Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

 spoke with Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), about the role industry plays in the 

.) development of pharmaceutical standards.

 What is EDQM’s role in fostering drug development? How can pharma companies participate in that role?

 The EDQM is, amongst other activities, in charge of the 

., a compendium of quality standards for medicines and their components legally binding in its member states and the European Union. In addition, it is applied in over 100 countries worldwide. The standards of the 

 are the benchmark for pharma companies when developing their products; they provide them with clear information on the requirements. Likewise, the 

 provides regulatory authorities with the standards against which to assess, harmonizing requirements throughout the 37 member states and the numerous other countries that apply the 


	Pharma companies are more than welcome to actively contribute to the development of these standards, be it by participating in their drafting and testing, or by commenting on drafts during public consultation.

 How can pharma companies work with EDQM to help develop standards and monographs?

 relies on the contributions from the currently more than 700 experts nominated by member states and observers. In addition, the 

 Commission has recently decided to open the nomination process to experts from around the world. Expert members of the more than 70 Groups of Experts and Working Parties draft pharmacopoeial texts and are involved in the experimental verification and validation of the methods described.

 How can EDQM help companies prepare for submissions to regulatory authorities in Europe, be it the EMA or one of the national competent authorities?

 The Ph. Eur. is legally binding in Europe; compliance with its requirements is a pre-requisite for product approval. The EDQM offers training, workshops, and webinars related to the Ph. Eur., which may help industry to ensure they have a clear understanding of the requirements. In addition, the EDQM is in charge of the Certification of Suitability to the monographs of the European Pharmacopoeia (CEP) procedure, which is a centralized assessment of the API part of a marketing authorization application for chemically-defined substances or herbals covered by a 

 monograph. In this context, the EDQM offers technical advice to CEP applicants.

 What role does EDQM play in the global harmonization of pharmaceutical regulations and standards?

 The Ph. Eur., as such, is a perfect example of successful harmonization throughout a continent. In addition, the EDQM and its 

 together with the Japanese and US pharmacopoeias, established the Pharmacopoeial Discussion Group (PDG) in 1989 to harmonize pharmacopoeial texts. The EDQM has actively participated in a number of different Expert Working Groups developing International Council for Harmonization (ICH) guidelines (e.g., ICH Q3A, Q3C, Q3D, Q7, Q11). In 2016, the EDQM became an observer to the ICH. Furthermore, the EDQM is an observer to the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the International Generic Drug Regulators Programme (IGDRP). In addition, the EDQM has a number of bilateral Memorandums of Understanding and Confidentiality Agreements with countries from all continents.

Articles

Susanne Keitel, director of the European Directorate for the Quality of Medicines and Healthcare (EDQM), discusses the role industry plays in the development of pharmaceutical standards.

Industry’s role in helping to create standards

To gain perspective on the use of single-use systems in pharmaceutical manufacturing, 

 spoke with Nandu Deorkar, PhD,vice-president of Research and Development at Avantor Performance Materials; Steve Miller, global head of Next Generation System Development, Life Science, Upstream and Systems Business Field Millipore S.A.S; Miriam Monge, director of process development and bioprocess platforms, Integrated Solutions at Sartorius Stedim Biotech; and Dr. Chris Chen, CEO of WuXi Biologics.
	
	

 Which manufacturing processes benefit most from the use of single-use systems?
	
	


	Both upstream and downstream manufacturing processes benefit from single-use systems, particularly when manufacturers are producing buffer solutions or cell-culture media. Single-use systems reduce the time required to perform cleaning and cleaning validation. They also allow manufacturers to more easily-and quickly-turn over from one product to another, or from one batch to another batch. In addition, single-use systems can connect two unit operations, thereby minimizing hold time and enabling continuous processing. Finally, single-use systems are shown to reduce overall operating costs by minimizing or eliminating the need for clean in place (CIP)/sterilize in place (SIP), reducing analytical quality control costs--specifically for raw materials--and improving facility utilization time.
	
