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Industry experts and FDA’s Office of Pharmaceutical Quality discuss the challenges, trends, and regulations involved in ensuring quality in solid and semi-solid dosage forms.
According to FDA, solid oral and semi-solid drugs make up the majority of drugs in the United States and are, therefore, a large percentage of FDA inspections. Michael Kopcha, PhD, RPh, director of the Office of Pharmaceutical Quality in FDA’s Center for Drug Evaluation and Research (CDER), states that some of the quality actions FDA has observed in the past in regards to solid-dosage manufacturing include insufficient quality agreements between sponsors and contract manufacturers, data integrity issues, and management of ingredients in the supply chain.
How should pharmaceutical companies address these and other quality issues when manufacturing semi-solid and solid dosage forms? Pharmaceutical Technology spoke with Kopcha and industry experts Anil Kane, executive director, Global Formulation Sciences, at Patheon; Jamie Clayton, operations director at Freeman Technology; and Dr. Paul Kippax, product group manager at Malvern Instruments, about the challenges, trends, and regulatory requirements involved in ensuring the quality of solid and semi-solid dosage forms.
Quality challengesPharmTech: What are the challenges for manufacturers in ensuring quality throughout a solid dosage or semi-solid dosage product’s entire lifecycle?
Kane (Patheon): Although FDA and the European Medicines Agency (EMA) introduced pharmaceutical quality by design (QbD) in international guidelines a few years ago, most drug developers remain unaware that the real benefits of sound science go beyond smoothing the regulatory pathway. A science- and risk-based approach to drug development and manufacturing, QbD is an opportunity to add value by building quality into products and thereby gaining a business advantage.
Adopting a QbD approach at the formulation design stage has become essential because it increases efficiency as iterations toward the target product profile are minimized, and it reduces overall risk to the project. Other best practices that create value and mitigate risk include statistical design of experiments (DoE), a branch of applied statistics that deals with planning, conducting, analyzing, and interpreting controlled tests; and failure mode and effects analysis (FMEA), a systematic, proactive method for evaluating a process to identify where and how it might fail and how to correct the problems.
By identifying and correcting the root causes of problems early in the design phase of the process- and product-development cycle, companies cut the risk of later-stage quality, yield, and supply-chain issues. A strategy of building a ‘phase appropriate quality’ into products would be beneficial.
Kippax (Malvern Instruments): A key challenge is transfer of the specifications that define quality from the laboratory through to commercial manufacture. For example, a particle size specification is often required to control fines content because of the influence this has on bioavailability, blend homogeneity, and throughput in the tablet press. Particle sizing is therefore required in the lab to develop the specification, and then for routine application in the manufacturing environment/QC [quality control]. Techniques, such as laser diffraction, that can be implemented at- or on-line can ease this transfer, transitioning with the product through to commercial production. Analytical imaging is a more information-rich technique that can add value when troubleshooting specification transfers by detecting changes in particle shape, which may impact particle size data or indicate a failure to achieve full dispersion of the sample.
Clayton (Freeman Technology): One of the greatest challenges is maintaining consistent quality throughout manufacture. This can only be achieved with stringent control of all stages of the manufacturing process, including control of the materials entering the process. Batch-to-batch variability, supplier changes, and environmental variations are all factors that can influence properties of feedstocks and intermediates and ultimately impact critical quality attributes of the final product. A thorough understanding of the material properties that are conducive to successful manufacture is crucial. This allows variations to be quickly identified so that incompatible materials don’t enter the process, or alternatively, critical process parameters can be adjusted to account for variations.
Kopcha (FDA): There are a number of challenges related to drug-product manufacturing processes. One quality issue that is particularly challenging is the scale-up from small-scale development to commercial batches that can be manufactured consistently over a product’s lifecycle. As formulations become more complex, such as modified release products, the manufacturing process and controls can become more complicated and scale-up in turn becomes more challenging. Additional commercial-phase challenges include monitoring the supply chain, use of contract manufacturing facilities, and implementing continuous improvement activities.
It’s important to take a lifecycle approach to ensuring quality, starting with product development. International Conference on Harmonization (ICH) Q10 and FDA’s process validation guidance include recommendations regarding the need to develop product and process understanding and minimize possible quality issues at each product lifecycle phase (e.g., pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation).
It’s also challenging for manufacturers to synchronize the approval of post-approval changes with FDA and other regulatory authorities, such as EMA. FDA is collaborating with key counterpart regulators through ICH to harmonize expectations for information for submission with applications. Manufacturers should be aware of and comment on draft guidance so that their perspectives can be considered in developing policy.
