As the need for innovation in drug development is increasing, so too is the requirement for companies to partner with a contract development and manufacturing organization (CDMO) early on in development. To find out more about the importance of considering the end-user and the role of an outsourcing partner in successful drug development, 

The panel of experts includes Lonnie Barish, vice-president, business development and marketing, Bora Pharmaceuticals; Richard Shook, director, drug product technical services and business integration, Cambrex; Steven Winling, product development technical specialist, Catalent; Manuel Leal, business development director, Idifarma; Frederique Bordes-Picard, manager, business development for innovative products, Capsules and Health Ingredients, Lonza; Rob Lee, president, CDMO division, Lubrizol Life Science Health; Paul Kippax, pharmaceutical sector director, Malvern Panalytical/Amplify Analytics; Jeremy Drummond, senior vice-president, business development, MedPharm; and Torkel Gren, science and technology officer, Recipharm.

 How are companies taking the end users’ opinions and preferences into consideration, in terms of drug dosage forms?

 When recommending solutions to product development challenges or performing routine release testing, the patient should be at the center of everything. It is important to work with external collaborators to uncover the needs of the patient groups being served. When patient preferences are not known, a patient first culture helps companies ask the right questions from the very beginning of a dosage form development project. It is important to make sure that the needs of the patient and the challenges of the molecule are well understood and taken into consideration when building any development plans. When the product profile has been determined, all scientists working on a development project should understand the patient needs that the formulation they are working on must address.

Kippax (Malvern Panalytical/Amplify Analytics):

 Once an API that demonstrates appropriate efficacy against the pharmacological target has been developed, a key requirement for getting the product to market is to formulate the API appropriately to maintain its efficacy, whilst taking patient preferences into account. Both patient compliance and the chosen market, and its associated local restrictions and requirements, can impact the selection of a particular dosage form. Complex formulation techniques are crucial for ensuring the maintenance of bioavailability, which often brings significant characterization challenges.

 There are examples of how companies are trying to get a better understanding of user preferences. It has been a common practice to use taste panels for selection of suitable taste-masking for a long time. However, today there is interest in going much deeper than just taste and skin feel. It is important to understand how the product as a whole is perceived by the patient in a realistic dosing situation, which may vary widely for different patient groups. To understand this [perception], it is necessary to form focus groups with patients and use qualitative and quantitative methods to evaluate preferences.

 The end users’ opinion and preferences are crucial from the start. These factors should be incorporated into the product profile established from the very beginning. That said, the product profile ought to also consider the API, which may limit options for patient suitability. The expertise of the product developer allows them to manage these constraints whilst still delivering a dosage form that patients are happy to use. This knowledge is particularly important for smaller companies, where it is not uncommon for some to not have thought about end users’ preferences, particularly at the early stage of a project. As patient preferences can be fully understood once a project has started, these new insights can be accounted for within the product and incorporated into any project goals.

 Patient compliance should always be a priority when developing a drug dosage form. When developing a new dosage form, pharmaceutical companies should take the targeted patient population into consideration to better understand how the final drug product will be received and dosed.

 Patient compliance will dictate design of the dosage form. It must be integral/intrinsic to any drug development strategy because compliance and getting the desired effect is paramount. Each dosage form presents its own challenges and that is further complicated by the API. Drug developers should start with the ideal patient delivery for that form and then work on issues with the API to get as close as possible to that ideal delivery. Fortunately, new techniques and mechanisms have or are being developed to deliver challenging APIs towards those ideal forms.

 More attention is being paid to this area through the formation of user groups, talking to key opinion leaders in the medical profession and then getting feedback from the end-user patient. From a marketing perspective, end-user input is key if the plan is to reposition marketed drugs to be more patient-centric.

 Manufacturers are more connected to patients than ever through representative associations and discussion forums, which allows companies to better understand patient preferences and limitations. Much of the discussion is focused on chronic diseases, but it could be extended to additional areas such as oncology and respiratory diseases.

Pharma companies are also collaborating more. A notable example of this is the use of connected devices to improve compliance but also to get rapid and direct feedback from the patient. The key for outsourcing partners, if they are to thrive, is to use the data and look at products in a more holistic manner so that they can design and develop the most effective, patient-centric dosage form.

 What role can/does an outsourcing partner play in optimizing a drug dosage form?

 Optimizing a formulation against delivery requirements is extremely complicated. The use of 

 approaches for assessing bioavailability is increasingly becoming accepted, but the physicochemical analysis techniques required are complex, and the specific knowledge required to get the most out of this type of characterization is not always present within pharma development companies. Hence, the increased propensity of organizations to select outsourcing partners who can address these knowledge and capability gaps.

When optimizing the dosage form, it is no longer sensible to simply rely on the data output of a scientific instrument. Coupling an understanding of the requirements of industry analytics with knowledge of how to maximize the output from analytical instrumentation and methods is critical. To increase development efficiency, pharma companies are now able to establish relationships with a wide range of technical partners to generate actionable data and direction they can consistently rely upon. This [capability] allows nonviable molecules or formulations to be eliminated early in the workflow, focusing attention and budget on those candidates most likely to succeed at all points in the pipeline.

 Choosing the right outsourcing partner is essential for the development of many drugs, because both technically and economically, it is the most sensible approach for many pharmaceutical companies that don’t have the knowledge or capabilities in-house. Finding a CDMO that meets the technical requirements of the product to develop as well as being the right fit for the client is not easy. For example, there are cases where working with a smaller, more specialized partner is the best decision, because the projects are managed closely with the client for quicker decision making and less delays.

 A reliable CDMO outsourcing partner should bring a wealth of drug dosage-form experience to the table. They should be able to balance innovative problem-solving with decreased complexity. An expert CDMO can fill manpower, knowledge, and capability/capacity gaps in the drug development process for smaller or virtual companies and offer efficiencies of scale for larger pharmaceutical companies.

 A sponsor really benefits from an outsourcing partner when there is an open relationship, allowing for collaboration during the development of a treatment. The outsourcing partner provides the sponsor access to specialized technology and expertise needed to develop novel dosage forms as well as access to a wide range of capabilities.

 It’s clear that one of the biggest changes to the pharma manufacturing industry is the increasing reliance on external partners. The shift has been positive for the entire pharma supply chain by promoting quality, innovation, and more efficient drug development and commercialization routes.

Pharma is also relying more on CDMOs to develop and manufacture increasingly complex drugs. It’s well known that more experienced project teams can help accelerate go-to-market schedules, and technical/operational mastery is a prerequisite. However, unlocking an API’s therapeutic value requires sound science, experienced technical expertise, and operational excellence to do it well and meet all commercial, financial, and regulatory expectations.

Companies have been engaging international manufacturing partners for a number of reasons. Some of the initial drivers have been access to lower-cost manufacturing and proximity to emerging markets. While managing costs has been a central theme, access to capacity, technical capabilities, and cutting-edge science have also prompted many partnerships, especially for more commoditized and high-volume products. Securing strategic experience and expertise is a big part of this trend.

 Ideally, your CDMO will have broad experience working with different routes of administration and a variety of different drugs, from a physical and chemical perspective. Experience with a range of dosage forms creates a wider perspective that can add significant value to your project.

Non-traditional dosage forms bring an added layer of complexity to a drug development project, requiring additional technology and expertise. An outsourcing partner’s experience with these kinds of challenges can ensure that technologies work more effectively, and any issues are anticipated early on.

