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

Susan Haigney

	Robert Iser, vice-president of PAREXEL Consulting, spoke with 

 about the role quality agreements play in outsourcing.

PTE: What is a drug company’s responsibility when it comes to ensuring the quality and safety of products or ingredients manufactured at a contract facility?

 Although a drug company (or an application sponsor or marketing authorization holder) is ultimately responsible for ensuring that products available for patients and caregivers meet quality and safety expectations, the assurance of quality and safety of products and ingredients manufactured at a contract facility is a shared responsibility between the drug company and any contracted facility. Both parties must adhere to the expectations set out by the appropriate regulations and guidance to ensure that the products are manufactured in accordance with current good manufacturing practices (CGMPs), meet the necessary quality standards, and are safe and effective throughout a product’s lifecycle.

	As noted in the current FDA [US Food and Drug Administration] guidance on quality agreements (1), ’when all parties clearly understand their CGMP-related roles and manufacturing responsibilities, the owners who use contract facilities, contract facilities that provide services to owners, and, ultimately, patients who take the drugs manufactured under these arrangements may benefit in many ways … each party engaged in the manufacture of a drug is responsible for ensuring compliance with CGMP for the manufacturing activities it performs.’ This demonstrates the importance of putting together a sound quality agreement and clearly defining roles and responsibilities of the company and the contract facility.

PTE: What are the most important aspects of a quality agreement?

 There are a number of important aspects for quality agreements between a drug company and a contract manufacturer. It is vital that the following aspects are clearly stated and agreed upon:

		The CGMP-related roles and responsibilities of the company and the contract manufacturer, including final approval for manufacturing activities

		How deviations and out-of-specification results will be investigated, communicated, and resolved

		How changes that may need to be made to the manufacturing process, equipment, analytical methods, specifications, etc., are managed.

	It is important to consider these aspects, along with other recommendations found in current guidance, when developing and implementing agreements with contract facilities.

PTE: What are the European expectations regarding quality agreements?

The European Commission published a revision to the European Union Good Manufacturing Practices (GMPs) (Chapter 7) (2), effective in 2013, to provide expectations for outsourced GMP-regulated activities. The revised GMP guide includes many of the same topics as found in the current FDA guidance for industry including roles and responsibilities of the contract giver (the drug company) and the contract acceptor (the contract facility), assessment of a facility to carry out outsourced activities, communication of information that is necessary to carry out the outsourced activities, change control expectations, etc. A company looking to enter into a quality agreement should utilize this guide. 

PTE: What are FDA’s expectations regarding quality agreements?

 FDA published a final guidance for industry in November 2016 on quality agreements with contract manufacturers (1). The guidance was developed as a collaborative effort with the Centre for Drug Evaluation and Research (CDER), the Centre for Biologics Evaluation and Research (CBER), the Centre for Veterinary Medicine (CVM), and Office of Regulatory Affairs (ORA) and lays out the current thoughts and expectations that FDA has for quality agreements. It is strongly recommended that companies refer to this guidance when initiating a new quality agreement or if they are reviewing an existing quality agreement with a contract facility. 

	It should also be noted that ICH [International Council for Harmonization] Q7 (3) includes helpful information regarding quality agreements with API manufacturing sites, which is augmented by FDA’s quality agreement guidance. Companies developing combination products should review the expectations found in the guidance on Current Good Manufacturing Practice Requirements for Combination Products, as it relates to contract facilities and quality agreements (4).

PTE: Do regulatory agencies want to see copies of quality agreements when performing inspections? 

 Per FDA’s current guidance on quality agreements, ‘quality agreements may be reviewed during inspections,’ and current regulations in the United States and Europe, as well as other regions, include expectations for the outsourcing of manufacturing activities. As such, companies that are being inspected by a regulatory agency should have available any applicable quality agreements so that they may be provided to the investigator/inspector upon request. 

PTE: What mistakes are companies making when drafting quality agreements?

 There are some common mistakes that occur when companies are drafting quality agreements. First, roles and responsibilities of the drug company and the contract manufacturer are not always clear, especially when it comes to stating and agreeing on the quality unit’s responsibilities. Second, some agreements are interpreted in a manner that deviates from CGMP expectations (e.g., a contract manufacture interprets that they do not need to perform an investigation of an out-of-specification result that they generate since the drug company is responsible for release of commercial batches), which may lead to observations being cited during an inspection. Third, a mechanism to periodically assess and revise-if necessary-the agreement is not always included in agreements. Lastly, some quality agreements include commercial contract or business aspects and should only focus on quality management aspects as laid out in current regulations, such as US 21

(CFR) 211 (5) or guidance documents such as ICH Q7 (3) or Q10 (6). Additional helpful information on avoiding these mistakes can be found in FDA’s current guidance for industry (1).

PTE: How can drug companies and contract manufacturers create quality agreements that clearly outline each company’s responsibilities?

 The best way for drug companies and contract manufacturers to create quality agreements that clearly outline each company’s responsibilities is to follow the recommendations for roles and responsibilities that are found in current guidance documents. Current agency documents clearly lay out expectations for documenting roles and responsibilities that are directly linked to the quality unit responsibilities included in CGMPs; and pharmaceutical quality system aspects found in health authority guidance and ICH guidelines.

