Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations,case studies from industry and considerations for continuous processing

Abstract

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.     

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.     

The role of the carrier in the formulation of pharmaceutical solid dispersions. Part II: amorphous carriers

ABSTRACT

Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion.

Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.

Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.     

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process.     

Current Trends in API Co-Processing: Spherical Crystallization and Co-Precipitation Techniques

Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.     

Selecting and controlling API crystal form for pharmaceutical development--strategies and processes

The success of designing, developing, manufacturing and introducing oral dosage forms of pharmaceutical products into the market relies on many steps, processes, stages and usually three phases of clinical trials. One key process is selecting an appropriate active pharmaceutical ingredient (API) crystal or amorphous form for the final dosage product: the ultimate goal of this selection process is to ensure that the manufactured product contains a stable and bioavailable active ingredient. A thorough knowledge of the solid-state chemistry of the API, the related excipients and the processes to make the product are critical in meeting this goal. Through recently published literature and the authors' experiences, this review describes the concepts and approaches that are used in the development of a truly knowledge-based crystalline API form selection process and highlights the appropriate studies which fit the Quality by Design (QbD) framework for pharmaceutical development activities. This review also discusses the potential API crystal form transformations in the API crystallization, post-crystallization and formulation stages, which are demonstrated by case study examples.     

API Quality by Design Example from the Torcetrapib Manufacturing Process

The concept and application of quality by design (QbD) principles has been and will undoubtedly continue to be an evolving topic in the pharmaceutical industry. However, there are few and limited examples that demonstrate the actual practice of incorporating QbD assessments, especially for active pharmaceutical ingredients (API) manufacturing processes described in regulatory submissions. We recognize there are some inherent and fundamental differences in developing QbD approaches for drug substance (or API) vs drug product manufacturing processes. In particular, the development of relevant process understanding for API manufacturing is somewhat challenging relative to criteria outlined in ICH Q8 (http://www.ich.org/cache/compo/276–254–1.html) guidelines, which are primarily oriented toward application of QbD for drug product manufacturing. This position paper provides a perspective of QbD application for API manufacture using an example from the torcetrapib API manufacturing process. The work includes a risk assessment, examples of multivariate design, and a proposed criticality assessment, all of which coalesce into an example of design space. Torcetrapib was a project in phase III development as a potent and selective inhibitor of cholesteryl ester transfer protein before being terminated in late 2006. The intent of Pfizer was to submit torcetrapib under the QbD paradigm (route selection, robustness, and reagent/solvent selection during phases I to III are significantly important in establishing a manufacturing process that would have the most flexibility in the final design space. For more information on this development phase for torcetrapib see Damon et al., Org Process Res Dev, 10(3):464–71, 2006, Org Process Res Dev, 10(3):472–80, 2006).     

Jet milling industrialization of sticky active pharmaceutical ingredient using quality-by-design approach

Jet milling is frequently used in pharmaceutical industry to achieve different objectives. It can be used as enabling technology to overcome poor water solubility linked to hydrophobic active of pharmaceutical ingredient (API) by reducing the particle size and therefore increasing the dissolution rate. Alternatively, jet milling can be used either to enhance blending efficiency of API with excipient in case of formulation at low dosage strength or to achieve the required particle size for inhalation therapy. In this study, development of commercial manufacturing process of sticky API and its industrialization are described. The methodology used is based on quality-by-design approach to deliver safe, effective and robust manufacturing process. The study showed that the specific energy is a key factor that drives particle size during jet milling and the scale-up from lab to industrial scale. After understanding the process, a design space was built where different zones such as operating point, operating space (where the product is compliant to specification despite variability of process parameters), and the knowledge space were outlined. Finally, an industrial installation was proposed to deliver product with high productivity yield, compliant with safety regulation, and cleanable in place.     

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry because of its simplicity and robustness. The designed control system consists of single and cascade (nested) control loops. The control system has been simulated in gPROMS ^TM (Process System Enterprise). The ability of the control system to track the specified set point changes as well as to reject disturbances has been evaluated. Results demonstrate that the model shows an enhanced performance in the presence of random disturbances under closed-loop control compared to an open-loop operation. The control system is also able to track the set point changes effectively. This proves that closed-loop feedback control can be used in improving pharmaceutical manufacturing operations based on the Quality by Design (QbD) paradigm.     

Evaluation of drug physical form during granulation, tabletting and storage

An active pharmaceutical ingredient (API) was found to dissociate from the highly crystalline hydrochloride form to the amorphous free base form, with consequent alterations to tablet properties. Here, a wet granulation manufacturing process has been investigated using in situ Fourier transform (FT)-Raman spectroscopic analyses of granules and tablets prepared with different granulating fluids and under different manufacturing conditions. Dosage form stability under a range of storage stresses was also investigated. Despite the spectral similarities between the two drug forms, low levels of API dissociation could be quantified in the tablets; the technique allowed discrimination of around 4% of the API content as the amorphous free base (i.e. less than 1% of the tablet compression weight). API dissociation was shown to be promoted by extended exposure to moisture. Aqueous granulating fluids and manufacturing delays between granulation and drying stages and storage of the tablets in open conditions at 40 degrees C/75% relative humidity (RH) led to dissociation. In contrast, non-aqueous granulating fluids, with no delay in processing and storage of the tablets in either sealed containers or at lower temperature/humidity prevented detectable dissociation. It is concluded that appropriate manufacturing process and storage conditions for the finished product involved minimising exposure to moisture of the API. Analysis of the drug using FT-Raman spectroscopy allowed rapid optimisation of the process whilst offering quantitative molecular information concerning the dissociation of the drug salt to the amorphous free base form.     

