Amber Lowry is an associate editor at UBM plc.

Amber Lowry

As focus on the development and manufacture of biologics increases, so does the necessity for competent cold-chain technologies. Over the past several months, manufacturers have released an assortment of products and efforts to preserve the physical integrity of temperature-sensitive pharmaceutical products.

	Softbox, a provider of temperature-control packaging solutions, released new pallet and parcel shipping systems that include the Tempcell ECO, Tempcell MAX, and Silverpod MAX (1).

	The Tempcell ECO is a recyclable parcel shipper made from recycled corrugated paper materials. The ECO uses the company’s Thermaflute patent-pending design and is qualified against International Safe Transport Association (ISTA) 7D summer and winter profiles and is able to control different temperature ranges, including 0 °C to 30 °C products.

	The Tempcell MAX is a single-use, high-performance phase change materials (PCM) parcel shipper that is qualified to ISTA 7D test profiles and maintains up to 96 hours of thermal protection. The MAX integrates the company’s SilverSkin radiant barrier to enhance thermal performance and uses next-generation recyclable Pharmacool MAX PCM coolants.

	New to the company’s Silverpod pallet shipper range is the Silverpod MAX, a high-performance PCM pallet shipper that incorporates PCM coolants that enable safe storage before and during shipping. The Silverpad MAX also has a SilverSkin reflective radiant barrier for enhanced thermal performance and, like the Tempcell MAX, uses next-generation recyclable Pharmacool MAX PCM coolants.

	The previously mentioned shipping solutions were showcased at the IQPC Temperature Controlled Logistics (TCL) conference in London on Jan. 28–31, 2019.

	Additionally, the company also pre-launched two temperature control packaging systems at TCL-the AEON Metro and Clinipod-for the delivery of pharmaceutical clinical trials.

	AEON Metro is a reusable multi-drop delivery parcel shipper that enables cold-chain delivery without the need for temperature-controlled vehicles. The Metro has reusable PCM coolants that support up to 48 hours of multi-opening thermal protection. The Clinipod is a lightweight carry-home shipper built to facilitate the last-mile delivery of clinical trials to the end patient. Using the company’s reusable PCM coolants, it provides up to six hours of thermal protection in extreme temperature conditions.

	Also presented at the 2019 installment of the TCL conference was progress on pharmaceutical ocean-freight network Poseidon’s ‘Plug & Play’ model (2). Poseidon is an industry reform initiative created to improve the conveyance of pharmaceutical products by ocean transport. The initiative includes an independent network of pharmaceutical manufacturers, specialist freight companies, and pharma logistics suppliers joining forces to improve cost, safety, and sustainability of the cold-chain process.

	“Poseidon takes the form of a strategic supply network comprising a group of independent pharmaceutical manufacturers in conjunction with all the principal actors involved in transporting a pharma product by sea,” said Alan Kennedy, executive director at Poseidon, in a press statement. “Designed from the ground-up, it involves shippers, logistics companies, marine insurers, and product suppliers all being seated around the same table as equal partners.”

	According to the Poseidon team, state-of-the-art thermal management and real-time shipment visibility are central elements in the Poseidon model, but what sets this initiative apart is its integrated approach, which brings together all cold-chain parties to collaboratively address fundamental problems in pharma logistics. The team also states that in addition to a standard full-container-load operation, Poseidon will be testing a flexible shared-container service in 2019 to cater for smaller consignments and provide maximum flexibility.

	Poseidon completed Phase I of a large-scale proof-of-concept pilot project in 2018 and is currently in Phase II. According to the Poseidon team, this field validation project aims to examine cold-chain processes, test-out protective packaging, and verify consignment visibility and data capture and is the largest pharma ocean freight project of its type ever conducted. The project involves the monitoring of several refrigerated container-loads of high-value pharmaceutical products during both summer and winter intercontinental logistics operations, including multiple ocean and overland stages.

	The LOG-IC 360 Bluetooth Data Logger by American Thermal Instruments (ATI) provides accurate temperature and humidity readings along with safe, secure data retrieval and storage (3).

