Increasing molecular diversity leads to more challenges in process development and control. Advancements in technology for manufacturing and online analytical monitoring have not caught up to the innovative drug candidates and emerging modalities present in the candidate pipeline today. Lack of pre-determined process and analytical platforms for these modalities often translates to longer development times. New modalities are more difficult to fully characterize due to their complexity, and some highly complex tests take weeks to complete. Therefore, failures in quality attributes are typically found post-production after testing is completed.

Supply chain constraints on critical raw materials in the form of lead times of months to years can be another serious bottleneck for production. Cold-chain requirements have also limited global distribution, storage, and access especially in regions with less developed infrastructure.

Biopharma manufacturers must find solutions to enable the acceleration of the development of the diverse array of novel drug candidates in the pipeline and thus ensure that safe and effective novel treatment options can be brought to patients more quickly.

Several new modalities are
challenging biopharma developers

Rapid evolution in therapeutic modalities is currently underway, with autologous and allogeneic cell therapies, viral vectors, plasmid DNA (pDNA), messenger RNA (mRNA), and oligonucleotide therapies, for example, under development as treatments for infectious diseases and cancer vaccines, some eventually as personalized medicines, and some already approved, according to Anne-Cecile Potmans, general manager, Fast Trak with Cytiva. Bispecific antibodies (bsAbs) also present new challenges concerning process development and control, adds Thaddeus Webster, lead scientist, R&D Biologics for Lonza.

“Biologics, especially complex or multimodal therapeutics, are an area of continued innovation but are difficult to scale up, manufacture, store, and deliver for a variety of reasons,” contends Don Owens, director of product development at TFF Pharmaceuticals.

For example, Owens notes, mRNA vaccines are unstable for prolonged periods at room temperature, are sensitive to shear stress and thermal and oxidative degradation, require ultra-low temperature (-80 ˚C) cold chain storage, and have short expiration dates. In addition, Jens-Christoph Matuszczyk, manager of Process Technology, Cell Culture Technologies Marketing at Sartorius, observes that mRNA in general exists as a variety of constructs, and as it has become popularized, process sub-varieties like modified nucleotides and synthetic templates have arisen to further complicate the space. “Add to this a quickly evolving intellectual property landscape, and the potential paths to pursue for process development become numerous,” he says.

The cost of goods for running mRNA process development experiments is also a challenge, and the existence of many different analytical strategies, each with its own set of benefits and drawbacks, further contributes to the difficulty in achieving a field consensus, Matuszczyk notes. In addition, process automation technology is still nascent, although he does comment that new toolkits are emerging.

Immune cells, meanwhile, suffer from large donor-to-donor variability, making both process characterization and development and the establishment of process control strategies difficult, particularly for autologous applications, according to Matuszczyk. “Process development work is often done using health donor cells, which characteristically could be very different compared to patient cells,” he says.

Lack of automation and real-time analysis is also an issue for stem cell process development and control. This shortage is exacerbated by long lead times for critical raw materials and the fact that process development must be performed for many different steps from media prep to cryopreservation of final product. “Some of the process steps are manual and ‘open’ to reduce cost, and thus technology transfer and scale up can be problematic,” Matuszczyk remarks.

Induced pluripotent stem cells (iPSCs) are another modality on the horizon with process challenges particularly associated with inducement, directed differentiation, and banking steps, comments Avi Nandi, VP and head of process development at the Center for Breakthrough Medicines.

Process development and control of gene therapy products such as recombinant adeno-associated virus (rAAV) pose significant challenges due to their relatively high dose requirements and generally low-yield processes, says Ranga Godavarti, vice president, bioprocess R&D and drug substance supply at Pfizer. Developing processes and controls for small-scale and complex cell and gene (advanced therapies), meanwhile, is challenging due to immature process understanding, especially for early clinical batches, the complexity of gene editing and modification, and the lack of ability to measure critical quality attributes in a timely manner, according to Nandi.

Making accurate measurements is another difficulty, according to Meg Ruesch, vice president of analytical research and development at Pfizer. Because the quality attributes and functionality of gene therapies are challenging to measure, analytical resources can become a bottleneck for process development. “More analytical scientists may be required to develop meaningful assays and test samples as compared with well-known product modalities,” she says.

New process techniques and approaches are needed so there is a steep learning curve where scientists need to learn, expand their knowledge and expertise, and diversify their capability skillset, Potmans concludes. “There are also challenges from the operational perspective regarding the need to establish new platforms and build new manufacturing lines adapted specifically to these new modalities,” she remarks.

Given that each new product modality brings with it a new set of challenges, Potmans emphasizes that the greater the pipeline diversity, the greater the complexity with respect to processes, analytic, manufacturing, facilities, supply chains, and workforce talent. “These complexities need to be identified, understood, and overcome. That includes ensuring that appropriate raw materials, consumables (resins, filters, cell culture media, single-use products, etc.), and sometimes equipment are available to support the development, manufacture, and the testing of these new modalities, which may require modification of existing or development of new solutions,” she explains.

There is also significant diversity within many of the classes of emerging modalities that adds to the complexity, according to Godavarti. He points to AAV vectors, which have multiple serotypes based on specific tissue targeting. “Each of these serotypes has unique molecular features requiring novel process and analytical methods, and thus development approaches that take more time and effort,” he says.

In addition, process controls tend to be more complex than those for traditional biologics for which there is better process understanding. “For the emerging modalities, we do not yet have that same amount of process and analytical knowledge on what molecular attributes are critical to control, leading to more difficult control strategies,” Godavarti observes. Furthermore, he notes that these new modalities often require novel raw materials that are not as readily available as those for established monoclonal-antibody (mAb) products. Finally, the limited stability of these new modalities at ambient temperature impacts not only the ability to provide final convenient dosage forms, but also requires minimizing hold and processing times during production.

The often-accelerated development timelines for new modalities create additional challenges, particularly given the desire to run multiple scenarios during process development to gather data for regulatory filings and scale up, adds Nandi. “Getting sufficient study data early on via high-throughput characterization can help avoid failures and risk later on,” he says. These issues are frequently compounded by a lack of experience with the bespoke processes and technologies, and as a result there is an ongoing focus on provision of training and motivation to increase retention across process development organizations, Nandi adds.

Bispecific antibodies are just one example highlighted by Webster. “These molecules combine two different fragment-antigen binding (Fab) arms capable of binding two different antigens into a single format. Ensuring that the produced bsAbs have the correct product quality attributes (i.e., correct pairing of heavy and light chains) every time presents unique challenges to process development and control that is not seen for traditional biologics,” he points out.

Experiments for immune-cell processes should ideally be performed at the lowest scale possible to take into account the cost and labor for testing, which can make sampling an issue as well. Process intensification is needed for stem-cell manufacturing to realize better costs and reduce the time and floorspace needed.

