Highly potent drugs represent a growing proportion of medicines, including therapies in development and those commercially available. As older products reach patent expiry, generic-drug companies are also moving into this space, creating an increasing demand for capability and capacity to manufacture highly potent APIs (HPAPIs), particularly for contract manufacturing organizations (CMOs).

	A significant proportion of HPAPIs are in the oncology field, and as approximately one-third of all new drug approvals are currently cancer medicines, this represents a substantial market opportunity. Other therapeutic areas where drugs may be highly potent include asthma and pain management.

	The chemistry to make these molecules is not necessarily difficult; however, the greater challenge is in the handling and containment of them to ensure operator and environmental safety. It is vital that a careful assessment is made of the hazards posed by each individual product, reagent, and intermediate involved in the synthesis ahead of manufacture. If the risks are underestimated, people within and around the plant will be in danger. Conversely, if the risks are overestimated, the result will be excessive amounts of money spent on containment and an increase in project costs.

	A compound is deemed to be potent in pharmaceutical terms if it has an eight-hour, time-weighted average occupational exposure limit (OEL) of 10 µg/m

 or less. There is, however, no formally agreed definition of the OEL level that constitutes a “highly potent” compound. To add to the confusion, the same compound might be classified differently by individual risk assessors. This variability in classification is exemplified by a study carried out by Cambrex in which a panel of 38 molecules was sent to three risk assessors. Three different results were provided: one assessor deemed five of the 38 to be highly potent, one assessed 37 of the 38 to be highly potent, and the third fell somewhere between the two extremes.

	The subjective nature of these results highlights that any CMO managing a facility to manufacture multiple APIs that may, or may not, be highly potent should consider each project on a case-by-case basis. A flexible approach allows manufacturing techniques, equipment, and containment options to be tailored to the molecule’s properties, and the requirements of each individual step of the synthesis. The result should be increased safety, lower costs, and enhanced capacity for the manufacturing of HPAPIs.

	When determining risk, the starting point is the OEL and other safety-related properties of the molecule determined as part of the drug development process. Once an investigational drug reaches the large-scale manufacturing stage, extensive safety data will have been compiled, including results from preclinical toxicology assessments, animal studies, and early-stage clinical trials.

	These data on potential hazards and dose–response effects are used as a basis by experts in risk assessment to generate OELs and occupational exposure bands (OEBs) that allow informed decisions to be made about engineering strategies and industrial hygiene requirements. Appropriate containment and personal protective equipment should be supplemented by comprehensive training to ensure their proper use.

	There is an important caveat. Although toxicological data offer a useful starting point, there is a difference between potency and toxicity. Potency is a measure of how much of the API is required to have a therapeutic effect; toxicity is a measure of its adverse effects. A cytotoxic drug to treat cancer may be extremely toxic but its potency might be low, and therefore, side-effects are likely. Conversely, for some drugs that only require very small doses to have a medical benefit, the dose that causes side-effects may be substantially larger. The handling requirements in the manufacturing plant will be very different for the two.

	Toxicology data gleaned from preclinical research or clinical trials are not designed for direct application to OELs, either. The aim of an early-phase clinical study is to determine optimal doses, balancing therapeutic benefit and what patients can tolerate. There is a huge difference between exposure in this context, and the inadvertent inhalation of dust in a manufacturing facility; there is no direct correlation between these clinical trial data and the safe exposure level for operators.

	The data will, however, provide indications to issues that might occur with acute exposure. If they highlight issues such as respiratory problems, lachrymatory issues, adrenergic concerns, or somnolence, for example, acute problems might be anticipated in manufacture. There may be indicators toward chronic exposure issues, also, if there are indications that the compound might be carcinogenic, mutagenic, a sensitizer, or a clastogen.

	With this information in hand, the next step is to identify any critical effects that exposure might have, such as target organ toxicity or pharmacological effect, and the dose-response curve. However, inter-person variation makes it difficult to make a definitive risk assessment.

	At the lower end of the dose–response curve (

) is no-observed-effect level (NOEL), where the chemical causes no effect at all. The next point moving up the curve is the no-adverse-event level (NOAEL), which is commonly cited in risk assessments. Next, there are the analogous low-effect level (LOEL) and low-adverse-effect level (LOAEL), and then doses that are well tolerated, followed by the maximum tolerated dose (MTD). Past this point, the APIs are likely to be hazardous. In animal tests, at the ED50 point, half of the animals will experience an effect; at the TD50 point, half will experience toxicity; and at the LD50 point, half the study animals will die at that level of exposure.

	OEL is occupational exposure limit
	PoD is point of departure for extrapolation (mg/kg-bw/day)
	BW is body weight (kg)
	UFc is composite uncertainty factor
	MF is modifying factor
	V is volume of air breathed during work shift (m

) that compensate for unknowns. The numerator comprises factors that will increase occupational exposure, while the denominator includes those that will reduce it, including uncertainty factors. Those components that can contribute to uncertainty include variation between species and between subjects, the duration of the study, the severity of the effect, bioavailability and bioaccumulation, and pharmacokinetics.

	Modifying factors are also considered by some risk assessors, including the slope of the dose–response curve, and the choice of critical effect and its clinical significance, its reversibility, and its relevance to workers. Susceptible subpopulations and read-across similarity may also be considered, as may a lack of independence for uncertainty factors.

	This uncertainty is at the root of the variability in risk assessments. Depending on the magnitude of uncertainty values that are applied, and whether modifying factors are given weight, there is the potential for as much as eight orders of magnitude of difference in the OEL determined by individual assessors. Reconciling this variability in the final risk assessment is a major challenge.

	The solution lies, at least in part, in applying real-world context to the uncertainty factors. Perhaps the most important is the acceptable exposure risk for an individual operator, and even for the most conservative risk assessor, a one-in-one-thousand risk may well be more realistic than the one-in-one-million risk to be an appropriate likelihood of an exposure happening. The one-in-one-thousand risk is not without context: it is commonly cited as the chance of a severe injury in a hazardous work environment.

	Three orders of magnitude difference in acceptable exposure risk can represent a major difference in cost. If an API is placed in a higher OEB in the absence of data and with a large weight placed on uncertainty factors, then far more costly containment will have to be employed, and the manufacturing process will take longer. How necessary is it that the API is treated as so much more hazardous? And what about the intermediates involved in its production? It is less likely that there will be a calculated OEL for those intermediates.

