Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	The United States is facing a national crisis of shortages of generic, sterile injectable drugs that are used in hospitals, says Martin VanTrieste, president and CEO of Civica Rx, a not-for-profit generic-drug company founded in 2018 to reduce and prevent drug shortages. “These medications play an essential role in surgeries, emergency care, and patient treatments. Over the past two decades, shortages of generic, injectable drugs critical to the lifesaving work of hospitals in the US have become commonplace,” says VanTrieste. Civica’s mission is to make quality generic medicines accessible and affordable, and many large healthcare systems representing hospitals have joined as members. 

interviewed VanTrieste and Russ Gall, chief manufacturing and supply chain officer at Civica, about the challenges of drug shortages and the company’s plan for addressing the problem by providing manufacturing capacity and ensuring quality.

What are the biggest challenges the industry faces in solving the drug shortage problem?

During the past several years, more than 200 drugs have been listed on the FDA’s and the American Society of Health System Pharmacists’ (ASHP) drug shortage lists. Drugs in short supply include older medications that are commonly prescribed and accessed by everyone. Many drugs in shortage are generic, sterile injectables. They can be challenging to manufacture and are sold at very low prices because they are not under patent. These chronic shortages are negatively affecting patient care. They can cause surgeries to be canceled or delayed and treatments to be suboptimal when providers must use a less effective drug.

	The root of the problem is an unsustainable economic model for the manufacture and sale of commonly used generic drugs. Despite their important role in hospital patient care, the fact that they are older generic medicines rather than innovative drugs creates competition to sell them at unrealistically low prices. The resulting low profit margins drive manufacturers to seek the least expensive suppliers, often from manufacturers in China and India, where quality control may not be as stringent as in the US. This can result in poor-quality products and quality-related recalls. Additionally, many US factories have not been modernized with improved quality systems, resulting in shortages at domestic facilities.

	Low margins also provide little incentive for manufacturers to enter or stay in the generics market. For those who do, low profits provide little motivation and few resources to maintain or upgrade manufacturing facilities, buy from suppliers of quality APIs, or ensure that business continuity plans, redundant manufacturing capacity, and well-stocked inventories to prevent shortages remain in place in the event of a natural disaster.

Can you summarize Civica’s manufacturing strategy, your progress so far, and next steps?

Civica’s manufacturing strategy begins with a well-vetted list of medically necessary products that have either been consistently on-and-off the FDA’s and ASHP’s drug shortage list or that have experienced predatory pricing. Civica utilizes feedback from its Drug Selection Advisory Committee (which is comprised of representatives from many Civica member hospital systems) to establish lists of target products and associated prioritization. 

	Civica’s manufacturing strategy is then to first identify abbreviated new drug application (ANDA) holders that are currently manufacturing the products and determine if there is a potential for contracting with the manufacturer (as a contract manufacturing organization [CMO]) to leverage that specific CMO’s ANDA to manufacture Civica-labeled product.  Long-term contracts with guaranteed volumes are often an incentive for the CMO.  However, final selection as a CMO partner only occurs following significant due diligence from the perspectives of reputation, regulatory compliance history, product quality, manufacturing capabilities, available capacity, and pricing.  All products subsequently manufactured and labeled for Civica must be released by the Civica quality unit prior to distribution.  Another critical part of Civica’s overall manufacturing strategy is ensuring redundancy of supply.  This includes sufficient sources for APIs, excipients, and components, as well as for finished product.  This can occur through multiple manufacturing facilities operated by a CMO, multiple CMOs for a specific product, and Civica-owned (autonomous) manufacturing facilities/capabilities.  In addition to redundancy of suppliers and/or manufacturing facilities, Civica will also ensure adequate levels of inventory as safety stock to further enable supply during potential shortages. 

	Civica is currently developing its own ANDAs through a partner CDMO for targeted products, the first of which will be in hospitals early in 2022, which will subsequently enable Civica to manufacture products from its own production facilities. An agreement was recently signed with Thermo Fisher Scientific to begin developing and subsequently manufacturing nine different generic injectable drug products for Civica.

	Finally, Civica has engaged a firm to help find a Civica-owned manufacturing facility. Civica is actively evaluating and negotiating with potential acquisitions and/or partnerships for autonomous manufacturing, which gives Civica the most control over the manufacturing of its products.