	


	The main drivers for single use have altered little over the past 10 years. The processes benefiting most have issues around contamination and cleaning, reducing water consumption, ability to run multi-molecules in the same facility, and small-scale commercial production with low numbers of batches per year.
	
	


	All those processes that require 1000 kgs per annum of product or less and can be manufactured in single-use bioreactors up to 2000-L scale or less can benefit enormously from working in single-use systems. Single-use [systems] offer increased flexibility to adapt to a wide variety of different processes at different scales coming through the pipeline. Single-use systems also enable increased productivity and reduced cost of goods. There are many end-user case studies out there to prove this is the case.

	Antibodies, proteins, vaccines, cell therapy, and gene therapy all fall into categories of molecules that can benefit from being manufactured in fully single-use, end to end processes.
	
	

 Production scales between 15 L to 2000 L can all benefit from the use of single-use systems. Traditional fed-batch cell culture process as well as perfusion processes can be easily implemented in single-use systems. WuXi Biologics, an open-access R&D capability and technology platform company dedicated to biologics and a WuXi AppTec company, has embraced single-use technologies at full steam since 2010. The rapid adoption of single-use technologies has enabled us to quickly build up and expand our production capacities.  As a contract development and manufacturing organization, single-use technology allows us to significantly reduce capital cost and facility construction time and increase running rate by quick turning-around between different products and eliminating cross-contamination risks.

 What measures should be taken when ensuring system compatibility between single-use systems? What about between single-use and stainless-steel equipment?

 Different single-use products could have significant differences on design details, which might pose different degree of challenges when it comes to system compatibility between products from different suppliers. For example, agitation/mixing and gas sparging designs are quite different among the single-use bioreactors from the several major suppliers. The end-users need to carefully understand and evaluate the design features of the various products. The same challenges exist between single-use system and the stainless steel systems. Process transfer using the actual production cell line and processes must be carried out to ensure system compatibility, with special attention on potential product quality impacts. Another challenge for a single-use bioreactor system is the lack of reliable scale-down model. Representative scale-down models of single-use bioreactors are typically at 50L scale, which is too expensive and also not practical/convenient to use.

 Implementing single use brings with it new challenges that traditional facilities do not face, such as ensuring skids from different vendors have compatible connectors and common spare components such as clamps. Other, lesser-known challenges are related to packaging, installation and disposal, as each manufacturer may have different approaches, making operator life more complex and introducing opportunities for more errors.

 Single-use system components are typically made using flexible polymer films or plastic. Because of this, you need to make sure there are no extractables or leachables, which could impact cell growth, coming out of the system. These issues can impact product yield, quality, or stability. More importantly, you should evaluate the equivalency of the yield and the product quality coming out of the single-use system versus a stainless-steel system. If there is a difference between the cell growth in the stainless steel versus single-use systems, you might see a difference in product, yield, and quality.

 There are certain connectors that have become pretty standardized across the different suppliers, so connectivity between different single-use systems is not really an issue today. When talking about connectivity between single-use and stainless (in the case that a hybrid process design has been selected), autoclavable stainless steel systems can be connected to single-use systems with a sterile connector, such as the Opta from Sartorius. The Opta is autoclavable and can be connected to a stainless-steel vessel and then autoclaved together with the vessel. This vessel can then be connected to a single-use system equipped with the Opta counterpart.

 Have you seen any specific challenges in compatibility between single-use systems? Can you provide examples?

 One of the challenges when testing single-use systems is that you need to compare the different testing methodologies used by the different suppliers. This is the case for extractables and leachables, pre-use and post-use integrity testing, and visible and non-visible particulates. It is not always easy to compare like with like.

 The long-term storage of solutions, such as buffers or cell-culture media, in single-use systems can generate extractables and leachables, which may cause impurities. One way to address this challenge is to prepare buffer or media on an as-needed basis by using solid materials that are customized for one single-use tank, rather than concentrated buffer solutions that are already in liquid form. We have provided customers with single-use powder materials in bags or other containers that are pre-weighed and compatible with single-use systems. The packaging that contains the solid can be attached directly to a tank and the biopharmaceutical manufacturer can then make the solution, avoiding the long-term extractable/leachable compatibility issue.