	It is important to carefully consider exposure modifiers. Is the process likely to generate dust? If so, the likelihood of airborne hazard is far greater. How long will the operator be exposed to the material? Theoretical OELs are based on an eight-hour exposure; however, the time of potential exposure may be only a few minutes. A case-by-case assessment of the actual facility, process, and procedures will give a far more realistic picture of the hazard. There may be limits on how long people can work on individual projects because of the potential for chronic effects. If an API is a known teratogen, it may be advisable for pregnant women to keep well away.

	Occupational exposure bands are a useful tool for matching a hazard with containment requirements. APIs that fall into OEB1 are non-toxic, and a standard exposure level of 500 µg/m

 will suffice. OEB2 compounds will have special hazards, such as carcinogenicity, and the OEL will need to be lower.

	At OEB3, where the hazards are greater but not extreme, the opportunity to customize handling to account for real-world situations is greater; this is where the greatest cost and time savings might be anticipated. Here, the containment could-and should-be designed around the process itself. The existing plant may suffice; alternatively, safety requirements might be met by introducing high-efficiency particulate air (HEPA) filters or soft-sided isolators, a more conservative approach than simply using personal protective equipment. The risk assessment should also consider the solvents and whether they can degrade processing or containment equipment. A program of surrogate testing is required to prove that the containment strategy is appropriate and working successfully before the hazardous material is introduced.

	OEB4 APIs are more highly potent and toxic, and special handling and careful containment will be required. An additional band, OEB4+, encompasses compounds that are so potent that their OEL falls below 0.1 µg/m

. For OEB4 and OEB4+ compounds, the opportunity for customization is limited, and the process must be designed around the containment, and not the other way around. Dedicated isolators will most likely be employed, and rapid transfer ports for APIs deemed to be OEB4+.

	This type of complete containment is extremely expensive, and while the conservative approach would be to use such containment for all highly potent compounds, in reality it may be overkill for OEB3 APIs. Instead, it may be more realistic to start out with the assumption that full containment is required, but then relax the handling requirements as further data become available, if the data suggest this will be safe. This level of flexibility will allow a CMO to offer its customers a more cost-effective solution, and faster timelines.

	Jeff Pavlovich is senior process safety engineer at Cambrex.

Supplement: Outsourcing Resources
	Vol. 42
	August 2018
	Pages: s18–s20, s33

	When referring to this article, please cite it as J. Pavlovich, "Classifying Potent and Highly Potent Molecules," 

Pharmaceutical Technology Outsourcing Resources Supplement

Articles

Features

Determining how much containment is needed for API handling requires evaluation of multiple factors.

Classifying Potent and Highly Potent Molecules

This article presents some examples of combination devices being tested or currently in use along with factors for consideration when developing them.

	Silicone has long been a favorite material of medical product designers who value its stability, physical properties, and biocompatibility.  For these reasons, medical grade silicones are commonly used across a wide variety of medical devices and drug delivery products. 

	In addition to the physical properties that make silicone a preferred material for medical devices, its chemistry and cross-linking characteristics make it an ideal material to use in many drug delivery applications.  Combination products include combinations of two or more of these three components: medical devices, drug, and biologics.  For this article, the combination of a medical device and active pharmaceutical ingredient (API) will be considered.  

	An API can be used with a medical device to enhance the performance or safety of the device, or both.  A good example of this would be a collar added to a pacemaker lead that is made from a mixture of silicone and Dexamethasone. The Dexamethasone enhances the function of the pacemaker lead by reducing the inflammation and swelling post-implantation at the surgical site. 

	On the other hand, medical devices can be used as a delivery method for an API. Inhalers and insulin pumps are good examples of devices that focus on drug delivery, with the drug and the device acting independently.  

	Implanted contraceptives combine a drug reservoir with a rate-release control membrane to elude a hormone in a closely controlled range over a lengthy period of time. In this case, the device function and the drug are functionally intertwined, with the drug and device attributes being combined to provide the specified therapeutic dose.  An API may be combined with polymers in many ways; two of the most common are mixing an API with a polymer, such as silicone, prior to manufacturing the component or drug formulation, or adding the drug to the component after component fabrication. Each of these approaches have advantages and limitations.  

In most controlled-release drug delivery applications, the API is added to the base polymer before the polymer is formed into its final shape. When the materials to be mixed are combined in a closely controlled process, the end result is that the final dosage is controlled well within dosage specifications.  In many manufacturing operations, material handling and mixing are completed in single-use, disposable vessels so that safety and contamination controls can be more easily implemented. Single-use systems are one way that the burden of validated cleaning methods is reduced, especially during early preclinical and clinical development. 

	At commercial scale, dedicated equipment and manufacturing cells are frequently used so that cross-product and cross-facility contamination risks are more readily controlled. At all stages, containment and cleaning plans must be designed and implemented as part of a risk-based hazard assessment.  

. There may be several advantages to adding an API to a previously manufactured product. Some of these advantages are: the manufacturing process for the initial product may continue without modification, the handling of the API/solvent mixture is performed in an isolated environment separate from the remainder of the facility, and the product lead time is relatively short compared to a product where the API is mixed with the polymer prior to shaping. There are several predicate products to be found, so development paths can be shortened. 

	The first step in developing a silicone implant to which the API may be added is by working with a silicone component manufacturer with an understanding of the silicone and the API chemistry in general, and the drug solubility in particular. Understanding the drug solubility is critical to determine which solvent is best for the application. The API must be dissolved in a solvent that can permeate the silicone.  The device is immersed in the solvent/API solution, and in this way, the solvent can penetrate the silicone material molecular chains, with the drug molecules left behind after the solvent flashes off.  Chloroform is a commonly used solvent; toluene and acetone are also options.

	The length of immersion is determined by a number of factors, including the type of drug, the overall device design, the thickness of the silicone wall, the density of silicone being used, and the size of the part. Typically, a short series of controlled tests (two to four) are completed to determine the optimal immersion time and establish a range of immersion times and concentrations of the drug/solvent combination. 

	There are limitations to this process; the content control and uniformity of the API in the component will be less than when adding an API to the base polymer; the drug content as a mass ratio is generally lower; and the total time of drug release is limited to shorter times (e.g., days or weeks). 