	Each aspect of Civica’s manufacturing strategy is simultaneously being developed and implemented to ensure all capacity and product availability needs are being addressed to support member and patient needs. Importantly, the intent is to continue utilizing all three parts of our manufacturing strategy indefinitely.

Can you share your perspective on refurbishing vs. new construction? What would some key considerations be?

We are actively considering both options and look forward to sharing our plans in the future. There are pros and cons associated with refurbishing an existing manufacturing facility versus building a new facility from the ground up. Depending on the extent of renovation required, refurbishing an existing facility can have financial and time to market advantages, as well as other advantages of potentially having an existing and trained staff and FDA inspectional history (if favorable). Although demolition can often add significant costs to a project, another potential advantage may be that key portions of the facility can still be used, such as critical utilities, equipment, etc. Although new construction can be a financial challenge, it has the advantage of being able to be designed for the exact company needs. Appropriate capacity, utilities, technologies, location, equipment, and personnel can all be established to best meet product quality, demand, and cost objectives. 

Do you see modular construction as useful parts of your strategy?

Civica has investigated this approach as part of its overall manufacturing strategy to create autonomous production capabilities. There are pros and cons to this approach too. Modular and prefabricated construction typically have the key advantage of being able to meet aggressive timelines. This can be a critical factor in being able to get products manufactured and to patients in need in the shortest amount of time possible. The potential downsides to this approach are: 1) modular or prefabricated cleanrooms may be limited in overall footprint for accommodating certain types of manufacturing lines or operations, and 2) the costs can be substantially higher than conventional construction. Furthermore, our observation is that, although modular systems arguably have the potential to be disassembled and moved to another location for reassembly, so far this has proven to be challenging.

Are GMP compounding facilities part of the solution for drug shortages?

These operations are typically a much smaller scale than those required for manufacture of commercial batch sizes for large-scale pharmaceutical products. Expiration dates are shorter for compounded products. Finally, compounded products are significantly more expensive. Civica members currently use compounding facilities, and since the members already have these relationships, they have asked Civica to focus on FDA-licensed manufacturing facilities. Today, compounding facilities serve a vital role reducing the impact of drug shortages; however, the question is whether compounding facilities will continue to have a role to play as drug shortages are resolved.

Articles

Civica Rx plans redundant manufacturing capacity to relieve and prevent shortages of generic, sterile injectable drugs. 

Addressing Drug Shortages

In adding manufacturing capacity-whether through new, greenfield sites or by refitting existing spaces-biopharma and pharma companies seek flexible and efficient production. Getting a facility up and running quickly with a tight budget is increasingly important. 

	Flexibility is crucial in biopharmaceutical manufacturing, because companies increasingly have multiple modalities (e.g., monoclonal antibodies, cell therapies, and gene therapies) in their pipelines. New biopharma facilities often use single-use technology, and modular buildings and systems are becoming more popular. 

	“The biggest challenge is to map the current need for flexibility in manufacturing processes to the facility,” says Stefan Kappeler, technology manager for life sciences at Exyte. He notes that facilities must be prepared for changes in process flow, in scale, and in manufacturing technologies.

	Flexibility is important in oral solid dosage drug (OSD) manufacturing, as well. Manufacturers are seeking to “right size” their operations and capacity based on their product portfolios and to upgrade processes, equipment, and technology for improved efficiency and faster product changeovers, notes Dave DiProspero, director of pharmaceutical process technology at CRB. Improving equipment and facilities for product containment and cleaning operations are other active areas in OSD, he adds.

	An ongoing drive toward closed processing simplifies facilities and allows lower room air cleanliness classifications, which corresponds to savings in capital and operational costs, adds Eric Bohn, partner at JacobsWyper Architects. Similarly, the smaller equipment associated with continuous processing and the smaller-scale processing associated with advanced therapy medicinal products (ATMP) result in smaller production suites that are easier to support and operate, says Bohn. “Facilities are being more closely tailored to the needs of the process,” he notes. 

