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

Susan Haigney

The safety and efficacy of pharmaceutical products is of utmost importance. Regulations in the United States require that pharmaceutical companies establish a quality control unit to perform quality functions to ensure their products meet specifications and are safe for use. This unit also has the task of assuring regulators that good manufacturing practices (GMPs) are being followed. Regulators in Europe and other parts of the world have similar but varied requirements.

	The consequences of failing to ensure the quality of drug products range from the most egregious-adverse effects on patients-to potential regulatory actions, such as consent decrees, import bans, and seizure of product. Regulatory responses can include reports such as FDA Form 483 observations, inspection findings from the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, or requests for urgent actions such as FDA warning letters. In addition to regulatory actions, an ineffective quality system may also affect a pharmaceutical company’s success. “Ultimately the consequences are reduced profitability, as scrap, rework, and downtime are increased,” says Karen Ginsbury, CEO of PCI Pharmaceutical Consulting Israel Ltd.

	Warning letters issued by FDA to various pharmaceutical companies located in the US and around the world in 2019, however, seem to have a common theme: a lack of a properly functioning quality control (QC) unit (1–4). The agency has cited companies for everything from failure to establish an adequate QC unit to QC units not performing their duties properly.

	“Many FDA 483 observations have been issued for quality units failing to fulfill all their responsibilities.  If a firm releases product (or other material) in the absence of a quality unit, this is even more egregious,” says Mary Oates, vice-president compliance services, at Lachman Consultant Services, Inc. “There may also be consequences for patients. If there is no quality unit, in all probability there will be significant gaps in the pharmaceutical quality system, potentially presenting risk to patients if processes and controls are not in place to ensure product quality.”

	Pharmaceutical companies are responsible for ensuring the standards of all drug components, including excipients, APIs, and packaging materials, says Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow at Regulatory Compliance Associates, and it is the QC unit’s responsibility to investigate why any of these components fails to meet those standards. “The quality control unit plays a huge part in making sure that products meet the proper applicable standards before they are released,” says Schniepp. “It’s interesting to note that the quality control unit is the only functional unit required by law. This is not to imply that the quality unit works in a vacuum, but rather that it facilitates the investigation into any failures. [The QC unit] has the sole responsibility of releasing product. No other department in an organization has this authority, and it cannot be delegated. Bottom line, we rely on the quality unit to make sure that product released to the market is safe and effective.”

	With quality being so imperative, how is it that pharmaceutical companies are improperly maintaining such a vital part of their operations? One could argue that a failure to create a quality culture in the organization from the top to bottom may be a cause for this failure. The following discusses why companies may be faltering in this area and what a company can do to maintain a more effective quality control unit.

	One of the challenges in ensuring quality may be the varied regulations and requirements pharmaceutical companies must follow. When it comes to the QC unit, there seems to be some confusion and debate about what exactly a QC unit is and what duties it performs. This confusion can be somewhat blamed on different names for the quality department itself and the language in the US and EU regulations.

	According to Ginsbury, the message in the GMP regulations is unclear and possibly misleading. “Based on the definitions in the GMPs, we can conclude that in the United States and the European Union, the QC unit apparently has a rather narrow role, limited to sampling, testing, and making judgements as to product quality (or lack thereof, i.e., release/reject).  This is not necessarily, nor ever was, the intent of the regulator,” insists Ginsbury. The GMP regulations are more product than process focused, says Ginsbury, “which can result in executives mistakenly believing that product meeting all release specifications may be released even when there are some serious GMP deviations related to the batch or other batches of product, or equipment or facility.

	“Under QC unit roles, there is not much to be found at all about establishing, maintaining, and continuously improving the quality system, measuring (quality metrics), and reporting to management as to how well the system is doing,” Ginsbury continues. “The QC unit is perceived as a sort of judge, who with unusual wisdom can ‘decide’ if faulty/flawed product produced with a deviation or non-conformity is ‘impacted’ or not impacted by the non-conformity.  The concept of zero defects and prevention of defects, which is the basis for any true quality system, and the Plan-Do-Check-Act process-based cycle are absent [in the written GMP regulations].”

	Russell Madsen, president of The Williamsburg Group, LLC, argues that, in the US, the QC unit has “sweeping responsibilities specified in 21 

) §211.22, including ‘the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product’” (5).

 210.3(15) defines the quality control unit as “any person or organizational element designated by the firm to be responsible for the duties relating to quality control” (6).

	According to Oates, the QC unit includes both quality assurance (QA) and quality control functions and should be involved in the approval of the drug product, testing results, production records, procedures, and all materials that might affect the final drug product whether that product is produced in house or “manufactured, processed, packed, or held under contract by another company,” says Oates.

	Both Schniepp and Ginsbury state it is important to understand the difference between QA and QC. Ginsbury further states that neither of these on their own are what the regulator intended regarding the QC unit. “The quality unit should be […] preventing defects and non-conformities from happening by planning (including proactive risk assessment/management during design of processes, checking [validation]), monitoring, and continuous improvement,” says Ginsbury. “This needs to be real time and not as current Product Quality Reviews are performed-annually with a lag of up to 18 months from when the data [were] collected.”

	The QC unit should be independent from manufacturing and should serve as oversight for the overall quality system and set the quality culture within the company. “The [QC] unit can be seen to have two tasks: quality testing and the decision to pass or fail on the basis of the results. These two functions are usually separated into a quality control laboratory (testing) and quality assurance (release and documents administration). There is a good reason for this because it takes the release decision away from the testing group and keeps it independent,” says Chris Moreton, partner at FinnBrit Consulting. Oates agrees, “The quality unit itself manufactures nothing. It is responsible for oversight.” 

