Susan Haigney

 spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM), responsible for both the 

) and the Certificate of Suitability to the monographs of the 

 (CEP) procedure, about API quality from their perspective.

 How crucial is it for pharma manufacturers to ensure the safety of APIs?

 It is crucial that pharmaceutical companies select APIs of appropriate quality. In the [European Union], the marketing authorization holder/applicant is by law fully responsible for the quality of the API they use, since low-quality and/or ineffective APIs put the patients at risk.

 What are the steps an API manufacturer must take to ensure quality throughout the development and manufacture of an API?

 The requirements are well described in the international guidelines (ICH [International Council for Harmonisation]) that API manufacturers shall follow, in particular, ICH Q11 

Development and Manufacture of Drug Substances

Good Manufacturing Practice for Active Pharmaceutical Ingredients

ICH Q11 comprises crucial requirements related to manufacturing process development, description of manufacturing processes and process controls, approaches to developing a control strategy, critical quality attributes, [and] quality risk management.

API manufacturers [must] develop an appropriate manufacturing process for their APIs. During this step, knowledge about the API (e.g., its by-products and degradation products) is gained and an appropriate control strategy can be put in place for the next steps. An understanding of the manufacturing steps leading to the formation of impurities enables the implementation of appropriate steps and analytical controls to ensure that the API complies with the expected quality requirements.

Last but not least, API manufacturers have to work according to good manufacturing practice (GMP), as described in EU GMP Part II, which is equivalent to ICH Q7 (i.e., an appropriate quality management system).

 What are the steps sponsors should take to ensure the quality of APIs sourced from a supplier used in final products?

APIs used in the manufacture of medicinal products should meet quality standards, in particular pharmacopoeial requirements. In the countries which are party to the European Pharmacopoeia Convention, the legally binding quality standard is the 

 covers the API, the manufacturer of this API and the medicinal products produced using this API shall meet its quality standards. In cases where a specification contained in a monograph (of the 

 or in another pharmacopoeia) is insufficient to ensure the quality of the substance, the regulatory authorities may request additional specifications from the marketing authorization holder.

 ICH’s Q7A GMPs for APIs touches on all aspects of API production from facilities to equipment to materials management. Of all the areas the guidance covers, is there one particular aspect of API manufacturing that is more crucial for ensuring API quality?

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

) is intended to provide guidance for the manufacturing of APIs under an appropriate quality management system (QMS). This guideline has been introduced in the EU legislation as GMP Part II. The QMS should encompass the organizational structure, procedures, processes, and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. The QMS for APIs needs to be in place for all of these aspects—and if even a single aspect is neglected, the efficacy of the QMS based on ICH Q7 and the quality of the APIs are at risk.

 What methods are available for testing the effectiveness and safety of APIs?

 Clinical and non-clinical studies are performed on APIs during the development phases of a medicinal product to establish their efficacy and safety. Data thus gained are part of the submission for a marketing authorization and are reviewed by the respective regulatory authorities. If these studies show a negative balance for benefit-risk, the medicinal product will not obtain a marketing authorization—and will not be marketed.

Medicinal products that have obtained a marketing authorization are monitored for their quality, safety, and efficacy over their whole lifecycle. This system is in place to detect any issues that may negatively impact the benefit-risk balance. There are mandatory requirements for pharmacovigilance, with which marketing authorization holders must comply in order to monitor the safety of authorized medicinal products and detect any change to their risk-benefit balance. In case of a quality issue with APIs, the manufacturers must take appropriate action to address the issue, under the supervision of authorities (e.g., withdraw batches from the market).

Have regulators and industry resolved the nitrosamine problem or is it continuing? What steps can be taken to ensure a similar situation does not occur in the future?

