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

Susan Haigney

The bio/pharmaceutical industry is a global network that ties together an array of developers, manufacturers, and suppliers. Bio/pharmaceutical companies, therefore, may source APIs and excipients from companies thousands of miles away. This global aspect of the industry, naturally, creates a complex supply chain that could leave patients vulnerable if not properly overseen. The discovery of nitrosamine impurities, including N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), found in angiotensin II receptor blocker (ARB) medicines (1) in 2018 is an example of how ingredient issues can affect patients and the supply chain and the importance of testing ingredients. Now, the global COVID-19 coronavirus pandemic has the potential to disrupt supply chains, site inspections, and other activities associated with supplier qualification and oversight.

	Sponsor companies and manufacturers are responsible for ensuring the components they use are safe and effective. FDA has cited companies for failing to test their incoming API and raw materials “to determine their identity, purity, strength, and other appropriate quality attributes” (2). According to a spokesperson for IPEC-Americas, sponsor companies must verify the quality of materials, which includes qualification of the supplier through on-site good manufacturing practice (GMP) audits and/or a third-party GMP certification. Incoming materials should have their identification verified and the quality department should give its approval to release the materials for use. This includes performing-at a minimum-an identification test, and may include other tests necessary to ensure the quality for the intended use as per 21 

	Risk assessments of both suppliers and materials should also be performed, according to IPEC-Americas, with a specific focus on the intended use of the material. The risk assessment should also evaluate possible concerns with efficacy, variability, safety, and quality. And this evaluation should not end with the risk assessment. The sponsor should “[establish] a process for continued monitoring of the supplier and the quality of incoming materials,” according to IPEC-Americas.

	How do sponsor companies choose and monitor material suppliers to ensure the ingredients they are purchasing are fit for purpose? Linda Evans O’Connor, vice president and chief of staff at Lachman Consultant Services, Inc., suggests that sponsors start by obtaining information from the supplier about its capabilities and compliance history through a questionnaire. Material samples should also be obtained to determine if they are fit for their intended purpose. Site audits should be performed, and quality agreements should be put in place, she says. Finished product trials should be performed if the materials meet the requirements. Batches should then be tested for stability. Periodic monitoring of the supplier should be performed with data reviewed on a predefined basis in addition to performing surveillance audits, according to O’Connor. IPEC-Americas stresses, however, that an appropriate risk assessment cannot be performed without onsite audit information. 

	Susan J. Schniepp, executive vice-president of post-approval pharma and distinguished fellow, Regulatory Compliance Associates, says that companies should begin the qualification with an onsite audit. “Once the audit is performed and any identified concerns resolved, the two parties, purchaser and supplier, can enter into a quality agreement. After the quality agreement is approved, the purchasing company can start the process of ‘qualifying’ the supplier. This qualification usually involves testing of the material to confirm the supplier’s certificate of analysis (CoA) is accurate and develop a history that demonstrates the ability of the supplier to continually provide a suitable product,” says Schniepp.

	The supplier should then be placed on an approved supplier list, according to Schniepp. “The initial qualification for a supplier to be considered an approved supplier usually involves complete confirmatory testing on the first 10 lots of material received and then a periodic check and confirmation by the purchaser of the entire testing regimen listed on the CoA received from the supplier.”

	Performing audits of material suppliers is key for ensuring the quality of materials, but how often should these audits be performed? O’Connor suggests that a risk-based approach should be used to determine when and how often a supplier is audited. “Many factors can go into the risk model, such as type of material (e.g., API, excipient, sterile, non-sterile, complex dosage form, etc.), location, past regulatory or audit history, recalls, quality of incoming goods, complaint history, importance to the business of the materials (i.e., Is this an API for your blockbuster drug and lack of supply would have a material impact on the business?). A minimum frequency per material type should be defined (i.e., for an API, every two years),” O’Connor says.

	IPEC-Americas agrees. “Whether the supplier is an excipient manufacturer, contract manufacturer, distributor, or service provider (e.g., a contract testing lab), the initial audit frequency should be based on results from the initial supplier/excipient risk assessment along with any additional mitigation measures identified. Based on on-going monitoring, a sponsor company should determine whether to adjust the audit frequency.”

	A quality risk management plan is key, agrees Schniepp. Frequency of audits should be based on the criticality of the material and the past performance of the supplier. “This plan should identify supplier vulnerability (i.e., single source, secondary supplier, etc.), which should help determine audit frequency. The quality agreement should reflect the risk plan but there should always be a contingency to allow for-cause audits as needed. Laboratories used by either the supplier or the purchaser should be audited and included as an element of the risk plan,” says Schniepp.