	The data logger allows for remote temperature excursion (thermal alarm) monitoring during product transport. Less than two inches by three inches wide, the device can read individual temperatures up to 300 feet from the unopened product. The lithium coin cell battery has a minimum one-year capacity, a temperature range of -20 °C to 70 °C, and relays data to Android, iOS, or any other Bluetooth-enabled device. 

	High-precision temperature accuracy is ± 0.25 °C, compared to other industry suppliers at ± 0.50 °C, the company reports. The logger tracks a humidity range of 0–80% relative humidity with communication certifications, which include Federal Communications Commission, Conformité Européenne (CE), and National Institute of Standards and Technology platforms.

	Global materials science company W. L. Gore & Associates has developed GORE STA-PURE Flexible Freeze Containers to protect high-value bulk drug substances from container breakage or leakage during frozen handling, which is typically a vulnerable stage in the product’s transport (4).

	The containers are constructed of a proprietary high-strength fluoropolymer material that is durable after freezing at -86 °C (-123 °F). In addition to durability, the container’s chemically inert, biocompatible, high-purity fluoropolymer composite film has a low extractables profile and offers users the convenience and scalability of a single-use system that efficiently uses freezer space, according to the company.

	1. Softbox, “Softbox Announces the Launch of New Innovative Temperature Control Packaging Systems,” Press Release, Jan. 24, 2019.
	2. Poseidon, “Poseidon Exposing its Unique Plug & Play Pharma Ocean-Freight Model in London,” Press Release, Jan. 14, 2019.
	3. American Thermal Instruments, “ATI Launches Innovative Electronic Data Logger for Cold Chain System,” Press Release, Sept. 18, 2018.
	4. W. L. Gore & Associates, “Gore to Launch GORE STA-PURE Flexible Freeze Containers at BioProcess International,” Press Release, Aug. 21, 2018.


	Vol. 43, No. 2
	February 2019
	Pages: 46–47

	When referring to this article, please cite it as A. Lowry, “Innovations Maintain the Cold Chain," 

Articles

Recent advancements in cold-chain technology offer improved transporting and storing of temperature-sensitive pharmaceutical products.

Innovations Maintain the Cold Chain

Over the past few months, contract manufacturing organizations (CMOs) and other contract service providers have expanded, invested, and acquired companies to increase pharmaceutical service offerings. The following news updates highlight such efforts.

MedPharm, a contract provider of topical and transdermal product design and formulation development services, announced the expansion of its center of excellence in Durham, NC (1).

	The $4-million expansion includes additional laboratory space for development programs and topical dosage formulation development services and performance testing on topical and transdermal pharmaceutical products. The investment in facility expansion and equipment will more than triple the existing footprint of the facility to 25,000 ft

	The company has also increased its liquid chromatography–mass spectrometry (LC/MS) capacity and the automation of sample handling. As part of the investment, MedPharm has installed the latest Waters LC-MS/MS for bio-analysis. This new model is equipped with the latest ultra-performance liquid chromatography for rapid separation and method development and offers mass spectrometry detection at picogram levels, according to MedPharm.

	“This expansion aligns with MedPharm’s strategy to keep increasing the sophistication and relevance of our proprietary 

human skin models and further increase our responsiveness to clients in formulation development, especially in ocular delivery,” said Eugene Ciolfi, MedPharm’s president and CEO, in a Jan. 11, 2019 press release. “The expansion complements the recent expansion we have completed in our facility at our headquarters in Guildford, UK, and reflects the positive demand for our services globally.”

Catalent, a provider of delivery technologies and development solutions for drugs and biologics, is set to invest $200 million in its biologics business to expand drug-substance manufacturing capacity and drug-product fill/finish capacity (2).

	Spanned over a three-year program, the investments will be carried out at the company’s biologics manufacturing sites in Madison, WI, and Bloomington, IN. The expansion includes the increase of mammalian cell-culture capacity at the Madison site, where the company will build-out two new suites, each with a 2 x 2000-L single-use bioreactor system, providing additional clinical and commercial production capacity at the 2000- or 4000-L batch scale as well as new laboratories. Work is expected to be completed by mid-2021 and will more than double Catalent’s commercial biomanufacturing capacity, the company reports.