PTE: Can you give a real-world example of when a lack of a quality agreement or a poorly-written quality agreement led to a FDA 483 and/or warning letter? 

 It is important that a quality agreement between a drug company and a contract facility clearly defines roles and responsibilities related to CGMP activities. It is equally important, as stated in the FDA guidance, ‘that quality agreements cannot be used to delegate statutory or regulatory responsibilities to comply with CGMP.’ It is likely that FDA would cite a company for deviating from CGMP expectations due to adherence to an inadequate quality agreement that violate the tenets of the GMPs. 

	A real-world example of a [FDA] 483 observation related to quality agreements is a contract testing facility being cited for not following a quality agreement regarding the destruction of remaining samples with the authorization of the contracting company. This ties back to the importance of establishing clearly defined roles, adhering to the roles under an agreement, and how it fits with the CGMP expectations.

	FDA guidance further states (as part of case examples), ‘no matter whom tests the products, the owners’ quality units are ultimately responsible for ensuring that the products are manufactured in accordance with CGMP. A quality agreement does not change that. FDA could cite the owners … for failing to evaluate, qualify, audit, and monitor their contract facilities.’ 

	A recent example of a quality agreement citation in a warning letter (7) was related to a quality agreement with the firm’s contract manufacturer that didn’t include provisions for sterilization processing along with other quality agreement provisions that were not being routinely followed. Although this warning letter was related to a device and should follow the purchasing controls expectations found in 21 CFR 820.50 (8), it also shows that clarity around roles and responsibilities and adherence to an approved quality agreements are important aspects that need to be considered when a company develops and implements a quality agreement with a contract facility, and may be assessed while an FDA investigator is on site. 

	Companies that are looking to develop combination products should consider how the current 21 CFR Part 4 regulations (9) impact their quality system and operations and are encouraged to read the current FDA guidance on GMPs requirements for combination products (4) for further information as the guidance includes language on entering into quality agreements, where ‘quality agreements may, for instance, specify expectations as to which facility will perform what activities and develop and maintain what documentation needed to demonstrate compliance with particular CGMP requirements … for example, an owner may contract for the manufacture of the final combination product with a contract manufacturing facility, and detail in the supplier agreements the CGMP responsibilities and approaches for that facility.’

	Overall, the best way to avoid inspectional observations that may lead to a warning letter is to initiate quality agreements that use the recommendations found in current health authority quality agreement or outsourcing guidelines, are reflective of CGMPs, and are part of an effective pharmaceutical quality system. 

Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry

 (CDER, CBER, CVM, November 2016).
	2. European Commission, 

EudraLex The Rules Governing Medicinal Products in the European Union

, Volume 4 EU, Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 7 Outsourced Activities (EC, 28 June 2012).
	3. ICH, 

Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products, Final Guidance

 (FDA, Silver Spring, MD, January 2017).
	5. 21 

Warning Letter FLA-15-30 to Ultroid Technologies, Inc.


	Vol. 30, No. 3
	March 2013
	Pages: 38-40

	When referring to this article, please cite it as S. Haigney, "Expectations in Quality Agreements," 

Articles

Robert Iser of PAREXEL Consulting answers questions regarding the regulatory expectations of quality agreements and how companies can ensure the quality and safety of their products.

Expectations in Quality Agreements

When it comes to outsourcing process validation of biologics, Abel Hastings, director of process sciences at FUJIFILM Diosynth Biotechnologies, says that the relationship between a contract development and manufacturing organization (CDMO) and sponsor is key in ensuring successful process validation.  “Customers that are open about their strategy, their data (good and bad), and their own strengths and weaknesses are most successful.” 
	
	

 spoke with Hastings about the specific challenges that arise in the process validation of biologics. 
	 

 What are the challenges of performing process validation during Phase III of biologics development? 

 A primary challenge we see is viewing validation as phase-specific. Ideally, process validation should be an extension of the development and refinement processes. To support this, develop a long-term strategy for implementing some of the validation-readiness tools in simple versions early in development so that a transition toward validation is less a change in course and more an acceleration of the project.
	
	

 What aspects of process validation should companies focus on when preparing to submit a biologics license application to FDA?
	
	

 As a CDMO, FUJIFILM Diosynth Biotechnologies has seen quite a variety of validation strategies. Some strategies are influenced by indication, regulatory designation, or client platform. Some common themes have shown themselves to aid in success of many of these projects. These themes include building clear attributeâparameter linkages, taking a systematic approach to validation, and leveraging data-driven risk management.

	Clear attributeâparameter linkage begins with a fundamental understanding of the molecule attributes, the measurement systems, and the potential points of variation and ambiguity therein. This knowledge of the measurement can then be applied to the process control strategy including any ambiguity and interaction with other attributes. A team’s focus on required control becomes increasingly clear by applying a logically mapped linkage from attribute to the controlling parameters.

	A systematic approach to validation that is based on consensus on both definitions and readiness criteria and is aimed at long-term commercial execution is recommended. We have refined our validation-readiness process to achieve a balance between lean efficiency and sustainability. This development required careful attention to details such as definition subtleties, systematic documentation linkage, quantitative assessment including leveraging previous data, and systematic manufacturing execution standards. This focus on mechanistically applying pre-built tools has proven to be successful with numerous clients efficiently driving their projects to success.