	In the past year, multiple life-sciences companies have updated or expanded manufacturing capacity by renovating existing facilities. GlaxoSmithKline (GSK), for example, completed a retrofit of its Rockville, MD site in October 2019 that increased capacity for its injectable drug Benlysta (belimumab) and involved demolition of existing suites and installation of new equipment (1). The company also renovated its Upper Merion, PA site and updated laboratory and manufacturing capabilities, including adding single-use bioreactors (2). A nearby, former GSK facility is being transformed into The Discovery Labs biotech campus, which announced in January that it would be the home of The Center for Breakthrough Medicines, a new contract development and manufacturing organization for cell and gene therapies (3). 

	Renovating an existing facility can save time compared to a greenfield site, where approvals can be complex and potentially last a year or more, says Bohn. Although renovations typically have costs for demolition, waste disposal, and the need to bring roof structures up to current building codes, for example, a significant cost savings is often found in site infrastructure, he notes. 

	“The most common refurbishments we see are from mothballed facilities,” says John Noble, vice-president and general manager, life sciences, at Jacobs. “If you can start with a building shell that accommodates your process and meets planning needs, you can save nine-plus months in construction.” 

	Facility refurbishment and renovations represent more than 60% of Fluor’s work, adds Dave Watrous, vice-president, advanced technologies and life sciences, Fluor Corporation. Reconfiguring existing life-sciences manufacturing space or using suitable vacant buildings for a box-in-a-box approach can both accelerate speed to market.

	Speed is crucial in biologics manufacturing, especially in the fast-growing cell therapy and gene therapy industry as products are reaching clinical phase and there is a lack of manufacturing capacity. 

	“For manufacturing these advanced therapies, CDMOs [contract development and manufacturing organizations], can be scheduling six to 18 months out, and this wait time is disruptive to a company’s go-to-market strategy,” says Joe Makowiecki, Enterprise Solutions director of business development at GE Healthcare Life Sciences. He says that despite CDMOs adding capacity, many cell and gene therapy companies are deciding to build their own capacity using modular, box-in-box facilities that can be delivered in a year or less.  

	“In many cases, having a facility up-and-running and licensed may be the critical path to gaining approval for a new product. As such, site startup timing is critical,” says Mitch Lower, vice-president of global engineering for AveXis, a Novartis company specializing in gene therapies. The company received an honorable mention in the 2019 International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards (FOYA) for being one of the first companies to scale up a gene-therapy manufacturing process and doing so on a short timeline. To build its Libertyville site near Chicago, IL, AveXis used G-CON Manufacturing’s prefabricated cleanroom PODS-built off-site in parallel with facility construction-which expedited startup.  

	AveXis also purchased and refurbished a facility in Longmont, CO in 2019 to add manufacturing capacity. The facility is operational and is undergoing the remaining steps to become licensed, which the company expects to occur in 2021. A facility the company is building in North Carolina is also anticipated to become licensed in 2021.

	“There are benefits and challenges to both purchasing an existing facility and building a new facility,” says Lower. “Purchasing an existing facility may be more cost effective and have an expedited startup schedule. However, the existing infrastructure and facility layout may drive additional costs to retrofit to accommodate the necessary manufacturing process. When building a completely new facility, the timeline may be longer; however, you will have the flexibility to build the facility to meet the needs of your unique and novel manufacturing processes.”  

	Although AveXis is today mainly using manual processes, it is moving towards automation in its existing and new equipment and facilities, says Lower. 

	The lack of automation that is currently common in the novel ATMP industry is changing, agrees Noel Maestre, Life Science Core team leader at CRB. “These novel therapies are quickly proving a need for process closure and automation, which in turn is driving equipment vendors to create and test novel equipment solutions,” notes Maestre. 

	Some equipment vendors are employing adaptable and flexible “plug-and-play” automation platforms. “Customers want options around automation,” says Makowiecki. “Some may prefer to start small with entry-level automation, but we aim to make flexible and scalable automation platforms that can grow and scale to more centralized and advanced levels.”