	Additionally, the company will expand fill/finish capacity at the Bloomington site by 79,000 ft

, with both GMP and non-GMP capabilities. A high-speed flexible vial line, using both ready-to-use components and bulk filling at a filling speed of 300 units per minute, will be installed along with a high-speed flexible syringe/cartridge line with a filling speed of over 300 units per minute, and a fully automated vial inspection machine.

	In December 2018, Catalent also announced plans to invest $14 million in packaging capabilities at the Bloomington site (3). Construction is expected to be completed in February 2019, with installation and commissioning of new equipment to be phased throughout the year. The 15,000-ft

 expansion of the facility, acquired by Catalent in October 2017, will include five new packaging suites and a new quality control laboratory, creating approximately 36 new jobs at the site. 

	New equipment will include both a semi-automated and fully-automated top loading cartoner, an accessorized combination syringe assembly machine, an automated auto-injector assembly machine, and two semi-automatic visual inspection machines.

On Jan. 7, 2019, Fujifilm announced plans to invest approximately JPY 10 billion (approximately US$90 million) to expand its biopharmaceutical contract development and manufacturing organization (CDMO) business, Fujifilm Diosynth Biotechnologies (FDB) (4).

	Investments will include the addition of 2000-L single-use cell-culture manufacturing trains, cell-culture purification suites, and new microbial recovery suites to its existing facilities in North Carolina. These additions will reportedly increase cell-culture manufacturing capacity by approximately 25% and microbial capacity by approximately 50% at its North Carolina location. The company expects that the increased production capacity will be ready for cGMP manufacture by early 2020.

PCI Pharma Services (PCI), a provider of outsourced drug manufacturing, clinical trial services, and commercial packaging to the global biopharmaceutical industry, announced in a Feb. 5, 2019 press release that it plans to expand its bottling-line capacity at its commercial packaging site in Rockford, IL (5). The expansion will enable filling of an additional 100 million bottles per year at the site. Construction of the additional packaging suites began in March 2018 to add footprint for primary and secondary packaging operations equipped with high-speed tablet filling, cartoning, in-line serialization, and aggregation in support of increased customer demand. 

	PCI’s investment at the Rockford location is the latest in a series of capacity expansion initiatives across its worldwide network, including multiple facility enlargements, cold chain and ultra-cold storage extension, installations of additional packaging lines, and expansion of its serialization solutions. To further support its existing biotech infrastructure, PCI’s commercial packaging site in Philadelphia, PA recently announced a $20-million investment in commercial packaging, as well as expanded cold-chain capacity at numerous global locations.

Biopharmaceutical CDMO Rentschler Biopharma completed the acquisition of a manufacturing facility from an affiliate of Shire the company announced in a Jan. 3, 2019 press release (6).

	Under the terms of the agreement, Rentschler Biopharma will continue to manufacture for Shire at the site. The 93,000-ft

site is Rentschler Biopharma’s first manufacturing facility in the United States, located near Boston in Milford, MA with approximately 70 employees.

	“The acquisition of this modern facility fits perfectly with our strategy to further strengthen and secure our world-class CDMO position in a growing and changing market,” said Frank Mathias, CEO of Rentschler Biopharma, in the press release. “The US is a key market for Rentschler Biopharma, and this site gives us a firm foothold in this important area of growth, enabling us to better meet our clients’ needs.”

	“We will continue to make investments in our business to ensure we have the advanced technologies to remain an innovation leader in the field and the capacity to remain competitive and grow with our clients,” added Dr. Ralf Otto, COO of Rentschler Biopharma, in the release. “This includes future plans to qualify the Milford site as a multi-product manufacturing facility.”

. Cambrex, a provider of generic APIs, small molecule, and finished dosage form products and services, announced that it completed the $252-million acquisition of Avista Pharma Solutions, a contract development, manufacturing, and testing organization, from Ampersand Capital Partners on Jan. 3, 2019 (7).