 For specialist dosage forms, such as topical products for eye, skin, airways, or mucosal membranes, working with an outsourcing partner has many benefits. The requirements for delivery are quite different from oral and intravenous routes of administration and require unique knowledge and experience that the majority of development companies do not have in-house. In particular, the sophistication of in-vitro models using human tissue, in the development of these products has greatly de-risked these development programs. What is also gained with a specialized contract developer is not only the formulation development experience in a specific area but also an in-depth understanding of what it takes to get a product to market, whether it is a new chemical entity, a repurposed drug for a new indication, an over-the-counter product, or a generic.

 CDMOs can provide access to more technology and competence for dosage-form development locally as well as globally. As well as accessing technical capabilities and a global manufacturing network, pharma companies can also access years of development expertise. Outsourcing also provides the organization with more flexibility to focus on core competencies such as further R&D. Those CDMOs that offer both development and commercial manufacturing services can help guide customers’ molecules from concept to market. Developing the dosage form with manufacturability in mind can have many benefits. Working with an end-to-end CDMO can help to reduce complexity and timelines and ensure smoother progress of a drug to market.


Supplement: Outsourcing Resources
August 2020
Pages: s6–s9

When referring to this article, please cite it as F. Thomas, “Opening the Door to Successful Drug Development,” 

Articles

Development

The right outsourcing partner should open up access to expertise and technical capabilities in a broad range of dosage forms to ensure commercial success.

Opening the Door to Successful Drug Development

The early promise offered by cell therapies and gene therapies that have thus far been approved by regulatory authorities is tempered by the challenges associated with developing, manufacturing, and delivering these types of therapeutics to patients. The complexities of producing these therapies are testing established practices—from starting materials, to process development, to current good manufacturing practice (CGMP) compliance, to supply chain security and reliability.

In a recent webcast, “Editors’ Series: Overcoming Commercialization Challenges for Cell Therapies and Gene Therapies,” held by 

 in conjunction with INTERPHEX on July 28, 2020 (1), industry experts discussed the challenges of bringing new cell and gene therapy products to market. Thomas VanCott, global head of product development at Catalent Cell & Gene Therapy; Alan Moore, chief strategy officer, The Discovery Labs; and Christopher Murphy, vice-president and general manager, Viral Vector Services, Thermo Fisher Scientific shared their insights on the major issues facing the cell and gene therapy sector.

Cell therapies, which are still “young” in the biopharmaceutical marketplace, in particular face many technical challenges moving from the clinical stage to commercial stage. Manufacturing a cell therapy is complex and involves multiple sequential steps, for example, from preparing the sample, to washing, to selecting the right phenotypes, to activation, to the transduction step, to expansion, to harvest, to formulating the product, noted VanCott in the webcast.

“In the clinical steps, these are often done in open steps with a high amount of labor and a high risk for contamination. When we think about scaling this to commercial, one of the things we really need to be thinking about is how to simplify and automate the process, and to go from open systems to more closed systems,” he said. VanCott pointed out that moving toward more automated closed systems can reduce labor cost and reducing the probability for contamination.

“We also need to look at the analytics. As complex as the manufacturing processes can be, so are the assays. To be able to optimize and validate assays, especially some of these potency assays and the phenotyping assays, is a challenge for this field,” VanCott added.

Other technical challenges for cell therapies, particularly autologous cell therapy, is dealing with the inherent variability of the starting material and the fact that there is often very little starting material to work with, Moore chimed in. “Often, there are very little materials available to conduct the studies needed to establish robust processes. In some cases, you can’t use normal human donor cells in lieu of the disease-state cell, so autologous products are certainly challenging,” Moore observed.

Moore noted that there are ways to attempt alleviating these challenges, such as the inherent variability issue, to some extent by, for example, providing kits, establishing processes at the sites where the raw material (cells) are collected, and also by ensuring that the vein-to-vein logistics are established. Furthermore, it is important to coordinate these logistics with the manufacturing schedule. Maintaining chain of custody, maintaining chain of identity, and also being able to come up with an effective manufacturing and distribution network are ways to alleviate stresses on the system, he said.

Capacity constraints for future cell and gene therapies

A big question for the cell and gene therapy market is, will existing or planned capacity for viral vectors meet the needs of the market moving forward?

Looking at the current success of cell therapies and gene therapies on the market today and taking into consideration that a large number of candidates are in development for future potential entrance into the market, there is currently insufficient capacity to meet anticipated demand, said Murphy.

One reason for the shortfall, Murphy pointed out, is that the facilities that were used for more common proteins and monoclonal antibodies (mAbs) are not well suited to do viral vectors manufacturing because of the need for specific requirements, such as a biosafety level 2 requirement, airflow considerations, and certain unique elements in the manufacture of viral vectors that are not needed with mAb manufacture. Another reason is that, for the volumes needed, yield is low, meaning that a significant amount of capacity is required just to make enough to meet the patient population. “I think capacity is growing, and certainly there is much investment, but if you look at the trajectory of the market that could be $17 billion by the end of this decade, there is going to be a need for more capacity,” Murphy asserted.

“The analysis I’m seeing of the market is that capacity is not going to be enough in the therapeutic indications that are growing, particularly as gene therapy moves to treating more commodity-type indications and indications that are not rare diseases with small populations. If we’re going to be seeing that, then we really need to drive up capacity as well,” Murphy said.

Moore agreed with Murphy’s assessment. “I’ve seen estimates right now where we’re looking at a capacity shortfall of five times what is needed, and in five years the market is going to be 50 times underserved. Now that assumes success of the cell and gene therapy field, but we’re beginning to see early success with indications that require massive doses of vector. I think we’re going to continue to need to build out capacity and continue to focus on improving yield per square foot,” Moore stated.

Moore explained that, to some extent, these fields of medicine were ignored for more than a decade because there was considerable doubt as to what the long-term future was for gene therapy, and certainly for cell therapy there was limited investment. “Now that folks are focused on making product that are going to serve a very large industry, I think we’ll see progress,” he affirmed.

VanCott concurred that capacity is not sufficient, but that the industry is seeing some movement towards building up needed capacity. “I think my colleagues stated it very well, but we (Catalent) have spent, and others have spent, much time looking at this market, and it is pretty remarkable. If you take a snapshot of all products, say, in preclinical development and add some success rates that we’re seeing so far in the market, and you use average doses for systemic vs. localized products, you get to see some staggering volume rates,” VanCott observed.

“If you then look at the supply that’s out there and take into account the new growth, there is much investment in additional capacity. Furthermore, if you take into account the potential for better efficiency, higher yield—which do happen, and is happening continually—it will still come out to be that demand will outstrip the supply,” VanCott continued. “So, I think a couple of things can happen. I think we will see more capacity, and I think we will see a drive by many companies out there to continue to invest in processes that can enhance and increase the yields that we’re getting. Certainly, it’s a challenge for all of us that are in the field, and we’re going to strive to scale up capacity to meet the demand.”

Cell and gene therapy drug developers facing manufacturing challenges while bringing a product candidate to market may benefit from looking at the well-established world of mAb manufacturing. The key to the growth of commercial manufacturing for mAbs lies in the heavy investments made in engineering technologies, said Murphy. The cell and gene therapy fields are, today, still heavily focused on the R&D stages in the development of manufacturing processes, but not so much focused on investing in the engineering element for scaling up and improving yields, he adds. In comparison, focus on engineering investments have been a big focus by industry for the commercial manufacture of mAbs.