	Auditing under difficult circumstances. Having a consistent and properly executed audit program is paramount to maintaining the timeliness and integrity of the supply chain, says Schniepp. Audits, and the information obtained during them, allow one to assess a supplier’s risk, especially during crises such as the COVID-19 pandemic. “Having the baseline knowledge of your suppliers’ operations will help assess where critical resources need to be allocated during a crisis period. While not ideal, audits can still be performed on suppliers through the use of questionnaires and video conferencing. If visuals are required for the supplier assessment, the use of an electronic device or video streaming options could be employed. Bottom line, to keep the supply chain viable during crisis mode we need to think outside of our normal operating procedures and experiences,” says Schniepp.

	If travel is limited due to global situations such as the COVID-19 epidemic, O’Connor suggests getting creative. “For example, performing a virtual audit, while not ideal, is a possibility, and would require cooperation of the sponsor and the manufacturer. Document review and interviews can be performed remotely. Companies could even look at virtual facility tours using appropriate technology. However, these types of audits are not ideal, and shouldn’t replace on-site audits. Another solution is to partner with a local company that has the local resources to perform the on-site portion of the audit. This will allow on-site audits to occur even when international travel bans are in effect,” says O’Connor.

	CoAs provide manufacturers with detailed information about materials including material manufacturer, quality testing information, specifications, batch numbers, and other information (3). FDA has been known to cite companies for incomplete or incorrect information on CoAs (4). So, how reliable are these documents and how much emphasis should sponsors put on them when it comes to ensuring material quality?

	O’Connor suggests that sponsor companies create a library of CoAs or labels so they can verify that the information is correct. “Also, maintaining a relationship with suppliers is key. Anything unusual needs to be flagged,” says O’Connor.

	Building trust between the sponsor and supplier is important, agrees IPEC-Americas. “A robust supplier qualification program, including an onsite GMP assessment of a supplier, by either the sponsor or a qualified third party, and development of a partnership with the excipient supplier are necessary to establish and build trust in the validity of their CoA.”

	Annual confirmation testing of CoA results is also necessary, says IPEC-Americas (5). “Full testing of an excipient is required until a robust supplier study has been completed and a reduced testing program has been approved. Only once trust has been established can the sponsor move to a reduced testing program. However, identification testing is always required to ensure the identity of incoming materials.”

	To establish that the quality testing information included in the CoA is accurate, incoming materials must be tested against the requirements in the CoA, Schniepp insists. “The best way to ensure the CoA is accurate is through complete testing. In cases of falsification of the CoA, results testing is mandatory to make sure the material is suitable for use; however, it must be coupled with a review of the supplier’s overall quality system. Even if the material meets the testing qualifications listed on the CoA, it may not be suitable for use due to other potential GMP violations that might be present at the supplier facility,” she says.

	“In the case of falsification, the purchaser should be concerned with data integrity issues that lead to the falsification in the first place. If a purchaser suspects a supplier is falsifying the results on a CoA they need to initiate a for-cause audit and quarantine the suspect material until they can confirm it was satisfactorily manufactured following cGMP expectations. Passing test results does not confirm compliance to cGMPs,” Schniepp explains.

	Many drug sponsors engage contract manufacturing organizations (CMOs) to conduct drug production steps. So, what is the CMO’s responsibility in ensuring that materials are safe and effective?

	O’Connor says that while both sponsors and CMOs share responsibilities, the sponsor has the “ultimate” responsibility of its supply chain. “Sponsors and CMOs share responsibilities, but the selection, qualification, and oversight of suppliers is the sponsor’s responsibility, whereas day-to-day testing is generally the CMOs/CDMOs, although sometimes that goes to the sponsor as well. The sponsor has ultimate responsibility for the entire supply chain, so even if it delegates part of that responsibility to the CMO/CDMO, it is ultimately responsible.”

	Sponsors must ensure that they have signed agreements in place with any CMOs and/or CDMOs they are using that identifies the responsibilities of each party when it comes to ensure the quality of materials, according to a spokesperson for IPEC-Americas.

	Both sponsors and CMOs/CDMOs must have an active role, according to Schniepp. “The specific level of involvement of the sponsor may depend on the confidence they have in the CMO/CDMO organization. The CMO/CDMO should make sure they involve the sponsor in decisions involving material quality, so the sponsor is aware of the impact on their product,” says Schniepp.

	Maintaining a safe supply chain is crucial in the bio/pharmaceutical industry. The efficacy and safety of the materials used in drug products is of utmost importance. And it is the sponsor’s responsibility to ensure the quality of all materials used in their products. Sponsors must not rely on others to ensure quality, says O’Connor. Also, not all suppliers should be treated the same. “Clearly, some suppliers have greater risk than others, either based on the product type, location, etc. These suppliers should receive more scrutiny,” she says. Sponsors also must not cut corners or do what is convenient, says O’Connor. For example, she notes, it is inconvenient, but necessary to audit suppliers in China and India. In addition, sponsors should also not make supplier decisions based on price or availability instead of quality and safety, says IPEC-Americas.