 Regulators and industry are still acting to resolve the issue and the knowledge regarding their formation in APIs and in medicinal products continues to evolve. Nitrosamines in blood pressure medications are no longer a concern, since all measures to mitigate these impurities have been taken. However, nitrosamines may be found at very low levels in other medicinal products. Regulators have created international task forces (Nitrosamines Implementation Oversight Group, Nitrosamines International Strategic Group), elaborated regulatory guidance, and are sharing emerging information with each other in order to harmonize the actions to be taken.

Articles

Pharmaceutical Technology Europe spoke with representatives from the European Directorate for the Quality of Medicines & Healthcare (EDQM) about API quality from their perspective.

Ensuring API Quality—The EDQM Perspective

 spoke with Ed Gump, VP Small Molecules at the US Pharmacopeia (USP) about API quality from the standards perspective.

 To ensure the quality (and by extension, the safety) of their products, it is crucial that pharma manufacturers ensure the quality of their drug product ingredients—the API as well as excipients. In the [United States] (and in many other countries), the legal burden to ensure the quality of each ingredient, including excipients, is on drug manufacturers.

Unlike APIs, excipients are often not pure and tend to be complex in nature and can be sourced from natural (animal, plant, mineral), synthetic, and semisynthetic origins. And many (if not most) excipients have uses beyond pharma, so it is especially important for manufacturers to test the quality of their excipients and ensure they are fit for pharmaceutical use.

 What are the steps an API manufacturer and sponsor must take to ensure quality throughout the development and manufacture of an API?

 Manufacturers should manufacture their products under CGMPs [current good manufacturing practices], adhering to all regulatory requirements at the federal, state, and local level.

When ordering APIs from suppliers, manufacturers shouldqualify their suppliers, perform regular quality audits of their suppliers’ facilities, develop specifications to ensure that API is fit for use in their product formulations and that API conforms to USP standards, ensure the quality of the API they receive such as by testing the API against the USP monograph and reference standard.

: What has the industry learned from the nitrosamine contamination problems in blood pressure medications?

 We have learned that it is not just blood pressure medications that are at risk of nitrosamine contamination.

Nitrosamines can form in a lot of different ways, based on fairly simple chemistry. Changes in manufacturing processes, ingredients (including excipients), ingredient sources, and even the API (sometimes referred to as the drug substance) itself can all be sources for nitrosamine to form.

Many recent drug recalls are due to a specific sub-category of nitrosamine impurities known as drug substance-related nitrosamine impurities (DSRNIs), a class of nitrosamines sharing structural similarity to the API.

DSRNIs (and nitrosamines in general) can form in several different ways. One of the most common reactions is when an API molecule has what’s known as secondary amine group in its structure, and when (1) nitrite and (2) acidic conditions are present. Under these conditions, the API molecule with a secondary amine can react to form a nitrosamine.

For example, excipients such as Sodium starch, Crospovidone, Povidone, Lactose, Croscarmellose, etc. are used in various pharmaceutical formulations as solubilizing agents, binders, disintegrants, etc. The presence of nitrate and nitrites has been found in these excipients at parts per million levels.

Nitrites from excipients could react with amines in APIs, or low molecular weight amine impurities. Because excipients are generally the greatest component of medicinal products, sufficient amounts of nitrite could be present as a reaction partner.

However, this is not the only chemical route that can potentially lead to formation of a nitrosamine.

Given that there are a variety of possible routes, it's critical for manufacturers to understand what medicines and associated manufacturing processes are at risk to form nitrosamines, confirm if they are forming, at what levels, and how they can establish controls to ensure they are not present at levels that could be harmful.

It’s also important for manufacturers to make sure that when risks exist, they are establishing control strategies using tests which are ‘fit for purpose’ for their products so that they can reliably detect and control nitrosamines. Establishing safeguards like these at appropriate checkpoints within the global medicines supply chain will mean patients have access to the safe medicines they need, when they need them, and that the medicines will deliver the intended therapeutic benefit.

Have regulators and industry resolved the nitrosamine problem or is it continuing?