	This independence contributes to overall product quality, says Oates, especially when it comes to quality decisions and the commitment to delivering quality products. “All firms in the pharmaceutical industry, no matter the size, must have robust processes and systems to enable right-first-time manufacturing (inclusive of all GMP activities along the supply chain) and, perhaps most critically, a culture that puts the interests of patients first.  Only then will product quality be assured,” says Oates.

	In Europe, the batch release/reject decision falls to the role of a Qualified Person (QP) as defined in the European guidelines (7, 8). Europe Directive 2001/83/EC (9) states, “Member States shall take all appropriate measures to ensure that the qualified person referred to in Article 48, without prejudice to his relationship with the holder of the manufacturing authorization, is responsible, in the context of the procedures referred to in Article 52, for securing: (a) in the case of medicinal products manufactured within the Member States concerned, that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization. ...”

	An understanding of the role of the QC unit is the first step in creating and maintaining the QC unit. A company’s standard operating procedures (SOPs) must clearly define the role of the QC unit, says Oates. Processes that are clear and easy to follow in repetition should be implemented, agrees Bo Henry, director of quality control at Catalent. Documentation should be standardized, and staff should be trained to ensure the integrity of data. “Finally, build a culture focused on the patient. With an effective training program and a culture of quality, the entire organization will be able to approach decision making effectively,” says Henry.

	The makeup of the unit is the next important step. The QC unit should be comprised of personnel with knowledge of the products and processes they oversee, says Madsen, and should be familiar with the GMP regulations. Oates agrees, “They must understand the processes and systems for which they have oversight.  For example, an employee in QA responsible for oversight of aseptic media fills must fully understand the critical aspects of aseptic manufacturing, grasping the ‘why’ as well as the ‘what.’  Ideally, a quality control unit would include some employees who have prior experience in manufacturing.  This deeper understanding of the production processes and systems enhances their ability to provide appropriate oversight,” says Oates. According to Ginsbury, in Europe, these requirements are stated in the EU GMP guidelines (10).

	According to Mark TePaske, senior director, global regulatory affairs, quality and compliance at Cambrex, the nature of pharmaceutical products requires more stringent controls than other industries. QC personnel operate complex analytical instruments and must follow approved written procedures, says TePaske. “QC needs metrology resources (often contractors) to qualify and maintain instruments; analysts to set-up and operate instruments and perform tests methods; persons to qualify/validate test methods; technically competent persons to draft procedures; personnel to perform peer review of data and supervisors (as required by the FDA out of specification  guidance document [11]), support investigations and troubleshoot; and persons to approve and report results.  All personnel need to be suitably trained by qualified trainers with training documented. This list assumes that QC relies on [the quality assurance department] for document control, issuance, and retention,” says TePaske.

	A QC unit should consist of personnel from quality assurance, quality control, validation, and sterility assurance departments, according to Henry. It may also include personnel from document management and quality engineering. All personnel must understand how their role ultimately affects patients, says Henry. “It is also critical to align with all applicable regulations and guidance for the product. Start by creating a quality manual, then build foundational standard operating procedures. Performing an initial process map of the quality and operational processes prior to generating quality management system policies and procedures is a very useful exercise,” says Henry.

	Best practices for quality control units

	The key aspects of an effective QC unit include well-written SOPs, well-informed personnel, and a clear understanding of roles and responsibilities of everyone involved. The development of a quality culture throughout the organization is also important. Ginsbury stresses that developing this quality culture is only possible if executive management is brought on board.

	To ensure continued quality and uninterrupted supply of pharmaceutical products that are distributed to patients, the QC unit must stay apprised with changing GMPs, says Oates. Procedures that at one point were compliant with the regulations may no longer be. “This is often seen in the areas of validation and aseptic manufacturing.  Regulatory expectations are increasing, and some firms are not remaining current,” says Oates. 

	Written procedures must be developed and followed according to the regulations. These procedures should be thorough and complete, says Oates. “For example, validation for a manufacturing process may not have been completed or the responsibilities of the quality unit may not be defined in a procedure.” Procedures that lack sufficient detail can lead to quality problems, says TePaske. “The most common problems here are that some procedures lack enough detail to ensure control, other procedures omit required information (e.g., the FDA out-of-specification guidance document includes an extensive list of considerations), and some procedures contain too many or contradictory details and are impossible to accurately follow.”

	Each individual’s role within the QC unit and the organization must also be clearly defined, says Henry. “The plan should outline which individuals need to be informed of a deviation, and who can make the decision on next steps if the next steps are not captured already in the procedure. As an organization grows, it can become difficult to maintain clarity on written procedures as more people are trained and asked to execute the procedure with a reproducible result. It is extremely important to revisit the procedure at an established frequency to revise it as needed for clarity.”

	Failure to develop and follow such procedures may lead to regulatory actions. “When a firm receives a finding regarding the quality unit, it must look more holistically at its controls than perhaps is evident from the observation itself,” says Oates.

	There is also the problem of a “misalignment” of practices and written procedures, according to Oates. “Operators may execute a manufacturing process in one way while the SOP indicates it should be done differently.  Additionally, it is possible that the validation document may not be aligned with either the actual or written practice,” says Oates.

	Ensuring that deviations are properly investigated is also imperative for the QC unit. Oates stresses that it is the QC unit’s responsibility to define what constitutes a deviation and that this definition must be clearly communicated to the rest of the organization. “Training with examples must be provided so that the understanding of what is a deviation is fully calibrated across the organization,” says Oates.

	The QC unit must have a system of “escalating” the investigation and resolution of deviations. Root cause must be identified and corrective actions and preventive actions (CAPAs) should be established. Henry states that investigations should remove human performance from the equation. “Most importantly, the product strength, identity, safety, purity, and quality should be considered when determining the impact of the deviation and ultimately the overall integrity of the batch by the quality control unit.”

