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

Susan Haigney

The bio/pharmaceutical outsourcing market has experienced a turn toward consolidation in the past
	year or so, but will this trend continue for 2016?

	“There is little doubt that further consolidation and the formation of close partnerships will occur throughout 2016 in the contract service market,” says Mark Rogers, senior vice-president, Life Science Services at SGS North America.  

	Will this market consolidation include branching into new and underserved pharmaceutical areas for some contract manufacturers? Ropack Pharma Solution’s Paul Dupont states that while “much has been reported on the rising demand for biologics development and manufacturing capacity,” his company is remaining focused on solid oral-dosage development, manufacturing, and packaging. Other companies are taking stock of industry needs and assessing where they may adjust their service offerings.

	To find out what the outsourcing industry may look like in 2016, Pharmaceutical Technology spoke with Elliott Berger, vice-president of global marketing and strategy at Catalent Pharma Solutions; Saharsh Rao Davuluri, president of contract research, Neuland Labs; Michael Lehmann, president, global PDS and executive vice-president global sales & marketing, Patheon; Paul Dupont, vice-president marketing and business development, Ropack Pharma Solutions; Marcus Spreen, head of strategic planning, Rottendorf Pharma; Mark Rogers, senior vice-president, Life Science Services, SGS North America; and Peter Soelkner, managing director Vetter Pharma International GmbH.

 The contract services and manufacturing market has experienced consolidation in the past year. What are the implications of consolidation for drug owners in terms of services available and the cost of those services?

 Ongoing consolidation enables major pharmaceutical companies to optimize their supply networks and source a greater range of services and technologies from fewer partners. With a more rationalized approach to sourcing, it is easier for buyers to work with long-term strategic partners to create joint quality and operational scorecards against which to measure suppliers, and this gives flexibility to monitor and improve global supply chains.

	Consolidation of allied services into larger organizations creates partners that are, on the whole, more flexible to clients’ demands and have an attitude of expansion and investment in new technologies, global capacity, and world-class quality systems to match the future demands of sponsors. This may include co-creating large custom manufacturing suites that can accommodate new launches or tech transfers with specific complex requirements from pharmaceutical clients who look to free-up internal capacity; or the placement of products which have been launched or acquired into the company’s portfolio and where no in-house capacity currently exists.

	As ever in the pharma industry, new medicines are becoming increasingly more complex, and the ability of contract service companies to create customized solutions is key to ongoing success. Products are becoming more ‘global’, and the ability of service providers to offer a global supply, with the oversight of multiple regulatory agencies, has never been more prescient.

 It’s true that the contract development and manufacturing industry has experienced significant consolidation in recent years. The good news is that there are solid benefits for pharmaceutical companies that come from outsourcing partners who have achieved strategic consolidations. The increased bandwidth, capacity, and capabilities, together with an expanded regional and/or global presence, are valuable to biopharma companies. Improved economies of scale and a simplified supply chain are also important benefits.

 Consolidation has a variety of implications for drug owners. It reduces the number of different supplier options for individual services. Also drug owners want to simplify their service provider network and reduce the number of providers, essentially creating a one-stop-shop-approach whenever possible. As a consequence, they expect their partners to be strategic, not tactical. In practice, this means that drug companies would rather look at outsourcing opportunities for a pipeline of several products, not just one drug. This includes looking for attractive cost models, which the provider can offer to successfully contribute to developing, commercializing and supplying this drug pipeline.

 As a result of consolidation, vertically integrated [contract manufacturing organizations] CMOs offer a ‘one-stop’ solution to drug owners. Although this idea has been promoted for quite some time, consolidation could potentially increase this focus. These integrated CMOs are pitching their services rather carefully to drug owners. As a pure play API CMO, we tend to focus on the advantages of being API specialists with a lot of depth in handling API-specific [chemistry, manufacturing, and controls] CMC issues. Integrated CMOs are also separating their proposals for APIs and drug products in order to avoid coming across as a company who insists that they do everything (or nothing) and demonstrate skills that are comparable to a standalone specialist who focuses purely on APIs or finished products. Integrated CMOs offer a potential cost savings that drug owners can realize if they choose the one-stop solution.

 As consolidation continues, benefits of long-term partnership between sponsors and [contract research organizations] CROs/CMOs become more apparent. Drug development is becoming more complex, and more venture capital funding and Big Pharma acquisition of smaller and mid-size pharmaceutical companies continues to fuel new product development. Both sponsors and venture capitalists require that candidates identify the drug candidate’s value point as quickly as possible. Yes, consolidation effectively reduces the individual options available to sponsors. However, consolidation provides sponsors with more single-source options [and] helps CROs and CMOs keep up with technology and develop more comprehensive service offerings.

 Like M&A activities in any market, the consequential reduction in competition is not generally an advantage to the consumer, and the contract services and manufacturing market is no different. However, such consolidation may also make it easier for the drug owners to find a ‘one-stop shop’, which alleviates the need for the coordination and management of several different providers but may also increase the compliance and operational risks associated with a single-source supplier.