	Bio-absorbable devices for drug delivery

	Polyvinyl acetate (PVA) and ethyl vinyl acetate (EVA) are bio-absorbable polymers that can be used to help control the rate of release of a variety of drugs. Small-scale implants that are completely absorbed once the drug has been fully released have the potential to reduce post-surgical infections and increase medication compliance.

	Similar technology is under development for ophthalmic applications. Rather than prescribing eye drops, which have a low rate of patient compliance and are prone to dilution from tears, a drug delivery on-lay containing medication may be placed under the eyelid by a physician. It would deliver a minute amount of medication (measured in micrograms per day), and the polymer wafer is absorbed at the same rate as the drug.

	These devices can be used for delivering minute amounts of a drug over a period of days or weeks. Typical drug delivery rates range from 10–20 micrograms per day, and the drug reservoir may hold 2–100 milligrams in total.

	Key considerations for combination product development

	When designing any device combining a polymer with an API, one of the first considerations is whether the device will stay in the body or be absorbed. Silicones, for example, are meant for long-term use, while PVAs or EVAs are bio-absorbable.

		Whether the dosage is flat or varied (i.e., a bolus of drug immediately after device implantation followed by a tapering dose)

		The frequency of the dose that will be dispensed

		The overall length of time the drug will be dispensed. 

	It’s important to work with a vendor experienced with combination devices to determine the viability of a proposed new device. Look for a vendor prepared to take a project from early-stage feasibility through development, clinical trials, and commercialization. The contract development and manufacturing organization selected to be a development partner must have the quality systems required for cGMP manufacturing, which starts with a commitment from upper management to high level quality systems and safety standards. 

	As with any new technology, the vast proportion of formulation work comes at the initial stages of developing a combination product. Pharmaceutical scientists must develop hypotheses and work with development and manufacturing partners to align with therapeutic, quality, and commercialization goals.  Additionally, devices with multiple APIs may begin appearing on the market, leading the way to personalized drug therapy in the future. 

	As these devices are tested, improved upon, brought into clinical trials, and commercialized, the methodologies for creating them should be established early in the development program.  It is crucial to characterize the manufacturing processes as early as possible to achieve quality and economic value for new medical and drug products.  

	When referring to this article, please cite it as A. Gaillard and M. Gordon, "Designing Combination Products," 

Pharmaceutical Technology Outsourcing Supplement

	Andrew Gaillard is global director, and Mark Gordon is product manager, both at Trelleborg Sealing Solutions Healthcare and Medical.

API can be mixed with silicone and other polymers to create drug-delivery combination products. 

Designing Combination Products

From boosting cell-culture capability to growing bioreactor capacity, contract manufacturing organizations (CMOs) have been making investments to expand biologic output. 

highlights some of the major biologics-based CMO activity in the past months.

	In March 2018, Fujifilm acquired Irvine Scientific Sales Company and IS Japan, both cell-culture media companies, in a stock purchase agreement valued at around $800 million. The acquisition expanded Fujifilm’s biopharmaceuticals product portfolio to include in-vitro fertilization and cell therapy. The company stated that the acquisitions will expand its biopharmaceuticals contract development and manufacturing business and accelerate regenerative-medicine R&D as well as expand its reagent business. The company also plans to establish a new site in Boston, MA, by March 2019 for marketing products and services that support R&D and new-drug manufacturing (1).

	In November 2017, Celonic, a biologics development and manufacturing services provider, acquired a biomanufacturing facility in Heidelberg, Germany, from Glycotope, a clinical-stage immune-oncology company. With the acquisition, Celonic expands its GMP manufacturing assets, including continuous perfusion manufacturing, which the company now offers in addition to fed-batch manufacturing and the ability to scale-up from pilot to commercial-scale production. Combining Glycotope’s GlycoExpress human cell-line platform with Celonic’s CHOvolution integrated development platform will create custom-tailored expression systems (2).

	In October 2017, Lonza Pharm & Biotech acquired a clinical-stage mammalian manufacturing facility in Hayward, CA, from Shire. The 58,000-ft2 site includes 1000-L and 2000-L single-use bioreactors and associated downstream capabilities and provides added cGMP capacity to supplement existing assets in Lonza’s Slough, Berkshire, United Kingdom site (3).

	Lonza plans to add mid-scale mammalian capacity at its facility in Portsmouth, NH, with the installation of multiple 6000-L bioreactors, the company announced in May 2018. Construction is expected to start in late 2018. The company will also include the addition of multiple cell-therapy suites as part of the expansion. The hybrid facility will house full-suite process analytic technology, multi-variate analysis, and single-use technologies in an existing building and is expected to be operational by late 2018 (4).

	Patheon, now a part of Thermo Fisher Scientific, is expanding its biologic drug substance manufacturing capabilities with a $50-million investment by Thermo Fisher into the Patheon Biologics Center of Excellence (COE) for Biological Commercial Manufacturing in St. Louis, MO. The site provides process development, clinical cGMP manufacturing, and commercial manufacturing using fed batch and perfusion processes. The investment, announced in April 2018, includes a 64,000-ft2 expansion to the existing manufacturing building #2 at the site and will feature Thermo Fisher bioproduction bioreactors, consumables, and factory automation. The expansion will double the site’s manufacturing capacity. The expanded site is expected to be operational in 2019 (5).

	WuXi Biologics, part of WuXi AppTech, announced a couple of expansion plans in recent months. In April 2018, the company said it plans to invest €325 million (US$381 million) in a new biomanufacturing facility in Mullagharlin, Dundalk, County Louth, Ireland. This new facility will use multiple single-use bioreactors for commercial biomanufacturing and is designed to be able to run continuous bioprocessing. The company intends to install a total of 48,000 L fed-batch and 6,000 L perfusion bioreactor capacity (6).

	Prior to that, in March 2018, the company announced that it would install 4000-L custom single run (CSR) disposable bioreactors from ABEC, a provider of integrated process solutions and biopharmaceutical manufacturing services, at its new 30,000-L commercial manufacturing facility in Wuxi City, Jiangsu, China. The 4000-L CSRs will enable scale-up of manufacturing up to 24,000 L (7). The new 500,000-ft2 Wuxi City facility, in which the company invested $150 million, became fully operational in December 2017. It quintuples the company’s existing manufacturing capability and will support the biologics commercial manufacturing pipeline coming from global partners. Following completion of the first phase of construction in September 2016, the facility offers two 1000-Ldisposable bioreactors for perfusion processes, making it the largest perfusion biomanufacturing facility using disposable bioreactors in Asia, as reported by WuXi Biologics. The facility was later equipped with an additional 14 2000-L disposable bioreactors for fed-batch cell culture (8). 