	“Firms can fall into a trap of being more focused on product release than on completing a holistic investigation, and the quality unit has the obligation to ensure the investigation is complete and appropriately supports any decisions being taken,” says Oates. Any trends found across multiple investigations should also have CAPAs implemented, and the QC unit should look for common themes. “Continuous improvement must be an objective of the quality unit and the firm as a whole,” says Oates. “Attention must also be given as to whether regulatory notification is required in a prescribed timeframe.”

	“Top management and the QC unit must work in harmony to ensure there are adequate resources to investigate and correct situations that result in deviations. The importance of finding and correcting root causes cannot be overemphasized, so that deviations do not recur and overwhelm the organization,” stresses Madsen.

	Establishing a quality culture throughout the organization is an important way to ensure that these steps are being taken. “It all comes down to training and motivation. Everybody, from the most junior to the most senior members of the organization, should be thinking ‘Quality’. This [quality culture] is obviously important in manufacturing and quality groups, but it is also important in finance, marketing, sales, etc,” says Moreton. “For example, there are always pressures to contain costs, but this should not be to the extent that people tend to gloss over things because there is not time or resources to deal with it properly. There are pressures to get the medicinal products into the supply chain as quickly and efficiently as possible, but this should not compromise patient safety,” says Moreton.

	An effective QC unit must be independent of the manufacturing unit, says Oates, and the QC unit’s final decision on the release of product must be respected. “It is never appropriate to pressure the quality unit to release product to meet business needs if the product is not acceptable for release,” says Oates. “The quality unit must have a single, final decision-maker who is ultimately responsible for quality decisions.” 

	Pharma company executives should be aware that the quality of their products is a responsibility of many components of the organization and not the sole responsibility of the QC unit. “Perhaps the biggest mistake is for the firm to assume that the quality unit is responsible for quality.  Manufacturing is responsible for product quality.  The quality unit provides the framework in which GMP activities occur and subsequent, ongoing oversight and support for continuous improvement,” says Oates.

	Ultimately, a successful quality control system requires a dedication to quality and investigating problems. “Small issues have a way of snowballing.  Additionally, quality units cannot ensure product quality. Product quality can only be ensured when all company organizational units work in harmony, with product quality and patient safety as their primary goals,” says Madsen.

Warning Letter to NingBo Huize Commodity Co., Ltd

Warning Letter to Spectrum Laboratory Products

, March 14, 2019.
	5. FDA, Responsibilities of Quality Control Unit, 21 

 §211.22.
	6. FDA, Current Good Manufacturing Practice In Manufacturing, Processing, Packing, Or Holding Of Drugs; General, Definitions, 21 

EudraLex–Volume 4–Good Manufacturing Practice (GMP) Guidelines

.
	8. EMA, Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use, Nov. 28, 2004.
	9. 

Directive 2001/83/EC of The European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal products for Human Use

EudraLex-Volume 4–Good Manufac–turing Practice (GMP) Guidelines

Guidance for Industry, Investigating Out-of-Specification Test Results for Pharmaceutical Production


	Vol. 43, No. 11
	November 2019
	Pages: 16–20

	When referrring to this article, please cite it as S. Haigney, "The Right Pieces for a Quality Program," 

Articles

An effective quality control unit is independent from manufacturing and ensures current standards are followed.

The Right Pieces for a Quality Program

Technology transfer is a multifaceted task that involves different departments and expertise within a pharmaceutical organization. It is a task, therefore, that can come with unforeseen challenges, even when the process may seem simple, according to Joerg Zimmermann, vice-president Vetter Development Service at Vetter Pharma-Fertigung GmbH & Co. KG. Pharmaceutical Technology spoke with Zimmermann about the tech transfer process and how companies can make this transfer as painless as possible.

 What are the first steps that should be taken when starting the process of transferring information and processes from one group or company to another?

 I think the most important thing is to perform a combination of a gap and risk analysis between the existing process at the sending site and the envisioned process at the receiving site. This practice assists in identifying and evaluating the manufacturing and testing steps along with organizational issues and logistics, and it assesses the risk of identified differences between the transfer sites. In the spirit of International Council for Harmonization (ICH) Q8(R2) 

 the results of a thorough evaluation of the quality target product profile (QTPP) of the product and the associated critical quality attributes (CQAs) define the scope of the transfer.

 Should both entities be involved in developing the tech transfer process?

 Certainly, as open communication and trust is key. The closer the sending and receiving sites work together, the better the transfer will work out. The sending site will usually have years of practical experience and defined routines, while the transfer itself offers the opportunity to redesign and modernize elements of the process. Wherever possible, you should involve the people that are actually making and testing the product since a good deal of know-how is not actually in the documents themselves, but in the heads of the people involved!

 How does tech transfer differ between in-company transfers and sponsor/contract facility transfers? Are the process steps different?

In general, there is no difference either in the process itself or in the regulatory aspects. However, there may be underlying resistance from the sending site in the case of a sponsor. This is something that must be dealt with within the ‘cultural’ part of the project. Procedurally, there will always be differences in the ways of working, including the quality systems. As such, these too must be evaluated.

	Evaluating processes during tech transfer

 Which manufacturing processes should be evaluated when it comes to tech transfer?

 All processes should be evaluated from start to finish including all unit operations. For aseptic fill/finish operations, processes would include compounding, sterile filtration, filling, visual inspection, and secondary packaging.

Which analytical processes should be evaluated in tech transfer?