“I think there’s something to be said about that kind of investment and that expertise used to drive up yields, instead of, what I call, more classical, empirical approaches where we’re trying different ratios of plasmids and transient processes, and so on, for instance,” Murphy said. There is something to be learned from the investment focus of mAb production. Murphy observed that companies are starting to invest in the process engineering side of cell and gene therapy manufacture, which is a positive development.

In return, the mAb manufacturing industry can learn from the cell and gene therapy innovators, which are improving analytics. One example is the advancement of analytics that can support the testing and release of viral vector molecules for gene therapy. In addition, there are some innovative rapid testing techniques being developed in the cell therapy field that are advancing sterility assurance. “In addition, because we are dealing with a very single-use-technology-heavy industry, I think there will be things we’ll learn in making vectors and scaling up these technologies that can be applicable to mAbs and recombinant protein manufacturers,” Murphy stated.

Meanwhile, Murphy believes that some testing methods and analytical techniques from mAb manufacture can be leveraged to benefit cell therapy manufacture. “There may even be some facility design and features from mAbs that we can leverage,” he added.

For gene therapy manufacturing, a focus on engineering and the idea of using formal mixing studies to ensure an understanding of the dynamics present in a transfection event—both of which have been used in the mAb industry for years—can be highly applicable to the scale up of gene therapies, Murphy also observed. “The good news is, we’re already using scalable technologies to make vectors, and we’re moving away from ultracentrifugation. By doing these things, I think we’ve already leveraged some of the mAb bioprocessing technologies in the cell and gene therapy fields.”

In addition to challenge of capacity constraints, cell and gene therapy commercial manufacturing faces an issue of starting materials supply. In going from clinical to commercial phases, will supply of starting materials be enough for scale up or scale out?

VanCott emphasized that, when discussing viral vector production for gene therapy, it must be taken into consideration that supply and demand for the starting materials for these vectors is similar to that seen in other products. Plasmid DNA, one such starting material, is essential to both cell therapy and gene therapy manufacture, for example. Analysis has shown that the demand for DNA technologies, such as plasmid DNA, is increasing rapidly and is exceeding current available supply, VanCott observed.

“Looking at the timelines of much of the viral vector manufacturing on the market, one of the biggest delays in product[manufacture] is based on the inadequate source of supply of plasmids,” VanCott said. “It is true that more companies, including Catalent, are investing in bringing this capacity (raw material/plasmid capacity) online for all, but also to integrate internally for in-house vector manufacturing processes. I think this will alleviate the constraint to some degree, but this shortfall is something that has to be considered.”

“One of the things we don’t really know as yet is the impact of COVID-19 on normal healthy donors [for cell therapy manufacturing],” Moore said, bringing up the pressure posed by the current pandemic. “There are a number of companies that have entered the field which recognize the need for curated and tested donor material. Even regional blood centers are seeing that they can play a role as a supplier.”

Moore considers that regional blood centers can potentially provide some benefit in terms of reducing cost. For one thing, blood centers have long-established supply chains. For another, they have established, robust methods for transmitting materials to clinical sites. Furthermore, they enjoy the low cost associated with a significantly high volume of consumables and materials, Moore elucidated.

“I think, from an autologous standpoint, there should be adequate materials to support both autologous and allogeneic manufacturing,” Moore said.

“I think what we’re going to see is a standardization of processes, which will make the supply chains a little less complex,” added Murphy. “Whether that’s going to be in transfection or one or two minor processes, I think the standardization of processes will help enormously, in addition to yield improvement.”

A particularly unique challenge faced by cell therapies, specifically autologous cell therapy, is meeting a strict turnaround time while maintaining GMP compliance. This is one of the greatest challenges that autologous cell therapy manufacturing poses, confirmed Moore.

An important practice in autologous cell therapy manufacture should be to evaluate the combined logistics for the vein-to-vein loop alongside the manufacturing. Moore emphasized that it is crucial to establish a link between the logistics (i.e., the logistics provider) and the manufacturing (i.e., the contract development and manufacturing organization [CDMO]). “Establishing that link will allow for control over the vein-to-vein,” Moore said.

Another important area is establishing processes, policies, and quality control (QC) paradigms that support parallel patient processing and manufacturing. This can often be difficult for personnel to embrace, Moore cautioned, because people are often coming from a field where it was a one product–one factory scenario. Multi-patient processing is possible, however, and there are products that have been licensed with that paradigm. It is possible to use placards and temporary segregation in the manufacturing facility for multi-patient processing, which is based on risk assessments and ensuring that the facility has the correct design for it, Moore stated.

“This is important, not just for the efficiency of getting the product back to the patient and for compliance, but also for driving down the costs of manufacture, which is prevalent in the minds of the ones developing these cell therapy products,” Moore said.

Moore also added the idea that holistic scheduling is another important consideration in the overall logistics of cell therapy manufacturing. “It is important to make sure that the logistics team and the QC team are doing environmental monitoring. It is also important that the analysts who are performing the in-process testing and the quality assurance (QA) staff who are going to be reviewing the product are all appropriately scheduled. More often than not, there are changes in the schedule of receipt of the patient material, and in many cases—in oncology, for example—these patients are in a bad way. They have failed multiple rounds of frontline therapies, so it is important to have the ability in the clinical site to have established coordination among the entire manufacturing team,” Moore explained.

The ability to review batch records in real time (i.e., establishing modular batch records) also comes into play. With modular batch records, a team can do reviews such that, when the end of the process is reached and the product is being prepared for release, only a small amount of time need be spent with QA review. “The team would really only be addressing exceptions in the batch record and communicating with the client and the clinical representatives about the transport of the material back to the site,” said Moore.

“So, it is challenging, but there are established methods and approaches that can allow for good CGMP compliance while speeding the product along,” Moore concluded.

In the Editors’ Series webcast, Moore, VanCott, and Murphy provided further discussion on the challenges, industry trends, and strategies on the road to commercialization for cell and gene therapies. 

 highlights insights gained from the webcast from participants who shared their individual challenges on their own path to cell and/or gene therapy commercialization.

Editors’ Series: Overcoming Commercialization Challenges for Cell Therapies and Gene Therapies

When referring to this article, please cite it as F. Mirasol, " Commercialization Poses Challenges for Cell and Gene Therapies," 

Manufacturing

The early success seen on the market for approved cell and gene therapies poses both technical and manufacturing challenges for pipeline candidates on the road to commercialization.

Commercialization Poses Challenges for Cell and Gene Therapies

Bio/pharma companies range from large, well-established pharma or biotech organizations with extended supply chains to virtual companies that focus on research and development while outsourcing all development, manufacturing, and fulfillment operations. Some bio/pharma companies work with a large number of contract manufacturing organizations (CMOs), others with just a few. No matter the size of the company or volume of outsourcing, there are some common ingredients to success.

Two separate areas to consider when developing a strategy that incorporates contract development manufacturing organizations (CDMOs) and CMOs are sourcing CDMO/CMO services and managing CDMO/CMO services.

Five areas are essential in cultivating a strong and successful ecosystem of CDMOs and CMOs: a smart supply chain, communication/collaboration, a strong governance structure, risk management, and data-driven metrics and analytics. These ingredients come with challenges, chief among them is cultivating a quality culture that promotes collaboration and communication—not just internally—but throughout the entire supply chain and with all partners.