PharmTech: Can you provide any examples illustrating problems your company has experienced in the manufacturing of solid dosage or semi-solid dosage products and how you have solved those problems?
Kane (Patheon): Product development and manufacturing, especially in a highly technical and specialized industry like drugs/pharmaceuticals, brings with it its own challenges, which can be broadly categorized into:
These problems are resolved by using special techniques and technology, modifying excipient composition or material modifications, or by adopting engineering solutions. The choice of the solution depends on the stage of the clinical program and due consideration of the impact of the changes to regulatory filing or clinical studies conducted. One such example is described in brief as follows.
A fixed-dose bilayer tablet formulation was developed on a small scale successfully. Clinical trials were conducted using this formulation and process. During scale-up to a pilot-scale tablet press, the individual layer weights of the bilayer components could not be achieved. A number of trials were conducted by changing the speed of the feeder, compression forces, press speeds, cam depth, etc. The formulation and process could not be changed due to regulatory and clinical impact. Finally, a change of feeder design resulted in satisfactory individual granule layer weights, which resolved the problem. Thus, an engineering solution helped to scale up and continue the program without any need to bridge clinical studies or any regulatory changes and impact on project target timeline.
Kippax (Malvern Instruments): A primary challenge in solid-dosage manufacture is to ensure that the properties of each individual component that define the product’s performance are maintained from the point of manufacture through to the point of delivery. For example, [by] using Morphologically Directed Raman Spectroscopy (MDRS), it is possible to look at the size and shape of specific components in a blend. Research has shown that these capabilities make it possible to differentiate the suitability of different milling processes--hammer vs. ball--for producing optimal drug particles for incorporation into the tablet. More generally, this analytical technique enables researchers to ‘follow the particle’ through the manufacturing process, safeguarding its properties up to the point of inclusion in the tablet.
Clayton (Freeman Technology): Wet granulation is a common operation in tableting, and one challenge is determining the end-point of the process (i.e., when the granulate is most compatible with the downstream stages of a process). Granule size is typically used as a key indicator, but this indicator potentially overlooks many other contributing factors. We worked with a major supplier of pharmaceutical equipment to demonstrate how the settings of a continuous granulator can be modified to tailor bulk and flow properties of a granulate that are known to have a direct impact on critical quality attributes of the resulting tablet.
Supply chain considerationsPharmTech: How has the ever-growing international supply chain affected the quality of solid dosage and semi-solid dosage products?
Kippax (Malvern Instruments): Sourcing from a wider number of suppliers intensifies the emphasis on highly effective quality assurance (QA)/QC. We’re seeing an increased appetite for techniques that are fast and robust, such as laser diffraction particle sizing, proving an attractive alternative to sieving in this environment. In addition, there is growing demand for instrumentation that provides far more rigorous checking. For example, imaging systems that enable the analysis of particle shape as well as size may be vital for differentiating the performance of alternative supplies. Combining automated imaging with Raman spectroscopy makes it possible to further drill down into the chemical composition of individual components within a blend, offering powerful capabilities for comprehensive QA/QC.
Clayton (Freeman Technology): A growing supply chain increases the need for robust, process-relevant material specifications. The economic benefits of procuring materials from low-cost suppliers are obvious, but they can be quickly offset if the material in question has a detrimental impact on quality and/or productivity. For example, excipients from different suppliers may meet well-defined physical specifications, such as particle size, density, etc., but then perform very differently in processes such as blending, granulation, die-filling, etc. This discrepancy is because the specification is not relevant to the process. Other properties critical to the process have not been quantified. If manufacturers want to take advantage of competitive markets, but retain quality, it is even more important to ensure a thorough understanding of materials.
Kopcha (FDA): The growth and complexity of the international supply chain has increased the challenge of oversight for drug-product manufacturers as well as FDA. FDA has traditionally inspected API and dosage-form producers, but has not performed routine inspections of excipient manufacturers.
FDA has worked with external groups on standards related to GMPs for excipients. For example, FDA participated in the development of a report on “Good Manufacturing Practices (GMP) for Pharmaceutical Excipients” in 2014 with the NSF International, the International Pharmaceutical Excipients Council, and the American National Standards Institute (1).