 Done well, consolidation can help to lower costs as companies leverage economies of scale. But from a customer perspective, it adds uncertainty. If I partner well with a CMO that is then acquired, will the new management shift focus or somehow change the relationship? Will I need to look for a new contract provider? Consolidation presents both risks and opportunities. It puts the onus on customers to vet contract partners for quality and cost as well as the ability to deliver. Because of our business model, Rottendorf cannot be acquired, so this is not a concern for our customers.

 Do you expect additional consolidation or other changes in the contract services market in 2016?

 We expect consolidation to continue in 2016 and beyond. Regularly, there is news within the industry regarding a merger or acquisition between large and small companies, or at times the consolidation of two equal large-market participants. We believe this will continue. But we do not see large changes that can disrupt the industry, but rather, the continuation of existing challenges such as the ever-increasing complexity of development projects, greater expectations for a high degree of flexibility at the service providers pertaining to timing and batch size, as well as ever-increasing regulatory demands.

 Certainly we expect that consolidation will continue, as Big Pharma turns more and more to outsourcing, and capital investment looks for opportunities in this sector. Though it does appear there are fewer--or perhaps we should say worthwhile--opportunities for potential investors. As for other changes, we see continuous manufacturing making more in-roads, and we’re keeping a watchful eye on its impact.

 On a global level, the pharma industry is still very fragmented and continues to consolidate, so we would expect the pharma services sector to do the same. There is increased demand for specialized outsourced services, including global solutions as well as customized and full service options. At Catalent, we have seen a marked increase in the demand for complex products requiring drug delivery expertise as well as specialty handling services including scheduled storage, cold chain logistics and handling of DEA-licensed drugs and potent and cytotoxic compounds.

 API CMOs will look at further modernizing technology. New drug applications are now required to include [quality-by-design] QbD data for any processes where there could be control or quality issues. Techniques such as QbD can be effectively implemented into development only if certain infrastructure for lab scale, pilot, analytical, safety, and computer software is in place. In addition, CMOs will have to look at using modern techniques in R&D and manufacturing such as usage of parallel chemistry, new chromatographic technologies, flow chemistry, etc. This requires an investment not just in infrastructure, but also in technologists with the appropriate training and, most importantly, a commitment from management to make these technologies commercially viable long term.

 We know that our clients are looking for partners who can work differently with them to deliver in a rapidly changing pharmaceutical landscape .... The expanding demand for sterile development and manufacturing, biologics capacity, and solutions for poorly soluble compounds drive some of the consolidation efforts in the industry.  

 Consolidation within the drug-development market continues to heat up.  Ideally, drug owners prefer to develop their candidates under one roof and benefit from a continuum of quality throughout the development process. This places greater pressure on CMOs to offer additional services supported by capital investments in infrastructure, in equipment, and in the recruitment of qualified personnel, while maintaining costing models acceptable to sponsors and clients. I believe that for these reasons, CROs and CMOs will require additional resources and revenue to support the growing demand for drug development and clinical materials. Meeting demand for comprehensive development capabilities can be attained in the near-term only through the M&A process.

 What segments of the bio/pharma development and manufacturing market are underserved? How does your company plan to address these areas?

 As a solid-oral-dose CDMO, our perspective is that spray-drying processing is underserved, as is high-potency development and manufacturing. It can be hard to find a quality outsourcing partner for developing high-potency products, and harder still to find a reliable manufacturer. Rottendorf is exploring high-potency development, which is a capital-intensive investment. But we’re listening to our customers’ needs and evaluating our options.

 Let me illustrate one of our experiences through an example. Several years ago, we lacked a US manufacturing presence for early drug-development support for injectable drugs. Since more than half of our customer base was headquartered in the US at that time, and approximately 30% of all injectable development projects were taking place there, we established a US operation. Since that time, company-wide, we can now offer customers a one-stop-shop service for injectable drug products from Phase I and II, on through late-development phases and subsequent commercialization, which includes lifecycle management options at a later stage of the commercialized drug. This approach has been eagerly embraced by our US and international customers.

 Looking at drugs under development from an API perspective, two current trends are the emergence of deuterated versions of drugs and an increase in peptide-based therapies. Deuterated molecules have to be synthesized under certain regulations with a focus on efficient use of deuterated starting materials. Neuland had identified this as an area of growth in 2009 and developed these capabilities. As a result, we have produced multiple deuterated versions of previously developed drugs as new chemical entities--some of which are in advanced clinical development. With regards to peptides, there is a dearth of experience in making short-chain peptides at larger scales. Conventional peptide CMOs tend to offer solid-phase techniques for all peptide APIs at any scale, which doesn’t necessarily help achieve lower costs, especially at larger volumes. There is a strong pipeline of short-chain peptides being developed for diverse therapeutic areas, like GI, respiratory, cardiovascular, and even orphan diseases. Neuland has developed several short-chain peptides using solution phase techniques for both clinical and commercial use. We have also recently developed a proprietary purification technique that enables a multifold increase in purification yields. This technology is applicable to both small molecules and peptides.