Life-sciences companies, more than companies in any other industry, must consider many factors outside of price in the CDMO/CMOs selection process, largely due to the combination of an intense regulatory environment, capability, capacity, availability, and the overwhelming need for a “right first time” process for the development, manufacture, and distribution of a potentially life-saving drug. A sourcing and a due diligence process should include the following components:

: Does the potential CMO have a good history of manufacturing the anticipated dosage form?

: Has the CMO had any quality or compliance violations over the past 10 years? Contracts with CMOs should state that the CMO will work closely with the contracting organization on regulatory filings, registration, and all quality, compliance, and regulatory issues. A quality agreement with the CMO or CDMO should define specific quality parameters and responsibilities and be part of the due diligence process.

: What volumes are required for the product and can the CMO meet that demand? Does the CMO specialize in the planned product’s dosage form, whether it be tablets, capsules, oral suspension, or something else? Specialization is an important consideration, as manufacturers may be held to stricter compliance requirements for different dosage forms.

 Even if the CMO has passed due diligence on capability, quality, compliance, and capacity, the possibility for failure remains high if the organization is not compatible with the bio/pharma company’s quality culture.

Life-sciences companies of all shapes and sizes—not just startup bio/pharma companies with limited resources that embrace a virtual manufacturing model that leverages CMOs exclusively—need a strategy for managing CMOs. Large pharma and biotech firms that turn to CMOs for specialized manufacturing of a limited-run or specialty drug, or to manufacture a product that may require specialized equipment or expertise also need a comprehensive oversight strategy.

Operating a full or partial virtual organization with support from CMOs from around the world calls for a strong level of communication and collaboration. A modern strategic approach should not view the supply chain as a strictly unilateral mandate with the bio/pharma company setting the rules and operating for their own benefit exclusively. This type of zero-sum approach that seeks to obtain the greatest benefit for the bio/pharma company alone is often at the expense of the CMOs. A more modern and effective approach sees sourcing and managing CMOs as a win-win approach, rooted in collaboration, where the benefit of all stakeholders is taken into account. This approach provides for a strategic partner that shares your company’s values, not a vendor that has a transactional focus.

Effective communication also calls for all parties to avoid data silos, instead establishing a positive flow of data between the CMOs and contracting organizations. The free flow of data will not only simplify regulatory oversight, it will also lead to an improved level of supply chain efficiency and better sourcing decisions. This free flow of information is led by the bio/pharma company’s CMO manager, who will lead the communication between the company and its CMOs, as well as internal peer-to-peer departments.

Different bio/pharma company representatives fulfill the role of the CMO manager during various phases of the drug’s development and commercialization lifecycle. A technical manager from manufacturing or manufacturing science and technology is typically the first to serve as CMO manager, up through production of Phase III clinical materials. When the drug product that will be manufactured by the CMO is approved for commercial use, this role usually transitions over to a planner/manager in the supply chain department; this new CMO manager will maintain a close working relationship with the technical manager and will team up with them for oversight of the CMO going forward.

Typically, the communications infrastructure will also include an internal manufacturing science and technology specialist who will have expertise about the product and will serve as point for communication while the product is in development. After a year of commercial production, that role is typically transferred to a supply chain manager; finally, there may be a transition to a supply chain director who is responsible for all product planning, and who also coordinates all functional relationships.

The CMO manager keeps the CMOs up to date on any regulatory issues and any upcoming inspections, and makes sure CMOs are adequately prepared. This communication is essential to ensure the CMO sites are always in compliance with all regulatory requirements and agencies.

Communication also implies good reporting; once the technical manager or supply chain planner/manager has established a routine process of managing the CMO, then standard performance reports on the CMO should be reviewed monthly or quarterly. The CMO manager will build the relationships and make sure performance metrics are in place. Metrics including quality, on-time batch deliveries, deviations, and other key performance indicators (KPIs) will be measured to give the CMO manager a comprehensive record of how well each CMO is performing.

A set of standardized reports should be required from each CMO, along with periodic (monthly or quarterly) meetings for reviewing the results and to hold the CMO accountable for any deviations or other non-conforming performances. The standardized reports include metrics on quality, batch performance, and deviations, other KPIs, and adherence to any relevant regulatory issues.

Reporting also includes all supply chain issues, adherence to the production schedule, and statistics for on-time shipments and deliveries, the latter of which may lead to changes in logistics or the selection of an alternate source closer to the company if shipping delays have occurred. Inventory reports should also be part of the reporting system, to guard against excess inventory that may lead to overly high warehousing costs or short-dated products; inventory issues may also affect decisions on frequency of shipments or the optimal batch size. Exceptions for standard inventory levels should be built into the system. For example, a contingency plan for obtaining and warehousing inventory to account for the disruption from a planned shutdown—such as a holiday—and an unplanned shutdown—such as a labor disruption or public health emergency—is necessary.

The regulatory, quality, technical operations, supply chain, and finance teams at the bio/pharma company all must be involved to assure proper governance; each group must be aware of the contract terms and conditions and the company’s and the CMOs’ obligations. The management of CMO activities related to clinical materials, APIs, drug substance, drug product, or packaging/labeling, can be handled by procurement, technical operations, or supply chain managers, depending on the sponsor company’s organizational structure.

The most efficient way to establish good governance, while establishing effective communication at the same time, is to set up a single point of contact at the CMO, even if each department has its own secondary points of contact. All questions and answers that go back and forth between the company and its CMO should be documented, with all primary and secondary contacts copied to ensure consistency and transparency in communication.

An annual supply chain planning calendar should map out specific dates, such as each CMO’s holidays, shutdowns for vacation or maintenance, or any other anticipated shutdowns or slowdowns. From that point, technical operations, quality assurance, and supply chain managers will schedule annual, quarterly, or monthly site visits to the CMO, depending on the situation. Outside of periodic scheduled visits, when an issue arises, an additional visit may need to be scheduled and the appropriate team members assigned to visit the site to investigate and remedy the problem.

Unexpected issues will arise occasionally regardless of adherence to quality procedures; having risk management protocols in place will help to assess and predict those issues. Predictive analytics may be useful in anticipating these issues and should be an integral part of the risk management process.

Use of a scoring template in each area covered—quality, regulatory, technical operations, supply chain, and finance—will assist in rating CMOs on an annual basis. Those ratings can determine how often site visits are necessary, how well each CMO is performing, where deficiencies may exist, and may also be useful in procurement decisions when it comes time to rebid supply contracts.

A broad rule of thumb is that the top one-third of CMOs deliver the best performance and the bottom one-third need improvement. It falls on the CMO manager first to rank CMOs by performance and with that information make decisions on reallocating contracts so that top performers gain more responsibility. The ranking also can be used to help determine whether lower-performing CMOs should not be renewed, or alternately, whether a plan for improvement should be created to bring them up to par with the rest of the CMO ecosystem.

The virtual company’s success and overall performance is directly tied to the CMOs’ performance, and consequently, proper management of CMOs will lead to a more compliant, successful, and profitable company.

Bill Connell is a principal and supply chain practice leader at Tunnell Consulting.


Supplement: Outsourcing Resources 2020
Volume 44
August 2020
Pages: s26–s28, s33

When referring to this article, please cite it as B. Connell, " Build CMO Relationships with Effective Management Practices," 

Quality

Contract service providers offer vital services to bio/pharma companies of all sizes. Establishing an effective working relationship and managing operations are key to avoiding compliance issues.

