.

Recipe model implementation

The purpose of this part is to illustrate the proposed methodology to assess the implementation of the ANSI/ISA-88 recipe model into continuous pharmaceutical manufacturing. Proven evidence has shown that developing a new product manufacturing process might be a difficult task. Although the ANSI/ISA-88 standard provides a practical reference model for sure, adapting a batch model to the continuous process will still be challenging. The implementation of the recipe model is divided into several steps to perform the activities in a structured way.

Step 1. ANSI/ISA-88 applicable area identification

The initial scope and project boundaries will be defined in this step-in order to discuss the main objectives. As mentioned above, the ANSI/ISA-88 standard is not strictly defined and can be expanded to continuous manufacturing in contrast. Moreover, since analytical experiments are performed by each sample, one sample can be treated as a “batch” in the analytical process. Therefore, it is also reasonable to consider the offline characterization experiment of material to be applicable to the ANSI/ISA-88 standard. In this situation, a technique-specific recipe containing detailed process steps could provide instructions for specific experiment types, as well as the designed structure for result documentation. As shown in Figure 3, after analytical tests are performed on samples according to the procedures in the recipes, experiment results will be recorded in the recipe as well.


Fig3 CaoProcess2018 6-5.png

Figure 3. Material and data flow in an experiment process

Preliminary data gathering is performed to provide a clear understanding of the stream process and the requirement of each particular case. The component that may be modified in the ANSI/ISA-88 recipe model could be a recipe type, recipe content structure, recipe representation, etc. The in-depth knowledge of process architecture, manufacturing execution systems, product and material information, and analytical platforms will be necessary in accomplishing this step.

Step 2. Recipe structure definition

An XML Schema is created for the implementation of an ANSI/ISA-88 standard to provide the recipe model a structured, system-independent XML markup. This step needs to be completed based on the data collected from the previous step. An XML Schema document works as a master recipe standard. The goals of this document include setting restrictions to the structure and content of the recipe, maximizing the recipe model’s expressive capability, and realizing the machine’s ability to validate recipes.

Step 3. Process analysis

Due to the master recipe’s equipment dependencies, it will be complicated and inefficient to develop a single master recipe to describe the whole continuous pharmaceutical process. The process itself consists of an ordered set of multiple unit operations, which may change from time to time depending on the equipment used. This does happen often in the product process development stage, especially in the early phases. Another barrier is the transformation from research and development (R&D) to production. Usually, R&D performs the product development process in small-scale pilot plants, which could be quite different from the primary production plant technology-wise. Moreover, the differences between technologies used in every plant are crucial to product manufacturing after the transformation. The entire problem stated above is critical to the implementation of ANSI/ISA-88 to continuous pharmaceutical manufacturing.

A suitable approach to the implementation of ANSI/ISA-88 into continuous manufacturing might be to develop a robust modular structure that could support a variety of equipment types and classes. In this case, a continuous process is divided into several unit operations, such as mixing and blending. Each unit operation could be performed by different equipment types that correspond to a different recipe module. In other words, each equipment type might take place in a continuous process and would be mapped to a recipe module individually. The ordered combination of these recipe modules would form the master recipe of continuous manufacturing.

PAT tools used in continuous pharmaceutical manufacturing, e.g., near-infrared NIR and Raman, are implemented in a continuous process to provide real-time monitoring of the material properties and are essential to manufacturing decision making. The PAT tools would optimally be treated as a unit operation that has a corresponding recipe module, in order to provide flexibility and reliability for the management of PAT.

Step 4. Process mapping

XML-based master recipes could be developed in accordance with an XML Schema to represent the manufacturing process. Firstly, the equipment information, operation procedures, and process parameters of unit operations would be mapped carefully to the ANSI/ISA-88 recipe model to generate re-specified recipe modules. These recipe modules could be transformed into the master recipe and used for the individual study and data capturing of unit operations.

Systematic framework of integration

The fast development of information and communication technology, such as big data and cloud computing, provides the capability to increase productivity, quality, and flexibility across industries. The process industry is also seeking a possible approach to bringing together all data from different process levels and distributed manufacturing plants in a continuous and holistic way to generate meaningful information.[22] For continuous pharmaceutical manufacturing, a data flow across the whole process is proposed in Figure 1, following the traditional design pattern, an automation pyramid[23], to create an information and communication infrastructure.

Enterprise resource planning (ERP) systems are placed at the top of the structure, shown in Figure 4. It demonstrates an integrated view of the core business process, based on the data collected from various business activities.[24] Long-term resource planning—primarily human and material resources—would be its primary objective. The "historian", on Level 4, is intended for collecting and organizing data to provide an information infrastructure. Meaningful information in different representations, based on the ANSI/ISA-88 recipe document, could also be generated from the organizational assets.


References

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Notes

This presentation is faithful to the original, with only a few minor changes to presentation, including with grammar and punctuation. In some cases important information was missing from the references, and that information was added.