 It is continuing, but now that regulators and industry are aware of the problem there is an incredible amount of effort being focused on fixing the problem. Every new recall is actually a sign of progress and shows that industry and regulators are working hard to identify nitrosamines in their products and when they are finding them at unsafe levels, they are recalling those products.

The discovery of nitrosamine impurities in some drugs over the past four years has prompted major efforts by regulators and industry to reduce or eliminate their presence in the medicines supply chain. FDA now expects drug manufacturers (for drugs approved in the US market) to assess on a regular basis the risk of any nitrosamine impurity formation in their products.

Pharmaceutical Technology spoke with Ed Gump, VP Small Molecules at the US Pharmacopeia (USP) about API quality from the standards perspective. 

Ensuring API Quality—A Pharmacopeia Perspective

Quality culture is a patient-focused approach to quality that is proactive not reactive or procedural, according to Rick Friedman of FDA, in a conference presentation (1). When an organization is focused on quality, it can detect problems earlier, experience fewer deviations and costly remediations, and protect its brand, according to Friedman (1). Creating a quality culture means an investment in quality including organizational structure, actions, quality standards, support for all levels of the company, and having quality be a part of business decisions (1). And the quality culture starts at the top.

“Companies with good quality cultures usually have transparency and collaboration between departments,” says Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. “This is critical when there are problems that impact manufacturing. Companies with a robust culture usually solve the problem faster, which helps them maintain high productivity rates,” she says.

Quality culture is not just the quality department

The quality department in a bio/pharmaceutical company plays a critical, but not exclusive, role when it comes to ensuring that biologics and drugs are safe and effective. The entire organization, however, must be involved in ensuring quality is built in.

“Let’s clear up one issue right away,” says Schniepp. “When we refer to quality culture, we are referring to the culture of the company and not the culture of the quality department. Having an established quality department does not mean a company has a culture of quality. In a robust culture, the attention to quality is a responsibility of all employees, not just those who work in the quality department. In a robust quality culture, the quality department is a partner with operations, it’s a policing function,” she stresses.

“Quality culture is an all-pervading attitude and sense of purpose in which quality is foremost in everybody’s activities. A quality department is a part of the organization that monitors quality, (e.g., by end-product testing). However, quality cannot be tested into the product, it is inherent, and has to be built in—by design,” agrees Chris Moreton, PhD, vice president of pharmaceutical sciences at Finnbrit Consulting.

According to Friedman, “senior management has a critical ongoing oversight role to ensure suitability of operational design, control, and maintenance.” Friedman points to behaviors that can lead to the development of quality culture that include shared accountability, teamwork, listening, continual improvement, coaching, and integrity (1).

Moreton agrees. “In my opinion, a quality culture means that everyone from the CEO down to the most junior staff put quality (and patient safety) at the top of their agendas. Quality requires ‘top-down’ and ‘bottom up’ approaches. If senior management are not committed/interested, then the junior staff will find it difficult to implement and maintain quality activities. Similarly, if the junior staff are not properly trained and
committed to and interested in quality, then quality will not be properly implemented. I have seen organizations where the commitment to quality was lacking, and there was, in effect, a lack of a quality culture,” says Moreton.

Creating a quality culture starts with the head of the organization, according to Moreton. “The CEO has to be committed in both words and deeds. [The CEO] has to hire people who will help shoulder the burden while maintaining the business. This then goes on down through to the most junior staff. People also have to be prepared to enforce the rules. (There is a line beyond which an individual must not step, because once they have stepped over it, they will be asked to do so again and again—to thine own self be true!),” he says.

Communication is key, says Schniepp. “Robust quality cultures have open communication and welcome feedback from all employees regardless of position within the company. When a company has a poor culture, the communication is top down, and employee opinion and input [are] not valued.”

How does one take stock in the robustness of quality culture in a bio/pharmaceutical company? “There are studies and data that suggest you can measure the quality culture of an organization by looking at the maturity level of the attributes in their quality management system,” says Schniepp. “The premise is if you can measure a company’s attributes (CAPA [corrective action and preventive action] system, communications), you can measure the quality culture of an organization.”