	In OSD manufacturing, facility layout is becoming more important as equipment and processes are moving toward greater integration, says DiProspero. Continuous manufacturing and processes such as direct compression, which are growing in use, are examples of integrated systems, but integrating unit operations is also preferred in more traditional OSD processes. “A typical integrated equipment train will incorporate material handling, high shear granulation, wet milling, fluid bed drying, dry milling, and granulation collection in a linked, semi-continuous contained operation,” explains DiProspero. Efficient product flow is crucial. “Good facility design is marked by uninterrupted uni-flow process direction, with appropriate hold and work-in-progress spaces and minimization of cross/backflow. Specifically, modern washing operations make use of a dirty-wash-clean uni-flow arrangement for improved efficiency and compliance.”

	Modular and prefabricated construction is being used in OSD manufacturing. “This type of construction is well suited for powder processing operations due to good cleanability, visual aesthetics, and the ability for use of glass to bring light into the spaces and provide for a user/operator-friendly working environment,” says DiProspero. 

	Modular approaches are transforming the way the industry builds facilities. Both modular design methods using standardized templates and modular construction methods for buildings and systems can improve speed to market, says a report by the BioPhorum Group (4).

	Modular construction includes factory fabricated utility skids, wall panels, or entire rooms or building sections, which can save time and improve quality and construction safety, explains Bohn. He points out that, although the initial cost of modular construction is typically more than that of field-built alternatives, the savings that comes from a shortened timeline is quantifiable. Factory testing reduces problems in the field and makes commissioning, validation, and start-up faster. 

	G-CON’s PODs, for example, are prefabricated, autonomous, plug-and-play cleanroom environments, which can be installed within an existing facility or as part of new greenfield construction, for any type of bio/pharma manufacturing, including OSD, aseptic filling, and cell and gene therapy, says Dennis Powers, vice-president of business development and sales engineering at G-CON. The mobile facilities provide flexibility because they can be transported anywhere to quickly add or subtract capacity. 

	Modular construction started out in the bio/pharma industry for building infrastructure in developing countries with a lack of skilled construction capabilities, but now speed is the primary driver. “Modular construction and prefab cleanrooms are often must-have components in any new facility. Even in very mature market locations, these strategies help simplify and accelerate the market delivery strategy for most products,” adds Watrous. 

	“The modular facility concept is a paradigm shift that provides companies with options for establishing rapid and flexible in-house production,” says Makowiecki. “With standardized, modular systems, typically 80% of the design work has been completed, which reduces design time and results in faster speed to delivery,” explains Makowiecki. 

	GE Healthcare’s FlexFactory is a modular end-to-end biomanufacturing platform, and the company reports that it has sold close to 70 FlexFactories globally to date. Four of these FlexFactories were installed inside of the company’s KUbio facility, which is the FlexFactory inside of a modular, prefabricated facility. Pfizer’s Biotechnology Center located in Hangzhou, China, for example, is a KUBio facility, and it won an ISPE FOYA 2019 award for project execution.

	In 2019, GE Healthcare launched the KUBio Box for viral-vector-based gene therapy manufacturing; in this box-in-box approach, the FlexFactory platform in a modular cleanroom facility is intended to be placed inside a new or repurposed space or shell-building. The KUBio box for viral vectors is a cGMP, biosafety level 2 modular facility solution. 

	“We’re also having discussions around building biomanufacturing campuses and shell facilities to house the modular boxes. A best practice approach here is to build for what you need today but allow for enough space in your facility or facility shell to expand,” explains Makowiecki. He expects the KUBio box offering will expand into additional product modalities and biomanufacturing scales. 

	Standardization of facility modules, equipment, unit operations, automation, and consumables are essential to the speed of deploying modular facilities and efficient and effective technical transfer. These capabilities support the trend to distributed manufacturing, with the same company manufacturing a drug in multiple regions rather than one centralized location, notes Makowiecki.

	“Standardized, closed systems provide optimal aseptic processes that support very high drug product quality,” adds Chris Procyshyn, CEO and co-founder of Vanrx Pharmasystems. He notes that other industries rely on standardization for reliability and safety, and he says that the pharma industry needs to move to this model. “If the process from one site can be repeated on the same machine at another site, that’s a positive change in our industry,” suggests Procyshyn. Vanrx designs closed robotic workcells with “purpose-built robotics and a standard method of handling all types of containers to achieve repeatability,” he explains. These systems remove human involvement to make the aseptic process more robust, which benefits drug quality. 