 At Ropack Pharma Solutions, we have decided to expand our commercial manufacturing and packaging capabilities to include early-stage development, formulation, process development, and the manufacturing and packaging of clinical supplies. We now can support our customers from formulation through Phase III clinical manufacturing, packaging, and distribution followed by commercial manufacturing, packaging, and distribution under one seamless service offering.

 As a contract testing company, SGS has clearly seen difficulties in the early phase of drug development; specifically in biopharma, deficiencies in the level of expertise, not only in the technical aspects of analytical development, but also in the regulatory knowledge. Our company is addressing these issues through strategic acquisition with a focus on expertise and the maintenance of a strong, multi-level, [quality assurance] QA system,

 Drug molecules are becoming ever more complex. One problem that the industry needs to address is the solubility and bioavailability of new therapies coming through to the market. Catalent has invested over the past years to draw together services and technologies … to address these issues, to ensure that the bioavailability challenges that affect over half of all new drugs can progress through clinical development towards the market place. Speed of development remains a challenge to all drug research.

	Addressing the need to serve global clinical trials with specialized services, Catalent continues to expand its clinical supply services network. By providing localized options and logistics capabilities in cold chain distribution, complex comparator procurement, and a variety of specialized handling and packaging solutions such as blinding and labeling, we can continue to serve the growing demands of the industry as biologics and biosimilars clinical trials increase. 

Articles

Industry experts discuss recent industry consolidation and what the outsourcing market holds for 2016.

Is Consolidation Good for Pharma?

Industry experts discuss what the outsourcing market holds for 2016.

The Market Consolidates for Better Service

The use of flexible and/or modular manufacturing is being driven by a combination of the pharmaceutical industry’s desire to reduce costs, increase capacity, and reduce development time. Olivier Loeillot, general manager, Asia, BioProcess, GE Healthcare’s Life Sciences business; Par Almhem, president of ModWave; and Tom Ransohoff, vice-president and principal consultant, BioProcess Technology Consultants (BPTC), spoke with 

 about the latest trends in flexible manufacturing.

 What trends is the industry seeing in regards to modular and/or flexible manufacturing?

 A facility’s flexibility depends on both the building itself and the process equipment that sits inside. We are seeing very strong interest from both Big Pharma and small, local biotechs for modular solutions, especially in emerging markets. Disposable equipment is also becoming the solution of choice for most companies wanting to maximize their flexibility and improve the cost of goods.

 There are several trends that point us in the direction of modular and flexible solutions. These include, but are not limited to,:

		Need for new capacity driven by the risk of drug shortages as well as new product approvals

		Needs for rapid deployment in many parts of the world, including but not exclusively, as response to pandemic threats

		An increasing number of products and formulations to be produced, pushing the need for flexibility

		The increasing interest in and focus on continuous manufacturing as a way to significantly reduce process development time and manufacturing cost.

	Note that modular and flexible is not the same thing. Rather, modularization is a tool to achieve flexibility, speed to market, quality, and repeatability--when implemented in an appropriate way. There are also different aspects of modularization.

	A functional module has defined inputs and outputs, and a clear definition of the transformation from input to output. An example could be a mixer, with a defined input stream, clearly specified mixing performance, and defined output stream. Another example is a bioreactor with the same criteria. The definition defines the input, output, and transportation, but not the physical aspects of this module. It could also be a software module or object performing a transformation of defined inputs and outputs.

	A physical module is designed to be designed, built, tested, transported, and installed as one unit. The goal here is most times off-site construction. A physical module can include more than one functional modules and could also be part of a larger functional module.

	A well-executed, functional modularization allows for combining standardization with configurability and thus quality, speed, and cost efficiency with flexibility. At the same time, a well-executed, physical modularization allows for off-site manufacturing with associated speed, quality, and repeatability benefits. The keywords here are ‘well executed,’ as a thorough understanding and experience is needed to fully take advantage of the potential of modularization when designing and building for quality and flexibility.

 One of the most important long-term trends in the biopharmaceutical manufacturing industry is the need to reduce the time and costs of development activities. Included in this category are the time and costs related to construction of new manufacturing capacity--either to support supply for clinical trials or commercial production. Technologies that enable more modular and/or flexible manufacturing facilities are being adopted more broadly because they enable companies to reduce time and/or costs of constructing new capacity in many situations.

 In what areas, processes, or markets is flexible manufacturing being used commercially?

 There is demand for and use of flexibility in most areas of pharmaceutical and biotech manufacturing. We see more single-use systems implemented for biomanufacturing, driven partly by flexibility demands. Well-known examples are bags for different types of media, single-use bioreactors, and use of plastic hoses rather than stainless-steel piping in biologics drug-product manufacturing. When we deliver isolators for containment, dispensing, etc., they are increasingly single use to allow for rapid changeover. When single use is not an option, cleaning between products is becoming more important. One way of improving cleaning efficiency is use of modular process equipment where components can be quickly switched out for offline cleaning. Contract manufacturers are often a driver for flexibility, as they have to be able to accommodate a wide range of products and processes.