Build CMO Relationships with Effective Management Practices

FDA warning letters often suggest that the pharmaceutical manufacturer receiving the letter hire a quality consultant to assist the company in fixing quality control problems at their facilities. What role can a quality consultant play in helping biopharmaceutical companies stay compliant? What measures should be taken to ensure the best match for the situation?

 spoke with experienced consultants—Aloka Srinivasan, principal and managing partner at RAAHA; Chris Moreton, PhD, partner with FinnBrit Consulting; Philip E. M. Crooker, J.D., vice president, Technical Regulatory & Access, Parexel; and Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates (RCA)—to gain insight on these questions.

What are the reasons a pharmaceutical manufacturer (sponsor or contractor) might hire a quality consultant?

 The reason for a pharmaceutical manufacturer or sponsor to hire a quality consultant may vary based on the size of the company, availability of in-house expertise, and the nature of the projects. In many cases, small companies prefer to use the service of quality consultants for their projects rather than hiring permanent staff. This gives them the flexibility of getting appropriate expertise based on the nature of the work, and can also be a better option, financially. However, mid-sized or bigger companies may also hire quality consultants when they are venturing into something new and the in-house expertise needs augmentation.

While in most cases the CMO/CDMO [contract manufacturing organization/contract development and manufacturing organization] may be hiring a quality consultant for the same reasons as the sponsor, there may be some areas where the CMO/CDMO’s reasons may be different. The CMO/CDMO may hire a quality consultant for a purpose which may be more specific.

Example, for a complex product, the CMO/CDMO may hire a consultant with a specific analytical skill related to a product that they are developing for better understanding the quality issues specific to the product or process. Overall, quality consultants are considered valuable by sponsor companies as well as CMO/CDMOs.

There are several reasons for sponsors to hire a quality consultant, but it all boils down to cost and head count. Many small biotechs do not have enough business to employ a full-time quality specialist and a consultant fits their model. For CDMOs, the reasons may be different. They may want to have someone review their quality systems and operations to point out any gaps ahead of a regulatory inspection. Or they may be moving into a new phase (e.g., from pre-clinical to clinical/commercial and need advice).

Start-ups and small companies may not have the resources to hire quality staff in-house and thus may seek experienced quality consultants to fulfill CGMP [current good manufacturing practice] regulations, which require a fit-for-purpose quality system and appropriate QA [quality assurance] functions at the manufacturer. Companies may need immediate access to deep skills in a highly specialized area (e.g., forensic investigation skills to examine data generated, collected, and reported during various stages of drug development, manufacturing, and regulatory submissions). Mock assessments and ‘pressure testing’ in between regular testing of quality systems helps manufacturers identify and mitigate gaps in advance of pre-approval inspections, post-approval audits, routine surveillance, and for-cause inspections after a product has been approved for marketing.

Health authorities may request, or require, the hiring of quality consultants to review a company’s quality systems and its remediation plans prior to or following enforcement action against a company, especially for serious or pervasive violations (e.g., when they enter into consent decrees or corporate integrity agreements with the US Department of Justice). Companies may seek quality consultants who were former regulators—such as field investigators, application reviewers, or compliance inspectors—to provide real-world insights about how a health authority would likely examine or respond to an issue.

 There are several reasons a pharmaceutical company might hire a quality consultant. In many cases the company may need expertise regarding special subjects that company personnel may not possess. For instance, a company may wish to upgrade their water system. They may wish to hire an outside consultant with significant experience in designing and installing water systems. A small start-up or virtual company may wish to hire consultants to help establish their quality systems and standard operating procedures because of the small staff that often plays multiple roles in the organization.

Companies might also hire consultants to help them work through significant compliance issues as a result of regulatory inspections. In some cases, the hiring of a consultant is in direct response to a warning letter recommending the firm hire outside expertise to assist the company in reestablishing compliant behavior and robust processes. The reasons for hiring consultants, whether you are a sponsor company or a CMO/CDMO, are consistent.

 What are the benefits or hiring a quality consultant? Are there any negatives to hiring a consultant?

Basically the advantages are head count and cost. The negatives are that the consultant may not be immediately available. In addition, a consultant may not be so intimately familiar with the activities of their client, and this can lead to misunderstandings.

There are several benefits to sponsor companies as well as CMO/CDMOs of hiring a quality consultant. The major benefit is that a sponsor or CMO/CDMO may be able to customize their engagement of a quality consultant to meet their specific needs. Several quality consultants with diverse expertise can be engaged at the same time to work on different projects. As the involvement of the consultants in most cases is for the duration of the projects, the process is advantage from the perspective of human resources management, as hiring several permanent employees for the same purpose may come with its own challenges. Also, based on the contracts between the sponsors/CMOs/CDMOs and the consultants, the timeliness of the deliverables can be assured, which in turn can help keep the projects in time and within budget.

There are a few downsides of depending fully on quality consultant. Hiring the right person for the right job can be challenging based on just the review of a CV or a brief interview of a consultant. Finding a good quality consultant can be difficult. Also, an external consultant, who is hired for a limited time may not feel the same ownership of a project that a permanent employee does. There may also be lack of quality in the deliverables, or lack of chemistry between the permanent staff and the consultant, which could cause unnecessary hindrance to the progress of the project. Finally, if the agreement with a consultant does not cover all aspects of the engagement, a consultant’s decision to discontinue with a project midway can inconvenience the company/CMO/CDMO significantly.

A specific skill or situation can be aligned with the consultant’s background and for the desired length of time needed to address the issue(s). Consultants who have experience in both private sector and a health authority confer a broader perspective and view manufacturing issues through a multi-faceted lens. A wide array of prior client engagements increases the consultant’s vantage point of possible gaps and thus their effectiveness in finding and remediating gaps in quality systems before they are identified by health authorities.

 The quality consultant typically has a number of years of experience and has seen a variety of issues that add depth to their understanding of issues. They also bring a third-party perspective, which allows them to view the organization with a fresh perspective and offer solutions that might be more effective in addressing issues facing the hiring company. Consultants usually have a broad base of experience and knowledge, and this allows them to view operations with a unique perspective. There are few negative issues when hiring a consultant provided the hiring company spends the time to review the qualifications of and interview the consultant to make sure they have the appropriate background, expertise, and demeanor for the project they are being consulted on.

What specific services can a quality consultant provide?

It depends; anything from advice on quality management systems and documentation to release of a batch of product. They can also advise on or undertake internal audits. Should it happen, they can also help in the remediation of FDA findings (483s and warning letters through to consent decrees)

 Quality consultants can provide a number of specific services to a company. They can assist in establishing a robust quality system, responding to regulatory inspections, performing supplier audits, helping implement new regulatory requirements, and advising on complex and challenging investigations.

They may help with development of quality assurance-related complex products, support with communications with regulatory authorities (483 responses, warning letter-related communications), train the staff related to various aspects of quality control, review regulatory materials, perform gap evaluations in the process, data acquisition and perform due diligence in mergers and acquisitions, perform audits, [and provide] support with solving numerous compliance related problems. Some of the quality consultants may have specific expertise in specific dosage forms [and/or] devices, which may be of great support to the sponsors/CMOs/CDMOs.

What to consider when hiring a consultant

 What are the steps for hiring a quality consultant?

 Companies identify quality consultants by surveying the marketplace (via websites, social media, online references), acting on recommendations, and using companies they’ve successfully engaged in the past. Once identified, consultants may be asked to submit a proposal to the company.