Regulatory agencies may take the organization’s history into consideration when assessing the effectiveness of a company’s quality practices, especially during an inspection. “How many FDA 483 observations have there been, and how efficiently did they respond and rectify the issues? The inspector will also take note of how people are working, etc. during an inspection. In some ways, it all comes down to the inspection process and the inspector,” says Moreton. “[Regulators] want quality (and patient safety) to be taken seriously, and not simply paid lip-service to. They will look to see who makes the decisions affecting quality. The general state of the facility and the attitude of staff (both senior and junior) during on-site inspections. They will also look at how complaints are handled and recall-readiness—how the organization would cope in the event of a recall,” says Moreton.

“Regulators have linked the lack of a quality culture with data integrity issues. Guidance documents released from the Pharmaceutical Inspection Co-operation Scheme, the UK’s Medicines and Healthcare products Regulatory Agency, the World Health Organization, and FDA all stress the link between a robust quality culture and reliable and consistent data. One thing they all stress is an open culture that embraces employee feedback and values employee contributions. They also stress that senior management must be involved and must fully participate in establishing a culture of quality,” says Schniepp (2–8).

Is the investment in creating a company-wide culture of quality worth the time and effort? It seems the alternative is worse; the repercussions of not having a robust quality culture include higher costs and increased scrutiny by regulators (1). “Ultimately, [the impact] is likely to be financial because there will be FDA 483 observations to remedy, possibly product recalls, and ultimately the possibility of a consent decree. These all take time and money. (If people think quality is expensive, try a long FDA 483 list, a product recall, or a consent decree). The company’s stock price will also likely take a hit,” stresses Moreton.

“Companies that lack a good quality culture usually have high deviation/investigation rates, which impact their ability to provide safe and effective medicine to patients. It also costs them more money to perform the investigations making them less efficient,” agrees Schniepp. And, in the end, the safety of the patient is what matters most.

“Establishing a Culture of Quality,” 

GMP Data Integrity Definitions and Guidance for Industry

A GxP Data Integrity Definitions and Guidance for Industry 

Draft version for consultation (July 2016).

Data Integrity and Compliance With CGMP Guidance for Industry Draft Guidance 

Annex 5, Guidance on Good Data and Record Management Practices

Draft PIC/S Guidance: Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments

Elements of a Code of Conduct for Data Integrity

Data Integrity and Compliance with Drug CGMP: Questions and Answers, Guidance for Industry


Volume 46, Number 5
May 2022
Pages: 44–45

When referring to this article, please cite it as S. Haigney, “A Robust Quality Culture Benefits All,” 

Establishing a quality culture from the top of an organization down to each and every employee ensures a safe and effective product, and saves costs.

A Robust Quality Culture Benefits All

Performing corrective action and preventive action (CAPA) activities is often necessary to investigate a manufacturing deviation and prevent it from reoccurring. 

 asked Jeff Elton, PhD, CEO of ConcertAI, about the role technology plays in performing CAPAs.

How can technology be used to prepare and perform CAPAs? In investigating deficiencies, and/or developing action plans?

 Technology and AI [artificial intelligence] can, and should, be used to create and maintain effective CAPA plans, in clinical trials, real-world evidence (RWE), and medical devices ecosystem. In FDA’s three draft guidance documents published at the close of 2021 on the use of RWE, a number of key technical characteristics were noted as foundation. Upon integration of those across all technical environments interacting with study data, technologies can allow a study dataset to be considered a ‘package’ of data that includes details on its source, source relevance, reliability, etc. These same technologies also allow surveillance of data for anomalies and errors can assemble data to a specified cohort and create registries and comparative data sets assuring consistency with the study plan and any preliminary analyses.

How can technology be used to track the progress of CAPAs and the impact of changes on products and processes?