	The transaction, announced in November 2018, strengthens Cambrex’s position as a small-molecule CDMO across the entire drug lifecycle, the company reports. Avista’s four sites in Durham, NC; Longmont, CO; Agawam, MA; and Edinburgh, Scotland, UK will be integrated into Cambrex’s global network, as well as its service offerings ranging from API and drug product development and cGMP manufacturing to stand-alone analytical, microbiology testing, and solid-state sciences. Cambrex now operates a total of 12 facilities worldwide and employs approximately 2000 people. This acquisition complements Cambrex’s acquisition of Halo Pharma in September 2018, which added formulation development and finished dosage manufacturing capabilities to Cambrex’s existing global API manufacturing network.

	“Acquiring Avista adds a full complement of early stage development capabilities to Cambrex’s larger scale capabilities for both APIs and finished dosage forms,” said Steve Klosk, president and CEO of Cambrex, in a company press release. “We are excited to start off 2019 integrating Avista into Cambrex’s global network of facilities. Adding Avista today and Halo Pharma in September significantly increases our customer base and funnel of projects, provides significant cross-selling opportunities and allows us to offer an integrated service offering for most small molecules from the pre-clinical stage through the commercial stage.”

	1. MedPharm, “MedPharm Announces Expansion of US Center of Excellence,” Press Release, Jan. 11, 2019.
	2. Catalent, “Catalent Invests $200 Million To Expand Biologics Capacity and Capabilities,” Press Release, Jan. 7, 2019.
	3. Catalent, “Catalent Invests $14 Million to Expand Biologics Packaging Capabilities Following Twentieth Commercial Drug Approval at Bloomington, Indiana Site,” Press Release, Dec. 3, 2018.
	4 . Fujifilm, “Fujifilm to Invest 10 Billion Yen in its Bio CDMO Business,” Press Release, Jan. 7, 2019.
	5. PCI Pharma Services, “Bottling Line Expansion to Support Customer Needs,” Press Release, Feb. 8, 2019.
	6. Rentschler Biopharma, “Rentschler Biopharma Completes Acquisition of US Manufacturing Site,” Press Release, Jan. 3, 2019.
	7. Cambrex, “Cambrex Completes Acquisition of Avista Pharma Solutions,” Press Release, Jan. 2, 2019.

	When referring to this article, please cite it as A. Lowry, “CMO Expansions and Investments," 

Suppliers set the tone for 2019 with strategic expansions, investments, and acquisitions.

CMO Expansions and Investments

Successful lot release testing for small-molecule drugs is dependent on efficient analytical tools and practices. This article explores the analytics of this testing process with Natalia Belikova, PhD, Analytical Services director, and Gayla Velez, general manager, both at SGS Life Sciences in Lincolnshire, IL; and Mark Shapiro, director, Analytical Research & Development, and Daniel M. Bowles, PhD, senior director, Chemical Development, both at Cambrex in High Point, NC.

: What are some common analytical methods used for the lot release testing of small-molecule pharmaceuticals? Have there been any recent advances to these methods?

): First, we have to distinguish whether we are talking about small molecules as active pharmaceutical ingredients (APIs) or small molecules as finished drug products (tablets, capsules, injectables, etc.). 

	Most common panels for the testing of APIs will include basic tests such as loss on drying (LOD), residue on ignition (ROI), water content, identification, assay/purity, residual solvents, heavy metals, and microbial tests. Pharmaceutical manufacturing companies have to be absolutely sure that they are dealing with APIs with sufficient quality. If a contaminated or adulterated batch of API is used in production, it can result in a big financial loss, production delays, and a loss of reputation. 

	There has not been much advancement in traditional basic wet chemistry tests, which are very conservative and have not changed for the past several decades. Recently, heavy metals testing has moved from non-specific wet chemistry color reaction to inductively coupled plasma (ICP) technology that distinguishes between specific elemental impurities, and can quantify them at very low levels down to parts per billion depending on the element. That change was officially accepted by the United States and European pharmacopeias. Many assays are traditionally done by titration or using high-performance liquid chromatography (HPLC), and there is a trend of moving from titration to chromatographic techniques as HPLC is more specific. Additionally, there is a trend of moving from traditional HPLC to high-throughput ultra-high performance liquid chromatography (UHPLC), although that is still not common in compendial methods. 