Many traditional biologics have been manufactured for over two decades. As a result, a vast amount of [standardized] process and manufacturing experience and knowledge have been accumulated, according to Godavarti. “These molecules fit pre-determined process platforms well, requiring little time for development and enabling a simpler transfer of manufacturing technology. For the new emerging therapies, such process and analytical platforms do not exist,” he states.

As a result, emerging modalities often require custom manufacturing and specialty equipment that may be too complicated or expensive to develop in-house, observes Kayla Hannon, manager, process engineering, with TFF Pharmaceuticals. For similar reasons, this equipment is typically not found at contract development and manufacturing organizations (CDMOs). “These complex modalities require expertise from manufacturers familiar with their novel structures and components and experienced with custom equipment,” she says. “Additionally, biologics in and of themselves are a very diverse class of materials, and each one will have its unique analytical characterization techniques that require specialized equipment, as well as trained personnel to operate that equipment and interpret that analytical data,” Hannon notes.

Finding new platforms and new molecule evaluation models is important and challenging, Potmans agrees. She also stresses that molecular diversification within the pharma pipeline reinforces the need for highly specialized talent. The talent pool is, however, already limited compared to the current and future needs of the biopharma industry, and product diversification will only further stress the talent crunch for these highly specialized resources. Facilities, too, may have different requirements, such as dedicated equipment, more rigorous cleaning procedures, and/or higher biosafety levels. “Manufacturers of new modalities must build flexible and modular manufacturing platforms to manage all of the various cell types and modalities,” Potmans comments.

The lack of platform processes is obvious when considering specific modalities. For mRNA, process and analytical standardization is a challenge due to diverse types of mRNA (messenger, self-amplifying, trans-amplifying, circular, or non-replicating) and templates (microbial-based circular plasmids or synthetic linear DNA), according to Matuszczyk. There are also different encapsulation technologies (lipids, nanoparticles, or lipoplexes). “All these factors contribute to changes in process steps and utilized technologies, making each process require development from the ground up,” he notes. “The high development need due to the diversity of RNA sub-varieties and minimal process standardization is combined with a high cost of goods and a lack of mRNA-specific workforce experience to create real challenges in the field,” Matuszczyk concludes.

Cell and gene therapies also encompass a wide range of highly complex product types that are produced using a wide range of manufacturing processes that are customized and often involve manual operations, Nandi comments. Allogeneic cell therapies support multiple patients and are produced in large batches from healthy donor material, while autologous treatments are derived from and returned to the same, single patient.

In vivo and ex vivo gene therapies also involve different manufacturing processes, with the former usually leveraging viral vectors for gene delivery and the latter as autologous products, says Nandi. Production processes for viral vectors vary widely as well and are challenged by many issues ranging from raw material variability to poor transfection yields to incompatibility with typical aseptic manufacturing unit operations, such as sterile filtration and filling/dosing by pumps. “Effort needs to be spent on process development and optimization before the volume requirements for clinical production can be achieved,” he contends.

Process analytical and digital technologies

The reduction of manual tasks, from both a cost and product quality perspective, becomes increasingly important for the development and manufacturing of novel therapies. For both autologous and allogeneic processes, high-throughput solutions are needed to speed up process development and reduce the time it takes to reach the clinic. Doing so, says Matuszczyk, is achieved by further deployment of higher automation, remote diagnostics, and real-time process monitoring and control that significantly reduce manual operations, thus decreasing contamination risks. “Data analytics tools in particular enable process optimization, further reducing the need for human intervention,” he says.

Implementation of process analytical technology (PAT) solutions, however, remains challenging for novel modalities because there is a lack of regulatory guidance around some automation and sensor technologies, such as spectroscopy sensors that measure multiple analytes, and how to validate chemometric models generated for use in good manufacturing practice (GMP) facilities, according to Matuszczyk.

PAT solutions that enable a quality-by-design approach through the measurement of several analytes simultaneously during design-of-experiment (DoE) studies are therefore important, Matuszczyk observes. “Integrated real-time PAT technology from process development though to manufacturing scale, such as integrated Raman spectroscopy, allows models to be built more rapidly and more easily transferred across scales for real-time monitoring and control,” he comments.

Maintaining sterility in the cell culture environment is, according to Matuszczyk, also of particular importance for the manufacturing of autologous cell-based therapies, where a lost batch has detrimental consequences for the patients to be treated. Therefore, the reduction or elimination of manual steps, enabled by the measurement of metabolites, cell viability, or nutrient consumption with in-line, integrated single-use PAT tools, has the ability to reduce the risk of batch contamination, according to Matuszczyk.

There is also a need for the development of real-time analytical solutions for use in the development of bsAb processes, according to Webster. “One of the main challenges to the process development and control of bsAbs production is the need to have adequate PAT to measure not only the same product quality attributes of traditional mAbs (i.e., N-glycan, charge variants, etc.), but additional technologies to measure product quality attributes unique to bsAbs (i.e., correct pairing, functionality). Current techniques involve offline analytical tools that are effective for development but don’t deliver the level of process understanding and control that at-line and in-line PAT tools have delivered in the past,” he remarks.

“Converting the offline analytics for desired product quality attributes to at-line via automated sampling (i.e., mass spectrometry) or in-line via multivariate process monitoring remains a gap that needs to be addressed,” Webster adds. For some bsAb attributes, PAT tools developed for mAbs can be applied, freeing up time to develop new analytical techniques to measure and monitor the product quality attributes unique to bsAbs.

Digital solutions in general within bioprocessing will be critical to overcoming some of the process development and control challenges presented by the molecular diversity in the clinical pipeline. In addition to PAT, simulation tools will allow for the development of more robust processes more quickly, according to Potmans. “The digital ecosystem of integrated process development that will bring future therapies to the market will focus on process modeling, safe and secure cloud-based artificial intelligence (AI), and limited, but focused, empirical testing,” she contends. “Digital solutions will improve how well processes and products are understood, optimized, and controlled, which will in turn dramatically improve speed and quality while significantly lowering risks as therapies progress through developmental phases,” Potmans explains.

Digital tools for in-silico modeling will also enable prediction of scaleup performance and thus augment process knowledge, Godavarti says. Modeling approaches can, in addition, be extended to analytical areas, such as stability studies.

Technologies such as machine learning will help drive insight from high volumes of data, adds Matuszczyk. “Many companies are implementing data-driven approaches from process development up to commercial manufacturing for faster time-to market and risk reduction, leveraging historical data (e.g., cell lines, clones, product yield, growth profiles) for model-driven approaches that help to faster develop and produce novel vaccines and therapies,” he states.

reinvention of process development and control

Strategic investments are made in developing novel technology and innovation specific to these emerging areas, Godavarti says. He adds that tools and learnings (high throughput-screening, PAT, digital technologies) from other modalities are applied to these emerging areas to capture efficiencies. “Applying molecular biology-based methods such as sequencing and polymerase chain reaction testing in combination with robust in vitro
cell-based activity assays is key to enabling success,” Godavarti observes.