GxP and other related processes can now all be electronically captured and maintained. This means that the technology development process for a dataset, technology enablement SaaS solution for clinical trials, or digital medical device can have the history and documentation available in a digital only version that further unpins critical certifications such as 21 

 Part11 that stands in assurance of reliability and reproducibility. Consequently, the prevention plan and any required corrective actions are fully available and integrated. We see these automation tools as improving accuracy, reducing manual effort, and fundamentally lowering risks.

How can technology be used to anticipate potential problem areas that might need a CAPA plan?

 A GxP plan is documented evidence that the system is fit for its intended use. This answers the question of ‘what will this system do?’ and ‘Is there evidence the system performed as expected?’. This underlies the CAPA, as we can automate the surveillance of performance relative to these expectations. The full lineage of data and metadata capture of performance would allow remediation of any failures to perform to these documented expectations. While some of this can be automated in design and capture, we see that these will advance towards intelligence systems where the deviations are identified by AI and ML tools that recognize departures from expectations, designs, and defined boundary conditions. While technology does not replace the need for human interventions whenever issues arise, it may certainly help prevent future problems by creating an ecosystem that is constantly evaluating itself against its desired inputs at various timepoints throughout the production and administration of life-saving care.

What kinds of data can be compiled during a CAPA, and how can these data improve product quality?

Multiple types of data can be collected, including a validation plan, traceability matrix, conformance to design specifications, test case summary reports, GxP risk assessment outcomes, automated functional end-to-end test results, etc. In data-centric solutions, this can include confirmation of data ingestion, data mapping, data transformation—all aspects determining initial quality for data being used for any RWE analyses. One aspect that receives less attention is the interoperability and perpetuation of errors across multiple systems. Therefore, the more integrated the CAPA across systems or the more integrated the system across use-cases with a single CAPA the more robust the plan will be. The creation of the initial data also allows the automated assurance that the performance in-use is consistent with the data compiled during the CAPA development.

In what other ways can data found during a CAPA be used for pharmaceutical development and manufacturing?

 Anything that contributes to the reliability of the system or the data captured by a system contributes to clinical development. Often the data for a clinical trial or ongoing post-approval surveillance as part of a Post-approval Safety Study can include aspects of data generalizability, completeness, and reliability. The higher the confidence levels are on all of these parameters, the greater the ability to accept confirming data or the more quickly an action can be taken on less data.”

What kinds of data do regulators request from CAPA plans?

 This varies by the product, technology, or solution, but broadly:

Product or QMS [quality management system] non-conformities—this is where automated GxP documentation, validation, and automated monitoring relative to the plan and conformance data can add enormous value.

Internal bug reports (e.g., by developers)—again automated and exhaustive documentation that is maintained progressively for all aspects of the system and for documentation of conformance to expected performance can deliver a highly robust CAPA.

Audit findings—some audits can now be run as a script. Others will be done on demand based on anomalies or where the criticality of the decision may be exceptionally high.

Post-market surveillance findings, including trends—this is where the new RWE guidance for registries can change how this is done, increasing the scale of data used, allowing for rapid detection of anomalies, etc.

Management review findings, including trends—This should be part of product development processes, acceptance process, and general releases. As we move towards digital and automated testing, it can become more ‘real-time’ versus period, discrete, or event-driven as it often is today.

Pharmaceutical Technology asked Jeff Elton, PhD, CEO of ConcertAI, about the role technology plays in performing CAPAs.

The Role of Technology in CAPAs

 asked Joe O’Gorman, head of Global Operations at LZ Lifescience, a Cognizant Company, about the role technology plays in performing CAPAs.

 How can technology be used to prepare and perform CAPAs?

When applied to manage quality systems, connected digital technologies and software offer managers a common set of tools and the rich high-integrity data they need to enforce the process of CAPA and its compliant management relative to regulators. Resolving a CAPA-causing event, for example, is accelerated, made more efficient and reliable with real-time traceability, automated notifications, and escalations management. Digital systems not only support
efficient CAPA management they allow the entire enterprise to access CAPA information.