	Standardized equipment improves speed to market. For example, WuXi Biologics moved from purchase order of the Vanrx workcell to their first GMP batch release in only 15 months, says Procyshyn. 

	Placing standardized filling machines inside a modular cleanroom further increases speed and gives companies the ability to implement a fully prequalified facility within months, says Procyshyn. 

	The Microcell POD is an integrated solution from Vanrx and G-CON that meets the “increasing industry need for rapidly deployable turnkey aseptic filling capability for small batch therapies, specifically in the cell and gene therapy space,” adds Powers. Standardization lends itself to “scaling out” rather than “scaling up.” The standard POD design can be replicated to rapidly increase manufacturing capacity, he notes. 

	Although standardizing improves quality and speed, integration of the equipment into the facility building is still important. For example, in building the Bayer facility in California in 2019 using GE’s FlexFactory, Fluor’s team helped design the optimal people, product, and material flows around the established FlexFactory set-up, and then integrated these flows in the building envelope and associated utilities and infrastructure. This collaborative process with an integrated end result reflects the future of the industry, says Watrous.

	1. PharmTech, “GSK Completes Retrofit of Maryland Facility,” 

, Oct. 4, 2019.
	2. GSK, “GSK Invests $120 Million in Next-Generation US Biopharmaceutical Manufacturing Facility,” Press Release, Sept. 25, 2019.
	3. The Discovery Labs, “The Center for Breakthrough Medicines is Building the World’s Largest Cell and Gene Therapy Contract Development and Manufacturing Organization (CDMO) to Launch in King of Prussia, PA,” Press Release, Jan. 23, 2020.
	4. BioPhorum Group, “Improving the Biomanufacturing Facility Lifecycle using a Standardized, Modular Design, and Construction Approach,” White Paper, June 2019. 


	Vol. 44, No. 4â¨
	April 2020
	Pages: 16–21

	When referring to this article, please cite it as J. Markarian, “Building Better Manufacturing Facilities," 

Whether refitting existing spaces or building new, the need for quick build times, flexibility, and production efficiency is driving trends in bio/pharma facility construction.

Building Better Manufacturing Facilities

	New tools for formulators of oral solid-dosage (OSD) drugs are being developed to improve understanding of the properties and variability of excipients and, thus, reduce risk. These tools include guidelines from the International Pharmaceutical Excipients Council Federation (IPEC), databases of excipient properties, and a new software program. 

	IPEC, in collaboration with the Parenteral Drug Association (PDA), published a joint technical report in December 2019 that formalizes a risk assessment for excipients (1). The report discusses the types of supply chains, and risks from these, and presents options for evaluating and mitigating risk. IPEC is also preparing to publish a guideline on quality by design (QbD) that will, among other topics, provide guidance on incorporating excipient variability into QbD formulation projects and assist users in addressing the impact of excipient variability on finished product quality in development and control strategy, explained Brian Carlin, director of QbD and Regulatory at DFE Pharma, in a presentation at IFPAC (2). “A certificate of analysis (CoA) is not enough,” said Carlin. “A CoA might not specify attributes that are crucial for your particular process, for example, the water binding capacity of microcrystalline cellulose when used in wet granulation.” He also noted the importance of working collaboratively with suppliers to set specifications for critical material attributes and recommended having a range rather than a fixed level of excipient with a CMA to ensure consistent finished product critical quality attributes. Continuous multivariate monitoring of the process can help identify “drift” caused by the inevitable cumulative changes in product, process, or excipient, he added. Drift may cause an otherwise innocuous excipient variability to interact with a finished product criticality, causing special cause variation.

	Considering the role of excipients in a formulation is particularly important in continuous manufacturing, noted Chris Moreton, vice-president of Pharmaceutical Sciences at FinnBrit Consulting and a member of the 

editorial advisory board, at the conference (3). He emphasized designing more robust formulations using QbD and the benefit of using process analytical technology (PAT), possibly with feedforward control, to make process adjustments to cope with variability. 

	Researchers at Rutgers, The State University of New Jersey, are developing a database of excipient properties for direct compression as part of their work on continuous manufacturing with the C-SOPS industry consortium, said Doug Hausner, associate director at C-SOPS (4). The team has set up a digitized system for collecting material characterization data, so that the material data can be analyzed in conjunction with process data and used for process modeling. 