	Another methodology that is used to confirm polymorphic structure (ID test) for small molecules uses X-ray powder diffraction. This allows an analyst to distinguish between small-molecule batches with the same molecular structure but different crystallinity. For the small molecules in drug product form, the most common test panel will include assay, related substances, water test (for lyophilized products), container-integrity test (for individually packaged products), dissolution (if applicable), and particulate matter (for injectable products).

): As a manufacturer of small-molecule APIs, all the batches of products we make undergo rigorous analytical protocols to ensure their quality. Depending on the type of molecule, we would generally use either HPLC or capillary gas chromatography (GC). Each method gives us the option to use various detection modes: for HPLC, there are ultraviolet, charged aerosol detection (CAD), a mass spectrometer or a triple quadrupole mass spectrometer (TQMS); and for GC, there are flame ionization detector (FID), electron capture detector (ECD), thermal conductivity detector (TCD), or again, a mass spectrometer. 

	We would also use other techniques such as inductively coupled plasma-mass spectrometry (ICP-MS) to ensure there were no elemental metal or inorganic impurities, as well as infrared spectroscopy and nuclear magnetic resonance (NMR). Additionally, we would test water content using Karl Fischer (KF) titration, and undertake any appropriate 

) tests, as well as analyzing particle size distribution, while also using X-ray powder diffraction to confirm that we have produced the correct polymorph. 

	In terms of advances, developments in HPLC in terms of porous shell columns and shorter columns, as well as the introduction of UHPLC across our sites, have shortened method times, and increased the efficiency of the analysis we undertake. The greater sensitivity that is also possible with modern mass spectrometers, as well as the increased use of CAD for non-UV active components, has also improved the ability and speed of analytical departments to both develop methods and undertake quality control (QC) analysis.

: Can you walk us through your small-molecule lot release testing procedures?

): For any molecule we manufacture, there will be a predefined procedure that contains all the information pertinent to its release, including specifications, methods, and any outsourced testing necessary. Once a batch is made, a sample is submitted to the QC team along with a material release form which tracks the data associated with the sample throughout the analytical process. An analyst is assigned the sample who will ensure the testing is carried out in accordance with its needs, and when completed the data are reviewed and verified to ensure compliance with all specifications. A certificate of analysis is then generated by the quality analysis (QA) department which then releases the material to the customer.

): As a contract lab, we rely on our individual clients’ needs, and usually they will provide us with a list of tests and specifications. If the small molecule is known and has a compendial monograph for it, we will follow procedures described in the monograph, but if the small molecule is new and not yet published in a compendium, our lab will offer to develop and validate methods for release testing. 

	All results generated in the laboratory have a thorough QC data review. Our quality assurance department also independently verifies all data packages prior to releasing the results, and our final ‘product’ is the certificate of analysis (CoA) that lists all tests performed and the results of each test.

: What are some products/instruments that have been recently incorporated into your small-molecule lot release testing procedures? How are these products improving testing quality and analytical capabilities?

): For the past five years, our laboratory in Lincolnshire,

	IL has extensively used Pinnacle PCX, a post-column derivatization system from Pickering Laboratories that allows us to perform analysis of amino acids for individual raw materials and small peptides. This instrument replaced thin layer chromatography (TLC) tests used in the past to monitor ninhydrin positive substances. HPLC technology is more specific than TLC, has better sensitivity, is faster, and costs less. Additionally, our laboratory has an X-ray powder diffractogram D2-phaser from Bruker that is used extensively for the identification of polymorphic form of small molecules. It also allows us to evaluate the purity of an API (qualitatively) and confirm that the polymorphic structure of API does not change when an API is incorporated into the final drug product during the manufacturing process. This methodology is very useful when clients ask us to evaluate if extensive storage (under International Council for Harmonization conditions or accelerated studies) affects the polymorphic form of an API as well. We also use Acquity H-Class UPLC systems from Waters for method development/validation and release testing of various client products. The use of UHPLC technology results in much shorter runs/higher throughput, better resolution between peaks, and higher sensitivity than traditional HPLC. 