	We also recommend building an iterative and logical risk-management program that is based on data-driven decisions. As progress continues toward validation, teams can often be influenced by process history (both recent and past), which can lead to decision making with unintended consequences. We push teams to iteratively refine risk-management documents when new data come available thereby allowing them to make decisions based on data, even in the ‘heat of the moment.’ To guide teams, we have built a series of risk-management tools that range from simple and focused on one problem to large and involved FMEA [failure mode and effects analysis]. This focus on regularly reviewing and documenting risk and data evolution has expedited project execution in a reliable manner.

What protocols or tools are used in process validation of biologics compared with solid-dosage drugs?

 Biologics, when compared with solid-dosage product, can be a sea of parameters and attributes, many with a high degree of variability. We have a systematic approach to process validation that draws on experience from more than 300 molecules; this allows us to focus attention on what matters most. We first begin with high-level process mapping intended to focus attention on parameter-attribute pairings. The next step, which includes smart use of a proprietary FMEA-like software tool, can help focus characterization and equipment adjustments to help improve process reliability. Finally, our platform quantitative assessment tool for parameter-attribute pairs confirms readiness for process validation. Taking this systematic approach, we have been successful in cutting through a large number of variables to reduce variation and ensure right-first-time success for validation campaigns with tight timelines.

 How can the data obtained during process validation be used elsewhere in the production cycle?

 Process validation should be designed to demonstrate the capability of the process to support commercial manufacturing. To this end, the data generated during process validation should be the forerunner to the commercial control charts. A primary question when reviewing an initial set of commercial data should be: how do these data compare with the expected variation from my validation-preparation activities? Ideally, we expect commercial manufacturing to flow seamlessly from validation, but due to the artificial-perfection that can accompany validation, some changes are expected. Recognizing these subtle changes, and mitigating them as early as possible, can substantially improve long-term manufacturing reliability.

 How can process validation help companies ensure their biologic’s supply chain is reliable?

 Process validation is not just about three batches in a row. It is about launching a reliable commercial process. This is why we design process validation campaigns around an expectation that sustained commercial supply must be planned for. 

	The quantitative pre-validation statistical guidelines and systematic tool-sets we use for validation-readiness have been developed and built around the expectations that projects must have data to support sustainable commercial success. Approaching statistical risk management with more pre-validation runs is a common practice for many companies, but our [process validation] philosophy extends beyond that to leverage a large body of pre-existing data and rigorous process-agnostic testing to augment process-specific data. To our clients, this means improved knowledge of their supply chain expectations prior to process validation.

	When referring to this article, please cite it as S. Haigney, “Process Validation in Biologics Development," 

Process validation is an extension of biologics development processes. 

Process Validation in Biologics Development

	Outsourcing in the biopharmaceutical industry had a productive 2017. A flurry of acquisitions, an expansion of biotechnology needs, and a growth in new facilities and services offered were seen. The following are some of the highlights from the year in pharmaceutical outsourcing.

	Acquisitions were robust in 2017, with more than 25 companies making moves to gain new facilities and services. On Jan. 19, 2017, WuXi AppTec announced the acquisition of the biology-focused preclinical drug discovery contract research organization (CRO), HD Biosciences (HDB), which is headquartered in Shanghai and has operating facilities in Beijing and San Diego, CA. HDB offers plate-based pharmacology and screening capabilities, hit identification, lead discovery, and 

 pharmacology, among other services  (1). 

	Catalent completed the acquisition of Accucaps, the Canada-based developer and manufacturer of over-the-counter (OTC), high-potency and conventional pharmaceutical softgels, in February. The acquisition complements Catalent’s global OTC and prescription pharmaceutical softgel capabilities and capacity, adding a portfolio of products supplied to pharmaceutical companies in North America and two facilities offering integrated softgel development, manufacturing, and packaging (2). 

	In June, Lonza completed the acquisition of Capsugel S.A. from KKR for $5.5 billion in cash, including refinancing of existing Capsugel debt of approximately $2 billion. The acquisition is in line with Lonza’s strategy to accelerate growth and deliver value complementing its existing offerings and by creating market opportunities in the pharma and consumer healthcare and nutrition industries (3). 

	Lonza also acquired Micro-Macinazione (Switzerland), which provides micronization of active ingredients for the pharmaceutical and fine chemical industries, in July. The acquisition boosts Lonza’s micronization services at its existing micronization clinical and commercial manufacturing site in Quakertown, PA, which Lonza gained through its acquisition of Capsugel. Capsugel had gained the Quakertown facility in January 2016 when it acquired Powdersize, a contract manufacturer specializing in particle engineering. Lonza/Capsugel has since invested in significant additional capacity at the Quakertown site (4). 

	On Aug. 29, 2017, Thermo Fisher Scientific announced its completed acquisition of Patheon, a contract development and manufacturing organization (CDMO). Patheon will become part of Thermo Fisher’s laboratory products and services segment. The acquisition adds Patheon’s CDMO capabilities to Thermo’s clinical trials services and bioproduction technologies (5). 