 How can technology be used to track the progress of CAPAs and the impact of changes on products and processes?

 With routine data capture and reporting automated, quality staff can leverage digital technology to build a detailed history of events and then mine and analyze [these] data to obtain a richer knowledge of root causes. With a well-integrated CAPA management platform, quality teams also have the ability to clearly assign ownership, notify various people/groups, and better manage and connect all collaborators to resolve CAPA-triggering events. With automated workflows to manage the CAPA process itself and automated reporting to monitor status as it moves through it, operators can achieve a much clearer and direct view of CAPA progress in real time.

 With real-time visibility and the ability to track the age of each action and escalate action automatically with email or an SMS alert, a CAPA management platform allows managers to better understand events and the necessary response. With historical root-cause analysis at their fingertips and a clearer view and reporting of actual outcomes, managers can apply these learnings to operations to prevent potential problems in the first place.

 A well-integrated solution can deliver rich data to the CAPA resolution process. For example, quality managers can access and leverage product details, type of defect, manufacturing facility or line, department, shift, crew, and more. A CAPA platform is a reliably efficient way to conduct and obtain root cause analysis as well. By leveraging the information, managers can gain a deeper understanding of root causes faster, allowing them to focus resources on higher severity items as well as identify and action potential issues before they occur.

 In what other ways can data found during a CAPA be used for pharmaceutical development and manufacturing?

 CAPA information is used to improve overall process and systems efficiency. By capturing the data and clearly identifying and categorizing root causes, actions and standard operating procedures can be implemented to prevent further occurrences. Digital technologies span and connect the entire enterprise, something paper-based systems have historically been challenged to accomplish, especially across networks of manufacturing facilities.

 What kinds of data do regulators request from CAPA plans?

A CAPA system offers regulators a roadmap of processes they expect manufacturers to follow to identify and solve compliance problems. Regulators want clear concise data on product, process and formulation, defect, facility, line, specific machine, nature of the CAPA, detail, date, quantity affected and quantity received, among other details. A CAPA program’s output provides a critical focal point during FDA inspections and quality system audits. As mentioned, an effective and compliant CAPA system requires a strong set of data to detect and correct problems, as well as find, implement, and document findings, solutions, and subsequent changes. Because FDA investigators and auditors rely on CAPA documentation for reviewing compliance issues, the digitally enabled processes that a CAPA management platform offer a more efficient way to respond [to] regulators and avoid compliance issues from the start. It is well known that inadequately established CAPA procedures were the most common types of Form 483 observations for device manufacturers and the most popularly cited inspectional observation in 2019.

Pharmaceutical Technology
Volume 46, Number 4
April 2022
Page: 52

When referring to this article, please cite it as S. Haigney, “Technology and CAPA,” Pharmaceutical Technology 46 (4) (2022).

Performing corrective action and preventive action (CAPA) activities is often necessary to investigate a manufacturing deviation and prevent it from reoccurring. Pharmaceutical Technology asked Joe O’Gorman, head of Global Operations at LZ Lifescience, a Cognizant Company, about the role technology plays in performing CAPAs.

Technology and CAPA

As cell and gene therapies continue to grow as novel treatments for unmet medical needs, biopharmaceutical companies will need to assess their options for meeting production demand. Two categories of cell therapies represent different production processes: autologous products use the patient’s own cells, and allogeneic products are manufactured using tissue from a healthy donor.

 spoke with Joe Codamo, PhD, head of Global Cell Therapy Business, Catalent, and Jose Cruz, director of Vector Manufacturing at Genezen, about the challenges of scaling up the production of cell therapies and ensuring capacity is met.

 What are the specific needs for scaling up commercial production of cell therapies?