Influence of physical factors on the accuracy of calibration models for NIR spectroscopy

The quality of pharmaceutical drugs is strongly influenced by a number of physical and chemical factors that require careful control during the production process in order to ensure that the end-product will meet the specifications. Near infrared spectroscopy has proved effective for monitoring changes in such factors and is currently the most widely used technique for controlling drug manufacturing processes. In this work, the authors determined an active pharmaceutical ingredient (API) throughout its production process. The influence of particle size, galenic form, compaction pressure and coating thickness on NIR spectra was evaluated with a view to developing effective methodologies for constructing simple, accurate calibration methods affording API quantization at different stages of a drug production process. All calibration models were constructed from data for laboratory samples alone and NIR calibration models for determining the API determination by using product weights as reference values. The proposed models were validated by application to samples obtained at three stages of a drug manufacturing process and comparison of the predicted values with HPLC reference values. The RSEP values thus obtained never exceeded 1.5%.     

Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds

Introduction: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for this interest as well as many considerations and challenges that exist today concerning continuous manufacturing.

Areas covered: Continuous processing is defined and many reasons for its adoption are described. The current state of continuous drug substance manufacturing within the pharmaceutical industry is summarized. Current key challenges to implementation of continuous manufacturing are highlighted, and an outlook provided regarding the prospects for continuous within the industry.

Expert commentary: Continuous processing at Lilly has been a journey that started with the need for increased safety and capability. Over twelve years the original small, dedicated group has grown to more than 100 Lilly employees in discovery, development, quality, manufacturing, and regulatory designing in continuous drug substance processing. Recently we have focused on linked continuous unit operations for the purpose of all-at-once pharmaceutical manufacturing, but the technical and business drivers that existed in the very beginning for stand-alone continuous unit operations in hybrid processes have persisted, which merits investment in both approaches.     

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

PURPOSE: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. MATERIALS AND METHODS: The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. RESULTS: The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile; Designing product and manufacturing processes; Identifying critical quality attributes, process parameters, and sources of variability; Controlling manufacturing processes to produce consistent quality over time. CONCLUSIONS: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.     

Quality control programme for the preparation of small-pool lyophilized heat-treated cryoprecipitates

International and national documents on and standards for quality control have been introduced for Blood Banks. Recently, the Standard Registration Document and a National Health Authority Licence for factor VIII preparations based on that Document were introduced in the Netherlands. In the course of developing a preparation of lyophilized heat-treated cryoprecipitates in our Blood Bank, we used this Standard Registration Document and the good pharmaceutical manufacturing practices to design a quality control protocol. The aim of this protocol was to provide documented evidence on the quality of both our product and the production process. The protocol included the validation or revalidation of individual installations and procedures used during production, validation of the whole process and quality control of routine production. With our quality protocol we have been able to demonstrate that our preparation is consistently of the intended quality.     

Dropwise Additive Manufacturing of Pharmaceutical Products for Solvent-Based Dosage Forms

In recent years, the US Food and Drug Administration has encouraged pharmaceutical companies to develop more innovative and efficient manufacturing methods with improved online monitoring and control. Mini-manufacturing of medicine is one such method enabling the creation of individualized product forms for each patient. This work presents dropwise additive manufacturing of pharmaceutical products (DAMPP), an automated, controlled mini-manufacturing method that deposits active pharmaceutical ingredients (APIs) directly onto edible substrates using drop-on-demand (DoD) inkjet printing technology. The use of DoD technology allows for precise control over the material properties, drug solid state form, drop size, and drop dynamics and can be beneficial in the creation of high-potency drug forms, combination drugs with multiple APIs or individualized medicine products tailored to a specific patient. In this work, DAMPP was used to create dosage forms from solvent-based formulations consisting of API, polymer, and solvent carrier. The forms were then analyzed to determine the reproducibility of creating an on-target dosage form, the morphology of the API of the final form and the dissolution behavior of the drug over time. DAMPP is found to be a viable alternative to traditional mass-manufacturing methods for solvent-based oral dosage forms.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Efavirenz

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the “high solubility” criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a “rapidly dissolving product.” Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:318–329, 2013     

Re-Envisioning Pharmaceutical Manufacturing: Increasing Agility for Global Patient Access

The traditional paradigm for pharmaceutical manufacturing is focused primarily upon centralized facilities that enable mass production and distribution. While this system reliably maintains high product quality and reproducibility, its rigidity imposes limitations upon new manufacturing innovations that could improve efficiency and support supply chain resiliency. Agile manufacturing methodologies, which leverage flexibility through portability and decentralization, allow manufacturers to respond to patient needs on demand and present a potential solution to enable timely access to critical medicines. Agile approaches are particularly applicable to the production of small-batch, personalized therapies, which must be customized for each individual patient close to the point-of-care. However, despite significant progress in the advancement of agile-enabling technologies across several different industries, there are substantial global regulatory challenges that encumber the adoption of agile manufacturing techniques in the pharmaceutical industry. This review provides an overview of regulatory barriers as well as emerging opportunities to facilitate the use of agile manufacturing for the production of pharmaceutical products. Future-oriented approaches for incorporating agile methodologies within the global regulatory framework are also proposed. Collaboration between regulators and manufacturers to cohesively navigate the regulatory waters is ultimately needed to best serve patients in the rapidly-changing healthcare environment.