 The term ‘flexible manufacturing approaches’ can be applied to many practices, including from multi-product manufacturing, to the use of single-use or disposable equipment, and to novel facilities or process concepts, such as ballroom-style designs or continuous manufacturing. Certainly multi-product manufacturing is routinely practiced today for commercial production of biopharmaceuticals. Additionally, while single-use technologies are more commonly used for clinical production, they are beginning to be used for commercial production as well. Finally, as is the case with many new technologies, emerging markets with little established infrastructure appear to be adopting novel flexible manufacturing technologies and approaches more quickly than established markets where companies already have significant investments in conventional facilities.

 Flexible manufacturing is now commonly used for monoclonal antibodies, as most of these products are based on a common platform. Many of the large vaccine-manufacturing companies are now trying to rationalize their R&D pipeline so that they will also be able to benefit from disposable technology in the near future. Amgen’s investment in Singapore is a great showcase of the most recent manufacturing trends, including a ballroom concept with mainly disposable technologies inside.

	JHL’s upcoming KUBio facility in China will be setting an industry record as far as construction speed is concerned, taking less than 12 months from beginning of construction to completion of the facility.

 What are the challenges involved in implementing flexible manufacturing and what are the strategies for handling those challenges?

 There are a number of challenges involved in implementing any new technology. Specifically, for adoption of single-use equipment the challenges include: increased requirements for leachables and extractables testing and characterization; greater reliance on the supply chain and increased importance of vendor qualification; potentially higher operating costs; and increased warehousing and waste disposal needs, to name a few.

 There aren’t any particular challenges when implementing flexible manufacturing. It is faster, easier, and cheaper when compared to traditional facilities. Running such a facility often requires training, as many operators may not yet be familiar with handling disposables. The biggest challenge may be regulatory, as some local agenices are not fully familiar with disposables. However, this is becoming less of an issue due to the increasing number of such facilities around the globe, as well as the number of Phase III products being produced in such facilities.

 Cost tends to always be one of the challenges. Designing for flexibility doesn’t have to involve higher cost of a facility, but it often does.  It is a good idea to include a cost-benefit analysis for different aspects of flexibility during the conceptual design phase. The same goes for the use of modular solutions--these have traditionally been perceived as being more expensive to implement than conventional execution, but there is an increasing awareness that modularization can offer the same or better cost effectiveness if it is executed and assessed correctly.

 What regulatory issues must be taken into consideration when switching to flexible manufacturing or modular facilities?

 (GE Healthcare): The key factor is to monitor extractables and leachables risks well. A disposables supplier must be in a position to confirm that its single-use product does not generate any of these risks and offer the right services to provide suitable evidence for specific customer processes.

 Manufacturers must comply with the same regulations, whether they are manufacturing product in conventional or modular/flexible facilities. In either case, it is advisable for manufacturers to apply a quality-by-design approach, using appropriate risk-based assessments in developing and validating their processes and methods, consistent with current regulatory guidance.

 When referring to this article, please cite it as S. Haigney, “Getting Flexible with Manufacturing,” 

The industry is moving towards more flexible manufacturing with the use of modular facilities and single-use systems.

Getting Flexible with Manufacturing

	The quality-by-design (QbD) initiative, which focuses on building quality into a product from early on in the development process, has created a shift in the way pharmaceutical companies develop and produce drug products. With a focus on patient safety, QbD helps drug manufacturers incorporate a risk-based approach to development and production. “Many firms leverage the understanding gained from adoption of QbD principles to implement innovative manufacturing approaches, such as continuous manufacturing and real-time release testing. Furthermore, QbD is a continuum approach that supports demonstration that a manufacturing process is always in a state of control and capable of consistently manufacturing desired quality product throughout its lifecycle. Consequently, manufacturers implementing the QbD paradigm are implementing a science-  and risk-based lifecycle approach that allows for continuous improvement,” states an FDA spokesperson.

	The industry has become accepting of QbD, and companies have worked to implement it into their processes.  “The introduction of QbD has triggered a paradigm shift in drug development and manufacturing and provided a new toolbox of quality principles with several opportunities for the pharmaceutical industry. QbD is applied widely in drug development today and represents the leading and most favored principles where applicable and appropriate,” says Sven Stegemann, director for pharmaceutical business development at Capsugel. And Brian A. C. Carlin, director Open Innovation, FMC Health & Nutrition and Chair of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) QbD Committee, believes that “the FDA Quality Metrics Initiative will further drive QbD manufacturing and quality approaches.”

	According to Siegfried Schmitt, principal consultant, PAREXEL, “QbD … requires intensive studies prior to the validation batches, resulting not only in higher success rates for validation, but an overall better controlled process during commercial manufacture. QbD therefore enhances control, understanding, and continuous performance.”