	Researchers with the National Institute for Pharmaceutical Technology & Education (NIPTE) at the University of Maryland are developing an excipient database as a risk determination tool. The goal is to create an information management system using failure modes and effects analysis to identify risk, explained Steve Hoag, professor at the University of Maryland (5). The initial database, with a limited number of excipients, was developed using a grant from FDA to NIPTE and is publicly available, said Hoag. The group hopes to obtain funding to add more excipients to the database.

	BASF has introduced a “virtual pharma assistant” web-based tool for aiding excipient selection that considers excipients and their interactions with APIs (6). ZoomLab, which is available on BASF Pharma Solutions’ website, is intended to eliminate pre-formulation trial and error by predicting potential tablet formulations for API parameters that are input by the user. The database used by the tool includes a range of excipients, fillers, and binders and combinations of these. In the initial version, data are included for processability in direct compression, but the company intends to expand the tool to consider other critical properties and other processes. The first version can be used for APIs in BCS Class I and III. 

	A new digital tool from BASF named RegXcellence aims to simplify the compliance process. The regulatory and quality portal gives customers the ability to instantly download documents, find audit information, and have a compliance overview of the customer’s portfolio, says the company (6). The virtual assistant provides a faster way to maintain documentation.

	1. PDA, IPEC, Technical Report No. 54-6: Formalized Risk Assessment for Excipients (Dec. 2019).
	2. B. Carlin, “Impact of IPEC Excipient QbD Guide on Design of Pharmaceutical Products,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
	3. C. Moreton, “An Introduction to Excipients and Excipient Variability,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
	4. D. Hausner, “Updates on Material Property Database Activities,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
	5. S. Hoag, “Excipient Variability and Risk Mitigation,” Presentation at IFPAC (Bethesda, MD, Feb. 2020).
	6. BASF, “BASF to Present Three New Digital Solutions for the Pharma Industry During CPhI 2019,” Press Release, Nov. 5, 2019.


	Supplement: Solid Dosage Drug Development and Manufacturing
	April 2020
	Pages: s12

	When referring to this article, please cite it as J. Markarian, “Mitigating Risk in Formulating with Excipients,” 

Solid Dosage Drug Development and Manufacturing 

Tools help improve understanding of excipient risk in formulating OSD drugs.

Mitigating Risk in Formulating with Excipients

Understanding the regulatory requirements in the countries in which a drug will be manufactured or sold is crucial. 

interviewed Yuwei Heinzel, head of Pharma Registration with Merck KGaA in Darmstadt, Germany, and Cloris Tian, senior regulatory manager for Merck KGaA in Asia-Pacific and China, about regulations of excipients for solid-dosage drugs. 

What do you see as the most significant regulatory changes related to excipients used in solid-dosage drugs?

Regulatory authorities are increasingly demanding stricter quality management in excipient production and use, which affects both excipient suppliers and pharmaceutical manufacturers. Since March 2016, excipient users in the European Union must define and implement good manufacturing practice (GMP) requirements for excipients, including comprehensive risk assessments for each excipient. The EU excipient risk assessment guidelines (1) capture both the intended use and source of the excipients. Its main topics cover the determination of appropriate GMP based on type and use of excipient, the determination of an excipient manufacturer’s risk profile, as well as confirmation of application of appropriate GMP. 

	However, while regulations regarding GMP for APIs clearly define what is needed for compliance, the EU excipient risk assessment guidelines are-as their name suggests-not more than guidelines that offer tools and a framework but do not prescribe how to implement them. They neither provide detailed instructions nor a clear definition of appropriate GMP for excipients. This is the responsibility of the manufacturing authorization holder.

	In China, regulatory authorities have gone a decisive step further: regulatory compliance is required not only for APIs, but also for excipients used in drug manufacturing. In fact, it is mandatory to register all excipients used in drugs sold on the Chinese market, including those used in imported drugs-a globally unique situation.

Can you summarize China’s co-review procedure and explain how this affects excipients?