Based on the combination of the firm’s review of the consultant’s credentials and the response to the proposal, the firm can decide to move forward in the process and award the work to the consultant and reach a contractual agreement, negotiate further with the consultant or the consulting company, or continue their search without reaching an agreement. Manufacturers may have internal processes hosted by numerous functions—such as quality, technical operations, supply chain, and human resources—that they use to evaluate and select service providers.

There is no specific rule for hiring a consultant. There are several organizations that have pools of consultants with diverse skills and may be able to provide a company/sponsor/CMO/CDMO with a list of qualified consultants who have experience in the specific area. However, one should never hire a consultant based on just the qualification. It is imperative that the hiring manager, and possibly the other members of the department who are expected to work closely with the consultant, interview the consultant before hiring.

Certifications in specific areas may be helpful. There are also some certification programs like the [Regulatory Affairs Professionals Society] RAPs Certification. Again, the value added by these certifications are questionable. There may be excellent consultants who do not have any certification. More than certification, the qualification and interpersonal skills of the consultant and references should be the prerogatives in the selection process.

It is important for a hiring manager to select a few consultants who have the required skills and come highly recommended. The hiring manager should personally interview them to assess if the personality of the consultant aligns with that of the staff and the general culture of the company and select the best match.

 The first step for hiring a consultant is to write a scope of work for the job you are wanting the consultant’s help with. After that is finished, you can search for consultants/consulting firms that specialize in the area you are seeking expertise. It is important to screen the consultants to make sure you obtain the best consultant.

Some quality consultants may have certification, especially those consultants specializing in auditing. What’s more important than certification is experience and active involvement in the industry. Many consultants maintain their credentials and stay up to date by being members of trade organizations or writing books and articles. This experience is sometimes more important than a certification.

There is no set process. The prospective client should undertake a thorough due diligence and ask for references or cerifications such as [American Society for Quality] ASQ certification. However, there is no obligatory certification in the United States.

How does a quality consultant work with a company’s inhouse quality departments?

There may be various ways that a quality consultant works with a company’s in-house quality departments. The simplest one is ad hoc consulting. The consultant may be contracted based on need by the members of the specific department. Alternatively, a quality consultant is embedded in the department for an extended period. In this case, the consultant will need to undergo training based on the company SOPs [standard operating procedures] specific to the service he/she is providing and made aware of the working norms of the company. It is the responsibility of the hiring manager to make the consultant aware of his/her responsibilities and the company staff aware of the boundaries related to interaction with the quality consultants.

I think it is important to introduce the concept of a contract worker versus a quality consultant. Companies could have both of these consultant types working for them, but the roles and interactions will be different. Contract worker consultants are usually filling in and performing a specific job. They would interact with management just as a full time employee would interact. A quality consultant who’s role is to advise, guide, and teach should interact with management in a mentoring role. They should give management choices and options for achieving the assignment. These options and choices should be ranked from least risky to most risky with an assessment explaining why the options are ranked as they are. Their recommendations should also be supported by the regulations. The consultant should also provide implementation recommendations and potential improvements to be introduced over time to ensure continuous improvement.

 It depends on the nature of the consulting. There can be resentment and denial on the part of the client staff and senior management needs to explain the reasons for engaging a consultant, and obtain staff buy-in.

 Collaborations vary according to the nature of the concern, timing, severity of the issue, and the company’s preferred style or approach. The consultant could be embedded within the firm’s QA unit as a dedicated resource, as a temporary employee, or as a ‘person in the plant.’ The consultant could function semi-independently, simulating the role of health authority personnel conducting or evaluating an inspection where the involvement with the firm’s QA unit is at arm’s length. And then there are situations that synthesize elements from both approaches, where the consultant collaborates with the firm’s QA unit to review the results from gap analyses, assists the firm in implementing CAPA and strategic changes, or participates in responding to health authority inspection results.

How long should a quality consultant be retained? Should the consultant be a embedded service or only hired to help investigate and correct specific quality issues/problems (such as an FDA warning letter)?

 There really is no set timeline for how long a consultant should be retained. It will depend on the scope of the project and the time the company sets for completion. What is important is for management to make sure that the consultant remains independent and provides the third-party advice they were hired to provide. Consultants must guard against getting too comfortable with their client, so they can retain their independence and unbiased view of the operations they are working to improve.

I think that consultants can be either embedded or assigned to specific projects. There is a need for both of these service categories. The best way to manage the consultants in either role is to make sure the scope of the work you want them to perform is clearly defined to avoid scope creep and that they adhere to the specified project timeline unless there is an acceptable and understandable reason for a delay.

The length of time for which a consultant is retained depends on the nature of the work and the company. A consultant may work for an extended amount of time with a company, where they provide advice when needed. There are instances where a consultant has been involved with a company for years, advising the staff, when needed, on various quality issues. Alternatively, when resolution of quality issues is sought (FDA 483s, warning letters), the consultant may be retained till the problems are resolved. In some cases, quality consultants may be proactively hired to perform gap analysis of various quality system as well as evaluation of data integrity. However, an important part of hiring a consultant is to have a clear view of how long the service is required. If a consultant has been in a site for more than a year and it appears that he/she will need to be there for more time, it is possible that a permanent employee is needed for the role.

I know of quality consultants who were hired over several years at the same company, especially in the early days of start-ups as they transitioned into clinical trials, etc. However, most quality consultants are engaged for short periods, for fixed projects.

 Should a pharmaceutical manufacturer rely only on a quality consultant or still retain their own inhouse quality control and quality assurance departments?

From the perspective of the health authorities, it is expected that companies—regardless of their size or the type of organization—will have a fit-for-purpose QA function to meet CGMP regulations. The number and type of in-house quality personnel will vary across companies, but product owners and contract manufacturers cannot fully delegate CGMP compliance duties. They are responsible for the quality of the products they own and their manufacture. Thus, it is highly recommended that a firm—whether a product owner or contract manufacturer—hire the necessary in-house personnel who will own responsibility for the firm’s quality operations and decisions. These personnel can be supported by consultants, but it enhances the companies’ ability to comply with the CGMP regulations if they have established QA functions and processes in place as part of their organizations.

 From my perspective, it is better to retain an in-house quality control/quality assurance department because they will have day-to-day familiarity and knowledge of processes which can help in deviations and investigations. This knowledge is also valuable during audits because they can explain the operations to the auditor and potentially clear up any misunderstandings before they become observations. I think it is also important for companies to have a network of consultants they also rely on to help out when things start to go awry. I think the most successful organizations rely on their internal staffs and their trusted consultants to set the best culture for the company while maintaining compliance to the regulations.

If [the company is] undertaking routine clinical and/or commercial manufacture in-house, they should have their own full-time quality control and quality assurance groups. They can bring in consultants as advisors and for special projects.

 It is preferable that a pharmaceutical manufacturer has an in-house staff in all departments, especially in the quality control and quality assurance departments, who are supported by consultants as and when needed. The reason for this is the importance of ownership and responsibility related to quality of products and process. It is well known that quality-related matters can be critical for a pharmaceutical company, and having at least a limited number of internal staff in charge, supported by quality consultants, is a better option. In case it is necessary to assign the responsibility of quality control and quality assurance entirely to a consultant, selection of the consultant should be made judiciously to assure that he/she is responsible, qualified, and capable of understanding the seriousness of the assignment.