 What should be considered in regard to media and buffer selection when using single-use systems?

 It is very important to review what tests are being carried out on the single-use systems and to which industry standards they comply. For example, at Sartorius we are aligning our testing methodologies with the industry standards that are identified as creating the greatest consensus in the industry both by suppliers and industry end-users and are recognized by the regulatory authorities. In this context, we are engaging actively notably with the American Society for Testing and Materials (ASTM) E55 working groups (E55: Manufacture of Pharmaceutical and Biopharmaceutical Products) developing standards for extractables and leachables, integrity testing at vendor factory and at end-user site, particulates at vendor factory, and at end-user site and cell growth.  

	When thinking about selection of single-use systems and films for media, the cell growth issue is of particular concern. Here we have proposed the development of a new standard assay assessing the suitability of specific plastics for cell growth applications in single-use. Recent industry reports demonstrate that current biocompatibility testing did not always detect cell growth issues. The discovery of a cytotoxic leachate raised industry awareness of the need for new evaluation techniques and testing to determine potential impacts of plastics used in single-use systems on cell culture plastics

 Before making a media or buffer selection, manufacturers should discuss packaging options with their materials suppliers. Often, the composition of packaging films in which a material is supplied is just as important as the material itself, because the packaging can impact the quality of the product.

	Manufacturers should consider the impact that different buffer solutions or cell-culture media may have on the integrity of the single-use component--bags, for example--in which they are supplied. For example, some packaging for liquids supplied for single-use systems may not be 100% impermeable to air. This could change the buffer pH, conductivity, or stability of some solutions. By seeking out a supplier that can provide pre-weighed solid materials in packaging that is compatible with single-use equipment, manufacturers may be able to avoid this common issue. This type of packaging may also eliminate time-consuming material subdivision and kitting steps, which can reduce total cost of ownership, improve efficiency, and reduce the potential for contamination.

Validation and qualification of single-use systems

 What steps should be taken when validating suppliers of single-use equipment?

 There are many similarities to validating suppliers of traditional equipment: checking that the proposed equipment matches the process and is compliant with regulations and surface contact compatibility. What is different is that choosing single-use equipment is the beginning of a multi-year relationship between the customer and the supplier. Therefore, ensuring the supplier’s commitment is more akin to a filter purchase than a system purchase. Assessing the supplier’s process know-how, supply chain, manufacturing processes, support organization, and field force are much more important.

	Another big difference for single-use versus traditional technologies is the importance of evaluating all scales of equipment, even if the procurement exercise is for the small scale only. A technology may work fine at a 50-L scale; however, when you scale to 2000-L processes, ergonomics and process robustness/optimization become a huge factor in the commercial operation. The difference with single use is that customers can be stuck with the technology they chose at the small scale and the conversion to alternative suppliers, even if there are significant advantages at the large scale, are too big a risk on the timeline to consider switching.

This is best verified through a supplier quality and supply chain audit. This includes reviewing the supplier quality system and manufacturing systems and ensuring that these are cGMP compliant. Ensure that the level of compliance is consistent across supplier sites, check the manufacturing environment in which the single-use systems are manufactured (ISO class 7 manufacturing environment for single-use systems is what the majority of end-users specify as a requirement), verify customer change notification process, and complaint management process.

	Another important part of your single-use supplier audit includes supply chain security to ensure that the supplier has the systems in place to ensure delivery performance and offer best assurance of supply and business continuity.

 What are the challenges of qualifying single-use equipment?

 The challenges here are making the process robust. Qualifying the perfect scenario is easy, but anticipating damaged or dropped assemblies, qualifying how assemblies move from grey to clean space, and disposal are all exaggerated versus traditional facilities.  These challenges can be minimized by ensuring equipment and assemblies come from the same supplier, as they should have qualification procedures as part of the total solution.


	When referring to this article, please cite it as S. Haigney, "Integrating Single-Use Systems in Pharma Manufacturing," 

Industry experts discuss the benefits and challenges of using single-use systems in pharmaceutical manufacturing.