	Communication is key to supplier oversight, says Schniepp. “Both parties need to be willing to talk as frequently as needed to address issues before they manifest into a disruption in the supply chain. The frequency of these conversations are not necessarily defined in a quality agreement. They are important in establishing an open relationship between the supplier and the purchaser so issues can be solved before supply chain disruption occurs. Not all problems can be solved through the terms included in the quality agreement and both parties must be willing to work outside the defined ‘communication schedule’ of the quality agreement to avoid unnecessary supply-chain interruptions.”

	1. FDA, “FDA Statement on the FDA’s Ongoing Investigation into Valsartan and ARB Class Impurities and the Agency’s Steps to Address the Root Causes of the Safety Issues,” Press Release, Jan. 25, 2019.
	2. FDA, 

Warning Letter to Henan Kangdi Medical Devices Co. Ltd, MARCS-CMS 587699

Warning Letter to Spectrum Laboratory Products, Inc.,

 MARCS-CMS 579958, July 31, 2019. 
	5. FDA, 21 

 211.84(d),  Title 21–Food And Drugs, Chapter I–Food And Drug Administration, Department Of Health And Human Services, Subchapter C–Drugs: General, April 1, 2019. 


	Vol. 44, No. 4
	April 2020
	Pages: 72–76, 83

	When referring to this article, please cite it as S. Haigney, "Being Vigilant in Supplier Oversight," 

Articles

Risk assessments, audits, and good communication between sponsor and supplier are key elements of supplier oversight.


Being Vigilant in Supplier Oversight

Biologics, including cell and gene therapies, have continued their upward trend in the pharmaceutical industry in the past few years. Pharma companies are investing in these therapies, and FDA has been encouraging the development of generic versions of already established biologics (1). Biologics, however, are costly to develop and manufacture, causing a variety of pharmaceutical companies to turn to contract development and manufacturing organizations (CDMOs). In response to this demand, CDMOs are continuing to invest in biopharmaceutical services and manufacturing facilities.

	“The industry is investing in an increasing number of API biologics (cell, gene, vaccine, and virus therapies), although this still accounts for a low proportion of CapEx [capital expenditure] projects in the period 2019–2025 (7%). The use of cell and gene therapies in the market is not well established, and the required manufacturing costs and level of expertise are high. CapEx projects involving API chemical or commercial solid-dose manufacturing as a percentage of total CapEx has decreased between the period 2016–2018 and 2019–2025,” says GlobalData Analyst Adam Bradbury.

	Shiva Khalafpour, vice-president, head of Commercial Mammalian and Microbial Development and Manufacturing at Lonza, agrees. “The biotechnology sector is projected to grow faster than the conventional pharma sector (9% vs. 6% CAGR [compound annual growth rate] 2019–2024). The strong venture capital funding for biotech companies will continue to support a healthy growth that positively impacts the outsourcing sector.”

Gene Therapy Market Opportunity for CMOs–2019 Edition

, shows an investment by CDMOs in greater capacity for anticipated gene therapy pipeline products, either through acquisitions or building facilities (2). “Some pharma companies including Pfizer and bluebird bio are also investing in gene therapy manufacturing facilities for excess capacity contracts or for in-house manufacturing of proprietary therapies. Cobra Biologics Ltd, Symbiosis Pharmaceutical Services Ltd, Novasep, LakePharma, Oxford BioMedica Plc, and Sanofi have also made recent major investments in gene therapy manufacturing, especially in viral vector manufacturing for gene transfection,” says Fiona Barry, editor, PharmSource, a GlobalData product.

	According to Eric Langer, president of BioPlan Associates, CDMOs offer expertise, cell and gene therapy processes, personnel, and capacity that pharmaceutical companies may not have. “In our research on the make-vs-buy decision process, we have found that many companies decide early in their development that they intend to become a fully integrated bio/pharma company, including seeing manufacturing as a core competency.  Others see manufacturing as potentially outsource-able and not part of their core competency. Still others need the flexibility to decide their manufacturing strategy as their pipeline develops and as their investment situation unfolds.  Nearly a third of biologics are produced using CMOs [contract manufacturing organizations] and CDMOs, and these organizations are now an integral and indispensable part of the industry,” says Langer.

	How has the push toward biologics changed or added to the processes pharmaceutical companies are outsourcing and CDMOs and CMOs are offering? According to Bernie Clark, vice-president, Marketing and Strategy, at Catalent Biologics, the contract industry will continue to evolve to meet the needs of the developing biologics market and to support the trend of personalized medicine.