	MilliporeSigma, the life-science subsidiary of Merck KGaA, announced in August an agreement to acquire Natrix Separations, an Ontario, Canada-based provider of hydrogel membrane products for single-use chromatography. This acquisition is part of MilliporeSigma’s efforts to drive next-generation bioprocessing. Specializing in the manufacturing of biopharmaceuticals through disposable downstream processing products, Natrix markets an anion exchange membrane and cation exchange membrane, and is developing additional products to enable a fully single-use, full-scale biological purification process (6). 

	Charles River Labs announced in August that it has acquired Brains On-Line, a CRO that provides data used to advance therapeutics for the treatment of central nervous system (CNS) diseases. With operations in San Francisco, the Netherlands, and Germany, Brains On-Line uses in vivo efficacy and pharmacokinetics testing to provide data necessary to advance potential CNS therapies through the development process (7). 

	In September 2017, Eurofins Scientific entered into an agreement to acquire EAG Labs, a scientific services company specializing in analytical and testing services to the agrochemical and pharmaceutical industries, from Odyssey Investment Partners. This acquisition by Eurofins Scientific was the latest move in a series of transitions for EAG Labs. In July 2015, EAG (Evans Analytical Group), a scientific services company that serves technology- and life-science-related industries, acquired Analytical Bio-Chemistry Laboratories (ABC Laboratories), which it later rebranded as EAG Labs in July 2016. With this acquisition, Eurofins Scientific aims to expand its reach in North America (8). 

	Catalent acquired Cook Pharmica, a Bloomington, Indiana-based biologics CDMO, in October. The acquisition strengthens Catalent’s position in biologics development and analytical services, manufacturing, and finished product supply (9). 

	CordenPharma entered into definite agreements to acquire the former Hospira Boulder high-containment API site from Pfizer, the company announced on Oct. 10, 2017. Located in proximity to the existing CordenPharma Colorado facility, Hospira Boulder produces APIs and intermediate products with specialized capabilities in small- to medium-scale highly potent and cytotoxic API manufacturing (10). 

	In January, GEA and Siemens AG announced a partnership to bring continuous manufacturing to the pharmaceutical and life-sciences industries by offering an integrated continuous tablet manufacturing line. Comprising GEA’s ConsiGma continuous manufacturing platform equipped with a Siemens Automation & Industrial IT solution, including Sipat for PAT Data Management, the combined technologies offer both wet granulation and direct compression for continuous tablet production (11).

	Catalent Pharma Solutions announced in July that it has entered into an exclusive long-term supply agreement to produce Pfizer’s Advil Liqui-Gels Minis (ibuprofen), which uses Catalent’s softgel platform OptiGel Mini technology. The new format, Advil Liqui-Gels Minis, delivers the formulation in a more concentrated fill, resulting in smaller capsules that are easier to swallow (12). 

	On Aug. 29, 2017, MilliporeSigma announced a collaboration with Angiex, a biotechnology start-up based in Cambridge, MA, to support the development of TM4SF1, Angiex’s lead oncology antibody drug candidate, to clinical use. The treatment is an antibody-drug conjugate (ADC) therapy for cancer against a vascular target. The collaboration is the first project to take place at MilliporeSigma’s biodevelopment center in Burlington, MA, set to open in October 2017. Angiex will be given end-to-end process development tools, education programs, and training by the company (13).

	In April, Catalent Pharma Solutions announced that it is increasing spray-drying capacity at its Pharmatek, San Diego, CA facility with the installation of an additional GEA Niro Mobile Minor unit. The expanded capabilities are being introduced in response to market demand for solubility enhancement solutions. To further support the development of spray-dried dispersions, Catalent has also installed a third Gerties Mini-Pactor, a high-pressure roller compactor, at its San Diego site (14). 

	EAG Laboratories announced on April 25, 2017 that the company is expanding a dedicated cell bioassay laboratory in Columbia, MO, tripling the footprint of its existing facility.  The expansion includes cell-culturing incubators and new instrumentation to increase capacity and assay throughput (15).   

	On May 8, 2017, Patheon completed an expansion project at its Greenville, NC manufacturing site. The company invested approximately $26 million to update its sterile pharmaceutical development service (PDS) suite and to build an integrated sterile PDS suite that is compliant with regulatory authorities. The PDS suite will manufacture sterile liquid and lyophilized drug products (16).

	In July, Avantor opened a new research center in Bridgewater, NJ, to help customers with a full range of upstream and downstream processes, from gene to protein expression through final formulation and drug delivery. The center includes life sciences and advanced materials research tools, including cleanroom facilities, multiple mass spectrometers, specially constructed bioreactors, and particle size analyzers to help companies with customized drug development (17).

	On August 30, 2017, Cambrex announced the expansion of its High Point, NC facility. According to the company, the investment is a response to customer demand for analytical development and validation services in support of cGMP products at the clinical stage (18).