In mRNA development, for example, Matuszczyk points to new trends in process development. Early-stage screening in very small volumes typically occurs with endpoint analysis as the only data point and larger volumes to investigate more complex process designs using fed-batch mode and PAT, such as Raman spectroscopy for real-time measurement of nucleoside triphosphate consumption. For stem cells, he notes there is a push to fully optimize and characterize processes at the R&D stage and then use integrated, automated, and closed end-to-end processes during process development before tech-transfer to manufacturing takes place to avoid rework, save time, and reduce costs.

Use of a rapid freezing process known as thin-film freezing is another example of process development innovation. This approach enables the formulation of biologics as dry powders with improved stability but without loss of structure and therapeutic integrity. TFF Pharmaceuticals is advancing this technique as a platform technology for improving the formulation of complex modalities, including vaccines, small molecules and biologics, as dry powders. According to Hannon, this approach provides key advantages, including access to more convenient routes of administration due to aerosolization properties (i.e., inhalation or intranasal delivery) and elimination of the need for ultra-cold chain storage due to temperature stability.

The use of statistical process control methods, meanwhile, gives operators confidence that processes are adhering to control parameters, according to Nandi. In addition, if a process is trending in an out-of-specification direction, these systems provide notification so action can be taken before a problem arises, often preventing the loss of valuable product.

Developing a stable production system with all components integrated into a stable producing line is another strategy observed more frequently as emerging modalities mature. The Center for Breakthrough Medicines is developing such a system for viral-vector production that is similar to systems used for manufacturing mAbs, and with it can obtain 5–25 times more product. The company has also established a pilot plant that enables GMP production at non-GMP scale, according to Nandi.

Future challenges for all emerging modalities, says Godavarti, include establishing platform technologies and building sufficient process knowledge so that work flows for process characterization and control strategies can be simplified. Other areas of focus, he adds, include identification of ways to enhance stability, yield, and assurance of the availability of GMP-grade novel raw materials.

Potmans highlights the need to increase capacity at CDMOs with expertise in new modalities. Owens adds that outsourcing and other strategic partnerships require significant planning and financial support by the parties involved. Managing supply chains in general will continue to be an issue for all drug products as well, Owens observes.

“There will continue to be a strong need for the development of innovative formulations, analytical characterization, and advanced process control technologies aimed at improving the development of complex modalities to circumvent some of the slowdown in manufacturing, processing, and logistics,” adds Hannon. Streamlining manufacturing processes is, agrees Matuszczyk, critical for future success (e.g., by increasing the use of automation and closed systems for immune-cell-therapy production processes or reducing the steps needed for stem cell production). Furthermore, researchers are currently looking at in-vivo generation of immune cells, which will add, if successful, a complete new level of complexity to treatment of patients.

The continued advancement of products that utilize alternative routes of delivery is needed to improve patient outcomes in certain diseases and with modalities that might have stability and other challenges when administered via traditional routes, Owens observes. “These other routes may use testing and controls that are faster to implement and use than traditional sterile injectable products,” he explains.While multiple challenges certainly need to be addressed with increasing molecular diversity, it is comforting to think that there is a parallel rise in the numbers and types of innovative solutions to match them.

Cynthia A. Challener, PhD, is contributing editor to BioPharm International.

BioPharm International
Volume 35, Number 11
November 2022
Pages: 10-15

When referring to this article, please cite it as C.A. Challener, “Process Development and Control for New Modalities,” BioPharm International 35 (11) (2022).

Articles

Cover Story

Increasing molecular diversity is creating a need for the reinvention of process development and control strategies.

Process Development and Control for New Modalities

Detection and removal of residual impurities is a critical and mandatory part of downstream processing (DSP). To find out more about the importance of detecting residual impurities in DSP, the challenges facing scientists when dealing with impurities in DSP, and the potential solutions available to help overcome the difficulties associated with residual impurities, 

 spoke with Olaf Stamm, PhD, technical business development director, Charles River Laboratories, and Luc-Alain Savoy, global head of Biologics, SGS Health and Nutrition.

 Why is it important to detect and remove residual impurities in DSP?

 The principle of ‘evidence-based medicine’ requires that the API is purified using best practices and scientifically sound technologies. The demonstration of the successful removal of process-/product-related impurities is mandatory. As such, impurities are considered a critical quality attribute, and any impure product would call into question the quality, safety, and efficacy of the compound.

 Some of these residual impurities are [extremely] toxic; it is therefore essential to remove them to guarantee the safety, the quality, and the efficiency of the drug.

 Could you highlight the challenges faced by scientists in relation to residual impurities in DSP?

 Residual impurities or process-related impurities are compounds that are usually present at [significantly] low concentrations in complex biomanufactured products and can vary from large biological entities to small chemicals. Therefore, their detection and evaluation require extensive knowledge of analytical methodology to cover a large range of products to be monitored.

The objective of DSP is to purify from the bulk [product] made in the upstream process (USP), the active ingredient. Hence, good knowledge of the USP is required to propose a list of impurities to follow, which may simply be

ingredients added in the bulk, but which also may be generated in the bioreactor during the incubation. A good knowledge of the DSP is also essential as residual impurities, such as leachable or solvents, may come from these purification steps.

In summary, the monitoring of residual impurities needs expertise and knowledge of all steps of bioproduction process (upstream and downstream), and in analytical testing.

 Host cell proteins (HCP) are an inevitable impurity of biopharmaceuticals, regardless of whether they are produced by recombinant fermentation or extracted from natural sources. Even after multiple sophisticated purification steps, HCPs remain or copurify.

HCPs represent a heterogeneous variety of different proteins that need to be quantified in the drug substance and in intermediates from the downstream purification process. The risk for adverse effects, such as immunogenic reaction, does not necessarily correlate with the amount of certain host cell proteins. That is to say, even small traces of certain ‘high-risk’ HCPs can be highly immunogenic.

 Do these challenges differ depending on the therapeutic being developed?

 In contrast to products from recombinant protein expression, the majority of advanced therapeutics are facing more challenges with respect to HCP impurities. Gene therapy products consist of multiple viral proteins, which significantly increases the complexity of the therapeutic compared to most biologic drugs that are typically expressed as single proteins in host cells. The gene therapy manufacturing process is associated with additional process related impurities (e.g., serum, bovine albumin, Benzonase, etc.), which are needed to check for contaminating proteins from several very different species.