	“Next-generation biologics, such as ADCs [antibody-drug conjugates], bi-/multi-specifics, gene therapy, and cell therapy, are growing sectors of the biologics industry, and providers are adding capabilities to support the unique needs of these novel modalities. For example, new analytical techniques are being developed to support these new therapies, and providers are evaluating whether it makes sense to adopt them as part of their offerings. Other capabilities being evaluated include potential process improvements, such as continuous manufacturing and automation, and providers are conducting cost-benefit analyses for adopting these technologies into their platforms. One driver to adopt continuous manufacturing, but also a more general industry trend, is the shift toward biologics that treat smaller patient populations, such as therapies that address orphan indications. This shift has resulted in a movement towards manufacturing smaller batch sizes, which has led to more investment in smaller bioreactors, with a heavy emphasis on single-use technology,” says Clark.

	Catalent has been evaluating possible new capabilities, says Clark, and acquired Paragon Bioservices as part of their expansion into the gene therapy market. “On the technology front, we adopted the Beacon system from Berkeley Lights to expedite clonal selection and improve titers for monoclonal antibodies and Fc fusion proteins. However, it is not enough to just acquire the right equipment or technology; contract organizations also need experts who are knowledgeable and experienced in the challenges that need to be addressed. We are focused not only on adopting new technologies for our customers but also on hiring or building the right expertise to support them across our global network,” says Clark.

	“Cell and gene therapy manufacturing is, of course, relatively new to the biopharma industry, and these will be seeing significant increases, especially as the cell and gene therapy innovators move their pipeline toward commercialization. As demand for clinical capacity increases, there will be a potential capacity crunch for CDMOs capable of meeting these needs.  But doing so will require having the skilled staff capable of work in this segment. And hiring of these experts is becoming increasingly challenging,” says Langer.

	According to Langer, the next two years will see more analytical testing being outsourced. “From our annual report (3), we find that analytical testing, including bioassays, leads the list with 32.8% indicating they will be doing more.  Following is cell line development (24.1%) and cell and gene therapy production (23.4%). Fill/finish operations appear to be contracting slightly over the past five years, from a high of 27.8%, indicating an decrease in outsourcing, to 19.7% this year who plan more fill/finish outsourcing over the next two years. Downstream process development is on the rise in terms of outsourcing trends. Validation services, on the other hand, have declined somewhat over the past nine years.”

	Khalafpour sees strong growth in mammalian-derived molecules, which may require the services CDMOs can provide. “Based on market assessment, mammalian appears to remain the preferred production technology with the highest growth potential due to pipeline increase and improvements in manufacturing technology,” says Khalafpour. Small and virtual biotech companies are expected to own these molecules, according to Khalafpour, and these companies may not have the expertise or services needed to produce these products. “In addition, the development and manufacturing of biopharmaceuticals is getting more complex in terms of production processes and regulatory environment while forecasting remains uncertain,” says Khalafpour.

	Lonza has announced the acquisition of a sterile manufacturing facility in Stein, Switzerland for clinical production and commercial launch of parenteral drugs, according to Khalafpour. The company is also building a development and manufacturing facility in Gaungzhou, China.

	Development of new and more complex molecules are in store for the industry, according to Khalafpour. Clark sees biosimilars as the next trend in outsourcing because of the amount of innovator products coming off patent and the unique needs associated with analytical testing. The promise of next-generation biologics is also becoming evident, according to Clark. “Mid/large pharma companies are taking notice and acquiring companies and molecules to expand their pipelines. The shift in focus to these new therapeutic classes may impact the types of programs that a sponsor company outsources. For example, they may choose to outsource the manufacturing of monoclonal antibodies or recombinant proteins that they had previously manufactured in-house to free up internal resources to focus on their next-generation therapies,” says Clark.

	Khalafpour agrees. “As far as drug manufacturing is concerned, we see smaller production volumes driven by personalized medicines, highly active compounds, [and] higher titers as well as continuous manufacturing and process intensification.”

Statement on Efforts to Help Make Development of Biosimilar and Interchangeable Insulin Products More Efficient

PharmSource–Gene Therapy Market Opportunity for CMOs–2019 Edition

, December 2019.
	3. BioPlan Associates, 

16th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


	Supplement: Partnering for Bio/Pharma Success
	February 2020
	Pages: s4–s8

	When referring to this article, please cite it as S. Haigney, “Growth in Biologics Market Inspires Outsourcing," 

Pharmaceutical Technology Partnering for Bio/Pharma Success 

CDMOs and CMOs will continue to invest in biopharmaceutical services and facilities as the bio/pharmaceutical industry looks to biosimilars and personalized medicine.

Growth in Biologics Market Inspires Outsourcing

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," 

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.