	1. WuXi AppTec, “WuXi AppTec Acquires Biology Focused R&D Service Leader HD Biosciences,” Press Release, Jan. 19, 2017.
	2. Catalent, “Catalent Completes Accucaps Acquisition to Expand Softgel Development And Manufacturing Capabilities and Capacity,” Press Release, Feb. 16, 2017.
	3. Lonza, “Lonza Completes Acquisition of Capsugel to Create Leading Integrated Solutions Provider to the Global Pharma and Consumer Healthcare Industries,” Press Release, July 6, 2017. 
	4. Lonza, “Lonza Acquires Micro-Macinazione to Create the Global Leader in Micronization Capacity and Capabilities,” Press Release, Aug. 4, 2017.
	5. Thermo Fisher Scientific, “Thermo Fisher Scientific Completes Acquisition of Patheon,” Press Release, Aug. 29, 2017.
	6. MilliporeSigma, “MilliporeSigma to Acquire Natrix Separations to Advance Next-Generation Processing Capabilities,” Press Release, Aug. 28, 2017. 
	7. Charles River, “Charles River Laboratories Acquires Brains On-Line,” Press Release,  Aug. 7, 2017.
	8. Eurofins, “Eurofins to Expand its Presence in North America with the acquisition of EAG Laboratories,” Press Release,  Sept. 18, 2017.
	9. Catalent, “Catalent Expands Biologics Business With Acquisition Of Cook Pharmica,” Press Release,  Oct. 24, 2017.  
	10. CordenPharma, “CordenPharma Acquires Pfizer API Manufacturing Facility in Boulder Colorado,” Press Release,  Oct. 10, 2017. 
	11. Siemens, “Siemens and GEA Partner in Delivering Continuous Manufacturing to Pharmaceutical Industry,” Press Release, Jan. 9, 2017.
	12. Catalent, “Pfizer Partners With Catalent For The Manufacture Of Advil Liqui-Gels Minis,” Press Release, July 12, 2017.
	13. MilliporeSigma, “MilliporeSigma Collaborates with Angiex to Speed Clinical Readiness of New Cancer Therapy,” Press Release, Aug. 29, 2017. 
	14. Catalent, “Pharmatek Adds Further CGMP Spray Drying Capacity In Response To Demand For Improved Pharmaceutical Solubility,” Press Release, April 25, 2017. 
	15. EAG Laboratories, “EAG Laboratories Expands Cell Bioassay Laboratory to Enhance Biopharmaceutical Development Service Offering,” Press Release,  Apr. 25, 2017.
	16 . Patheon, “Patheon Completes Sterile Expansion Project at Greenville, NC Manufacturing Site,” Press Release, May 8, 2017.
	17. Avantor, “Avantor Opens New Life Sciences Research Center,” Press Release,  July 18, 2017.
	18. Cambrex, “Cambrex Invests In New Analytical Development And Method Validation Laboratory At Its High Point, NC Facility,”  Press Release, Aug. 30, 2017. 

	When referring to this article, please cite it as S. Haigney, “Pharma Outsourcing: A Year in Review," 

In a productive year, 2017 was filled with acquisitions, facility expansions, and new biopharma technology. 

Pharma Outsourcing: A Year in Review

Editor's Note: This article was published in 

	Outsourcing in the bio/pharmaceutical industry had a productive 2017. A flurry of acquisitions, an expansion of biotechnology needs, and a growth in new facilities and services offered were seen. The following are some of the highlights.

	Acquisitions were robust in 2017, with more than 25 companies making moves to gain new facilities and services. The following are some of the notable mergers and acquisitions of 2017.

	Recipharm completed the acquisition of Kemwell’s pharmaceutical businesses located in Bengaluru, India in February 2017. As part of the transaction, Recipharm also has a right of first negotiation to acquire Kemwell’s Indian biopharma business, which was not included in the transaction and will continue to be retained by the sellers. 

	The acquired business, Recipharm Pharmaservices Private Ltd, offers development services and commercial manufacturing of solid, semi-solid, liquid, and topical products. The development business provides formulation development, small-scale manufacturing for clinical trials, and analytical services (1). 

	In April 2017, Sartorius Stedim Biotech (SSB) acquired Umetrics, a specialized provider of data analytics software for development and manufacturing processes headquartered in Malmö, Sweden. SSB has been a cooperation partner of Umetrics since the end of 2012, distributing and co-marketing their software to players in the biopharmaceutical industry. Umetrics’ software has applications in critical process steps of biopharmaceutical manufacture and development, including cell culture processes and specific purification steps (2). 

	Lonza announced in August 2017 that it acquired Micro-Macinazione (Switzerland), a contract manufacturer providing micronization of active ingredients for the pharmaceutical and fine chemical industries, from Cross Equity, a Swiss private equity firm. The acquisition boosts Lonza’s micronization services at its existing micronization clinical and commercial manufacturing site in Quakertown, PA, which Lonza gained through its previous US$5.5-billion acquisition of Capsugel (US) in early July 2017 (3). 

	In September 2017, Roquette completed its acquisition of Itacel, an excipient division of Blanver, a Brazilian multinational company specializing in the development, manufacture, and commercialization of raw materials and drugs. The acquisition is part of a series of investments made by Roquette to position itself globally, according to the company (4). 