Integrating Single-Use Systems in Pharma Manufacturing

 spoke with Melissa Topp, director of Global Marketing at ICONICS, about the latest in process analytical technology (PAT).

 What are the benefits and challenges of PAT?

 The key benefit to PAT is in providing users with the means to measure performance, productivity, and quality and thereby provide guidance toward improvement. However, in order to best guide decision-making, as many factors (or data points) as possible need to be included for analysis. A challenge for PAT going forward, as more companies seek to move their production data to the cloud, is ensuring that any increase in the complexity of process measurement can be visualized, stored, and analyzed as quickly and cost-effectively as possible, using the right combination of hardware and software.

 How can PAT be used to improve system productivity and quality?		

 A comprehensive PAT strategy can include both productivity and quality analyses. Solutions like ICONICS Productivity Analytics help establish manufacturing context with knowledge point indicatiors (KPIs) such as overall equipment effectiveness (OEE), cycle time, mean time between failures (MTBF), Takt time, efficiency, and throughput. Quality AnalytiX provides real-time statistical process control (SPC) that can guide users towards increased production yields, reduced scrap, and variation prevention. 

 How can PAT be used in tech transfer of pharmaceutical manufacturing operations?

 Any solution that helps users capture, store, and analyze their data is a valuable application of process analytical technology. But true insight is only achieved when real-time data are visualized alongside retrieved historical benchmark production performance data. Quality analysis, including standard SPC calculations such as X-bar, R-bar, Sigma, moving range, Media, moving average, exponentially weighted moving-average (EWMA), process capability index (Cpk), and process performance index (Ppk), can work in tandem with a robust (one capable of over 100,000 tag per second logging) data historian. This stored comparative performance data can then be useful in tech transfer between organizations, facilities, departments, etc.

 Are there any new and innovative PAT tools being used in the industry? What does the future hold?

 One of the most exciting developments is the emergence of the Internet of Things (IoT) and cloud-based technology in production environments. The connection of production equipment (via low-cost bridging devices known as ‘gateways’) to large, external, Web-connected networks (e.g., Microsoft Azure, Amazon Web Services, etc.) via comprehensive software suites allows users to make a decision as to where the process analyses take place; either via on-premises IT hardware or in the cloud. Either choice has its benefits. The innovation lies in now being able to make that choice.  

Pharmaceutical Technology spoke with Melissa Topp, director of Global Marketing at ICONICS, about the latest in process analytical technology (PAT).

Improving Pharma Systems with Process Analytical Technology

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? 

 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.

 What are the challenges for manufacturers in ensuring quality throughout a solid dosage or semi-solid dosage product’s entire lifecycle?
	
	

 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.  
	
	

 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.
	
	

 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.
	
	

 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. 
	
	

 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?
	
	

 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:

		Exposure or absorption challenges due to poor solubility of the drug substance

		Challenges due to the material properties of the API (segregation, flow, static, etc.)

		Chemical instability between the API and excipients or packaging components

		Challenges during scale up from development and clinical stage to pilot or commercial scale.

	
	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.
	
	

 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.
	
	

 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.

 How has the ever-growing international supply chain affected the quality of solid dosage and semi-solid dosage products?
	
	

 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.
	
	

 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.
	
	

 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 

 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 quality

 What new trends or techniques do you see for testing or maintaining quality in solid dosage and semi-solid products?
	
	

 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.
	
	

 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.
	
	

 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.
	
	

 Which guidelines or regulations should pharmaceutical manufacturers pay special attention to when developing quality assurance processes for solid dosage and semi-solid dosage forms?
	
	

 When developing quality assurance processes for all dosage forms, companies should pay special attention to several policy documents, including:

Guidance on Process Validation, General Principles and Practices

Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations

Guidance on Contract Manufacturing Arrangements for Drugs: Quality Agreements

Guidance on Development and Submission of Near Infrared Analytical Procedures

Questions and Answers on Current Good Manufacturing Practices for Drugs

; see in particular the discussion on sampling powdered blends and in-process testing.