To conclude, a quality consultant can be an asset to pharmaceutical manufacturer/CMO/CDMO when appropriately engaged. However, the industry representatives should use good judgment in hiring the right person and work collaboratively with the consultant to assure the best results.


Supplement: Outsourcing Resources 2020 
Volume 44
August 2020
Pages: s29–s33

When referring to this article, please cite it as S. Haigney, "Consulting Quality," 

Quality/Regulations

Hiring the right quality consultant can provide expertise and save costs.

Consulting Quality

Nitrosamines are a group of genotoxic compounds that have been studied widely in the food, water treatment, and chemical industries. In fact, the compound N-Nitrosodimethylamine (NDMA, also known as dimethylnitrosoamine) may be one of the most closely studied carcinogens in the world, noted David Light, CEO of Valisure, an independent analytical pharmacy, who spoke on a webcast on nitrosamine contamination on July 14 (1). First identified as toxic in 1956, NMDA was the topic of a US Senate panel investigation in 1977, and a World Health Organization and United Nations Summit in 1978, Light told attendees at the webinar. Analytical methods have been available to detect the compound and other nitrosamines for over 50 years, he noted.

Yet the pharmaceutical industry was blindsided in 2018, when trace levels of NDMA were found in finished blood-pressure and heart medications, the ARBs (angiotensin receptor blockers) valsartan and losartan and a number of their APIs (2). The problem led to a cascade of product recalls around the world and confusion, as healthcare providers and patients sought substitutes.

This particular set of recent contamination events was traced to a number of problems. One API manufacturer had optimized its manufacturing process yet failed to detect potential chemical synthesis problems that could lead to generation of contamination. In other cases, manufacturers had been using recycled solvents and other materials but failed to work through the potential manufacturing risks.

In September 2019, for very different reasons, NDMA was found in ranitidine and the name-brand drug Zantac. As Ramin (Ron) Najafi, CEO of Emery Pharma, noted during the webinar, ranitidine products had been on the market since the 1980s, and in 2017 ranitidine was the 48th most widely prescribed medication in the United States.

In this case, extensive research verified that the NDMA was not a process impurity, but the result of the ranitidine molecule’s inherent instability, so that it formed NDMA when exposed to high temperatures and humidity. Emery and Valisure both filed citizen’s petitions with FDA (3,4), and Emery developed an ultra high-pressure liquid chromatography-mass spectrometry (UHPLC-MS/MS) method to quantify NDMA down to 1 ng/tablet. Eventually the drug was taken off the market. However, in late 2019 and early 2020, NDMA contamination was found in yet another high-volume pharmaceutical, metformin, used to treat diabetes and a number of other illnesses. Valisure filed a citizen’s petition with FDA to draw attention to this problem in March 2020 (5).

As these events suggest, gaps remain in the industry’s knowledge regarding genotoxic compounds and how they may form in pharmaceutical processes, and how to prevent their presence in pharmaceutical products.

An informal poll of the audience at the July webcast, even if statistically irrelevant, sketched the framework for potential problems. When asked whether their companies had formal quality control (QC) testing procedures in place to test for NDMA and nitrosamines, 32 professionals responded, with nearly 41% saying that their companies had no QC procedures in place identify nitrosamines in their products and process streams. Approximately 16% said that they routinely test all products for nitrosamines, 24% that they test for nitrosamines in some products, and 19% that they only test for products that are in developmental, rather than commercial stages.

Although the agency’s scientists continue to study the problem, FDA has not issued any new guidance on nitrosamines since 2017, although FDA supports the use of the International Council for Harmonization’s (ICH’s) M-7 guidance, a key reference for many in the industry (6).

During the July webcast, Ed Gump, vice president for small molecules with the United States Pharmacopeial Convention (USP), emphasized the need for risk-based approaches to preventing genotoxic contamination. As he noted, the ICH M7 guidance requires identification, categorization, qualification and control of DNA reactive mutagenic impurities to limit carcinogenic risk. A risk level of 1 in 100,000 is currently considered negligible, he said, but where a potential risk has been found for an impurity, manufacturers must develop an appropriate control strategy that leverages process understanding. In addition, analytical controls should be developed to ensure that any mutagenic impurities are present at or below the acceptable cancer risk level.

To this end, Gump suggested, manufacturers of all types must prioritize the evaluation and testing of specific drugs, drug classes, and manufacturing materials that are more likely to contain unsafe levels of genotoxic impurities, using predictive and risk-based approaches. In addition, he noted the need to use an analytical method that has been widely demonstrated to be fit for its intended purpose for testing impurities.

Finally, Gump said, there is a need for greater transparency and more sharing of information within the industry. He sees long term opportunities to harmonize global approaches for dealing with this issue.

In July 2020, USP launched a broad-based outreach program to provide more direction to pharma manufacturers on how they might prevent supply chain vulnerabilities relating to nitrosamines. The organization released six new reference standards designed to support manufacturers and regulators in analyzing and monitoring potentially harmful NDMA and other nitrosamine impurities in the supply chain. USP will soon propose for public comment a new United States Pharmacopeia—National Formulary general chapter standard to provide guidance on assessing materials for nitrosamine presence, establishing control strategies for these impurities and ensuring the performance of analytical procedures to monitor nitrosamine levels in drug products.

Specifically, USP is proposing a new informational General Chapter <1469> Nitrosamine Impurities, which is aligned with current scientific and regulatory approaches for controlling nitrosamine impurities. This chapter provides a science-based approach for identifying and assessing the presence of these impurities in drug products in order to eliminate or reduce levels to help ensure quality as it relates to safety. General Chapter <1469> is scheduled for publication in September 2020 in USP’s online Pharmacopeia Forum, with the goal receiving stakeholder comments to proposed standards, says USP spokeswoman Theresa Laranang-Mutlu. The comment period will be open for 90 days, and stakeholders are strongly encouraged to provide input.

The chapter provides an introductory overview of concerns related to nitrosamine presence and identifies possible sources of nitrosamines in drug products along with observed or assessed risks associated with each source. It also includes a list of nitrosamines of recent concern in the pharmaceutical industry compiled from information shared by multiple global health authorities and input from members of USP’s Nitrosamines Joint Subcommittee.

The chapter would provide recommendations on nitrosamine risk assessment and the development of relevant control strategies to ensure that nitrosamine presence is avoided or below acceptable intake levels. A section on test method performance characteristics provides guidance on the verification process, procedures being implemented in the laboratory, and validation of alternative procedures.

The general chapter would also contain analytical procedures that have been validated or verified in USP’s laboratories and includes examples of quantitative analytical procedures. It also provides a compilation of procedures currently referenced on the websites of FDA and the European Directorate for the Quality of Medicines & HealthCare (EDQM), which users can verify as alternative procedures by meeting the requirements recommended in this chapter, says Laranang-Mutlu.

Focused on predictive tools and approaches, USP has gathered a group of volunteer experts to develop the nitrosamines general chapter, the USP Nitrosamines Joint Subcommittee, chaired by Mark Schweitzer, PhD, global head of analytical science and technology at Novartis, as well as representatives from FDA and the EDQM, which is responsible for drug quality standards in the European Pharmacopeia.

In August, USP will also be launching a new training webinar, “The ICH Q3 Impurity and the M7 Mutagenic Impurities Guidelines.” Designated as an ICH officially recognized training program, it will address the application of the ICH guidelines Q3-A, B, C, D and M7 for controlling organic, inorganic and solvent impurities. It will also aid professionals in developing strategies for dealing with actual and potential impurities that are most likely to arise during synthesis, purification, manufacturing, and storage of drug substances and drug products.