	PCI Pharma Services (PCI) acquired Millmount Healthcare, a pharmaceutical and healthcare contract packaging services provider, in October. Millmount provides services in blister packaging, bottling, and tub filling, as well as in late-stage customization and cold chain packaging services. The acquisition supports PCI’s efforts to expand its clinical trial service offerings. The addition of Millmount, based near Dublin, Ireland, will be PCI’s fourth acquisition outside of the United States in four years (5). 

	Sanofi and Lonza announced on 27 Feb. 2017 that they have entered into a strategic partnership to build and operate a large-scale mammalian cell culture facility for monoclonal antibody production in Visp, Switzerland. The strategic partnership enables Sanofi to react quickly to fluctuations in demand in a short timeframe, reinforcing their capability to launch biologic medicines and ensure consistent access for patients. It also provides Lonza with needed capacities to respond to growing manufacturing demands for large-scale mammalian cell culture-based therapeutic proteins (6). 

	Vetter and medical-device company Microdermics entered into a strategic cooperation agreement to develop innovative microneedle drug-delivery systems in May 2017. The companies have joined forces to enable the progress of the microneedle technology to late-stage process development and device manufacture on a commercial scale. Vetter’s primary role will be in the fill/finish aspect, but the it will also jointly conduct proof-of-concept studies on selected drugs and drug classes. Vetter will jointly design devices for testing, including how to integrate the microneedle technology into injection devices (7). 

	In June 2017, Rentschler Biotechnologie GmbH and Rentschler Fill Solutions GmbH announced a strategic partnership to provide new fill/finish facilities and solutions for biopharmaceutical products. Under the terms of the agreement, Rentschler Fill Solutions will serve as the exclusive partner for the fill/finish services of Rentschler Biotechnologie’s manufacturing projects. Rentschler Fill Solutions is owned by the Rentschler family and will begin operations in mid-2018. In addition to servicing Rentschler Biotechnologie’s clients, Rentschler Fill Solutions will offer its fill/finish services on a clinical as well as commercial scale to its own client base. The company will employ advanced aseptic filling technology at the Rentschler Fill Solutions facility in Austria (8). 

	Recipharm announced on 20 Sep. 2017 a long-term manufacturing pact with Roche. The pact will add 
	€35 million to Recipharm’s annual sales, matching more than 6% of the company’s current sales. Under the agreement, Recipharm will acquire a manufacturing facility located in Leganés, Spain, from Roche. The pact will also extend a collaborative opportunity to Recipharm’s nearby facility in Parets, Spain (9).
	In September 2017, Recipharm also signed a contract with Kancera for the development and manufacture of drug candidate KAND567 as a capsule formulation for oral administration. Recipharm will develop the preparation required for effective release of KAND567 from the capsules, as well as manufacturing the pharmaceutical product. The work will be performed at Recipharm’s development facility in Solna, Sweden (10).

	SGS announced on 12 Oct. 2017 that it has entered into a collaboration with biotech company Bavarian Nordic A/S to develop a new respiratory syncytial virus (RSV) challenge strain. The collaboration will assist with the advancement of a universal vaccine candidate designed to induce protective immune responses against both subtypes (A and B) of RSV. The project will build upon the results of Phase II trials conducted by Bavarian Nordic, and will include a human challenge study, which will be carried out at the SGS Clinical Pharmacology Unit in Antwerp, Belgium, using the new RSV challenge strain, once it has been fully developed and validated (11).

	MilliporeSigma announced in January 2017 the opening of a facility in Mollet des Vallès, Spain dedicated to the manufacture of meglumine, a US Food and Drug Administration (FDA)-approved excipient for pharmaceuticals and a component of medical imaging contrast media. The FDA-validated facility in Spain is solely dedicated to the production of meglumine, an amino sugar derived from glucose (12).

	On 26 Jan. 2017, Almac Group announced that as part of its ongoing global expansion, the company has secured a new facility in Dundalk, County Louth, Ireland. The new facility will be located at IDA Business Park. The new facility will increase the group’s European footprint by 32,000 ft
	2 (13).

	In February 2017, Novasep announced the opening of its new €11-million bioconjugation unit in the company’s Le Mans site in France. The 2000-m2 facility includes two flexible GMP production suites equipped with 10-L to 400-L vessels to support both clinical and commercial manufacturing of antibody-drug conjugates. The stand-alone facility is purpose-built and offers R&D services, quality control, and scale-up laboratories (14).
	Eurofins Scientific announced on 20 Mar. 2017 that it will be establishing a pharmaceutical chemistry and microbiology facility in Livingston, Scotland. The announcement follows Eurofins’ acquisition of Exova’s pharmaceutical, food, and water testing business in the United Kingdom and Ireland in July 2016, and the subsequent purchase of ILS’s pharmaceutical business in October 2016 (15). 

	FUJIFILM Diosynth Biotechnologies announced in September 2017 the opening of its new 10,000-ft2 cell culture Process Development Laboratories in Wilton Centre, Teesside in the United Kingdom. The laboratories were built through a JPY 1-billion (US$9-million) investment, part of a greater JPY 14-billion (US$130-million) expansion. The new laboratories will be dedicated to supporting activities in the Saturn mAb Platform (16).

	Sartorius announced on 13 Sept. 2017 the official opening of its new facility for the manufacture of laboratory instruments in the Sartorius Campus in the industrial zone of Grone in Goettingen, Germany. Approximately €42 million has been invested into the 25,000-m2 building, representing the largest single investment of the Sartorius Campus (17). 