Additionally, gene therapy products are often manufactured on human cell lines—the proteome of which is far more complex than that of CHO [Chinese hamster ovary] cells. The increased proteomic complexity adds challenges to the development of suitable immunoassays for HCP control for several reasons described below.

First, full-cell lysate needs to be used as an antigen rather than the much less complex cell culture supernatant, because many virus products lyse the host cell or require active lysis of the host cell during the harvest. Second, human HCPs are less immunogenic in standard species, such as rabbits and goats. Third, there is currently no single commercial ELISA [enzyme-linked immunosorbent assay] capable of detecting such a heterogeneous mix. As such, there is much more emphasis on having project-specific assays even at an earlier stage in development. Fourth, gene therapies are mostly fast-tracked by regulators due to the fact that they are typically aimed at treating the most serious illnesses. This adds additional pressure to the early process development activities. If a gene therapy is delayed getting regulatory approval because of inadequate HCP detection, clearance etc., the setback could hold up drug development long enough for a competitor to bring their gene therapy to market first.

 Yes indeed. The bioproduction of peptides, proteins, oligonucleotides, cell lines, or viruses requires very different USP and DSP; therefore, challenges differ. The monitoring of residual impurities in new therapeutic modalities may be more challenging because of the limited experience we have on their production mode. On the contrary, the manufacturing of a mAb [monoclonal antibody], for example, is now [highly] standardized, and the residual impurities needing to be followed [are] well identified.

 What solutions are available for developers to help them overcome the challenges of residual impurities in DSP?

 The development of online LC–MS [liquid chromatography–mass spectrometry] method to monitor in real time critical quality attributes, such as residual impurities, will allow a better understanding of the manufacturing operation. Moreover, when coupled to a semi-continuous downstream process this will result in consistently shorter processes, an improved control strategy, and a reduction in the number of QC tests needed for batch release.

 In the past, the HCP mixture has been a ‘black box’, so to speak. The overall content was measured by a set of polyclonal antibodies, which are raised against an antigen that has been derived from a mock fermentation. The knowledge about the coverage/specificity of this antibody cocktail has historically been very limited and based on the spot pattern comparison of 2D-SDS-PAGE [two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis] and corresponding Western blot.

The 2D gel approach is quite illustrative, but the pattern only provides an approximation of the relative linear coverage as the method is, by definition, focused on linear epitopes due to the use of detergent. The protein spots typically remain unidentified and quantitated.

However, despite the limited intelligence gained on the reagents of the assay, such HCP immunoassays are powerful tools and essential in drug development due to their extreme sensitivity, agnosticism for different matrices, and ease of use and validation in a GMP [good manufacturing practice] environment.

Over the past decade, proteomic tools such as mass spectrometry have become extremely powerful, much easier to use, and far more affordable than ever before. Meanwhile the analysis of several hundred or even several thousand proteins present in one sample has become routine in the hands of experienced CROs [contract research organizations].

Today, mass spectrometry can identify and quantitate each individual HCP present in samples from crude harvest to the highly purified drug substance. This new level of granularity better enables a ‘quality by design’ approach during DSP development with respect to impurities. Knowing identity and concentration of each individual HCP at every step of the purification process enables manufactures to identify the so called ‘hitchhiker’ HCPs. These HCPs co-purify with the drug protein, and it is imperative to determine whether any of them belong to a group of ‘high-risk’ HCPs that are known to cause adverse effects.

By using an immunoaffinity chromatography approach with a mass spectrometry readout, the ‘conformational’ coverage of the antibodies used in a corresponding HCP immunoassay can be determined—this is another way to lighten the ‘black box’.

In contrast to the 2D gel/blot approach, this experiment mimics the physiological conditions of the immunoassay to check the antibody cocktail for potential detection gaps. A detection gap would mean that a high-risk HCP co-purifying with the drug protein would be inadequately recognized by the antibodies present in the immunoassay.

Once such gaps are identified, the immunoassay can be tailored by a targeted approach using peptide immunization to achieve complete coverage for the final-release testing.

 Are there any gaps/areas that are lacking perhaps where novel approaches/techniques to help overcome the challenges of residual impurities are required?

 As alluded to in the previous question, the novel approaches are available. The tools (mass spec applications) have become standard in the hands of experienced CROs—so much so, in fact, that these projects are typically executed within a few weeks. However, 10 years ago, such work would have filled several PhD thesis projects.

The main gap is in the mind of the manufacturers who are not aware or have not yet fully adopted the advantages of mass spectrometry and improved immunoassays. Leveraging such tools during the early stages of drug development significantly improves process/product quality while reducing the risk of running into unwanted surprises in later stages.

 The emerging therapies such as cell therapy or gene therapy products are dynamic, heterogeneous, and, hence, very complex entities making them impossible to be fully characterized. Therefore, distinguishing them from an impurity which may be closely related can be very challenging and will require the use of innovative analytical techniques. These techniques will include PCR [polymerase chain reaction]-related assays, NGS [next-generation sequencing], and biological assays. Developing methods to identify and quantify impurities that are distinguishable from the desired product only by their genetic signature is certainly a serious challenge requiring novel approach/techniques.

Felicity Thomas is the European editor for 


Vol. 35, No. 11
November 2022
Pages: 22–23, 26

When referring to this article, please cite it as F. Thomas, “Removing Residual Impurities,” 

Downstream Processing

A thorough knowledge of both the upstream and downstream processes is required to ensure effective removal of residual impurities in biopharmaceuticals.

Removing Residual Impurities

Consumers favor sustainable products. A survey by Shorr Packaging shows that 76% of shoppers surveyed have made a conscious effort to purchase more sustainable products in the past year. An even stronger majority, 86%, are more likely to purchase a product from a brand or retailer if the packaging is considered sustainable. Additionally, 77% expect more brands/retailers to offer 100% sustainable packaging for their products soon (1).

When shopping, 64% of the consumers surveyed consider whether the packaging can be recycled; 60% look for packaging with recycled content; 60% seek source-reduced designs (no overpackaging); 45% want biodegradable packaging; and 28% like paper-based packaging. Approximately 68% are open to switching to a brand that offers sustainable packaging. This is particularly true of younger consumers (1). A report from Euromonitor International comes to the same conclusion, noting Millennials and Generation Z feel they can make a difference through their choices. This largest spending cohort of the future will rely on tech tools, such as digital product labeling and mobile tracking apps, to check environmental claims and ensure minimal climate impact (2).

Clear labeling of sustainability attributes also is important, with 69% saying they are more likely to purchase a product when there’s clear language/symbols on the packaging that states it uses sustainable materials (1). With recyclability, recycled content, and biodegradability top-of-mind, paper-based packaging ticks all the boxes and is favored by almost one-third of the consumers in the Shorr Packaging study.