Excipients came into regulatory focus in China in 2001 when article 11 of the Pharmaceutical Administration Law (2) stipulated that excipients used for pharmaceutical production should meet the requirements for medicinal use. This very general wording led to quite inconsistent approaches. In 2005, the China FDA (CFDA) proposed that excipient registration be done according to the same process as APIs. This included a stand-alone review by the Centre of Drug Evaluation (CDE) for import and novel excipients, and by the local FDA for excipients described in the 

	The reforms were triggered by a substantial backlog in drug review. China’s pharmaceutical industry had developed rapidly in the interim, resulting in a broad range of new, improved medical products. However, the approval process couldn’t keep pace with these rapid innovations. In 2015, the Chinese State Council initiated substantial reforms aiming at establishing a more transparent and more efficient process for drug approval and, as a result, also for excipient approval. The number of reviewers was increased from the previous 100 to approximately 800 and a ‘co-review’ process was established. 

	As of December 2017, according to CFDA announcement No. 146 (3), all pharmaceutical excipient manufacturers or owners, domestic or foreign, must submit their dossiers to the CDE. After a successful completeness check, a registration number is created on the CDE registration platform. Then the registrant can issue a Letter of Authorization (LOA) to its customers (i.e., the drug manufacturers) for their respective drug application. In fact, the drug manufacturer or owner can only submit an application if it provides valid registration numbers for all excipients used.

	After successful submission by the drug manufacturer, the CDE commences the assessment process. The applicant must answer questions regarding the product and is informed if there is a deficiency letter for the API, excipient, or packaging material. If so, the CDE contacts the respective excipient registration owner. Once this assessment has been finalized, the drug approval is issued to the drug manufacturer. At the same time, the status of the co-reviewed excipients is changed to ‘A’ for ‘Active’ on the CDE platform. 

	In the first quarter of each year, pharmaceutical excipient manufacturers must submit annual reports to the CDE to keep their registration number active. If certain excipients have already been successfully registered in the context of previous drug reviews and have maintained their registration number, there may be no need for a new review and the National Medical Products Administration (NMPA) (formerly the CFDA) can use the excipient registration data directly. However, another technical review may be necessary if the CDE decides that the use of the excipient has changed.

Have there been any regulatory changes for other ingredients, such as colorants? 

In China, the classification of excipients as listed in the Chinese Pharmacopeia (ChP) was proposed in 2018 (4), which has since then served as the basis for the dossier requirements for excipients. The revised dossier requirements were published in a recent announcement in July 2019 (5). The amendments also include changes to the exemption list for low-risk excipients.

	Apart from corrigents, flavors, spices, pH adjusters, and inorganic salts, the exemption list for low-risk excipients also includes pigments (colorants) and inks, more precisely iron oxide, plant carbon black, and cochineal, as well as benzene-free inks for capsule inscription. Generally, the exempted excipients can be used without going through the complex review and registration process. However, the final registration exemption of an excipient needs to be confirmed by the CDE and depends on how the excipient is used in the drug formulation. 

Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use

	2. Drug Administration Law of the People’s Republic of China (2001), Article 11, p. 3, 

	3. CFDA, Circular of China Food and Drug Administration on Adjusting the Review and Approval Matters of the Drug Substance, Excipients and Packaging Materials (2017 No. 146) (2017). 

	5. National Law Review, “China Amends DMF System on Drug Packaging,” 


	Supplement: Solid Dosage Drug Development and Manufacturing
	April 2020
	Pages: s10-s11

	When referring to this article, please cite it as J. Markarian, “Considering Excipient Regulations,” 

Understanding European GMPs and new rules from China for excipients are crucial for formulating solid-dosage drugs. 

Considering Excipient Regulations

	Drug shortages of common injectable drugs have been blamed partly on lack of manufacturing capacity and on quality problems at aging facilities. And as cell and gene therapies move through the pipeline and into commercialization, there is an urgent need for GMP manufacturing capacity for these products. 

interviewed Maik Jornitz, president and CEO of G-CON, about current trends in facility construction. 

In 2017, the Parenteral Drug Association (PDA) published 

Points to Consider for Aging Facilities 

(1) to help companies recognize when action is needed to modernize aging facilities. You co-chaired the industry expert team that wrote this technical report. What has taken place since then?