FDA is a co-sponsor of the internationally harmonized CGMP guidance, ICH Q7, for API manufacturers. FDA inspects API facilities to ensure conformance with CGMPs and collaborates with Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) counterparts in the regulatory oversight of API manufacturing. For application products [NDA, IND, ANDA, etc.], we see an inconsistent quality of submissions from API producers worldwide.
Drug-product manufacturers are ultimately responsible for verifying the purity and suitability of the ingredients they source and use in manufacturing. Even one contaminated shipment of an inactive ingredient can be hazardous to a patient, or at the least can result in production delays or product shortages. These risks can be prevented if drug-product manufacturers improve their awareness of their ingredient supply chains and work with responsible suppliers and manufacturers.
Trends and techniques for ensuring qualityPharmTech: What new trends or techniques do you see for testing or maintaining quality in solid dosage and semi-solid products?
Kippax (Malvern Instruments): First, QA/QC labs are facing the need to apply a wider range of analytical techniques with a reduced head count, to meet profitability targets. This issue is exacerbated, especially in certain geographies, by relatively low analytical experience levels. Software features that help minimize training requirements and ensure data integrity, while also reducing manual input, are an increasingly prominent and valued feature of our instrumentation.
Another trend that is having an impact is the expanding international supply chain. This too calls for instrumentation that can be used easily and efficiently by a wide range of variously skilled operators.
Kane (Patheon): Small, virtual companies, as well as biotech or specialty and emerging pharmaceutical companies, are now open to the idea and philosophy of performing ‘risk assessment’ and ‘gap analysis’ at specific critical milestones during clinical product development. They are now willing to consider investment of time, resource, and some quantity of the API in developing a phase-appropriate robust quality product.
Clayton (Freeman Technology): FDA’s process analytical technology (PAT) and QbD initiatives mean that quality management features more prominently throughout the manufacturing cycle as opposed to simply screening batches of final products. The application of QbD requires a robust understanding and control of both the materials and the processes. In terms of understanding materials, analytical techniques that deliver process relevant data are critical, so from Freeman Technology’s perspective, we see ever-increasing interest in the technology we provide for characterizing powder behavior. It’s becoming widely acknowledged that traditional techniques, even USP [United States Pharmacopeia]-recommended methods, have limitations, and a more comprehensive toolkit is required.
Regulatory guidelinesPharmTech: Which guidelines or regulations should pharmaceutical manufacturers pay special attention to when developing quality assurance processes for solid dosage and semi-solid dosage forms?
Kopcha (FDA): When developing quality assurance processes for all dosage forms, companies should pay special attention to several policy documents, including:
The CGMP regulations (21 Code of Federal Regulations [CFR] Sections 210-211) apply as well. There are several subparts of 21 CFR Section 211 that deserve special attention for this group of dosage forms [such as]:
Kane (Patheon): In December 2015, FDA issued a draft guidance called The Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base. Essentially this guidance provides recommendations to pharmaceutical companies interested in participating in a program involving chemistry, manufacturing, and controls (CMC) information containing emerging technology. This program is open to all companies that intend the technology to be included in filing an investigational new drug (IND), new drug application (NDA), abbreviated new drug application (ANDA), or biologics license application (BLA). The guidance encourages the industry to adopt new and emerging technology and describes a pathway for pre-submission discussions. This may lead to improved manufacturing and, therefore, improved product quality and availability throughout the product lifecycle.
Kippax (Malvern Instruments): Over the past decade or so, there has been a fundamental shift from the more prescriptive validation practices enshrined in ICH Q2 through to ICH Q6, to the risk-based QbD approach defined in ICH Q8 onwards. Selection of appropriate quality assurance processes now starts with an acknowledgement of the required product performance and how this links to specific product and process parameters. Innovative analytical techniques can help accelerate the knowledge gathering required to support this assessment, enabling manufacturers to generate the comprehensive product and process understanding required to identify risks and bring these under control.
The principles of QbD are also being applied to the development of analytical methods for product quality control. Method parameters and specifications are set based on the requirements for product control rather than via a basic assessment of the technique’s capabilities in terms of measurement reproducibility alone. This not only ensures that relevant data are reported but also aids method transfer by ensuring that only critical method parameters are specified precisely.
1. NSF, “National Standard for Excipient Good Manufacturing Practices Published by NSF International,” Press Release, March 11, 2015, accessed March 16, 2016.
Article DetailsPharmaceutical Technology
Vol. 40, No. 4
Citation: When referring to this article, please cite as S. Haigney, "Ensuring Quality in Solid and Semi-Solid Dosage Forms," Pharmaceutical Technology40 (4) 2016.