	Although many have adopted QbD, others are limited by what they see as barriers. 

 annual manufacturing and equipment survey found that while 28% of respondents stated they fully use QbD in process development/optimization for solid-dosage manufacturing and 56% apply QbD to some extent, 16% said they do not use QbD. Respondents indicated that a lack of knowledge, training, and clarification from regulators contributed to their reluctance to use QbD. Cost and time also factored into the decision to not incorporate QbD into their processes (1).

	But are these real or imagined barriers? “The barriers are in the peoples’ minds. They can no longer simply rely on a set of tight rules, but must use their powers of deductive reasoning rather than their memories (to paraphrase Leonardo Da Vinci),” says Chris Moreton, partner at FinnBrit Consulting and active member of the IPEC-Americas QbD Committee.

	According to an FDA spokesperson, several International Conference on Harmonization (ICH) guidelines were developed to help the industry implement QbD (2–5) as well as several Q&A documents drafted by the Implementation Working Group to answer industry questions and clarify guidance documents. “It has been the agency’s observation that there is some confusion amongst the manufacturers. There is currently an ongoing QbD pilot program with the European Medicines Agency (EMA), which has identified enhancements to the regulatory assessment process. The first and third Q&A documents from the FDA-EMA pilot clarify the agencies’ expectation regarding criticality and level of detail in submissions. Additionally, this topic is addressed in the just published FDA draft guidance on 

Established Conditions: Reportable CMC Changes for approved Drugs and Biologic Products 

(6). Additionally, the agency published the Manual of Policy and Procedures (MAPP), ‘Chemistry Review of Questions-based Review (QbR) Submissions,’ which provides transparency regarding the agency’s expectation for the submission of abbreviated new drug applications (ANDAs),” says the FDA spokesperson.

Applying QbD to solid-dosage manufacturing

 spoke with Carlin, Moreton, Schmitt, Stegemann, and FDA about the benefits and challenges of incorporating QbD into solid-dosage manufacturing.

 What specific aspects of the solid-dosage product lifecycle are most affected by implementation of QbD? Can you provide examples?

 is a patient-centric approach that encourages manufacturers to design a product and a process that always meets the needs of the patient. This starts with first identifying the product’s quality target profile such that it meets the need of the patient and then identifying critical quality attributes (CQAs) (i.e., measurable attributes) of the finished product that would ensure that the product always meets the desired quality target profile. Thereafter, a science- and risk-based approach is used to design a manufacturing process and control strategy that ensures that the product consistently meets the desired CQAs. For example, one of the aspects of solid oral-dosage manufacturing that has evolved since adoption of the QbD approach is delineating risks of each manufacturing step and then designing a control strategy that ensures that the risks are appropriately mitigated. Additionally, QbD has spurred implementation of novel approaches. For example, we have come across use of near infrared (NIR)-based procedures that include: identification testing of raw materials, blend uniformity monitoring, detection of blending end point, measuring moisture content in tablets/granules, detection of drying end point, detection of polymorphic forms, and measuring active content of tablets. Also, many solid oral-dosage manufacturing firms are looking to implement continuous manufacturing. In a recent interview, Dr. [Janet] Woodcock [director, Center for Drug Evaluation and Research (CDER), at FDA] commented that though making the switch from batch to continuous manufacturing may be difficult, costly, and time consuming, pharma manufacturers and CMOs should begin to consider the switch, because in the long-run it will end up saving companies time, money, and space (7).

 A fundamental understanding of the solid-dosage product and processes can be achieved by applying QbD principles early in development. This understanding can be augmented as development progresses and QbD is utilized to simplify the formulation and process development. During scale up, QbD can be applied to enhance product quality by determining and managing the critical product and process parameters. The knowledge gained through a QbD development program enables the shift from a batch-based process to a continuous process, increasing manufacturing efficiency and flexibility. QbD can also support technology transfer into regional manufacturing sites. Finally, monitoring the critical quality attributes and parameters can be used to ensure continuous commercial supply.

Design and development (and regulatory filing) have so far been the aspects of the solid-dosage product lifecycle most affected by QbD due to the increasing requirements to scientifically justify the product and process design. An interesting raw material example is the request for applicants to justify their reliance on pharmacopeial or supplier specifications.
	New manufacturing and analytical technologies are evolving in response to QbD. A good example is the rise of continuous manufacturing. The Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University has recently agreed to help FDA draft guidance on continuous manufacturing.

 All aspects of the solid-dosage form lifecycle are potentially affected by QbD, from pre-formulation through to commercial manufacture. The objective of QbD is to ensure we make the correct decisions based on good science, and that this translates into robust medicinal products where performance may be any combination of consistency in process output, stability, and/or in vivo performance.

 What challenges have pharmaceutical companies overcome in incorporating QbD into the manufacturing process for solid-dosage products? What challenges do they still face?

 The agency often observes that the main barrier to change is often internal to the company. For more than a decade now, FDA has been encouraging modernization of manufacturing. We have had countless public discussions on the topics and individual meetings with industry. The agency encourages continued dialogue with applicants to help lower their anxiety toward change.