	AGC Biologics, a contract development and manufacturing organization (CDMO), is adding a 2000-L single-use bioreactor to its Berkeley, CA, facility and plans to build a new complex that will house the company’s headquarters in Bothell, WA. The bioreactor addition at its Berkeley facility will support the company’s growing biologics capacity, which has tripled over the past three years. The Berkeley facility uses both single-use and stainless-steel bioreactors for cell-culture manufacturing in scales of 100–3000 L (9). The new 15,000-ft2 complex to be built at Bothell will provide expansion space for additional manufacturing capacity as well as in-house process development labs and corporate administrative offices. The Bothell expansion will also include a new R&D center dedicated to novel therapeutic protein manufacturing technologies (10). The company announced both these investments in March 2018.

	CMO Emergent BioSolutions is equipping its bulk manufacturing facility in Bayview, Baltimore, MD, with a 4000-L custom single run (CSR) bioreactor supplied by ABEC, a provider of engineering, equipment, and services to the biopharmaceutical manufacturing sector. The company announced the addition in October 2017. The 4000-L bioreactor, designed specifically for Emergent’s process needs, operational requirements, and facility constraints, will expand cell-culture capacity at the Bayview site and is expected to improve process transfer and scale-up, according to ABEC (11).

	1. Fujifilm, “Fujifilm to Acquire Irvine Scientific Sales Company and IS Japan, Leading Companies of Cell Culture Media,” Press Release, March 29, 2018.
	2. Celonic, “Celonic Acquires Glycotope’s Bio-manufacturing Facility,” Press Release, Nov. 3, 2017.
	3. Lonza, “Lonza to Acquire a US Clinical Manufacturing Site to Support Ongoing Customer Demand,” Press Release, Oct. 3, 2017.
	4. Lonza, “Lonza to Invest in Portsmouth, NH (USA) Site, Including Mid-Scale Biologics,” Press Release, May 4, 2018.
	5. Thermo Fisher Scientific, “Thermo Fisher Scientific Announces $50-Million Investment to Enhance Biologics Capabilities,” Press Release, April 23, 2018.
	6. WuXi Biologics, “WuXi Biologics to Invest €325-Million to Build Largest Biomanufacturing Facility Using Single-Use Bioreactors in Ireland,” Press Release, April 30, 2018.
	7. WuXi Biologics, “WuXi Biologics to Install Industry’s Largest Single-Use Bioreactor from ABEC at its New Commercial Manufacturing Facility,” Press Release, March 20, 2018.
	8. WuXi Biologics, “WuXi Biologics Initiated cGMP Manufacturing in the World’s Largest Biologics Manufacturing Facility Using Only Single-Use Bioreactors,” Press Release, Dec. 6, 2017.
	9. AGC Biologics, “AGC Biologics Expands Capacity at Berkeley, California Facility,” Press Release, March 6, 2018. 
	10. AGC Biologics, “AGC Biologics Increases Footprint in Bothell, WA,” Press Release, March 29, 2018.
	11. ABEC, “ABEC 4,000-Liter Single-Use Bioreactor to Expand Emergent BioSolutions Manufacturing Capability,” Press Release, Oct. 24, 2017.

	When referring to this article, please cite it as F.Mirasol, " CMO Roundup: Expansions for Biomanufacturing," 

Pharmaceutical Technology Outsourcing Resources Supplement 

CMOs have been active over the past year in expanding their biologics production and capabilities.

CMO Roundup: Expansions for Biomanufacturing

Small-molecule contract service providers have advanced their capabilities and offerings to help clients accelerate innovations and tackle industry challenges. This article will explore some recent small-molecule expansions and investments, as well as acquisitions.

	In May 2018, Cambrex completed its previously announced pilot plant expansion at its High Point, NC facility (1). The expansion includes the installation and commissioning of a fourth 400-ft

 reactor suite with two 2000 L glass-lined reactors and a Hastelloy C22 filter dryer, allowing the manufacture of batch sizes ranging from 10–100kg under cGMP conditions for clinical-phase projects. According to a May 15, 2018 company press release, the installation increased the site’s reactor capacity by approximately 30%. Additionally, the company upgraded its analytical chromatography data systems for quality control and analytical R&D to Waters’ Empower 3 software. 

	Also in May 2018, Cambrex shared progress on the construction of a $24-million facility at its Charles City plant for the manufacture of highly potent APIs (1). A 4500-ft

production area, which will have a reactor capacity of 2200 gallons and manufacture batches from 50–300kg, will operate to an occupational exposure limit down to 0.1µg/m

. The existing small-scale manufacturing area will be reconfigured, providing a single high-containment building to support early stage development and manufacturing. The company states that the facility is expected to be operational in the first half of 2019.

R&D laboratory at its facility in Paullo, Milan, Italy (2). The laboratory will combine chemistry and analytical development capabilities and include 14 fume hoods, glass-lined reactors, and liquid chromatography and gas chromatography systems. In a June 12, 2018 press release, the company reported that construction will be completed by the end of 2018, with installation and validation of instruments to take place in the first quarter of 2019. 

	The Milan site contains seven production departments, including a pilot plant, kilo-scale plant, and development and analytical laboratories. The company will also recruit additional scientists to increase the number of generic APIs in the company’s development portfolio.

	In August 2018, Minakem, the contract development and manufacturing division of Minafin, will open a new, closed-controlled environment, high-containment production facility (3). The new facility, based at the Louvain-la-Neuve plant in Belgium, will extend the company’s capacity to develop and manufacture high potency API compounds, such as antibody drug conjugate toxins, from small-scale development to full GMP batch releases. According to the company, this high-class production facility is among only a dozen of its kind in the world; roughly half are located in Europe.

	The facility will be equipped with a preparative chromatography system that allows the isolation and purification of target molecules at varying scales (milligrams to hundreds of grams) and suited to addressing a range of needs, from routine activity to analytics. Equipment includes nine fume hoods and new-generation glove boxes dedicated to dry powder handling and weighing, air locks, high efficiency particulate arresting air filters, and cascading flow. Minakem’s HPAPI production will be carried out with an occupational exposure limit below 0.1 g/m3/8h. Operations in the new high-containment facility will begin in September 2018.