 There will always be several analytical processes that need to be transferred, for example, in-process testing as well as release testing. The extent of the transfer itself depends on the analytical capabilities of the receiving site. It is possible to establish and run all analytical procedures, be they chemical, biological, microbiological, or physical tests for in-process testing, product release testing, and stability testing. The test can be something simple like pH, or more complex like an SDS–PAGE [sodium dodecyl sulfate polyacrylamide gel electrophoresis] for proteins.

Which quality and/or validation process should be evaluated in tech transfer?

 The inception of any process transfer is the process qualification campaign, which is based on FDA’s approach of first (process design), second (process qualification), and third (continuous process verification). Its purpose is always to achieve a robust, reproducible manufacturing process with consistent quality at the receiving site.

Which team members/departments should be included in the tech transfer process?

 Process transfers are usually run as projects with dedicated cross-departmental teams. These include development, manufacturing operations, quality assurance and quality control, qualification/validation, and regulatory affairs. It also includes production planning and logistics. All are organized and coordinated by a project manager who reports to the project sponsor. Ideally, all functions from both sites are involved to a certain extent with respective partners in the other organization. In this way, subject matter experts can directly communicate with their peers.

 How can tech transfer operations affect current/other manufacturing operations both at the sponsor site and the outsourcing site?

 It is the nature of the business that to a certain extent, the introduction of new products and processes will interrupt running operations. Thus, the goal is to always keep interruptions to a minimum. The receiving site should always have a vested interest in both a smooth transfer and a robust process as they will be running it for years, or even decades into the future.

 Are there specific tools used in tech transfer? If yes, what, where, and why?

Most certainly. Strong project management is paramount in any tech transfer. The roles and responsibilities for all team members must be agreed upon and a system that enables adequate communication and feedback of information must be established. All pharmaceutical process steps can be directly derived following ICH Q8(R2) (1) and FDA guidance (2). Based on prior knowledge of similar products and processes, a smooth and swift process transfer can be designed and executed.

Guidance for Industry, Process Validation: General Principles and Practices


	Vol. 43, No. 11
	November 2019
	Pages: 53-54

	When referring to this article, please cite it as S. Haigney, "Evaluating the Tech Transfer Process," 

Unforeseen challenges can be avoided in technology transfer by evaluating the variety of processes involved.

Evaluating the Tech Transfer Process

The burgeoning cell therapy and gene therapy market segments continue to spur new partnerships and business expansions for contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) in the second half of 2019.

	CombiGene, a gene therapy company located in Sweden, announced it signed an agreement with Cobra Biologics-a CDMO that provides DNA, viral vectors, and microbiota for preclinical, clinical, and commercial supply-for the production of the epilepsy gene therapy candidate drug CG01 (1).

	The agreement includes a Master Service Agreement that details the terms under which the two companies will collaborate. There will be three separate contracts: quality, production of plasmids, and production of CG01.The agreement includes manufacturing of CG01 by Cobra for clinical studies and future commercial production, according to a company press release.

	In October 2019, Lonza announced an extension to its partnership with Genmab, a Denmark-based biotechnology company specializing in antibody therapeutics for cancer, which covers preclinical and clinical development and manufacturing for part of Genmab’s pipeline (2). Lonza’s Ibex Solutions in Visp, Switzerland can be used for Genmab to take their candidates from gene to investigational new drug applicaton in 12 months and move to reserved manufacturing capacity in Ibex Develop for clinical manufacturing and biologics license application submission. The new agreement will cover development and clinical manufacturing of drug substance and drug product for certain programs in Genmab’s pre-clinical and clinical pipeline.

	Lonza also announced it is entering into a manufacturing service agreement with Cellectis, a clinical-stage biopharmaceutical company that specializes in developing immunotherapies based on allogeneic gene-edited chimeric antigen receptor (CAR) T cells (UCART), for the clinical manufacturing of Cellectis’ allogeneic UCART product candidates targeting hematological malignancies (3).

	Manufacturing of the cell line will take place at Lonza’s GMP facility in Geleen, Netherlands where the frozen, off-the-shelf, non-alloreactive engineered CAR T cells will be industrialized with defined pharmaceutical release criteria for the patient population.

	Catalent announced it has entered into a long-term commercial supply agreement with Minerva Neurosciences, a Waltham, MA-based biopharmaceutical company focused on the development of therapies to treat central nervous system disorders (4). The companies will focus on roluperidone (MIN-101), an investigational compound under development by Minerva, for the treatment of negative symptoms of schizophrenia.

	A Phase III clinical trial is currently being conducted in Europe and the United States, according to a Sept. 24, 2019 press release. If successful, roluperidone (MIN-101) will be the first treatment approved to treat symptoms of schizophrenia in the US, according to the companies.

	1. Cobra Biologics, “CombiGene Signs Agreement with Cobra Biologics for Production of Candidate Drug CG01,” Press Release, Oct.r 14, 2019.
	2. Lonza, “Lonza’s Ibex™ Solutions to Support Genmab’s Growing Clinical Portfolio,” Press Release, Oct. 14, 2019.
	3. Lonza, “Cellectis and Lonza Enter cGMP Manufacturing Service Agreement for Cellectis’ Allogeneic UCART Product Candidates,” Press Release, Oct. 1, 2019.
	4. Catalent, “Catalent and Minerva Neurosciences Enter Commercial Supply Agreement for Schizophrenia Drug Roluperidone,” Press Release, Sept. 24, 2019.


	Vol. 43, No. 11
	November 2019
	Page: 57

	When referring to this article, please cite it as S. Haigney, "Developments in the Pharmaceutical Outsourcing Industry," 

Contract manufacturers are making strategic partnerships and expanding services in the last quarter of 2019.

Developments in the Pharmaceutical Outsourcing Industry

The growth of the biologics industry has created expansion in the contract development and manufacturing (CDMO) space. Liza M. Rivera, senior director, global marketing, at Fujifilm Diosynth Biotechnologies (FDB), says biologics have seen success especially in the treatment of cancer and autoimmune diseases. The following highlights some of the latest news from CDMOs in the biomanufacturing space.