A resulting task force from the work on aging facilities is the Post-Approval Change Innovation for Access to Medicine (PAC iAM) Task Force. This group is working on easing the post-approval change scrutiny to allow new technologies to be implemented faster into processes and also to lower the hesitance to bring new technologies and improvements to facilities. This task force is making good progress, and hopefully we will see the outcome of lower post-approval burdens and possible acceptance of the review of one major regulator by the majority of regulators. 

How is industry addressing the lack of manufacturing capacity/manufacturing quality as it relates to drug shortages? 

We see the move away from the traditional design-and-build mode for facilities and processing areas. Vast amounts of time are consumed by lengthy design phases, designing the same facility over again. Furthermore, traditional facility construction is sequential, meaning first the building is constructed, then the utilities and cleanroom infrastructure, followed by the equipment placement. All in all, an onsite sequential construction can take up to three years before product leaves the door. New, offsite-build cleanroom modalities allow the parallel construction of the shell building, utility modules, cleanrooms, and equipment to bring it all together in eight to 12 months. This approach is especially valid when the design phase is abbreviated by utilizing a standardized, turnkey facility solution. An example for this is iCON from IPS and G-CON. 

	In aseptic fill/finish, we see the need for much faster deliveries of isolator-based fill systems. Right now, the delivery time can range up to one and a half to two years, although there are new isolator/robotic-based standardized fill systems which can be supplied off the shelf. The isolator-based fill line can now be placed and prequalified in a mobile cleanroom unit, which allows more rapid buildup of filling capacity.

For what facility or location types are modular construction or prefabricated cleanrooms best suited?

Modular and prefabricated cleanroom infrastructures are replacing the traditional stick-built structures, due to the speed of build and the higher quality of the materials used. Some larger pharma companies have decided to stop using stick-built, as the underlying weaknesses of the wall materials and potential mold contamination represented too high a risk. Moreover, companies investing into new or refurbished facilities require reliable delivery times and cost budgets. The traditional infrastructures could not meet these requirements, and the majority of end-users see time to completion shifts and cost budget drift to painful degrees. The modular and prefabricated cleanroom systems can be used in applications including bioprocessing, vaccines, continuous oral solid dosage processing, fill/ finish, compounding pharmacies, and most certainly the cell and gene therapy segments. 

	We see a major demand within the cell and gene therapy industry for manufacturing space, as the contract manufacturing organizations do not have the capacity and the wait time for a capacity slot can be two years. Since a lot of these products are now mature and reaching the clinical, if not commercial phase, demand for fast-track-built facilities is rapidly rising. In addition, the cell therapy processing space and facility layout are much different of what we have seen in classical pharma and biopharma. The batch processed within cell therapy is a patient, which means the volumes are so small that the processing space can be a lab size, but the containment has to be extremely robust to avoid any contamination. We believe this facility segment will experience the highest growth. 

In what situation might a company choose to refurbish vs. build new? 

It depends on the application. Large-scale applications will most commonly be a greenfield site, as it is much more difficult to push such large projects into a brownfield system. However, smaller volume, newer therapy applications are utilizing existing mothballed sites; companies gut them, use the existing utilities, and then bring in cleanroom infrastructure. Large shell buildings with some existing infrastructure are ideal for off-site fabricated cleanroom infrastructure, as the time-to-run will be reduced further.

When choosing new construction, what are some of the key factors in designing the facility and choosing the equipment?

Again, it depends on the application. If the application is mature, such as monoclonal antibodies, there will not be a lot of surprises in regard to the process and equipment, which determine the layout and footprint of the facility. However, with newer processes, such as viral vector production, new innovations and productivities are needed. These processes are ‘in flux,’ therefore, the cleanroom space around these processes must be flexible and configurable. 

	Energy efficiency is certainly another topic when one looks at cleanroom space, as the air handling is a major energy consumer. There have been initiatives to reduce the air circulation rate when there are no personnel present in the cleanroom, to change from single-pass to recirculation, or the reclassification of cleanrooms to a lower grade due to functionally closed single-use processes. 

Technologies and methods for new and refurbished manufacturing facility construction expand capacity for new modalities and to ease shortages.