] Sections 210-211) apply as well. There are several subparts of 21 

 Section 211 that deserve special attention for this group of dosage forms [such as]:

		Subpart E governing control of components and drug product containers and closures, particularly the requirement to assure the quality of incoming ingredients and use of reliable suppliers (e.g., reliable availability as well as quality).

		Subpart G governing packaging and labeling controls, especially controls (automated as well as procedural) to prevent labeling mix-ups.

		Subpart J governing records and reports, particularly the requirement to evaluate data at least annually to verify that the process remains stable and capable of yielding high quality product.

 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.
	
	

 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,” 

, March 11, 2015, accessed March 16, 2016.

 When referring to this article, please cite as S. Haigney, "Ensuring Quality in Solid and Semi-Solid Dosage Forms," 

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.

Ensuring Quality in Solid and Semi-Solid Dosage Forms

	In January 2015, FDA created the Office of Pharmaceutical Quality (OPQ) within the Center for Drug Evaluation and Research (CDER) to address challenges posed by the increasing globalization of the pharmaceutical industry as well as the industry’s increased use of contract manufacturers. OPQ’s goal is to make regulatory decisions based on science and to ensure that the industry is providing safe and effective pharmaceuticals.
	
	“FDA is putting into practice solutions to integrate application review and inspection in a risk-based way.  This provides an integrated quality assessment of applications and inspections for drugs,” says OPQ Director Michael Kopcha, PhD, RPh. 

 spoke with Kopcha to get the agency’s insights on how the industry can ensure quality in solid and semi-solid dosage products.
	
	

 What is FDA looking for from companies to assure the agency that the company is following GMPs and producing quality products?
	
	

 Some of the key things FDA is looking for include a commitment from management regarding the implementation of ICH Q10 [International Conference on Harmonization Q10 

] principles within its pharmaceutical quality system. We also look for commitment of adequate resources and oversight into critical elements, such as knowledge management, and systematic attention to quality assurance principles:  sound design, robust maintenance, and diligence in assuring the process and control strategy are followed, along with developing quality metrics, monitoring of product and process quality, and robust product reviews. Robust product reviews, which are required at least annually under 21 

) 211.180(e), will include assessments of trends in control charts and other production information, as well as compilation and assessment of other quality indicators including stability data, complaints, and failures to determine whether the process remains stable and capable of making a quality pharmaceutical. Furthermore, we are gratified when we see manufacturers go above and beyond the minimum requirements in the CGMP regulations by continuously monitoring key production and process control parameters, which are part of ICH Q10 and continued process verification as found in the process validation guidance.
	
	

 Are the regulations for ensuring product quality different for solid dosage forms and semi-solid dosage forms? If yes, what are the differences?
	
	

 There are regulations regarding the content and format of an abbreviated new drug application (ANDA) (21 

 Section 314.94) that identify different types of information, including bioequivalence, for submission depending on product type.  These regulations also provide information on the changes to inactive ingredients permitted in drug products intended for topical use.
	
	There also are product-specific guidance documents available to address bioequivalence (and in some cases, chemistry, manufacturing, and controls [CMC] considerations) in keeping with these regulations for different products.
	
	Additionally, there are several relevant FDA guidance documents that address these dosage forms [such as]:

Nonsterile Semisolid Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation

Immediate Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing, In Vivo Bioequivalence Document 

Modified Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing, In Vivo Bioequivalence Document

 Is FDA seeing any new trends or techniques developing in the way companies are testing their products’ quality and/or maintaining that quality?
	
	

 FDA is seeing new trends in the way companies are testing and maintaining product quality. These include trends toward use of continuous manufacturing and real-time release approaches that use process analytical technology including online monitoring. For instance, in July 2015, FDA approved the first application using continuous manufacturing for Orkambi, a product to treat cystic fibrosis, after much in-depth work to evaluate the unique manufacturing processes involved for this solid dosage form. To further encourage appropriate advanced technology, FDA released a guidance entitled Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base, which outlines how CDER’s Emerging Technology Team (ETT) is working with companies to facilitate understanding and review of new manufacturing technology.  We are performing site visits (in which manufacturing facilities invite FDA staff for an educational visit) to better understand this new technology and how to appropriately regulate it. Continuous manufacturing naturally lends itself to online monitoring and real-time monitoring that may contribute to the manufacture of consistent quality products.