	CDMOs are adding facilities and services to their portfolios in anticipation of the industry’s continued growth. Fujifilm is one of the companies making significant investments in their biomanufacturing offerings. “In recent years, we have prioritized the expansion of our production facilities, principally 2000-L medium-sized tanks, in response to the rapid increase in production demand for biologics,” Rivera says.

	“As outlined in our medium-term management plan, VISION2019, with fiscal year ending in March 2020, we set our sights on enhancing the growth of our healthcare business. To meet this goal, we have actively made capital investments in our bio-CDMO business, achieving double-digit growth in sales, exceeding market growth.  Going forward, we intend to continue to promote growth along these lines, expanding the bio-CDMO business as the growth driver for the healthcare area,” says Rivera.

	In March 2019, Fujifilm acquired a large-scale biologics manufacturing facility in Hillerød, Denmark from Biogen as part of their goal of expanding its global business. The facility allows for the support of high-volume production of biologics that requires large-scale culture tanks and is equipped with six 15,000-L bioreactors. The facility also houses an assembly, labelling, and packaging facility; quality control laboratories; and warehouses. “Most importantly, the nearly 800 women and men of the Hillerød facility will contribute their world-class CGMP [current good manufacturing practice] manufacturing capabilities to FDB’s existing leadership bio-CDMO, immediately strengthening our overarching goal to advance tomorrow’s medicines and guarantee distribution of their lifesaving properties to all who need them,” Rivera says.  

	At its manufacturing site in Songdo, South Korea, Samsung BioLogics (SBL) has demonstrated the viability of using alternating tangential flow (ATF) technology in a perfusion reactor at commercial scale. ATF perfusion has been applied in clinical development projects at small scale, according to SBL, but few companies have used the approach at large scale. The company said in a press release issued on 12 August 2019 that this approach should reduce production time by up to 30% for its clients (1).

	The new technology adds to the manufacturing options that the CDMO can offer its biopharmaceutical manufacturing clients.  According to SBL, the ATF perfusion system allows for a 10-fold improvement in cell culture densities while retaining cell viabilities of over 98% at the seed stage. This enables inoculation within 15,000-L bioreactors at higher cell densities, enabling peak cell densities to be achieved within shorter culture durations.

	Samsung worked closely with the ATF system vendor to design the stainless-steel-housed system, and to assure closed-system integrity and full compliance with CGMPs. Validation, including ATF system water and media tests as well as extensive autoclave cycle development and sterility performance testing, was completed within six months, the company disclosed in its press release.

	Samsung expects to reduce consumable cost with the stainless steel ATF filter, although its engineering experts note that single use ATF filters can also be applied in the future.

	HALIX, which specializes in clinical and commercial proteins and viral products, completed its new cGMP manufacturing facility in Leiden Bio Science Park in the Netherlands in August. The 6700-sq.-m. facility will be used for the development and production of biopharmaceutical drug substances. The facility contains a manufacturing line for viral vaccines and viral vectors in addition to a separate protein manufacturing area with a capacity of up to 1000-L single-use bioreactors. Lab space is also available for process development, analytical development, and quality control. All cleanroom areas have a unidirectional process flow and are designed to allow commercial manufacturing of biopharmaceutical products (2).

	“This new facility offers our current and future clients’ capacity and flexibility for future expansion and will allow for cGMP manufacturing solutions for viral products, proteins, gene therapy, and client-specific new technologies,” said Roland Hecht, HALIX chief customer officer, in a company press release.

	Sartorius Stedim Biotech (SSB), a supplier of biopharmaceutical manufacturing products and services, is now offering GMP mammalian cell bank manufacture, the company announced on 8 Aug. 2019. The services will be offered through its subsidiary, Sartorius Stedim BioOutsource, a contract testing organization based in Glasgow, United Kingdom, and in Cambridge, MA, in the United States (3).

	The services will feature the manufacture of GMP master and working cell banks for mammalian suspension cells, which will be conducted in a 260-sq.-m. GMP cleanroom dedicated to mammalian suspension cell lines. The facility enables closed-system manufacture of GMP-compliant cell banks, from vial thaw to automated filling, as a qualified broth technology platform. The company expects this platform to maximize process reliability and assurance of sterility.

	SSB offers its cell bank manufacturing in a package along with cell bank characterization services, making the company a single-source provider from vial thaw to released cell banks.

	With these new services, the company can offer combined cell-line development, cell bank manufacturing, and cell bank characterization and provide biomanufacturing solutions from DNA to released GMP cell bank within a 10-month timeline.

	In August 2019, Eurofins Genomics completed its acquisition of Blue Heron Biotech, a Bothell, WA-based gene synthesis company. The deal bolsters Blue Heron’s production capabilities while expanding Eurofins Genomics’ gene portfolio into cloning and complex gene constructs, according to the company. The acquisition also strengthens Eurofins Genomics’ product portfolio in the synthetic biology market (4).

	The companies share similar main product segments including oligonucleotides, sequencing, and synthetic genes. Eurofins Genomics’ product offerings include oligonucleotide synthesis, Sanger sequencing, next-generation sequencing, and gene synthesis. With the acquisition, the company can now provide holistic solutions to customers, including regulatory coverage for its products-ISO 13485, ISO 9001, CLIA, CAP, good laboratory practice, and FDA compliance-for the manufacturing of cGMP oligonucleotides used in analyte-specific reagent and 

 diagnostic products for the clinical industry.