To meet this demand, Keystone Folding Box has completed a $5 million upgrade that boosts capacity by 20% for its product line that includes secondary blister packages made from recyclable and compostable paperboard. Its Ecoslide Series of blister packs features a safety feature that provides the most stringent F=1 child resistance while eliminating the need for a two-step “peel/push-through foil,” which many consumers find difficult to open. Including Ecoslide-OTC for over-the-counter medicines as well as its signature Ecoslide-RX pack for prescription drugs, the sustainable package platform reduces the amount of disposable plastic needed for peel/push CR blisters (3).

Blister cards themselves also are becoming more sustainable. TekniPlex Healthcare has launched a fully transparent, recyclable, mid-barrier blister package. Certified via third-party testing, the recyclable polypropylene (PP)/cyclic olefin copolymer/PP base material with barrier PP lidding is said to be a first in the healthcare industry. From a manufacturing standpoint, initial machinability analyses have been positive, with large-scale tests scheduled. TekniPlex Healthcare also has premiered a fully recyclable polyester mono-material blister. It’s suitable for products that do not require barrier protection (4).

Incorporating post-consumer-recycled (PCR) content in packaging is viewed as highly desirable by the industry and consumers, but can pose challenges due to supply chain and quality issues. Avient’s PCR Color Prediction Service for polyolefins and polyethylene terephthalate (PET) resins and Cesa Nox A4R Additives for Recycling eliminate the trial-and-error of adopting PCR content and associated color choices. The PCR Color Prediction Service helps brand owners understand what colors are achievable based on the amount of PCR used. Proprietary software determines—through prior color matching—what colors are feasible in an application that incorporates PCR content. It also calculates how much PCR content can be added without affecting the package’s signature color. The faster evaluation process is particularly helpful if it becomes necessary to switch sources of PCR material (5).

The Cesa Nox A4R Additives for Recycling protects PCR polyolefins against oxidation, which can lead to defects like black spots, gels, and
discoloration. The antioxidant can be added to PCR content early in
the recycling process or incorporated in virgin resin to prepare it for
future recycling (5).

Schreiner MediPharm has set goals to increase its use of recycled/renewable materials, including the simplification of disassembly for recycling and reducing carbon dioxide emissions. As a result, it recently introduced more sustainable options of its Pharma-Tac label for infusion bottles and its Autoinjector-Label. Both new designs rely on film materials that are either recycled or produced from renewable raw materials. Extensive in-house testing shows the more sustainable materials perform as reliably as conventional substrates. For example, the Pharma-Tac label passed load and gravitational trials, and both the hanger label and Autoinjector-Label passed tests for adhesion, ink adhesion, print durability, and laser marking viability (6).

More sustainable tube options also are available. Hoffmann Neopac now offers Neopac mono-material barrier tubes, which are recyclable in the polyethylene (PE) or PP material stream. Neopac’s Polyfoil MMB mono-material barrier tubes have undergone successful testing by RecyClass, an initiative of Plastics Recyclers Europe. MMB structures, with and without thin film metallization, met recycling requirements set by the US-based Association of Plastic Recyclers (7). The MMB tube can reduce packaging carbon footprints by up to 38% compared to traditional laminated tubes. The tube body is made possible through a first-of-its-kind adhesive-laminated process, an alternative to conventional blown-film and extruded-film methods. Key advantages include advanced barrier and aesthetic options in the tube body. The tube’s shoulder and cap are made with low-melt-flow-index high-density PE and only 2% foreign material (8).

However, the majority of tubes used in Europe are aluminum barrier laminates (ABLs). These multi-material tubes currently cannot be industrially separated and recycled in existing recycling facilities. To solve this problem, Hoffmann Neopac has partnered with Saperatec, which has developed washing technology and established a pilot plant to separate the PE and aluminum for recycling in existing facilities. A laboratory study at Saperatec in spring 2021 with various ABL tubes from Neopac showed that its Polyfoil tubes can be completely separated (8).

“In addition to the already existing environmentally friendly and recyclable tubes from our EcoDesign portfolio, we are committed to a recycling solution for our conventional Polyfoil ABL tubes,” said Peter Bossert, head of materials development at Hoffmann Neopac. “With this new initiative, we will offer our customers the best possible balance between product safety and sustainability. As early as this year, we will make a portion of our production waste available to Saperatec to demonstrate its recyclability on an industrial scale, per the promising laboratory tests that have been performed. With the pending recycling of ABL tubes, we are closing a recycling gap in our portfolio.” After testing the separation of production waste, Neopac and Saperatec plan to study the possibility of using the separated materials in the production of new tubes (8).

Saperatec began construction of its industrial separation facility in December 2021 in Dessau, Germany. Scheduled to start up in mid-2023, the plant will recycle composite packaging waste made of aluminum, plastic, and paper. The process will be further developed by refining technologies such as digital watermarking, eddy-current detection, and near-infrared detection to enable intelligent sorting of ABL packaging into an ABL packaging material stream. “With the construction of the first recycling plant for composite materials made of plastic, paper, and aluminum, we aim to produce high-quality, film-ready plastic recyclates for packaging applications while returning the recovered aluminum to the material cycle,” concluded Thorsten Hornung, managing director of Saperatec (8).

Members of the pharmaceutical value chain are looking beyond product development to meet sustainability goals. Schreiner MediPharm, for example, is a founding member of the Alliance to Zero, a non-profit partnership dedicated to enhancing sustainability throughout the pharmaceutical supply chain. Launched in June 2021 and based in Switzerland, the initiative is designed to support pharmaceutical and biotech companies in their transition to net-zero emissions in line with the Paris Climate Agreement (9).

The Alliance to Zero pursues the goal of launching net-zero pharmaceutical products in regulated markets by 2030 at the latest. To achieve this, the founding members have committed to developing a joint net-zero offering by 2026 to provide pharmaceutical companies with enough time to finalize their overall product on this basis.

The Alliance has developed a roadmap for a net-zero emissions concept for pharmaceutical production and the supply chain. Currently, necessary steps and a harmonized language are being developed, and principles are being defined for evaluating and monitoring the entire emissions footprint of pharmaceutical end products. In addition, the Alliance is planning to collaborate with academic and non-profit organizations pursuing similar goals.

Dr. Thomas Schweizer, president of Schreiner MediPharm, emphasized the importance of the company’s membership in the Alliance: “For Schreiner MediPharm, as a pioneer in the production of innovative functional labels, sustainability starts as early as in product development that considers all life cycles to achieve a reduced environmental footprint. For us, co-founding the Alliance to Zero means another important step toward holistic sustainability. We are convinced that, together with the other Alliance partners, we will be able to drive the development of net-zero pharmaceutical products.”