 In production, it is essential to maintain a high level of automation with integrated feedback loops to exercise process controls in real time. It is also critical that expertise at the personnel level reaches across the R&D/commercial production divide to assist with technology transfer and troubleshooting. Another ongoing challenge includes the difficulty in finding regulatory professionals with appropriate expertise to put the QbD approach into expert dossier filings.

 The promised reduction in ‘extensive regulatory oversight’ in return for QbD has yet to be realized and may have to await quality culture/risk stratification. Reviewer interest and learning in QbD is to be welcomed but not on an applicant’s critical path. It may be difficult to justify investment for QbD in older legacy products.

	Incorporating QbD into the manufacturing process for solid-dosage products not only requires internal alignment, but should involve all stakeholders, including suppliers.

 The biggest challenge is the corporate mindset, particularly in my experience in regulatory affairs groups, but also in development and manufacturing. This type of resistance can only gradually be broken down. It may take another 5-10 years before the benefits of QbD are broadly seen.

 Are there specific challenges for companies working in international markets? Are the guidelines for QbD different in different markets? If yes, how are manufacturers addressing these differences?

 Basic principles of implementation of the QbD approach are based on ICH guidelines, which have been adopted in Japan, Europe, and the United States and are widely followed by other health authorities. For the countries in the ICH, there is an ongoing effort to harmonize regulatory expectations regarding implementation of the QbD approach.  The FDA-EMA QbD pilot program that was started in March 2011 is an example of one such initiative. This pilot program provides a platform for the regulators to engage in dialog with their global counterparts regarding new QbD-based concepts. One such example is implementation of continuous manufacturing for manufacture of solid oral-dosage forms. Additionally, the pilot has led to the publishing of  three Q&A documents. For example, the Q&A on design space verification explains  the similarities and differences between FDA and EU on this topic (8).

 The application of QbD will support a global product launch and secure product quality in the case of technology transfers or production changes. Nevertheless, there are still different regulatory opinions that might restrict filings solely based on QbD principles in product -development.

 Not all regulatory authorities have adopted QbD, so companies working in international markets have to employ a mix of QbD and traditional filings.

 Though QbD is part of the international regulatory harmonization effort, many regulators are not equipped to professionally review QbD applications. Unlike FDA, few other regulators have put such emphasis on the benefits of QbD, and staffed their offices accordingly.

 How has QbD improved the solid-dosage product supply chain? Are excipient manufacturers, API producers, and other material suppliers applying QbD to their processes?

 QbD has put more emphasis on quality and variability of excipients in pharmaceutical manufacturing, leading to some QbD projects at supplier levels and the recognition that QbD principles can be applied to the same extent to excipient manufacturing. Some suppliers have taken responsibility and provided QbD data on their excipients for use in drug product development. For example, the variability of critical product parameters of hard capsules across a two-year manufacturing period was recently published to help companies make a science-based risk assessment in their capsule development program. Moreover, any regulatory quality initiative should trigger a reflection on suppliers’ own quality systems, leading to advancements. A good example is the development of enhanced and tighter process capabilities, which reduce the product variability, build better quality into the product and the process in order to reduce reject rates at the finished product manufacturing level. These enhancements in capsule manufacturing provide the means to move from AQL quality assurance scale to a Six Sigma scale and level. Producing capsules at Six Sigma quality levels for pharmaceutical product manufacturing will become the new quality standard due to the value it offers to pharmaceutical manufactures. Further, as industry leaders, Capsugel works to stay ahead of regulatory requirements to provide the highest quality products to its customers.

  Where a raw material, such as an API, is sold to clients who may not be willing to take on the additional expense, suppliers are very reluctant to invest without guaranteed payback. Excipient manufacturers are often reluctant to even apply GMP as their customer base may not require such controlled standards. Therefore, QbD is most successfully applied in vertically integrated enterprises where at least R&D, API, and drug product manufacture are all managed in-house. Achieving the same result with outsourced services is still a significant challenge.

 QbD has increased awareness that greater understanding of excipients is required beyond the specification or certificate of analysis. QbD as a pharma concept has been applied to both APIs and drug products, but one could criticize the disjointed approach where the quality of APIs (generally very pure crystals) is not related to their fitness for purpose in pharmaceutical manufacturing (insoluble, poorly compactible, and non-flowing). Regulatory uncertainty has hindered incorporation of excipients into composite APIs with optimized manufacturability. Is a co-crystal an API or drug product intermediate?

	Most high-volume pharmaceutical excipients have been manufactured continuously, decades before pharmaceutical industry awareness of QbD or continuous manufacturing. The level of material and process understanding required for excipient continuous manufacturing is essentially QbD, but may not be congruent with the QbD for a specific pharmaceutical product, especially if the major markets for that excipient are non-pharmaceutical.