 When referring to this article, please site as S. Haigney, "FDA Insights on Quality in Solid Dosage Manufacturing," Sidebar to S. Haigney, "Ensuring Quality in
	Solid and Semi-Solid Dosage Forms," 

Pharmaceutical Technology spoke with FDA to get the agency’s insights on how the industry can ensure quality in solid and semi-solid dosage products.

FDA Insights on Quality in Solid Dosage Manufacturing

	Pharmaceutical and biopharmaceutical companies will continue to use outsourcing services, especially drug manufacturing, due to cost concerns and mergers and acquisitions, according to a market survey of drug manufacturers by ISR Reports. The survey showed that the top five activities that drug companies outsource are drug product manufacturing, packaging and labeling, distribution, small-molecule manufacturing, and holding and storage, according to 

	The ISR survey suggests that the majority of companies are outsourcing their small-molecule manufacturing. ISR’s 2016 small-molecule outsourcing survey also showed that other popular outsourced activities include packaging and labeling, distribution, and holding and storage. Respondents to ISR’s survey indicated resources, an increased product demand, cost, and mergers and acquisitions as some of the reasons small-molecule companies outsource these activities.

	For large-molecule companies, distribution was the number one outsourced activity indicated by ISR’s survey, with packaging and labeling coming second. Cost was the number one reason large-molecule companies indicated as the reason for outsourcing.

	Service providers are expanding their services and capabilities to keep up with the high demand. The following are some examples of the growth the outsourcing industry is experiencing.  

Company developments, expansions, and acquisitions


	The first few months of 2016 has seen an array of investments, expansions, and acquisitions in the pharmaceutical outsourcing market. Outsourcing companies appear to be looking to the early-phase development and clinical trial markets to increase their portfolios.

	MPI Research, an early-stage drug development contract research organization (CRO) based in Michigan, is investing more than $5 million in a facility renovation to begin in 2016. The company plans to renovate more than 55,000 square feet of facility space.

	Ed Amat, executive vice-president of global sales and marketing, said in a 

that the expansion reflects the increasing demand for investigational and preclinical pharmaceutical and medical device studies (2). In the upcoming year, MPI hopes to increase the company’s workforce by approximately 10%.

	LabConnect, a Seattle-based provider of laboratory services to biopharmaceutical, medical device, and contract research firms, has built a 

 in Johnson City, TN, that includes space for ambient, refrigerated, cold (-20 °C), and ultra-low temperature (-70 to -80 °C) storage as well as liquid nitrogen vapor phase storage (-190 °C) (3).

	The facility includes storage capacity for more than eight million samples, validated and mapped backup freezers and generators, redundant HVAC systems, building and biorepository security systems, and a temperature monitoring system for freezers and refrigerators with a 21 

 Part 11 compliant audit trail. LabConnect also tracks sample locations and consolidates data within a centralized database.

 (4) an investment of $4.6 million to expand its Singapore clinical supply facility by building GMP space for secondary packaging. The investment doubles the ambient storage space and quadruples cold-storage capacity, the company reports. The site provides clinical supply services including project and supply-chain management, comparator sourcing, clinical label printing, secondary packaging, clinical storage, import/export management, importer of record service, and returns and destruction management services. It has served as a regional hub for studies in Australia, Singapore, Korea, Hong Kong, and other countries in Southeast Asia.

	Onyx Scientific, a UK-based CRO and small-scale API manufacturer, has announced an investment in 

located adjacent to its existing facility in North-East England to increase its laboratory facilities, GMP suites, and storage of GMP materials (5). In addition, the company has recruited several more chemists to support clients’ pre-clinical, development, and early-stage API manufacturing projects. In 2015, the company grew its GMP space following an increase in demand for its small-scale API manufacturing services.

 on Jan. 28, 2016 that the company’s Schuetzenstrasse multi-functional building in Ravensburg, Germany, has been completed on schedule and departments critical to its operation have started to move in (6). The $32 million (€29 million) investment is part of a $331 million (€300 million) total investment strategy announced by the company in September 2015 for further development to its manufacturing sites.