	1. Samsung Biologics, “Samsung BioLogics Implements Large Scale N-1 Perfusion for Commercial Application,” Press Release, 12 Aug. 2019.
	2. Halix, “New cGMP facility starting operational production in Q4-2019,” Press Release, 9 Aug. 2019.
	3. Sartorius, “Sartorius Stedim Biotech Launches New Services for Mammalian Cell Bank Manufacturing,” Press Release, 8 Aug. 2019.
	4. Eurofins, “Eurofins Genomics US Expands Gene Synthesis Capabilities with Acquisition of Blue Heron Biotech,” Press Release, 5 Aug. 2019.


	Vol. 31, No. 9
	September 2019
	Pages: 48-49

	When referring to this article, please cite it as S. Haigney, "Biologics Continue to Grow and Create Outsourcing Opportunities," 

CDMOs are adding facilities and services to their portfolios in anticipation of the biologics industry’s continued growth.

Biologics Continue to Grow and Create Outsourcing Opportunities

The pharmaceutical industry has been experiencing an increase in demand for drug products that contain highly potent APIs (HPAPIs), both in the United States and in Europe. According to Adam Bradbury, associate analyst at PharmSource, a GlobalData product, the number of innovative pharma product approvals requiring containment has been increasing since 2008 (see 

). A majority of these products have been in the oncology and pain treatment areas. “The most commonly approved US product types requiring containment were (highest to lowest) controlled drugs, cytotoxics, steroids, immunosuppressants, kinase inhibitors, and nucleotides, which is indicative that many of these treatments are for oncology or pain relief,” says Bradbury.

	Maurits Janssen, head of Commercial Development, API Development & Manufacturing, Lonza Pharma & Biotech, agrees. “We are witnessing a rise in the importance of drugs that include one or more HPAPI component. These molecules are useful in treating cancer, diabetes, autoimmune diseases, and other indications, and pharma and biotech companies are taking notice and incorporating them into innovative therapies.”

	GlobalData’s Drugs by Manufacturer database reports that 532 novel approved drugs approved in the US and the EU require containment. “There is a tendency for both high potency drugs’ API and dose manufacture to be outsourced rather than manufactured in-house, although some of these products will also be dual sourced (both manufactured in-house and outsourced),” says Bradbury. 

	GlobalData’s research supports that statement; API manufacturing is outsourced for 255 of those drugs; 317 drug products are produced by contract manufacturers. In-house production is used for 201 highly potent drug substances and 295 HPAPI-based drug products.

	Approximately 60% of HPAPIs in development are for oncology drugs (see 

), which, according to Bradbury, points to an increase in demand for HPAPI manufacturing capacity. Because HPAPIs have special requirements for handling and containment, those companies looking to outsource HPAPI production may encounter challenges locating a contract development and manufacturing organization (CDMO) to develop and manufacture these hazardous materials.

	“There is sufficient capacity in the market but obtaining additional capacity to boost business growth via acquisition is not economical for most pharma and biotech companies and CDMOs,” says Janssen. “Many customers we work with developing HPAPI products are small or emerging biotech companies, which have developed an excellent product but don’t have production capabilities or assets in-house. What they value is access to flexible and scalable manufacturing assets that can serve their specific needs-extending from drug substance into drug product technologies, in an integrated manner-and hopefully grow with them seamlessly toward commercial production as there is increased demand for their product.”

	During a presentation at the 2019 CPhI North America conference, however, audience members indicated current capacity may not be able to handle future demand. Anil Kane, executive director, global science and technology, pharmaceutical development services, at Thermo Fisher Scientific, suggests it might be all about planning (

). “In my opinion, there is capacity [for development-scale and commercial-scale], but of course the infrastructure is limited, so it’s all about planning and scheduling,” says Kane.

	According to Bradbury, there are 209 facilities across 148 companies in the US that offer containment capabilities. Europe has 403 facilities in 247 companies. “All of the evidence indicates that containment facilities are in high demand, and this trend will increase as the oncology pipeline continues to flourish,” says Bradbury. “CDMOs with containment capabilities are likely to be at an advantage compared to those without, as the number of marketed HPAPIs tends to increase over time as more HPAPI drugs gain approval,” says Bradbury.

	To meet this demand, CDMOs may need to tailor services and facilities for specific clients and add facilities, equipment, and services to meet demand. These organizations may also have to balance manufacture of HPAPIs alongside non-potent APIs. Being flexible and tailoring manufacturing techniques, equipment, and containment options to a molecule’s properties and synthesis requirements may result in increased safety, a reduction in cost, and enhanced capacity for HPAPIs (1).

	Contract manufacturing organizations (CMOs) that offer containment capabilities have an advantage over those that do not and may also see an increase in revenue, Bradbury says. “There is a direct correlation between CMOs that offer HPAPI capabilities and generation of high revenues; as those facilities/capabilities are very expensive to build or acquire, only the largest CMOs can afford them, allowing those CMOs to take on projects that others cannot, therefore boosting revenues,” says Bradbury. Many CDMOs and CMOs, as a result of the increase in demand, have been making investments in the HPAPI area.

	“As we continue working with customers to develop and commercialize these medicines, we are always looking to enhance and expand our capabilities and manufacturing capacity to continue to meet their needs,” says Janssen. Lonza announced on June 13, 2019 plans to add two production lines in an expansion of the company’s HPAPI capacity at its Visp, Switzerland site (2), which houses the company’s Center of Excellence for HPAPI Manufacturing.

-scale, multi-purpose lines to the company’s existing capabilities for lab- to large commercial-scale HPAPI production. The new lines are expected to be online by July 2020. Janssen states that a long-term manufacturing agreement Lonza reached with AstraZeneca was one of the reasons for the investment. In addition, he states, the expansion allows further improvement of flexibility in existing production lines, to reduce time-to-market and accelerate approval timelines for partners.