Practical steps: it’s not rocket science

In the meantime, there are some basic steps that companies can take every day to help prevent nitrosamine contamination, says Najafi, who has also been called as an expert witness in a number of cases and has seen scenarios of what can go wrong within a typical company when approaching this problem.

Ensuring that the right staff is involved in the problem is crucial, Najafi says. “The first step will be to employ experienced process development professionals and analytical chemists to oversee any outsourced manufacturing processes, specifically if changes or optimizations are being made at the partner site,” he says, “and it is important to evaluate the entire workflow with regard to use of amines, nitrosating agents, and recycled solvents, and to implement modern analytical testing for nitrosamines at strategic intervals.” He also suggests that the quality assurance department work in tandem with process chemistry and play a complementary role in preventing contamination. “This includes establishing Standard Operating Procedures for change control, frequent audits to ensure compliance, and launching investigations (e.g., during Phase I) when out-of-spec observations are made for impurities, and/or if unknown impurities are detected, however insignificant they seem,” he says.

“It is imperative that ‘for-profit’ corporations strive to increase revenue and implement changes to make manufacturing more efficient. However, the sponsor and the contract partner should collaborate on any such optimizations to ensure that efficiency does not come at the cost of patient safety. For example, recycling solvents is good for the environment and great for the company’s bottom line, however, there is a potential for carryover and new impurity introduction to an established manufacturing process from solvent reuse,” he says. Hence, the recycling process should be thoroughly validated, and stakeholders should incorporate extensive analytical tests for detection of unwanted contaminants that may result, he explains.

He notes problems that he has seen in the field. “Launching investigations is critical to ensuring process quality and compliance to regulatory guidance documents. One of most common errors I see is not conducting a thorough Phase I investigation when needed—companies either outright fail to launch one, do not properly document the process, or come to premature or faulty conclusions that are not backed by data or that lack scientific merit. I have seen all of these being committed by a company recently for a single manufacturing process,” he says.

Do not overlook cleaning and cleaning validation

It is also very important that contract manufacturers involved in multiple APIs and processes pay special attention to equipment cleaning to ensure that processes do not cross-contaminate each other. “Cleaning protocols should be validated, and suitable analytical tests performed to ensure that equipment is residue-free. In another recent example, I have seen a company implement an unvalidated cleaning strategy, and then apply an irrelevant analytical workflow to test for residues. Needless to say, that the company was cited by regulatory inspectors,” Najafi notes.

During the webcast, Najafi offered the following advice. First, to process development chemists: “If you intend to change or optimize manufacturing processes, look for potential development of NDMA. “If any of your processes contain an amine or nitrosating agent, be overly cautious and plan on testing for nitrosamines at every step,” he said.

Quality control departments, meanwhile, should be careful not to dismiss unknown peaks as “ghost” or “air” peaks, Najafi said, while quality assurance teams should be sure to conduct headspace gas chromatography and MS (HS-GCMS) on API routinely and identify all peaks. If the process is new, conduct HS-GCMS tests on the drug product as well, Najafi said.

“Aim to identify every unknown compound. Use HS-GCMS or liquid chromatography and mass spec (LCMS) if available and specifically look for NDMA and related nitrosamines,” he said. Attention to fundamentals is key, Najafi noted, cautioning manufacturing departments to remember that 96 ng of NDMA per pill can disqualify a batch “Proper cleaning of the equipment, and use of clean-in-place is important. One should be cognizant of potential cross-contamination problems,” he said.

Although Najafi joked, “It’s not rocket science,” on the webcast, it is clear that careful work and collaboration are key. New guidance and educational programs aim to address this need within the industry.

1. PharmTech, “Preventing Genotoxic Contamination: Lessons from the Nitrosamine Contamination Crisis,” Webcast, July 14, 2020.
2. A. Shanley, 

42 (10), pp. 60-64.
3. Emery Pharma Citizen’s Petition to FDA, 

, January 2, 2020.
4. A. Shanley, “Problems with Ranitidine May Transcend Manufacturing Issues,” 

, Oct. 2, 2019.
5. Valisure, Citizen’s Petition to FDA, 

, March 3, 2020.
6. ICH, ICH M7(R1), Assessment and Control of DNA-Reactive Impurities in Pharmaceuticals, 


Supplement: Outsourcing Resources 2020
Volume 44
August 2020
Pages: s18–s20

When referring to this article, please cite it as A. Shanley, " Collaborating to Prevent Genotoxic Contamination," 

Analytics

Carcinogenic compounds have been found in a number of top-selling drugs, leading to recalls and bans. Preventing problems requires working closely with contract testing and development partners as well as API and other suppliers.

Collaborating to Prevent Genotoxic Contamination

As the biopharmaceutical industry races ahead with development of vaccines and therapeutics to address the COVID-19 pandemic, experts have acknowledged that building up adequate capacity for fill/finish and ensuring the supply of materials for primary packaging containers are crucial requirements. In an unprecedented compression of manufacturing timelines and with significant investment from government and non-profit sources, commercial fill/finish manufacturing capacity is being built at-risk, while drug development and clinical trials are ongoing.

“A vaccine will only be effective if we can make and distribute adequate supply,” John Shiver, senior vice-president of Vaccines Global R&D at Sanofi pointed out in a March 23, 2020 post (1). He expressed confidence that industry is up to the task, saying, “If we can develop a safe and effective vaccine, the global pharmaceutical industry has the capacity to make and deliver it. [Sanofi] has the established capacity and infrastructure to make up to 600 million doses in two existing facilities based in New York and Pennsylvania, without compromising the supply of vaccines for other illnesses, including influenza. Other companies have similar capacity.” Furthermore, he noted, “Fighting an emerging pandemic is an enormous undertaking requiring the entire pharmaceutical ‘ecosystem’ to come together at pace and at a scale that are both extraordinary.”

Contract development and manufacturing organizations (CDMOs) are crucial components of this ecosystem for handling the expected surge of capacity needed for vaccines and therapeutics to treat COVID-19.

Over the past few months, CDMO Catalent, for example, has announced manufacturing agreements with COVID-19 vaccine candidate developers including Johnson & Johnson’s Janssen (2), Moderna (3), and AstraZeneca (4) to provide fill/finish capabilities. Catalent says it is working with more than 40 customers on COVID-related antivirals, vaccines, diagnostics, and treatments for symptoms and effects of COVID-19 (5). At the Catalent Biologics business unit’s facility in Bloomington, IN, the company reported that the scale-up in production would include the use of two new high-speed machines, including an Optima vial filling line and a Dividella NeoTOP 1604 top-load cartoner (2). The company is rapidly scaling segregated manufacturing capacity at the Bloomington facility to support dedicated production of Johnson & Johnson’s investigational vaccine candidate and plans to hire approximately 300 additional employees “to meet operational readiness and 24x7 manufacturing schedules by January 2021” (2).

Outsourcing partners provide capacity and tech transfer expertise in the pharmaceutical industry response to the COVID-19 pandemic.

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Commercialization Poses Challenges for Cell and Gene Therapies

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Consulting Quality

Collaborating to Prevent Genotoxic Contamination

All Hands on Deck for Fill/Finish of Vaccines and Therapeutics

Blockchain and IoT: Determining ROI in the Pharma Supply Chain

Pharma Contract Market Update