The Alliance to Zero encompasses component suppliers, machine manufacturers and assembly/manufacturing service providers, manufacturers of primary and secondary packaging, and companies responsible for final product assembly or handling products that have been returned after use. Other founding members include Dätwyler, Harro Höfliger, HealthBeacon, Körber Pharma, SCHOTT, Sharp, and Ypsomed. The close collaboration across traditional company boundaries, as well as the specialized expertise of each partner, will result in the development of holistic solutions that will move the pharmaceutical industry closer to net zero.

1. Shorr Packaging, “The 2022 Sustainable Packaging Consumer Report,” White Paper, July 20, 2022.

3. Keystone Folding Box, “Keystone Folding Box Co. Completes Multi-Million-Dollar Production Equipment Installation,” News Release, October 2022.

4. TekniPlex Healthcare, “At PACK EXPO, TekniPlex Healthcare to Debut World’s First Fully Transparent Recyclable Mid-Barrier Blister Package,” News Release, October 2022.

5. Avient, “Avient Debuts Next-Generation Solutions to Facilitate Use of Recycled Plastics in Packaging Applications,” News Release, June 16, 2022.

6. Schreiner MediPharm, “At PACK EXPO, Schreiner MediPharm to Debut Functional Labels Designed from More Sustainable Materials,” News Release, October 2022.

7. Hoffmann Neopac, “Neopac’s Polyfoil MMB Tube Approved by USA’s Association of Plastic Recyclers,” News Release, Jan. 30, 2022.

8. Hoffmann Neopac, “Closing the Loop with Aluminum Barrier Tubes,” News Release, Feb. 22, 2022.

9. Schreiner MediPharm, “For a Sustainable Pharma Supply Chain: Schreiner MediPharm Among Founding Members of ‘Alliance to Zero,’” News Release, Oct. 7, 2021. 

Hallie Forcinio is packaging editor for BioPharm International.

BioPharm International
Volume 35, Number 11
November 2022
Pages: 27-29

When referring to this article, please cite it as H. Forcinio, “Consumers Seek Sustainable Products,” BioPharm International 35 (11) (2022).

Manufacturing

Pharma companies set goals and adopt more sustainable alternatives.

Consumers Seek Sustainable Products

After early market failures, antibody drug conjugates (ADCs) have made a comeback in recent years. Innovations in technology and a better understanding of disease mechanisms have helped advance the development of ADCs. This success has been evidenced by the growing proportion of ADCs gaining regulatory approval.

ADCs remain an area of intense focus for many biopharma companies for good reason. The ability to specifically target diseased cells and spare healthy cells has been the quest for the biopharmaceutical industry as a whole and was not something that was thought to be a viable option in early days, according to Lisa McDermott, director of Process and Analytical Development (PAD) Global Contract Manufacturing Services, MilliporeSigma, the US and Canada Life Science business of Merck KGaA Darmstadt, Germany. Nowadays, the ability to see impact on patients even in Phase I studies in oncology brings an immediacy to ADC drug development that has kept it such an engaging field, she notes.

From a science perspective, developing ADCs should be approached in a collaborative way, where the best characteristics of both large and small molecules are combined, according to McDermott.

When developing a new ADC, there are a few key decisions that must be considered upfront. In the preclinical space, for instance, one needs to have deep knowledge about the target and have theories on how to address it. “Once you have identified a candidate that meets your target profile, then the ability to scale and control the process for producing enough material for clinical and commercial supplies is critical,” McDermott states.

“Once you start the CMC [chemistry, manufacturing, and controls] development, it is important to understand if your process is adaptable to existing templates, or if there is a need for a novel process,” McDermott adds. She also points out that using a contract manufacturing and development organization (CDMO) partner is wise because CDMOs that work on these platforms regularly will have deep experience. It’s a benefit to work with them early to understand roadblocks and address them.

The current environment in which a greater number of ADCs have been approved by FDA and are in the process of regulatory review shows that the industry has learned from the early failures of past ADCs. Improvements in ADC development have stemmed in part from ADC developers having optimized the selection of target antigens and expanding their toolboxes with new antibody constructs and payloads, confirms Michael Mulkerrin, PhD, vice-president, head of CMC, ADC Therapeutics.

“As a result, we’re able to develop and manufacture ADCs with the potential for increased potency, better efficacy profiles, and reduced side effects compared to earlier generations of ADCs,” Mulkerrin explains.

“We have seen ADCs evolve over the past 20 years as the field has learned better targeting mechanisms, understanding the delivery of the payload and the modulation of the drugability of the conjugate. From my perspective, we continue to challenge the historical limitations for bioconjugates and that is helping move the field to second and third generation successes,” adds McDermott.

McDermott also explains that there are now many new tools on both the process development and analytical front. These new tools are providing the ability to control the quality of the final materials that go into making an ADC. “All these advances are bearing fruit as we see the number of approvals increase,” she states.

In particular, linker technology has an influence on the process development for a new ADC. As McDermott points out, linker chemistry has been a rich area of modulation for ADCs. “The linker is a part of the construct that can be more easily modified to help with stability or delivery. Linkers can have solubilizers, additional handles for payload cleavage, and [linkers can] provide additional locations for multiple payloads for high DAR [drug/antibody ratio] constructs. From a manufacturing perspective, the linker can improve solubility during the conjugation process and improve the ability to clear the residual payload from the final product,” she explains.

In moving from the lab bench to commercial manufacturing, developers must look at what factors enable a robust scale up in ADC manufacture. Each ADC is unique and carries its own challenges, McDermott emphasizes. For each construct, it is important to understand the critical quality attributes early on, use proven scale-down models to develop the manufacturing process, and ensure close collaborations between development group and manufacturing teams, she states.

“Over the years we have developed templates for accelerating both the development and manufacturing of these complex molecules. This allows us to use prior knowledge to both accelerate early development as well as de-risk the unit operations needed for production,” says McDermott.

McDermott goes on to explain that it is important for the development team to design a quality-by-design process with a tight analytical control strategy and deep process understanding. She notes that, with a limited number of production runs before commercial supplies, having a historical database with trending data is critical to demonstrate control of the manufacturing process.

“ADCs are complex,” Mulkerrin iterates. “The development and manufacturing of ADCs requires significant planning and expertise.”

Mulkerrin emphasizes that toxin manufacturing can be particularly challenging and may involve several manufacturers to ensure the pathway is scalable and that the supply chain is able to provide all needed materials. In addition, deep knowledge of the supply chain is tantamount to success.

“Once the manufacturing pathway is established, the plan for future scale up should be created to ensure the necessary steps and process will fit in the manufacturing facility,” Mulkerrin states.

Addressing bottlenecks in manufacturing is another important task when it comes to ADCs. “We have spoken about templates being an important tool for de-bottlenecking bioconjugation development, and, as new conjugation chemistries are invented, additional templates will also be needed,” says McDermott. From her perspective, the industry also needs to continue to invest in single-use options, which offer a significant advantage in this high-potent space, both for the safety of the product and for the safety of colleagues.