	Another expansion Lonza made at the Visp facility took place in October 2018. The company built HPAPI capacity for the specific support of antibody-drug conjugate (ADC) payload manufacturing (3). “We are seeing an increase in projects in the highly potent API space, including ADCs, and we anticipate that additional capacity at larger scales will be necessary in the near future. This expansion offers companies a seamless integration to our ADC development and manufacturing suites in Visp, that from 2020 onwards will be the first site worldwide where all components to this type of product (i.e., antibody, payload, and conjugation to final product) can be served. We are always seeking ways to better serve our customers of all sizes and help bring innovative life-saving drugs to market,” says Janssen.

	On June 20, 2019, CDMO Piramal Pharma Solutions announced the opening of a new wing at its Riverview, MI, site, into which the company has invested $10 million to upgrade (4). The new wing will produce HPAPIs with low occupational exposure limits (OELs).

	The upgrade includes a new quality control (QC)/analytical lab and two kilo-labs in addition to a doubling of the office space to support growth at the Riverview site. To date, the site has had “the containment capability and engineering controls to safely handle HPAPIs with OELs down to 1mcg/m

, at scales ranging from grams to ~250 kilos,” according to the company. The new wing, with its two kilo-labs and QC/analytical lab, strengthens the company’s position in this area. The new wing is designed with “the required engineering controls and containment solutions to handle HPAPIs with OELs <1mcg/m

.” Materials will be produced in this new wing at kilo-lab scales; and amounts of <5 kilos can also be produced.

	“This new, enhanced capability opens the site up to a new base of customers, including the antibody-drug conjugate market. We are equipped to offer ADC customers a seamless end-to-end solution, since we can develop the HPAPI payloads and linkers here in Riverview, send them to our site in Scotland for the antibody conjugation, then back to our Lexington, KY, site for sterile fill/finish,” added Vince Ammoscato, vice-president and Riverview site head, in the press release.

	In April 2019, Cambrex completed construction of a $24-million HPAPI manufacturing facility in Charles City, IA (5). “The production area will operate to an OEL down to 0.1µg/m

 and contain four reactors ranging from 200- to 1000-gallon capacity,” according to the company. The facility will be capable of manufacturing batch sizes up to 300 kg.

	“Across our sites, Cambrex has a strong reputation in the handling and supply of potent molecules, and this investment allows us to increase the capacity we can offer our customers,” said John Andrews, vice-president, operations and site director, Cambrex Charles City, in a press release. “We have seen an increased number of molecules in the clinical pipeline being designated as potent and highly potent, so having the flexibility within our manufacturing network to scale up with existing customers as projects progress, as well as accommodate new projects, is crucial to meet those market needs.”

	It’s apparent that the contract manufacturing industry is recognizing the increased demand for HPAPI containment capabilities, and companies are making investments and adjusting their services to meet that demand. As the pharmaceutical industry continues to develop complex treatments requiring complex ingredients, the industry will soon know if these adjustments are enough.

Classifying Potent and Highly Potent Molecules

	2.  Lonza, “Lonza to Expand HPAPI Development and Manufacturing Capacity,” Press Release, June 13, 2019.

	3.  Lonza, “Lonza Expands HPAPI Development and Manufacturing Capacity for ADC Payloads,” Press Release, October 8, 2018. 

	4. Piramal Pharma Solutions, “Piramal Pharma Solutions Invests $10 million USD to Expand its High Potency API Capability in its Riverview Facility in US,” Press Release, June 20, 2019.

	5. Cambrex, “Cambrex Completes Highly Potent API Manufacturing Facility at Charles City, IA,” Press Release, April 10, 2019.

Supplement: Outsourcing Resources
	August 2019
	Pages: s6–s10

	When referring to this article, please cite it as S. Haigney, “HPAPI Capacity Challenges," 

Pharmaceutical Technology Outsourcing Resources

Does the pharmaceutical industry have adequate access to contained equipment, facilities, and infrastructure for the manufacture of highly potent APIs?

HPAPI Capacity Challenges

	Gene therapies are becoming a fast-growing area in the biopharmaceutical industry, creating a crowded pipeline of products in need of manufacturing. FDA expects the agency will receive more than 200 investigational new drug applications for cell and gene therapies by 2020, with the agency predicting that it will be approving 10–20 cell- and gene-therapy products each year by 2025 (1).

	Because gene therapies use the patient’s own body to manufacture the active ingredient, the treatment is specific to that patient. This tailoring can often be a more effective and longer-lasting treatment, according to Chris Murphy, general manager for viral vector services at Thermo Fisher Scientific. “Because of these developments, novel, life-changing therapies are being realized that may transform the lives of patients in need.”  

	This growth is causing contract development and manufacturing organizations (CDMOs) to take a look at their portfolios as their clients require more and more biologics-related services. Catalent has been focused on the clinical pipeline of gene therapies and anticipating the need for commercial manufacturing. “There is an abundance of gene therapy product candidates in the pipeline, and on the heels of market approvals of gene therapy products in 2017 and the influx of venture capital funding for gene therapy companies, FDA approved a second gene therapy this year. We see this as a watershed moment, where gene therapies are gaining regulatory acceptance and setting a precedent for other programs in the pipeline,” says Bernie Clark, vice-president, marketing and strategy, Catalent Biologics & Specialty Drug Delivery.

	According to Clark, outsourcing the manufacture of gene therapies requires relatively low volumes to fulfill demand, making it an attractive option. To better service its clients’ outsourcing needs in this area, Catalent acquired Paragon Bioservices, Inc., a viral vector development and manufacturing company for gene therapies with expertise in adeno-associated virus vectors, in May 2019 (2).