	Catalent has agreed to acquire Juniper Pharmaceuticals to expand Catalent’s formulation development, bioavailability, and clinical-scale oral dose manufacturing services (4). The acquisition would also include Juniper’s Nottingham, UK-based Juniper Pharma Services division.

	Catalent states that Juniper’s expertise in formulation development and supply will strengthen Catalent’s portfolio of solid-state screening, preformulation, formulation, analytical, and bioavailability capabilities including development of spray-dried dispersions, with integrated development, analytical, and clinical manufacturing at the Nottingham facility.

	Under the agreement, announced in a July 3, 2018 press release, a subsidiary of Catalent will commence a tender offer to purchase all of Juniper’s shares for a price of $11.50, net to the seller in cash. Following the tender offer, Catalent plans to acquire the remainder of the Juniper shares at the same price through a merger with a newly formed wholly owned subsidiary of Catalent. The acquisition is subject to certain customary closing conditions and is expected to close in the first quarter of Catalent’s 2019 fiscal year, which Catalent states began on July 1, 2018.

	Juniper provides bioavailability enhancement for poorly soluble compounds, including nano-milling, spray drying, hot-melt extrusion, lipid-based drug delivery, as well as cGMP clinical manufacturing for potent and controlled substances. Catalent will continue to support Juniper’s Crinone (progesterone gel) franchise marketed by Merck KGaA outside of the United States. Catalent also announced that the Nottingham facility will provide similar capabilities at its centers of excellence for early drug development in San Diego, CA and Somerset, NJ.

	Recipharm is set to expand its presence in the respiratory drug market with the acquisition of Sanofi’s Holmes Chapel manufacturing site in Cheshire, UK, for £45 million (US$59 million) (5).

facility manufactures metered-dose inhalers and nasal sprays and develops dry-powder inhalation technologies. The site’s 450 employees will transfer to Recipharm, according to the company. The transaction is expected to close in the fourth quarter of 2018.

	The acquisition provides Recipharm with additional inhalation commercial drug product manufacturing capabilities, adding to services already offered by Recipharm’s inhalation development facility in the US, as stated by the company in a June 13, 2018 press release. Sanofi has also entered into a long-term supply agreement for the products currently manufactured at the facility.

	In July 2018, Cambrex announced it entered into a definitive agreement to acquire dosage form contract development and manufacturing organization (CDMO) Halo Pharma for approximately $425 million in total cash consideration (6). The acquisition will be funded with a combination of cash on hand and borrowings against Cambrex’s $500-million senior credit facility. Completion of the transaction is subject to customary closing conditions and is expected to occur during the third quarter of 2018.

	With the acquisition of Halo, Cambrex will enter the finished dosage form CDMO market. Halo provides drug product development and commercial manufacturing services, specializing in oral solids, liquids, creams, sterile, and non-sterile ointments. Halo’s core capabilities include developing and manufacturing highly complex and difficult-to-produce formulations, products for pediatric indications, and controlled substances. 

	Halo operates two state-of-the-art, GMP-compliant facilities located in Whippany, NJ, and Montreal, Québec, Canada, comprising of 430,000 ft

of plant space. Cambrex reports that Halo is currently engaged in more than 100 product development projects for over 70 customers and is expected to generate over $100 million in annual revenue in 2018. The release also states that Halo’s 450 employees will join Cambrex’s 1200 employees across the US and Europe.

	1. Cambrex, “Cambrex Completes Pilot Plant Expansion at its High Point, NC Facility,” Press Release, May 15, 2018.
	2. Cambrex, “Cambrex Expands Generic API Research and Development Capabilities at Milan, Italy Site,” Press Release, June 12, 2018.
	3. Minakem, “Minakem Opens New High Containment Facility for Production of the Highest Class of HPAPI,” Press Release, June 19, 2018.
	4. Catalent, “Catalent Signs Agreement to Acquire Juniper Pharmaceuticals, Inc.,” Press Release, July 3, 2018.
	5. Recipharm, “Recipharm Expands Inhalation Capabilities with GBP 45 Million Acquisition of Sanofi CMO Business Located in UK,” Press Release, June 13, 2018.
	6. Cambrex, “Cambrex to Acquire Halo Pharma, Adding Drug Development and Finished Dosage Capabilities to Global API Manufacturing Network,” Press Release, July 23, 2018.

	When referring to this article, please cite it as A. Lowry, " Small-Molecule Contract Services Update," 

This article provides a sampling of the latest investments, expansions, and acquisitions by small-molecule contract service providers.

Small-Molecule Contract Services Update

Long-term strategic planning must always contend with uncertainty about future business conditions, but the current bio/pharmaceutical industry environment makes forward planning especially difficult. Macro-economic conditions are changing; long-established business practices are being disrupted; and political instability is widespread. It is increasingly difficult to have confidence in one’s assumptions about the context in which any industry must operate.

	In such a volatile environment, contract development and manufacturing organization (CDMO) executives must test how their strategies will hold up in the event that long-held assumptions about the external environment are upset by new realities. They need to play out “what-if ” scenarios that test the robustness and appropriateness of their strategic initiatives and investment plans in the event actual business conditions diverge from their expectations.

	Here are five what-if developments that CDMO executives need to consider carefully as they prepare and implement their business plans.

	What if payers in the US crackdown on drug prices?

	Expenditures on drugs account for just 10% of all healthcare expenditures in the United States, but they draw inordinate attention because consumers must pay a significant portion of drug costs out-of-pocket.

	CDMO executives need to consider multiple scenarios if US drug prices are attacked by government and private payers. Bio/pharmaceutical companies could respond by insisting on better pricing from their suppliers, including CDMOs, and by bringing contract manufactured products back in-house to absorb more fixed manufacturing overhead. Alternatively, they could decide to pare down their manufacturing networks and reduce capital expenditures, which could be a boon for CDMOs.

	The greatest and most negative implications are likely to be for R&D spending. Companies that self-finance R&D spending will likely reduce costs by shrinking the number of candidates they have in their pipelines.

	For emerging bio/pharma companies that depend on CDMOs, the impact would be more severe. Lower or uncertain drug prices would reduce valuations of in-licensed and acquired drug candidates, and the emerging bio/pharma companies that develop them. That would reduce the flow of external funds available for their R&D activities, most of which get spent with discovery and clinical contract research organizations (CROs) and CDMOs.