 QbD encourages manufacturers adopting this approach for product design to establish specifications for the incoming raw materials (API and excipients) that would ensure consistent manufacture of desired quality finished product throughout its lifecycle. This, in turn, would encourage API and excipient manufacturers to design their processes such that the manufactured API and excipients consistently meet the quality desired by the finished product manufacturer. QbD also encourages the manufacturers to identify the risks in the supply chain and to come up with appropriate risk mitigation techniques.

 How can QbD be applied specifically to excipient manufacture, API manufacture, and ultimately final product manufacture?

 Quality needs to be built into the product. This means that QbD must start at API and excipient manufacturing, as these are the components that go into the pharmaceutical product formulation and development process. The application principles do not differ if it is the API, excipient, or finished product being manufactured. The principles aim to provide product and process understanding targeted to ensure that the final targeted product profile is constantly met over the lifecycle.

	Moreover, where the design space is limited by the excipient base properties, QbD can facilitate innovation through research initiatives. While gelatin capsules were the main polymers for capsules 10 years ago, additional capsule types are available today with gelatin-like properties, including hydroxypropl methyl cellulose (HPMC) capsules manufactured by thermal gelation and HPMC capsules with delayed-release properties.

 QbD is patient-centric, so QbD must necessarily focus on the final product. API QbD will reliably deliver consistent API but not necessarily be congruent with performance or manufacturability in finished product.

	For excipients (and third-party APIs), the question is how can the suppliers support the final product QbD. This assumes they are made aware of the application, in which case they can advise:

		potential application-specific failure modes

		potential critical attributes (which may not be on specification)

		true variability of continuously produced material 

	This will improve robustness, strengthen the risk analysis, and inform control strategy.

 Relative to the cost of the finished product, API costs are typically in the range of 1-5%. Very rarely are API costs really high, maybe 20% or higher. Given the low cost contribution of excipients and APIs to a finished drug product, price is and remains the driving force. This is in direct competition to scientific progress. Thus, QbD for these product categories remains mostly out of bounds for QbD approaches, except for cases where these are part of the same company (i.e., all being part of the same company quality philosophy).

 QbD, as the concept introduced by Duran, can be applied to any product or service, and excipients are no exception. However, I would submit that excipient manufacturers have been applying their own form of QbD for many years in the form of process capability studies and process improvement projects. It is not recommended to build a plant capable of manufacturing thousands of tonnes of material per annum without having undertaken some serious development work. In addition, there is the lifecycle aspect, and the excipient manufacturers have been managing the lifecycle successfully for many years.

 39 (8) 24-28 (2015).
	2. ICH, Q8(R2) Pharmaceutical Development (ICH, November 2009).
	3. ICH, Q9 Quality Risk Management (ICH, June 2006).
	4. ICH, Q10 Pharmaceutical Quality System (ICH, 2009).
	5. ICH, Q11 Development and Manufacture of Drug Substances (Chemical Entities And Biotechnological/Biological Entities) (ICH, May 2012).
	6. FDA, Draft Guidance, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products Guidance for Industry (CDER, CBER, May 2015).
	7. Z. Brennan, “FDA Calls on Manufacturers to Begin Switch from Batch to Continuous Production,” 

Guidance for Industry, Q8, Q9, and Q10 Questions and Answers(R4)

:
	When referring to this article, please cite it as S. Haigney, “Quality by Design in Solid-Dosage Manufacturing," 

QbD is improving the safety of solid-dosage drug products as well improving manufacturing processes, despite some industry reluctance.

Quality by Design in Solid-Dosage Manufacturing

 posted on FDA’s website, top FDA officials present an update on China’s pharmaceutical industry and FDA’s involvement in helping keep the country’s pharma exports safe. The trip to China was made by Howard Sklamberg, FDA’s deputy commissioner for Global Regulatory Operations and Policy; Richard Moscicki, MD, FDA’s deputy director of the Center for Drug Evaluation and Research; and Alonza Cruse, FDA’s acting director, Pharmaceutical Quality Program, Office of Regulatory Affairs.

	The FDA officials were in China to observe the Chinese drug industry and meet with representatives of the Chinese Food and Drug Administration (CFDA). They noted that the face-to-face meetings they had with CFDA were “the most important by-product of our trip.” The US FDA officials took a tour of a pharmaceutical manufacturing plant and addressed students at China’s Pharmaceutical University in Nanjing. The trip also included a meeting with 17 leaders of Chinese pharmaceutical companies to discuss quality, data integrity, and the drug approval process. 

	Talks with CFDA included the importance of securing the global supply chain. The FDA representatives stressed that the agency applies “the same quality and data integrity standards to all countries shipping drug ingredients into the United States.” Discussions also included revisions to China’s Drug Administration Law, implementation of the US Food and Drug Administration Safety and Innovation Act, regulatory science issues, and the importance of collaboration.