Investments in ADC technology include the development of ADC-specific products that can be used specifically in the conjugation reactor. In some cases, advancing digital toolkits and investing in in-line and at-line process analytical technology has facilitated development. Some companies are also adding more capacity for both potent and novel-format conjugates, McDermott states.

Thus, with the lessons learned over the past decades, a once challenging category of therapeutic molecules are now reaping the benefits of deeper knowledge, understanding, and technological developments that have facilitated the growing approval of ADCs in the market.

Feliza Mirasol is the science editor for 


Vol. 35, No. 11
November 2022
Pages: 16–17

When referring to this article, please cite it as F. Mirasol, “Improving the Fate of ADCs,” 

Development

Learning from early market failures, the biopharma industry has worked to improve the fate of antibody drug conjugates.

Improving the Fate of ADCs

Sourcing biochemicals adds a layer of complexity on top of an already complex process of sourcing raw materials. Development lifecycles must be considered in addition to good material specification and supply chain risks. 

 interviewed Ryan Crisman, chief technical officer; Sarah Gould, associate director of MSAT (manufacturing science and technology); Jessica Freeman, MSAT process engineer III; David Mandeix, associate director of supply chain; and Christopher Lewis, senior director of quality, all of Umoja Biopharma, on biochemicals and raw materials in upstream processing.

According to Crisman, Umoja Biopharma specializes in immunotherapy, specifically in reprogramming T cells 

, which allows a patient’s immune system to target cancer cells.

 Where do biochemicals come into the pharma development and manufacturing process? What does this look like for upstream processing, specifically?

 Biochemicals define the final drug product; their quality and composition can impact the critical quality attributes (CQAs) significantly. Biochemicals do not so much come into the process as they are the process, having a prominent role in the identity, purity, and strength of the final drug product. The quality of the biochemicals is one of the most important factors in creating safe and effective drug products. For upstream processing, the cell line dictates the mode in which we run the upstream process. Thus, having the right producer cell for our lentiviral process can really make or break process performance—and, by extension, our ability to intensify the process to commercially-relevant scale.

 How do you determine what biochemical type is best?

 We want a high quality and reliable vendor who can partner with us to develop new solutions for lentiviral manufacturing and ensure consistent supply. Most of what is commercially available was designed for other virus types. We have the opportunity to apply some strategies or materials from AAV (adeno-associated viruses) to LVV (lentiviral vectors), but it does not always transfer successfully. Therefore, there is a significant opportunity for biochemical developers to partner with lentiviral development companies.

 How does selecting biochemicals compare to raw materials sourcing in biopharma?

 For many biochemicals, you not only have to evaluate the performance in your process but also how it will be characterized. In some cases, this requires a release method to demonstrate clearance of the biochemical. Sometimes, analytical support is available from the same vendor—an ELISA (enzyme-linked immunosorbent assay), for example—to show clearance in your process. Thus, you are often evaluating both the utility of the biochemical in your process and your analytical ability to demonstrate removal in the process. These requirements necessitate locking arms with vendors to ensure appropriate execution of specialized work. Furthermore, much of that custom work has less clear guidance and practices. Critical industry standards (like a multi-compendial grade) do not currently exist for biochemicals. Biochemicals often make up such intrinsic components of the process (plasmids, cell line, etc.); as such, it is more difficult to ensure a universal standard, such as multi-compendial grades for raw materials. In addition, biochemicals are actively being developed and improved upon, which also makes their standardization more difficult compared to raw materials.

 How do you define current good manufacturing practices (CGMP), specifically as it relates to biochemicals? What does that entail?

 When we refer to CGMP for biochemicals, we would expect suppliers to adhere to GMP requirements in the manufacturing, documentation, testing, release, and distribution of those materials. This would include quality systems that adhere to regulatory requirements and industry standards to provide the appropriate level of control and oversight for their (our) intended use. These systems and processes should be appropriately robust and auditable. When someone claims CGMP, they should have their act together to meet all requirements and standards defined by the agencies.

 What are best practices for sourcing biochemicals? For raw materials?

 The cost of poor-quality materials—raw or otherwise—cannot be understated. This issue often rears its head when trying to source things fast or cheap. Best practices for sourcing raw materials start with having a good material specification, a robust supplier qualification system, and an understanding of how your needs compare to that of the market at large. Sourcing biochemicals adds complexity to this process, as companies must also account for a development cycle (or sometimes several) and can then be called upon to help your CDMO [contract development and manufacturing organization] de-risk their own supply chains in order to facilitate the production of your biochemical. In either case, strong relationships with your suppliers and an in-depth knowledge of your material are table stakes for any company’s sourcing process.

 What does the process of sourcing raw materials look like for your company?

 As a relative newcomer to the biotech space that had to deal with the challenges of the pandemic shortly after its founding in 2019, Umoja has had to develop some extremely flexible sourcing strategies. Raw material is sourced with phase-appropriate control and supplier scrutiny (i.e., the specifications for both raw material and supplier tighten as we move from Phase I to Phase III). These systems are still being built out, with an eye towards an end state of commercial compliance for the quality systems. The best practice is to identify several suppliers that can provide what we need within a reasonable timeline and then work with them as we tighten our specifications or change what we need out of the material.

 What is one thing you wish the pharma industry knew about biochemicals and raw materials?

 Companies in the pharma industry should be less fearful of implementing new biochemicals and raw materials into their processes. Companies often fall back on tried-and-true technology ‘because the FDA has seen it,’ and it will make their regulatory submissions more easily digestible. But that doesn’t foster process innovation and is not always the best material for the given use. Larger companies have the advantage of resources to take on that risk instead of falling back on what has worked historically without investigation of new novel solutions.

 What trends do you see on the horizon for biochemicals and raw materials? Are there any up-and-coming technologies we should be aware of?

 Expect to see process intensification for lentiviral processes that are starting to mirror what continuous mAb [monoclonal antibodies] processes look like. This means there is a lot of interest in other biochemicals and raw materials to enable intensification, such as continuous filter setups and producer cell lines instead of transient transfection. Producer cell lines and continuous processes enable the higher process throughputs required to meet the expected growth in demand in the gene therapy space.

Meg Rivers is a former senior editor for 

Pharmaceutical Technology, Pharmaceutical Technology Europe


Vol. 35, No. 11
November 2022
Pages: 20–21

When referring to this article, please cite it as M. Rivers, "Upstream Processing: Biochemicals and Raw Materials," 

Upstream Processing

Experts reveal how to identify the “right” biochemical, the process of sourcing biochemicals, sourcing challenges, and what industry professionals should know about the space. 