	Sartorius Stedim Cellca is building a new €30-million Cell Culture Technology Centre at Science Park III in Eselsberg, situated at the northwestern scientific hub in Ulm, Germany, the company announced on 28 Sep. 2017. The new laboratory and office complex will approximately double the company’s space and is scheduled to be completed by the end of 2019 (18).

	1. Recipharm, “Recipharm Completes Strategic Acquisition in India,” PressRelease, 20 Feb. 2017.
	2. Sartorius Stedim Biotech, “Sartorius Stedim Biotech (SSB) Acquires Leading Biopharma Software Developer Umetrics,” Press Release, 3 April 2017.
	3. Lonza, “Lonza Acquires Micro-Macinazione to Create the Global Leader in Micronization Capacity and Capabilities,” Press Release, 4 Aug. 2017.
	4. Roquette, “Roquette Completes the Acquisition of Itacel and Reinforces its Ambition of Being a Leader in Pharmaceutical Excipients,” Press Release, 1 Sept. 2017.
	5. PCI Pharma Services, “Acquisition of Millmount Heathcare,” Press Release, 2 Oct. 2017.
	6. Lonza, “Sanofi and Lonza Enter into a Strategic Partnership to Establish a Large-Scale Biologics Production Facility,” Press Release, 27 Feb. 2017.
	7. Vetter, “Vetter and Microdermics Enter into a Strategic Cooperation Agreement,”
	Press Release, 31 May 2017.
	8. Rentschler Biotechnolgie, “Rentschler Biotechnolgie and Rentschler Fill Solutions Announce Strategic Partnership for One-Stop Solutions with New State-of-the-Art Fill and Finish Facilities,” Press Release, 13 June 2017.
	9. Recipharm, “Recipharm Signs Long-Term Manufacturing Agreement with Major New Customer and Acquires Facility in Spain,” Press Release, 20 Sept. 2017.
	10. Recipharm, “Recipharm and Kancera Collaborate to Manufacture Clinical Trial Supply,” Press Release, 14 Sept. 2017.
	11. SGS, “SGS and Bavarian Nordic to Develop a Novel and Differentiated Challenge Model for RSV,” Press Release, 12 Oct. 2017.
	12. MilliporeSigma, “MilliporeSigma Opens Production Facility Exclusively for Meglumine in Spain,” Press Release, 17 Jan 2017.
	13. Almac, “Almac Group Announces Further Global Expansion as it Secures New Premises in Republic of Ireland,” Press Release, 26 Jan. 2017.
	14. Novasep, “Novasep Opens €11M New Antibody-Drug Conjugate (ADC) Bioconjucation Unit,” Press Release, 23 Feb 2017.
	15. Eurofins Scientific, “Eurofins to Invest Millions in New UK Facility,” Press Release, 20 March 2017.
	16. FUJIFILM Diosynth, “FUJIFILM Diosynth Biotechnologies Opens Dedicated State-of-the-Art Cell Culture Process Development Laboratories in Wilton Centre,” Press Release, 12 Sept. 2017.
	17. “Sartorius Opens New Manufacturing Facility for Lab Instruments,” 

, 13 Sept. 2017.
	18. Sartorius, “Ground-breaking Ceremony for Sartorius Stedim Cellca,” Press Release, 28 Sept. 2017.

	When referring to this article, please cite it as S. Haigney, “Awards Recognize Industry Contributions," 

Outsourcing: A Year in Review

Innovation is key to any growing industry, and pharma is no different. Processes in the manufacturing of solid-dosage forms have stayed relatively the same for years. Innovations such as continuous manufacturing, however, have been making strides. In August 2016, FDA stated it was “working with drug makers in a new way to help the industry adopt scientifically sound, novel technologies to produce quality medicines that are consistently safe and effective-with an eye toward avoiding drug shortages” (1). As part of its commitment to fostering innovation, FDA created the Emerging Technology Program (2), which includes the Emerging Technology Team (ETT). The ETT has been working with companies on continuous manufacturing processes such as continuous aseptic spray drying and model-based control strategy. It has also been part of the development of ultra-long-acting oral formulations. 

	One novel approach that entered the market a couple of years ago was 3-D printing of solid-dosage drugs. It has been said that 3D-printed drugs may be useful for orphan drugs and/or personalized medications that require smaller production lots (3). The first 3D-printed drug approved by FDA in August 2015, however, is produced in commercial scale. Aprecia’s Spritam (levetiracetam) uses a specially developed platform to produce rapidly disintegrating high-dose drugs that are easy to swallow (4, 5). 

	But has FDA seen more from manufacturers on 3D printing, continuous manufacturing, or other technologies? 

 spoke with FDA’s Center for Drug Evaluation and Research (CDER) to catch up on what the agency has been seeing regarding solid-dosage manufacturing.

: Since the approval of the first 3D-printed drug in 2015, has FDA developed any further regulations or guidelines for the development of 3D-printed drugs?