 Autologous and allogeneic therapies are at various stages of their product lifecycles, with some shared and some unique manufacturing needs. The starting material for autologous products can be highly variable given the disease state of the patient. The ‘vein-to-vein’ process lead time is critical, so the manufacturing, product testing, and release timelines should be compatible. For allogeneic therapies, the scale-up and generation of a reproducible cell expansion process is key, as well as robust formulation and high-throughput fill/finish capacity. Shared needs include implementing a secure, robust supply chain that can support the necessary scale, throughput, and reproducibility needed once a product has been commercialized. The associated cost of goods must be appropriate, especially as some may become second- or even first-line treatments.

 There are several challenges that all developers can expect to face when scaling up cell therapies to commercial production. A key need is to manage variability seen in development data that can be magnified upon scale-up. A structured quality-by-design (QbD) development approach fit to transition into commercial manufacturing upon regulatory approval will also need to be implemented. With increasing IND [investigational new drug] applications for novel and innovative cell therapies, it is likely that existing processes will not easily fit to new projects. It is therefore essential that critical core technologies are developed in a way to allow quick tailoring to these specialized processes.

 Are there specific concerns regarding capacity for cell therapies?

The upsurge of IND applications in the cell therapy space has led to an increasingly crowded pipeline. Cell manufacturing technologies are typically very specialized, as opposed to ‘one-size-fits-all,’ resulting in further capacity challenges due to the requirement for highly customized processes.

It is essential that pharmaceutical companies can quickly and thoroughly characterize and release vector technologies. This will enable generation of qualified data that can sustain a candidate through clinical trials, as well as supporting the transition into commercial manufacturing. However, increasingly crowded pipelines can impede these processes.

With cell therapies using autologous (patient) cells specifically, such as CAR [chimeric antigen receptor] therapies, we see a need to ensure sufficient physical capacity to manage the different cells for facility processing. This is due to the requirement for isolation and separate cleanrooms when working with patients’ cells for clinical trials.

This work is predominantly manual, but there are self-contained systems available; there are moves towards automating transduction and expansion of patient’s cells in the future.

 As the number of cell therapies in the clinical pipeline grows and more reach later-phase studies, demand for late-stage and commercial-scale manufacturing is growing correspondingly. This demand will only increase as market acceptance expands and cell therapies are potentially introduced at earlier stages of a patient’s treatment. The CDMO [contract development and manufacturing organization] industry has taken steps to help address the growing demand, as evidenced by the significant number of acquisition and expansion announcements in manufacturing capacity made over the past few years. Getting new facilities online, staffing with appropriately experienced scientific and technical personnel, and having a robust supply chain to meet the markets’ needs are concerns for all advanced therapies, including cell-based ones.

 What are the steps for ensuring a contract partner has the capacity to manufacture cell therapies to commercial scale?

When evaluating a potential manufacturing partner, it is important to understand what its scale-up strategy is. For example, has it designed or optimized its infrastructure to deliver larger-scale and/or higher throughput, and is it working with its own supply chain to help assure high-quality production and consistent material quality? CDMOs should have a clear technical transfer and ramp-up strategy to go from clinical to commercial manufacturing. This [strategy] includes a process validation strategy and the supportive studies to demonstrate process and analytical robustness. Finally, the CDMO should have a global strategy to prepare for, and support, commercial launch, including topics spanning communication with regulatory authorities to a robust strategy for business continuity (staffing, material contingency, facility operations, etc.).

 One of the biggest concerns highlighted by clients is the need to find a CDMO offering both the roadmap to commercially manufacture cell therapies as well as the technical skill set to solve the inevitable challenges along the way. Selecting a partner with future commercial capacity while demonstrating cross-industry experience in the clinic, regulatory, and manufacturing sciences is key to successful commercialization, but they can be difficult to find.

Once a suitable partner is identified, early engagement between developers and the technical team is needed to develop a ‘best-launch’ process with an overarching aim to create a ‘best-in-class’ scope of work.

What are the benefits of outsourcing the production of cell therapies?

 Outsourcing cell therapy production has many benefits, particularly for smaller and younger companies with limited financial capital aiming to minimize the fixed costs that can be associated with building physical infrastructure.