Upstream Processing: Biochemicals and Raw Materials

Certificates of analysis (CoAs) are used by materials suppliers to identify the product they are providing to a pharmaceutical manufacturer. They include information such as product name, material grade, batch number, expiration dates, testing dates, information on analytical testing performed on the material, as well as additional product information. According to Quincy Mehta, senior manager, Consumables Product Management at SCIEX, “CoAs are vital in ensuring both the outcome and quality of a product. CoAs contain key information relaying to a customer that each lot or unit of a product is manufactured, tested, and qualified for their application of use. SCIEX assigns test parameters and information in CoAs based on the needs and target applications of our customers. This provides a key level of support and confidence that SCIEX products are ready for use in our customer’s own quality controlled environments.”

spoke with industry experts about the importance of CoAs and best practices for writing and working with these important documents.

Experts interviewed include: Agata Ochocinska, head of Quality (Europe) at Actylis; Peter Phillips, VP of Quality Operations at BIOVECTRA; Sarah Breen, senior manager, Quality, at C

 PHARMA; Subbareddy Inta, senior director, Quality and Compliance, Swati Tipnis, lead, Analytical Quality and Compliance, and Mayank Nagar, vice president and head, Tech. Services & Product Launch Management, all at Dr. Reddy’s Laboratories; IPEC Americas; Shailesh Vengurlekar, senior VP, Quality & Regulatory Affairs, at LGM Pharma; Siegfried Schmitt, vice president, Technical, at Parexel; and Susan J.Schniepp, distinguished fellow at Regulatory Compliance Associates.

 How does one assure regulators that CoAs are accurate and reliable?

 Each organization must establish strict procedures governing the development of CoAs, including QC [quality control] methods, documentation practices, analytical methods and QA [quality assurance] processes in line with regulatory requirements.

These procedures should be outlined in SOPs [standard operating procedures] to guide the employees who sample, test and issue these documents. The system must be regularly verified, and its compliance confirmed (ex. by audit) providing proof of compliance and thus assuring regulators of the accuracy of generated documents, CoAs.

 Regulators from FDA and Health Canada carry out regular inspections to audit the manufacturing process and product release to ensure it includes the generation of an acceptable CoA. They review the raw data that is included and the methods used to transcribe data onto the CoA.

 Easing regulators’ concerns regarding CoA accuracy is best done through a comprehensive risk assessment and supplier qualification. If due diligence is performed, which should include an on-site audit, if possible, in which testing records and data traceability to the CoA are reviewed and verified, the concerns regarding CoA accuracy should be mitigated.

 By performing on-site audits, regulators are able to review the data in person and ensure it is accurate. Once this has been done, with subsequent CoAs, the regulators can request the data electronically. Having a quality assurance representative also sign the CoA verifies that the information has been reviewed and verified by a second party.

A standard operating procedure must be in place to document the creation, review, and approval of certificates of analysis. The [SOP] must detail the level of review that is performed on the CoA. Adequate control must be in place to ensure that the possibility of an incorrect CoA being released are kept to a minimum. For example including several level of review both within and between departments for CoA creation, review, and approval. Employers should champion quality culture making employees take quality focused actions.

The best practice to be able to assure regulators you have control over your supplier is to establish a robust quality agreement, periodically audit the supplier, and periodically verify the analytical results listed on the CoAs.

Nagar, Inta, and Tipnis (Dr. Reddy’s Laboratories):

 The tests mentioned on the CoA should be verified if they are compendial and validated. If they are in house tests, ensure they are accurate to be used for testing the product. Also, having one person to prepare the CoA and another review and approve it ensures reliability of the CoA. If the CoA is approved by QA who is independent of the manufacturing or QC unit, it adds an additional level of confidence and prevents bias.

Who is ultimately responsible for incorrect information on a CoA?

 An excipient CoA is a legal document that certifies the quality of the excipient and demonstrates that the batch conforms to the defined specifications, has been manufactured under appropriate GMP [good manufacturing practice], and is suitable for use in pharmaceuticals. The excipient manufacturer or supplier who has generated the CoA is responsible for its accuracy. The 

IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients

 provides best practices for ensuring the quality of excipients and integrity of CoA data.

This responsibility solely lies on the supplier, and more specifically, it falls upon the person who is generating and entering the information in the CoA. Most of the time, this responsibility will fall upon quality control as it is their role to ensure the information is accurate and complete.

In the rare event a mistake is made, it is whoever generated the CoA who is responsible. We have audit trails, all electronically recorded, to identify when in the process a mistake occurred.

To avoid incorrect information, an analyst tests the product, generates the result, and records it onto the CoA. Then, our quality assurance team reviews all the raw data and ensures accurate transcription onto the CoA. These processes help avoid mistakes.

On a manufacturing site some of the following people have the potential to impact the final CoA. The research chemists that create the synthetic route for the product must ensure that any impurities that are not purged are included in the final specification. The process team involved in the validation must ensure that the final output material is a homogeneous mixture as only meaningful results come from a homogeneous material. The quality control analyst must ensure that methods are validated correctly and are capable of detecting the required impurities. They are also responsible for ensuring the methods are executed appropriately and the data is transcribed correctly into the CoA. [QA] does a review of the batch record and the [QC] data in order to ensure compliance before creating the final CoA. [QA] are the final approval on the CoA, but rely on the competence of those in the previous steps.

Ultimately everyone on a site is responsible if incorrect information appears on a CoA as quality is everyone’s responsibility.

 What are some best practices for writing CoAs?

 They should be auto-generated by suitably configured documentation management systems. The data required to populate the CoA should not be entered manually, but should be electronically transferred from the instrument to the CoA-creating system, where this is possible. Typically, CoAs are created in Portable Document Format (PDF). To assure compliance with archiving requirements, PDF/A should be used. In fact, unless mandated by law, CoAs should only be created, signed, and issued electronically.

 One of the best practices for writing CoAs is to avoid listing ambiguous test results (i.e., pass/fail, < X, > X, ). When information on the CoAs isn’t specific, it is much harder for companies to perform deviation, investigation, or CAPA [corrective and preventive action] analysis into product failures.

 There are very specific guidelines already put into place for drafting a CoA by governing regulatory bodies. Each regulatory body is clear in their expectations for what information must be included, including the expected document format as well as the specific required information. It is best practice to stick to those expectations, so all information is accurately captured.

BioPharm International, November 2022

Process Development and Control for New Modalities

Removing Residual Impurities

Consumers Seek Sustainable Products

Improving the Fate of ADCs

Upstream Processing: Biochemicals and Raw Materials

The Role of CoAs in Supplier Oversight

Addressing the Key Pitfalls Hindering Technology Transfer Success

The State of Contamination Control

FDA User Fees Reauthorized

Conference Time Brings Gifts

Principles of Equipment Qualification

Voice of Regulators