	What if funding for emerging biopharma slows down?

	There is now a symbiotic relationship between CDMOs and emerging bio/pharma companies: because there is a robust CDMO sector to serve the development needs of emerging bio/pharma companies, those companies can be set up on a virtual model that requires much less financing than if they had to invest in their development infrastructure. That means that the fortunes of CDMOs are now tied closely to emerging bio/pharma’s access to external financing. That financing has historically been cyclical, and the industry has benefited from the current, historically-long run of funding availability. When the cycle dips down again, as it did in 2007, the consequences could be devastating for the CDMO industry: a number of CDMOs may go out of business and others may have to impose deep staff cuts and postpone capital investments to ride out the downturn.

	CDMO executives preparing for this eventuality will need to be aware of several factors. One is the nature of their offerings: CDMOs dependent on early development projects, which tend to have short timeframes, will feel a slowdown more quickly than CDMOs that have a strong mix of Phase II and III projects. Secondly, they should monitor the financial health of their major clients to determine if they have sufficient cash on hand to complete the program they are working on. Finally, CDMO executives will want to keep a close eye on their company’s spending, which can get out of hand when the business is growing rapidly.

	What if trade in pharmaceuticals becomes a victim of the trade war?

	The uncertainty surrounding international trade should be a matter of great concern for CDMO executives. Bio/pharmaceutical ingredients and products are among the most actively traded goods in the global economy.

	Responding to the imposition of tariffs and non-tariff barriers would be difficult for the bio/pharmaceutical industry, whose supply chains are particularly inflexible. In the best of circumstances (i.e., when spare capacity is readily available), it takes several years to qualify new production sites. But spare capacity is not readily available, especially for small- and large-molecule APIs and injectable drug products, and especially in the US. So, if bio/pharmaceuticals get caught up in a trade war, costs will likely increase to reflect tariffs and bio/pharma companies will expect their CDMOs to absorb some of the higher costs.

	Longer term, bio/pharma companies could redesign their supply chains to localize more production, giving up economies of scale to avoid the tariffs. That could be favorable to CDMOs as contract manufacturing for a particular market could be more cost effective than building a captive facility.

	But companies would have to believe that the restricted trade environment was a fixture before undertaking the massive capital expenditures and effort that such a redesign would require. Bio/pharma and CDMO executives would likely be reluctant to move ahead with such a plan given the risk and uncertainty it would entail.

	What if new processing technologies become widely adopted?

	CDMOs have generally been followers in adoption of new technology as they lack the resources available to global bio/ pharma companies to do technology R&D. As bio/pharma companies develop products incorporating new technologies such as continuous manufacturing, CDMOs will have to figure out how to underwrite the capital expenditure and develop the expertise to implement them. This is likely to require skills in partnering with clients to co-develop and co-invest in the technologies. It is also likely to favor financially-sound CDMOs that can provide assurance that they can be reliable long-term partners in innovation.

	What if industry restructuring dumps capacity into the CDMO space?

	Large global bio/pharmaceutical companies of all stripes are restructuring their manufacturing networks and supply chains. The CDMO industry has gained most of its capacity as a result of plant divestitures by large bio/pharma companies, but the result has been a large amount of undifferentiated available capacity and a number of CDMOs facing financial difficulties, especially in Europe.

	CDMO executives must consider the implications of a large amount of new bio/pharma capacity coming into the market on top of the capacity that CDMOs are investing in themselves. A market already awash in capacity for low-value solid and liquid dose forms is likely to be pressured as more capacity becomes available. There are still investors new to the industry that are looking for a way into the CDMO market, and political pressures to maintain marginal facilities remain high. Even a small amount of incremental capacity from bio/pharma companies could severely impact profit margins and cause the contract services industry a lot of pain.


	Supplement: Outsourcing Resources
	Vol. 42
	August 2018
	Pages: s6, s8

	When referring to this article, please cite it as J. Miller, "What Ifs in the Five-Year Plan," 

Heightened uncertainty means CDMO executives need to play out planning scenarios.

What Ifs in the Five-Year Plan

For pharmaceutical and biopharmaceutical manufacturers today, a key success factor is time to market (1–4). When it comes to processes and manufacturing facilities, time to the first product run is crucial. The faster a drug moves through the development pipeline and the faster a facility is up and running, the higher the return on investment. In addition, a fast-moving facilities project can allow capital expenditures to be delayed until later in the development cycle, minimizing risks and maximizing the amount of cash on hand until needed.

	Traditional facility designs and infrastructures do not permit such fast-track implementation (5). It takes months to generate designs and even longer to build these manufacturing sites, and construction proceeds sequentially. 

	The process generally follows this pattern: a building shell is built first, followed by utilities, then ancillary and cleanroom spaces, and finally production equipment is installed. Typically, this approach means a time-to-first-product run of 24–48 months, depending on the size of the facility. The same is true for smaller projects such as laboratories.

	Modular construction onsite involves building processing space at the ultimate production location using modular wall panels. Many companies provide such panels. This approach differs from traditional construction in that the panels are rigid and therefore do not require framing material. The panels also come in a variety of sizes, reducing the amount of cutting required onsite.

	The panels also reduce the amount of finishing work that is required, because they are supplied as finished pieces such as coving at the wall-to-ceiling and wall-to-floor connection points. The use of standardized components can shorten the design phase for modular panel projects, compared with the time required by traditional approaches.  Significant engineering knowhow is still required, however, to make modular construction work.

	Because this approach reduces the amount of onsite construction required, these projects can be completed faster than a traditional construction approach, with project timelines that can range from 18 to 36 months depending on the size of the project.

	Prefabricated cleanrooms are modules that are built offsite that provide clean space including floors, walls, ceilings, windows, and doors in appropriate finishes. In some instances, such modules include their own mechanical space where automation equipment such as programmable logic controllers (PLCs), heating, vacuum and air conditioning (HVAC) equipment, fire suppression systems, utility connections, etc. are housed. 

	The cleanrooms are built entirely at a vendor’s manufacturing site. At the close of the manufacturing process, they are factory tested. After this testing, they are shipped and moved into the ultimate host facility. Due to the utility infrastructure within the cleanrooms, connections to the host facility are minimal,  and infrastructure within the host facility is also minimal. High level advantages include being able to build the modules rapidly without the need for special permits, the lack of required infrastructure at the ultimate destination, the ability to move and repurpose the cleanrooms, and depreciating the cleanrooms on an accelerated basis as process equipment, as opposed to the traditional facility timeframe (6). 