Working with a dedicated CDMO partner also provides access to cross-functional expertise from process development, manufacturing sciences, operations, engineering, quality assurance, and regulatory. The seasoned expertise offered by CDMOs can act to bridge the path between discovery and clinical, as well as development and commercial manufacturing.

Working with CDMOs that have standardized development processes
built on QbD principles while offering tailored-fit technologies to manage inherent variability of cell processes will also help to increase speed to market.

An outsourced manufacturing partner can offer scalability, quality, and the regulatory experience gained from producing a variety of products and modalities. A CDMO provides opportunities for supply-chain streamlining and the leveraging of strong, global supply arrangements, as well as the necessary manufacturing capacity to help an early-stage cell therapy company ready itself for production within fast-paced timelines. CDMOs that can support end-to-end services including starting materials (plasmid DNA, viral vectors) and clinical logistics can simplify the supply chain. Outsourcing allows companies to avoid investing in CGMP [current good manufacturing practice] facilities, which may not be cost effective, and pose a financial risk when product demand and its clinical or market success
is unknown.

 What are the challenges of outsourcing cell therapy production?

 These can include the management of timelines and communication with manufacturing partners, especially if multiple partners are involved in the process. Gene-enabled cell therapies require viral vector manufacturing as well as the production of the final product, and manufacturing of the cell therapy cannot begin until the viral vector is available. The cell therapy company may need to manage the communication between the CDMOs and their timelines, or if using a single manufacturing partner with integrated services, ensure that the partner provides one main point of contact and streamlines the integration between the supply chain stages.

 As well as the challenge of identifying a CDMO offering both expertise and capacity, it is also necessary to ensure the availability of this capacity in the required timeframe and availability of analytical technologies.

These analytical methods include master cell bank (MCB) and vector product release testing, RCL assays, HEK293T host cell protein (HCP) assays, and others that are essential in determining quality at different stages of the process.

Developers looking for a CDMO partner should also consider whether they are looking for a short or long-term investment. If they envisage the project scaling up from discovery to clinical supply and then to commercial manufacturing, they must determine whether they wish to eventually bring specific steps in-house. If aiming to bring the product to market with support from a CDMO, they should determine whether their partners have these capabilities early in the project’s lifetime to ease transitions and avoid delays.

 What is the ratio of in-house vs. outsourced production of cell therapies? Do you see the industry increasing the amount of outsourcing for these therapies?

For small-scale needs, such as in the early-phase studies, we estimate that more in-house production is currently conducted. However, once either larger batch sizes are needed, or a wider distribution of manufacturing is necessary, the ratio of in-house to outsourced manufacturing changes. Outsourcing partners with established clinical supply capabilities as well as manufacturing expertise are better suited to manage larger scale or larger numbers of batches and the vein-to-vein logistics. For those with in-house capabilities, there is the potential for secondary and back-up supplies to be provided from outsourcing partners as therapies receive worldwide approval.

Currently, the ratio of in-house to outsourced viral vector manufacturing is around 40:60 with lentiviral vector and adeno-associated viral vector manufacturing constituting 66% of total projects (1). Outsourcing is expected to further increase to 68% in the next five years.

Cell therapies using allogeneic (donor) cells, as opposed to autologous cells, could drive greater outsourcing. As managing or handling autologous cells is a critical step, companies are often keen to keep this process in-house. Unlike autologous cells, allogeneic cells have the potential to be produced in one large batch before being packaged into individual doses. Although less personalized, these therapies require processes that are much more manageable at large scale as compared with autologous cell handling and may be more suited
to outsourcing.

1. E. Harris, “A Summary of Cell & Gene Therapies Market Outlook Report,” 


Volume 46, Number 4
April 2022
Page: 54–56

When referring to this article, please cite it as S. Haigney, “Scaling Up Capacity for Cell Therapies,” 

The booming cell therapy market has created a need for capacity that outsourcing partners are ready to fill.