: FDA’s Center for Drug Evaluation and Research established an Emerging Technology Team (ETT) to examine and advance applications for new technologies, including 3D printing. What makes this approach novel is that this dialogue can occur during early technology development prior to the submission of a drug application to FDA. Such early engagement enables FDA to proactively identify and address potential roadblocks and helps eliminate potential delay in the adoption of promising new technologies. 

	FDA issued a draft guidance in December 2015 entitled, 

Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base

. While not specific to 3D-printing, the guidance document provides recommendations to pharmaceutical companies on effective ways to work with FDA’s Emerging Technology Team. The document explains the ETT and provides specific recommendations to drug manufacturers for obtaining important early feedback from FDA regarding their efforts to develop novel manufacturing technologies. With respect to 3D printing more generally, in the context of medical devices, FDA issued a draft guidance document in May 2016 entitled, 

Technical Considerations for Additive Manufactured Devices

: Has the agency seen any problems regarding the manufacture of 3D drugs?

: FDA inspects drug manufacturing to verify that operations are in control and adhere to the approved application methods and control strategy. Drug manufacturing is not without risk and, like other manufacturing operations, must be well-managed and maintained to ensure production and availability of high-quality drugs. FDA collects and evaluates a variety of information about drug quality, and to date we have not seen any noteworthy manufacturing problems with a drug produced by 3D technology.

	Drug manufacturing is not without risk and, like other manufacturing operations, must be well-managed and maintained to ensure production and availability of high-quality drugs. 

: What other new technologies in solid-dosage drug development or manufacture has ETT dealt with?

: The ETT also worked closely with the manufacturer of Prezista, a solid oral-dosage drug for treatment of HIV-1 infection, as they worked on a switch from batch manufacturing to continuous manufacturing technology. The company’s efforts were facilitated by the use of the 

: Data integrity has been a hot topic in the past year or so. Are there any other areas FDA is focusing on when inspecting solid-dosage manufacturing facilities?

: Solid oral and semi-solid drugs account for most of the dosage forms consumers take. Thus, facilities that make them still remain the subject of a large percentage of FDA inspections. In addition to attention on data integrity issues, common themes in compliance actions that FDA is observing related to solid-dosage manufacturing include insufficient quality agreements between the sponsor and contract manufacturing organizations, or drug substance manufacturers and quality control labs; and management of the component (active and inactive ingredients) supply chain.

: What can you tell us about some of the new and planned guidance documents in regard to solid-dosage products, such as the variety of ANDA guidance documents and 

Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products; Revised Draft

: As reflected in CDER’s 2017 Guidance Agenda (6), the agency is diligently working to issue a revised draft guidance on 

Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products

, as well as a number of guidance documents with respect to generics. When the documents are published, stakeholders will have an opportunity to review the guidance documents and provide comments to the dockets. In addition, FDA recently published a draft guidance for comment on 

Extending Expiration Dates of Doxycycline Tablets and Capsules in Strategic Stockpiles

. Other guidance documents listed in the agenda, such as the guidance on drug products that contain nanomaterials, may also include recommendations relevant to solid-dosage products.

, accessed June 30, 2017.
	3. PharmTech.com, “A Vision for 3D Printing in Pharma Manufacturing,” Sept. 29, 2016, 
	4. J. Markarian, “

,” PharmTech.com, Aug. 17, 2016.
	5. PharmTech.com, “

FDA Approves First 3D-Printed Drug Product

,” PharmTech.com, Aug. 3, 2016. 
	6. FDA, 

Guidance Agenda: New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2017

	When referring to this article, please cite it as S. Haigney, “Update on 3D-Printed Drugs and What’s Ahead for Solid Dosage Forms,” 

FDA is working with manufacturers to encourage industry innovation.

Update on 3D-Printed Drugs and What’s Ahead for Solid Dosage Forms

 spoke with Archana M. Akalkotkar, PhD, research scientist I at Charles River and a member of the Contract Research Organization focus group in AAPS, about how companies can use process validation to ensure the quality of their product.

 What are some of the tools that can be used to ensure process and product quality?

 One of the most important tool to ensure the process and product quality is developing an appropriate quality program depending on the needs of the company. The model for quality should meet the needs and culture of the target audiences. Implementation of set of techniques and tools for process improvement including Six Sigma, lean methodologies, root cause analysis, failure modes and effects analysis, or health failure modes and effects analysis (HFMEA) could help to better streamline the process.

 How can companies integrate the various regulatory documents/requirements into a comprehensive process validation approach?

 Companies should follow the regulatory guidelines for process validation. The cGMP regulations require that the manufacturing processes be designed and controlled. If the guidelines are not available for a particular process, efforts should be put in to identify the key parameters that affect the process validation. These key points should be further drafted into a white paper to harmonize the practices for process validation in the companies.

 What are the most crucial aspects of process validation and why?

 Some of the crucial aspects of process validation are the process design, its qualification, and continuous verification of the process. The process design step allows for creating a process that has the ability to constantly produce quality material. Process qualification identifies the acceptance criteria for the outcomes and confirms if the current process design is capable of delivering reproducible quality products. The last step of continuous process verification is important to make sure that the current process is reliable and the processes are running in a controlled manner.

Archana M. Akalkotkar, PhD, research scientist I at Charles River, discusses the use of process validation to ensure quality.