	Engineering expertise is required both for the cleanroom and the outer structure. Compared with the fairly standard cleanroom approach in most cases, however, there is less to engineer using this approach. 

	A leading architecture and engineering firm considered the amount of time required to build a 2000L monoclonal antibody (mAb) facility. The study considered three types of facility options: traditional, modular wall panel, and prefabricated cleanrooms. 

, the time differences among the three models are substantial, with prefabricated systems being much faster. For one manufacturer, using the prefabricated approach allowed the facility to be ready for operation 16 months after the start date (1) compared with 25 months for the paneled approach and 27 months for the stick-built approach. Construction of the prefabricated system solution was faster due, in part, to the fact that the cleanrooms were built in parallel with the building or refurbishment of the host facility (

). Such an approach is not possible with the other construction options, because the structures must be constructed after the host facility is substantially complete.
	

	An additional factor that also saves time, which this study did not consider, is the fact that prefabricated cleanrooms use standard designs. Instead of creating new designs from scratch, these standard designs can be used to reduce the design time and cost effort. 

	As noted, some standardization of cleanroom options can reduce the time required to build out a facility, using a prefabricated approach. But could standardization also lead to other advances as it has in other industries, enhancing speed to market without sacrificing quality or utility? 

	Procter and Gamble showcased an example of what might be possible for pharma at the International Society for Pharmaceutical Engineers’ (ISPE’s) 2014 Annual Meeting. The presentation discussed the use of standardized shell buildings that could be erected in weeks. Parallel to the construction of the building shell, prefabricated manufacturing modules were assembled and then added into the shell when it had been completed. 

	Mixing and matching, in synch with demand

	The prefabricated manufacturing modules were standardized and could be mixed and matched into the shell building. Depending on demand, they could also be exchanged, in case regional demand for one product rose or fell. Standardizing the system created budget and timeline robustness, as well as scaling effects to reduce costs (7).

	Another example comes from the automotive industry. In automobile manufacturing today, the core product is standardized, but also configurable, with options that are related to aesthetics or performance. Standardizing the core product keeps costs low and delivery times short, and adding options to that core does not increase either factor significantly. 

	If carmakers sought to design each vehicle anew, with no standard platform in place, costs would be astronomical and the efficiency of production and delivery would be exceedingly low. The question is: Can the biopharmaceutical industry mirror these two examples, especially in the cell and gene therapy space? Why shouldn’t it be possible to standardize these processes, unit operations, and surrounding cleanroom infrastructures all the way to the facility platform? 

	Why has such standardization been achieved, or even become the norm, in other industries but not the biotech industry? Is it because the engineering or processing needs are that much more sophisticated than other industries, or is it because the supplier infrastructure in the biotech industry prefers self-preservation to innovation? 

	More to the point, couldn’t a prefabricated, standardized but configurable cleanroom infrastructure solution be provided much like a car, bioreactor, or filler? Shouldn’t such infrastructures be available from a catalogue where they can be chosen for delivery? And is there any reason why that cleanroom couldn’t be delivered in 48 hours? 

	Amazon and FedEx deliver hundreds of thousands of items in two days. Mobile homes can be ordered. Contractors build and sell “spec” houses every day. So why can’t biotech companies choose from available options instead of re-inventing the wheel every time they have to build a new manufacturing facility? 

	The goal for the industry should be to configure a cleanroom on-line or at a showroom and get it delivered consistently with the same quality at a fixed price and timeline. End-users who adopt this standardization approach will gain desired speed, with tremendous flexibility and greatly reduced costs. That can only be good for the industry and, ultimately, for the patients it serves. 

Efficient, Flexible Facilities for the 21st Century

Continuous Solid-Dosage Manufacturing Platform Nears Prototype Installation

www.pharmamanufacturing.com/articles/2012/008/

, 2 (1), pp.12-14 (2013).
	5. P. Almhem, “

, July/August, pp. 28-30 (2014).
	6. M.W. Jornitz, “

Podified Manufacturing Facilities and Risk Mitigation of Aging Pharmaceutical Facilities


	Supplement: Outsourcing Resources
	Vol. 42
	August 2018
	Pages: s26–s28

	When referring to this article, please cite it as S. Backstrom and M. Jornitz, " Reducing Cleanroom Complexities and Cost," 

	Sidney Backstrom is vice president of business development (sbackstrom@gconbio.com), and Maik Jornitz is president and CEO, G-CON Manufacturing, Inc. 

Why shouldn’t biopharmaceutical manufacturers be able to leverage standardized construction practices to improve time to market?

Reducing Cleanroom Complexities and Cost

A year’s worth of FDA warning letters suggest that API and finished drug manufacturers should strengthen their approach to continued process verification.

	In 2011, when FDA revised its process validation guidance (1), it introduced the idea that validation must continue throughout the lifetime of a pharmaceutical product. FDA advocated three stages:

		Process design, using the principles of pharmaceutical quality by design (QbD)

		Process performance qualification (PPQ)

	Pharmaceutical manufacturers have been developing novel methods and solutions to support this new definition of process validation, and FDA has been encouraging science- and risk-based approaches for all three stages.

	Other regulatory agencies have also embraced the lifecycle approach to process validation, including the International Council for Harmonization (ICH) in its Q8, Q9, and Q10 Questions and Answers (R4) (2) guidance for industry. ICH views the entire product lifecycle as: development, technology transfer, manufacturing, and discontinuation (3). 

	Best practices call for approaches such as:

		Taking a design-of-experiments (DoE) approach to product development, sampling, and testing plans

		Using data-driven statistical tools for CPV. 

	The European Medicines Agency’s (EMA) 2014 process validation guidance, the World Health Organization’s 2015 Appendix 7, and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) 2015 Annex 15 all reflect the expectation that process validation should continue throughout the lifecycle of the process. Pharmaceutical manufacturers would do well to take an integrated lifecycle approach to process validation that works across multiple markets. 

	As the industry’s approach to lifecycle-based process validation has evolved, some companies now divide Stages 1, 2, and 3 into the following: 

		Stage 1A – Product Development, Stage 1B- Scale Up

		Stage 2A – Equipment/System/Utility/Facility Qualification, Stage 2B – Process Performance Qualification

		Stage 3A–a heightened verification program for newly introduced molecules and Stage 3B-routine continued process verification.  Implementing the process validation lifecycle approach globally demands that pharmaceutical manufacturers be especially careful in selecting the most effective statistical tools and Stage 3 strategies (4).