	Clark believes the acquisition will help Catalent accelerate its growth. “Paragon offers its partners GMP-compliant manufacturing capacity, scale-up expertise, and customized downstream processing without the added time, costs, and risks of building a new viral facility,” says Clark. “The acquisition also brings complementary capabilities that will fundamentally enhance our biologics business and our end-to-end integrated biopharmaceutical solutions for customers. We have also gained the experienced leadership and dedicated team at Paragon, who will continue to run the business going forward, bringing their expertise and capabilities to the Catalent family.”

	Thermo Fisher Scientific Inc. took a major step into the viral-vector manufacturing arena with the announced purchase of Brammer Bio, a leading viral vector CDMO, with 600 employees and locations in Massachusetts and Florida. The purchase agreement, announced in a March 24, 2019 press statement, is for approximately $1.7 billion in cash. Brammer Bio joins Patheon, acquired in 2017, and Fisher Clinical Services, which have been combined to form the Thermo Fisher’s Pharma Services business (3).

	The acquisition enhances the company’s pharmaceutical and biotechnology customer value proposition by combining cell-culture media, single-use bioprocessing capabilities, analytical instruments, and related consumables. “Brammer Bio is an exciting addition to our Pharma Services business. By sharing our combined capabilities, expanding commercial scale and broadening deep customer relationships, we will strengthen our position as a trusted partner to our pharma and biotech customers. We will accelerate advancements in gene and cell therapy, meet the increasing demand of the customers we serve and bring life-changing medicines to patients in need,” says Murphy.

	Viral vectors are crucial to gene therapy because they deliver the therapy into the patient. “Viruses are evolutionarily designed to enter mammalian cells and reproduce themselves. Gene therapy harnesses this feature to transport the genetic material-or ‘active ingredient’-to target tissue or cells. Viral vectors are engineered to be safe for humans and can target specific cells or tissues in our bodies to maximize the effect of the treatment,” says Murphy. Thermo Fisher Scientific’s acquisition of Brammer Bio’s viral vector process development and manufacturing leverages capabilities in the company’s biologics business.

	Clark also emphasizes the importance of viral vectors. “During gene therapy biomanufacturing, cells package the therapeutic genetic material into viral vesicles and secrete the vesicles into the media to be purified, then undergo formulation development to be ultimately filled into a vial or syringe,” says Clark. According to Clark, however, few innovators have the capacity, expertise, or resources to manufacture viral vectors. Catalent’s acquisition of Paragon helps the company manufacture viral vectors for their clients. “There are several types of viral vectors that can be utilized for gene therapy. Adeno-associated virus (AAV) is the vector most commonly used today in clinical trials and approved gene therapies, due to its safety and tissue-specific targeting abilities, and Paragon is one of the leading development and manufacturing providers for AAV vectors,” says Clark.

	In May 2019, Thermo Fisher Scientific announced that it is investing more than $50 million into its global bioproduction capabilities. The expansion will provide additional capacity for manufacturing single-use bioprocess container (BPC) systems. In Cramlington, United Kingdom, the company will expand assembly capacity and add BPC systems manufacturing. The proximity of these capabilities to customers in Europe will shorten lead times and improve overall global efficiency, according to the company (4).

	In the United States, the company will expand cleanroom space for BPC chamber and related assembly production processes at its site in Logan, UT, and further expand capacity at its site in Millersburg, PA. Construction is expected to be completed by the end of 2020.

	“The demand for our bioproduction products and services continues to outpace the market,” said Cory Stevenson, president of Thermo Fisher Scientific’s bioproduction business, in a company press release. “These investments will expand capabilities across our existing bioproduction network while we look to extend our footprint into new regions to meet increasing customer demand for our industry-leading single-use technologies.”

	To further develop its biologics offerings, Catalent is launching OneBio Suite, a new offering for the integrated development, manufacturing, and clinical supply of biologic drugs. The Suite is designed to address challenges that arise when accelerating programs to clinic or market, while also Â­reducing Â­complexity and risks from projects. The OneBio Suite is built on Catalent’s track record in biologic drugs development, which includes more than 115 global clinical trials and 11 commercially marketed monoclonal antibodies using the company’s GPEx cell line development technology, and 20 approved products through fill/finish and commercial supply to global markets, the company reports. According to Clark, the company has multiple initiatives in the works to shorten timelines and increase efficiency (5).

	“Time is often lost for sponsors on the path to clinic from contract negotiation, site inspections, handoffs, and poor communication between multiple vendors,” commented Clark in a press statement announcing the service. “Through our new OneBio Suite, Catalent is uniquely positioned to provide an integrated offering that can accelerate biologic development potentially shaving weeks to months off standard timelines and allowing our customers to get to clinic and market faster.”

	1.  FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies,” 

	2. Catalent, “Catalent To Acquire Gene Therapy Leader Paragon Bioservices, Inc. for $1.2 Billion,” Press Release, April 15, 2019.

	3. Thermo Fisher Scientific, “Thermo Fisher Scientific to Acquire Brammer Bio, a Leader in Viral Vector Manufacturing,” Press Release, March 24, 2019.

	4. Thermo Fisher Scientific, “Thermo Fisher Scientific to Invest $50 Million to Expand Bioproduction Capabilities,” Press Release, May 20, 2019.

	5.  Catalent, “Catalent to Launch OneBio Suite For Integrated Biologics Development, Manufacturing and Supply at BIO International 2019, Press Release, May 23, 2019.


	Vol. 43, No. 7
	July 2019
	Pages: 52-53

	When referring to this article, please cite it as S. Haigney, "Gene Therapies Propel Outsourcing Investment," 

The increasing growth in the cell- and gene-therapy markets is inspiring CDMOs to expand their services in this emerging biologic drug arena. 