	The continued demand by large and small customers for enhanced drug development services, as well as the need for ever-more future-oriented sophisticated IT systems to protect their data, created the need for the new facility, the company reported in a press statement.

	The 91,500-sq-ft, six-story building contains non-cGMP laboratories for development support, laboratory space for microbiological analysis, office workplaces for Vetter Development Service and IT, and a data processing center with enhanced security systems, including a safety cell that protects technology and data from external physical hazards in the event of an emergency.

 and adding kilogram-scale production at its existing US facility in Boothwyn, PA (7). This extension will allow Novasep to offer both chemistry and purification services and to produce the initial kilogram-scale batches of synthetic molecules that are needed for biological testing and preclinical trials.

	The investment is in response to increasing demand from US customers for closer proximity to Novasep’s contract manufacturing services for early-stage development and production scale-up. Novasep has provided purification development services to North American customers for more than 15 years at this location. The new laboratory, equipped with reactors up to 50 L in size, will start operation in May 2016. It will offer cryogenic capacities and standard chemistry, as well as preparative purification chromatography processes.


	The Pharma & Biopharma Outsourcing Association (PBOA), founded in 2014, has been advocating for the pharma outsourcing industry as the global market changes and expands. “We’re focused on working on the reauthorization of the Generic Drug User Fee Amendment (GDUFA), while keeping an eye on FDA’s Quality Metrics initiative, and helping make sure that CMO/CDMOs [contract manufacturing organizations/contract development and manufacturing organizations] are prepared for track-and-track/serialization regulations as they roll out in the US and the EU in the next few years,” says PBOA President Gil Roth.

 (8). IDT Biologika and Ei SolutionWorks joined the PBOA as general members; 3M Drug Delivery Systems (DDS) joined as a sustaining member. Diego Romeu, manufacturing and supply chain director at 3M DDS, was also voted to a three-year term on the board of trustees, along with Rajan Puri, director of business development at Therapure, and Lee Karras, CEO of Halo Pharmaceutical.

	“As we continue our mission to represent the CMO/CDMO industry before FDA, Congress and other stakeholders, it’s critical that we increase our membership and provide a true voice for our industry,” said Roth. “We’ve been successful in bringing the CMO/CDMO perspective to issues such as GDUFA, quality metrics, and serialization, and we’re delighted to bring in new member companies and add fresh points of view to our Board of Trustees.”

, 40 (13), 32-33,.
	2. PharmTech Editors, “

MPI Research Invests in Upgrades and Department Expansions

LabConnect Builds New Biorepository, Expands Services, Offers Absolute Sample Protection

,” Press Release, Feb. 3, 2016, accessed Feb. 16, 2016.
	4. Catalent, “

Catalent Invests $4.6M to Further Expand Asia-Pacific Clinical Trials Hub in Singapore

,” Press Release, Feb. 2, 2016, accessed Feb. 16, 2016.
	5. Onyx Scientific, “

Facility Expansion at CRO Following Record Year

,” Press Release, Jan. 29, 2016, accessed Feb. 16, 2016.
	6. Vetter, “

Vetter Announces Completion of Multi-Functional Building for Development Service and State-of-the-Art IT

,” Press Release, Jan. 28, 2016, accessed Feb. 16, 2016.
	7. Novasep, “

Novasep Adds Synthesis and Kilo Lab Extensions at US Facility

,” Press Release, accessed Feb. 16, 2016.
	8. PBOA, “

” Press Release, Feb. 10, 2016,  accessed Feb. 16, 2013.


	When referring to this article, please cite as S. Haigney, "Pharma Outsourcing Market Expands," 

The pharma outsourcing market starts 2016 with expansions, acquisitions, and new offerings.