	A good knowledge-management strategy is essential, starting from Stage 1 to Stage 3 of the process validation lifecycle. Scientifically identifying sources of variability requires a robust QbD-based product development program along with a Stage 3 CPV program that allows for continual gathering of product and process knowledge. 

	Process drifts, or times when the process fails to perform at its best, trigger identification of sources of variability, ensuring improved control and allowing for continuous improvement. Ongoing collection of product and process knowledge is required for continuous improvement, and also to improve the development process for similar products (5).

	This article asks how well pharmaceutical manufacturers have been addressing new process validation requirements by analyzing FDA warning letters (WLs) from 2017 to date. The goal of this study is to understand which parts of the process may need to be strengthened in order to improve regulatory compliance and minimize risk.

	Since the FDA process validation guidance is applicable to drug substances, drug products, and biologics, insights from WL assessments (6) can provide ample supporting evidence to justify an integrated approach to process validation.

	For this research, 85 FDA WLs issued in 2017 and 2018 were analyzed, 61 for 2017 and 24 for 2018. Inadequacies were found in both API and finished pharmaceutical facilities, but occurred mainly in finished pharmaceutical facilities, as outlined in 

	In 2017 and 2018 FDA warning letters, process validation issues were more frequently noted in finished pharmaceutical than in API manufacturing sites, with noncompliance increasing by 5% between 2017 and 2018.  Of the warning letters analyzed, 40% contained observations that were related to process validation. Since 2017, 29 finished formulations sites have been found to be noncompliant with process validation approaches, and the number of facilities that were out of compliance increased in 2018 (

	Approximately 20% of the API sites that received warning letters during the period under examination had problems that were related to PV noncompliance. Two of the five warning letters related to API sites cited inadequate process control monitoring, resulting in the inability to ensure stable manufacturing operations and consistent drug quality. 

	Regulators who had inspected the facilities identified the strong need for engaging a qualified consultant to assist the organization in meeting current good manufacturing practice (cGMP) requirements. Another warning letter cited inadequacies in the sampling plan during the PPQ stage. It highlighted the need for a statistically sound sampling and testing plan as stipulated in the PV guidance. 

	In addition, inspectors found that the manufacturer was not monitoring critical process parameters adequately. In a third API process-related observation, the regulator cited that the organization did not demonstrate adequate process understanding, which includes failing to consider operating parameters for critical operations. Regulators focus on all three PV stages during an inspection. In its inspection, FDA staff called for hiring external help, especially when the manufacturer could not implement the Stage 3 CPV program independently.

	In 14 warning letters, regulators noted the manufacturers should follow FDA process validation guidance for the process validation elements. Additional assessment revealed a consistent pattern. As the warning letters make clear, the following are very important in process validation:

		Having a data-driven and scientifically sound process-validation program that appropriately identifies sources of variability

		Performing process performance qualification studies

		Establishing an ongoing program for monitoring process controls to ensure stable manufacturing operations and consistent quality. 

	The problem that inspectors most often found at finished pharmaceutical facilities was failure to establish a continued process verification program to identify sources of variability.  This gap was cited in 17 warning letters. Eight of the citations pointed out that the manufacturer did not perform PPQ studies.

	Observations about Stage 3 CPV-related operations were found across prescription, over-the-counter (OTC), and sterile manufacturing sites alike. The regulator used consistent language and quoted from the 21 US Code of Federal Regulations (CFR) Part 211, Subpart F- Production and Process Controls, Sec. 100–Written procedures, deviation (a). The 21 CFR 211.100 (a) section states: “There shall be written procedures for production and process controls designed to assure that the drug products have the identity, strength quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit” (7).

	There were five instances in which regulatory inspectors noted a failure to prevent microbial contamination in sterile manufacturing, including lack of established procedures as well as inadequate validation of aseptic manufacturing processes and sterilization. The drug manufacturer is required to implement elements of cGMPs for sterile drug products using aseptic processing. Additional observations that were cited included deficiency in performing smoke studies for classified areas, which include Restricted Access Barrier Systems (RABS).

	For this assessment, warning letter trends were analyzed to provide manufacturers with some insight into regulators’ objectives. Both API and finished pharmaceutical manufacturing sites are consistently being cited for violating best practices in recent process validation guidance.  Analysis of the observations confirms the need for a well-defined continued process verification program that continually monitors the sources of variability and enables an organization to embark on continuous improvement initiatives prior to encountering quality issues. 

	Regulators around the world are encouraging the use of data-driven, science-based approaches to process validation. In some cases, inspectors have suggested that manufacturers enlist the help of qualified consultants, which will require that they invest time and resources in establishing a Stage 3 CPV program and supporting team. 

	More biopharmaceutical manufacturers are now striving for data-driven approaches to Stage 3 process validation, and solution providers are offering integrated software to help manage such programs. The convergence of regulatory guidance, current inspection trends, and the emergence of solutions allows existing monitoring programs to be enhanced, but there will likely be a need for additional elaboration and training across quality, operations, R&D, and regulatory functions. 

	Ensuring that process validation programs and training bridge different functional groups within the organization helps all groups understand their role in enabling continuous improvement. This kind of approach will help manufacturers prevent process failures, and can also help guard against having people overreact to individual events. It can also ensure that they catch sources of variability that might otherwise go undetected. 

: This article was prepared by the authors in their personal capacity. The opinions expressed are their own and do not reflect the view of their employer, government, or any agency with which they are affiliated.

Guidance for Industry: Process Validation-General Principles and Practices

, (Silver Spring, MD, Jan 2011).
	2. ICH, 

Pharmaceutical Technology-08-01-2018

Classifying Potent and Highly Potent Molecules

Designing Combination Products

CMO Roundup: Expansions for Biomanufacturing

Small-Molecule Contract Services Update

What Ifs in the Five-Year Plan

Reducing Cleanroom Complexities and Cost

Lifecycle-Based Process Validation Emphasizes the Need for Continued Process Verification

How to Address Roadblocks During Technology Transfer: A CDMO’s Perspective

Pharmaceutical Technology, 2018 Outsourcing Resources (PDF)