	Other analytical equipment that we extensively utilize for routine small-molecule testing are: differential scanning calorimeter (DSC) for melting point (ID test); thermogravimetric analyzer (TGA) for ID and water test; elemental analyzer (CHNS/O) to confirm carbon/hydrogen/nitrogen/sulfur composition; and a Malvern Mastersizer 2000 to evaluate particle size distribution.

): The use of a TQMS alongside HPLC allows the sensitive and specific analysis of potential genotoxic impurities (PGIs) to sub-1 ppm level. ICP-MS allows us to test for elemental impurities as per the new 

<233> inhouse, and we have an autosampler on this instrument to allow us to undertake efficient method development and validation. Our use of coulometric oven KF reagents removes the dependence on the solubility parameter with the traditional direct KF. This can be critical in early-phase molecules where a small change in production parameters can result in large changes in solubility, resulting in the inability to perform direct KF in the qualified solvent.

: What are some best practices for conducting small-molecule testing?

): The pharmaceutical industry is highly regulated, and so as analysts we must adhere to these regulations by using appropriate, qualified, and verified or validated methods to ensure product and patient safety at all times. At Cambrex, we have clear and effective standard operating procedures laid out to ensure we can maintain a proper compliance stance at all stages, in line with good manufacturing, distribution, and laboratory practices.

	Internally, these include the development and writing of clear, safe procedures that can be easily and effectively executed by all QC staff, and we encourage open communication between disciplines (manufacturing, QC, and QA) throughout the process of method development. Our testing procedures are passed from the analytical R&D team to the QC department through an intermediary validation stage to provide enhanced method robustness. During the QC stage of lot release, we parse the testing across a number of colleagues to enhance the throughput and efficiency of the process.

): Our facility in Lincolnshire, IL has recently been expanded to accommodate the increasing demand in both chemistry and microbiology/sterility testing. If a client sends us a sample for both (chemistry and microbiology/sterility) release testing, then we often ask clients to send samples in multiple vials, so that each department can work with its own sample to run tests concurrently. Otherwise, the microbiology/sterility department will work with a sample first under aseptic conditions and then all chemistry tests will be performed. 

	For hygroscopic materials, our standard practice is to perform a water test first (in a low humidity-controlled environment), so the sample is not compromised with possible moisture uptake. For the tests that require a relatively long test procedure (for example, loss on drying for constant weight or residue on ignition to constant weight), we coordinate between different analysts on different shifts so we have workflow continuation and can deliver results to the clients in a timely manner. 

	Highly toxic, potent compounds and controlled substances require special handling and safe disposal, which SGS offers to its clients as a service.


	Vol. 42, No. 10
	October 2018
	Pages: 46, 50–51

	When referring to this article, please cite it as A. Lowry, "Lot Release Testing Analytics for Small-Molecule Drugs," 

In this article, industry experts explore efficient analytical practices and products for small-molecule lot release testing.

Lot Release Testing: Analytical Practices and Products for Small-Molecule Drugs

Experts weigh in on up-to-date analytical procedures for the lot release testing of small-molecule pharmaceuticals.

Lot Release Testing Analytics for Small-Molecule Drugs

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," 

Pharmaceutical Technology Outsourcing Resources Supplement

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

Small-Molecule Contract Services Update

Fill/finish processing is one of the most crucial operations in biopharmaceutical manufacturing. Considering how much is at stake once a product reaches the fill/finish manufacturing stage, it is important to seek the most up-to-date technologies for this process. This article highlights a sampling of recently introduced equipment, products, and systems are designed to streamline the fill/finish operations.

Pharmaceutical Technology’s Biologics and Sterile Drug Manufacturing 2018

 Biologics and Sterile Drug Manufacturing 2018

	When referring to this article, please cite it as A. Lowry, " New Technologies Streamline Fill/Finish Manufacturing," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 2018 

Recent technological advances help streamline the fill/finish manufacturing process.