	The FDAVoice blog post also discusses FDA’s role in inspecting facilities in China and working with the local regulatory bodies. “Given the volume of US trade with China, we are working to expand our presence there to significantly increase the number of inspections we conduct. Staffing increases will allow FDA to enhance its training efforts and technical collaboration with Chinese regulators, industry, and others. In fact, in November 2014, we signed a Memorandum of Understanding with the Chinese government that expands our cooperation and will facilitate those staffing increases.”

	The agency also reaffirms its commitment to keeping products safe when they are imported into the US. “The FDA’s office in China has also strengthened relationships with regulators and helped expand the country’s expertise in regulatory operations. And we have worked with industry and academia to explain our regulations and analyze trends and events that might affect the safety of FDA-regulated products exported from China to the US.”

Agency officials visit China to meet with Chinese regulators and industry representatives about keeping the pharma supply chain safe.

FDA Officials Comment on China Visit

	On June 1, 2015, the European Directorate for the Quality of Medicines & Healthcare (EDQM) announced the publication of its 

 for 2014, which was also the agency’s 50

 anniversary. Director Susanne Keitel detailed the directorate’s achievements during the past 50 years in the report’s forward. She also thanked the EDQM’s member states, saying “none of the EDQM’s achievements would have been possible without the unwavering support of its member states and all those who have helped build the EDQM and taken part in its activities.”

	An update on EDQM’s status with the International Organization on Standardization (ISO) shows that EDQM has maintained ISO 9001:2008 certification for the evaluation of applications for monograph suitability in the 

); management of site inspection programs; postmarketing surveillance studies for drug products and databases; coordination of Official Control Authority Batch Release procedures for biologicals; management and distribution of the writing and revision of 

 texts; and performing laboratory studies. The EDQM laboratory underwent an ISO 17025:2005 audit by BELAC, the Belgian accreditation body. The audit maintained the lab’s certification as technically competent and “able to generate technically valid results.”

	The report highlighted feedback from workshops performed during a three-day conference held in Strasbourg in October 2014 in honor of the 50

 anniversary. The following are some of the highlights:

 Monographs and Expectations for the Future” workshop was positive, according to the report, with recommendations including, “early availability of reference standards, provision of guidance on the cross validation of alternative methods, and the frequency of revisions to cover impurity profiles and new scientific and regulatory developments.”

		A workshop on quality by design (QbD) revealed that participants felt that more experience in the application of QbD was necessary and analytical methods and manufacturing processes should be examined.

		Participants of the “Finished Product Monographs” workshop identified the dissolution test as crucial. They also requested more harmonization of monographs among different pharmacopeias.

		New guidelines regarding impurities were discussed during the “Impurities” workshop. Collaboration between the Ph. Eur. and the industry was considered crucial for the workshop participants. Support for the International Conference on Harmonization (ICH) Q3D guideline on impurities was also expressed.

		Combatting counterfeit and illegal drugs was the topic of the “Combatting Illegal Medicines” workshop. Participants recommended the development of strategies to raise awareness regarding counterfeit drugs, providing new monographs, and developing new approaches to the problem, including a link to pharmacovigilance signals.

		The “Biologicals” workshop attendees expressed the need for flexibility and harmonization. “The application of the P4 procedure was considered to be a two-phase process; as a starting point, an evaluation of users’ needs and the elaboration of monographs on innovator products were considered necessary, followed, as more biosimilars emerged, by further evolution and standardization of thinking,” according to the report.

Monographs, general chapters, and reference standards added in 2014

	The EDQM Annual Report mentions the adoption of 26 new monographs including two on patent-protected active substances: imatinib mesilate (2736) and rosuvastatin calcium (2631). Two new general chapters cover the topics of methyl, ethyl, and isospropyl toluenesulfonate in active substances (2.5.40) and monographs on herbal drug extracts (5.23). Additionally, 191 texts were revised, including Reference Standards (5.12) and the monograph on herbal drug extracts (0765).

	The Ph. Eur. Commission adopted 76 batches of new reference standards and 172 replacement batches. Of the 55 assay reference standards established, 27 required collaborative study.

	Manufacturers applied for 347 new Certifications of Suitability in 2014, up from 338 in 2013, and 1632 applied for revisions, up 15% from 2013. EDQM issued 355 new certificates and 1374 revised certificates in 2014.

	Ph. Eur. Commission work programs initiated in 2014 included the following:

		a pilot phase for writing a product-specific monoclonal antibody monograph using a multisource approach in order to test such an approach

		approval of general principals for monographs on finished products containing chemically defined active substances

		addition of a general monograph on coprocessed excipients

		the appointment of members to the Live Biotherapeutic Products Working party

		collaboration on the “PaedForm” project to improve access to suitable and age-appropriate drugs for children.

	The Ph. Eur. Commission considered the following industry developments important in 2014:

		the approval of the Ph. Eur. bacterial endotoxins policy

		revision of guidance on second identification tests.

	The report goes on to detail EDQM event activities, results from a variety of working groups, training courses, and collaborative efforts by the Commission on a number of topics and initiatives from 2014. The full report can be downloaded from EDQM’s website.

The directorate highlights achievements accomplished during the year of its 50th anniversary.