Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Highly potent active pharmaceutical ingredients (HPAPIs) make up the fastest growing segment of the worldwide API market, according to market research firm RNCOS, which predicts that the value of the global HPAPI market will reach $15.3 billion by 2017. Consultancy Transparency Market Research, meanwhile, estimates that the total HPAPI market will increase at a compound annual growth rate of 9.9% from $9.1 billion in 2011 to $17.5 billion in 2018.


  While the majority of HPAPIs have thus far been developed for the treatment of cancer (cytotoxics and cytostatics), particularly tyrosine kinase inhibitors and derivatives, newer hormone, narcotic, and retinoid-based drugs are also highly potent. In addition, HPAPIs are generally thought of as small-molecule drugs, but many biopharmaceuticals have occupational exposure limits (OELs) of 10 μg/m

 or less, a general guideline for classifying APIs as highly potent, according to Srinivas Achanta, regulatory affairs manager with Hetero. Of particular interest are antibody-drug conjugates (ADCs), which include a small-molecule, cytotoxic payload and an antibody connected with a linker and are designed to deliver the highly potent payload to targeted cells, reducing the likelihood of harm to normal cells. 


  Drivers of the HPAPI market, according to RNCOS, include a rising demand for cancer HPAPIs, increased private player participation, particularly in developed regions, and technological advances in process manufacturing of these challenging APIs. The number of ADCs in development has grown rapidly in recent years and is also a factor in the growth of the HPAPI market. The entrance of a growing number of competitors in the HPAPI market is, however, resulting in a highly fragmented market and may have a negative influence on growth, according to Transparency Market Research. The consulting firm also notes that a shortage of US FDA-approved manufacturing sites may act as a further restraint on growth for the HPAPI market. 

North America currently accounts for the greatest share of the market, followed by Europe. The greatest growth, however, is expected in Asia Pacific, with major activity taking place in India and China due to rising health awareness, continuing expansion of these economies, improving healthcare systems, and a rapid increase in the production of generics, according to Transparency Market Research.


  Because ADCs enable the targeted delivery of HPAPIs to specific cancer cells (or other problematic cells), they have attracted significant attention, and the number of ADCs in development has increased dramatically. “The toxin that is conjugated to the antibody in ADCs has been the fastest growing segment of the HPAPI market, with demand quickly increasing in recent years,” says Cynthia Wooge, global strategic marketing manager at SAFC. With three components to manufacture and combine together under containment conditions, the production of ADCs can be a complex process, adds Achanta. In addition, Wooge notes that certain new types of ADC compounds, which may be considered the next generation of ADCs, are considered to be even more potent than existing products and are pushing the limits on current capabilities with respect to the handling of low OEL materials.


  Single-use manufacturing technologies are on the rise for small-scale highly potent products such as ADCs, according to Jeff Marcoux, technical business development manager at Novasep. “Another important trend is the widespread acceptance of portable dedicated equipment, including both single-use and permanent systems for small-scale production of very highly potent compounds such as ADC payloads, which often have OELs lower than 0.1 µg/m

·8 h,” he notes. “Dedication of equipment and the adoption of single-use technologies can play an important role in controlling cross-contamination and maximum carry-over limits after cleaning (MACO) when implemented as part of a risk-based approach,” he adds. 

“All high potency APIs must be produced under conditions that not only protect the operators from exposure to the compounds, but also prevent contamination and the inadvertent carryover of a different product that was previously produced or is simultaneously being manufactured. While today’s modern HPAPI facilities are meeting today’s requirements, there is a continual need to improve these technologies going forward. To accomplish this task, we need to focus on the development of production and handling methods including single-use systems and/or new technologies that can provide increased protection of the API from cross-contamination. Such protection systems must focus on the cleaning and removal steps,” observes Achanta. “The development of such new technologies is of increasing importance as the number of multiproduct facilities, which post the greatest risk of contamination of HPAPIs, are growing around the world in order to meet the greater demand for these products,” he adds.


  Appropriate process design is in fact critical for the entire HPAPI production operation. “Most very highly potent APIs and ADC payloads require small clinical and commercial quantities, and the production of gram-scale GMP APIs and payloads can be challenging. The control of containment using flexible and small equipment, including glass equipment, is always a challenge and requires a tailored approach for each process and each unit operation,” Marcoux says. Appropriate process design at the development scale is also necessary to ensure that the process will fit the equipment and capabilities of the facility upon scale-up, according to Wooge. 

Achanta believes that one of the biggest challenges at large scale is the handling of powders and solids. “Up to a scale of a few kilos, it is relatively straightforward to manage solids, because bottles with alpha–beta split butterfly valve connectors can be used for charging reactors to maintain containment. On a larger scale, however, this approach is impractical,” he explains. 

Wooge also notes that appropriate cleaning methods must be implemented in order to achieve the required limits for residue levels in multi-use equipment. “The use of analytical methods that provide very low detection limits is necessary in order to confirm that the required residue levels have been achieved,” he says. He also adds that there is certainly an interest in continually achieving lower detection limits when handling HPAPIs.
  Finally, Achanta points to the ambiguity surrounding the classification of HPAPIs given that different pharmaceutical companies often have proprietary systems and the fact that often the classification of new APIs is unknown due to a lack of data as issues that must be managed with appropriate process design and containment controls.        

Articles

Appropriate process design and engineering are critical for the production of small-molecule and biologic HPAPIs.

HPAPIs: Fast-growing Segment Presents Challenges and Opportunities

Players across the biologics value chain are attracted by the advantages of continuous biopharmaceutical manufacturing.

Potential Benefits Drive Interest in Continuous Manufacturing

A global contract manufacturer of biologics discusses the increasing impact of health-based exposure limits in assessing cross-contamination risks.

Determining Cross-Contamination Risks in Multiproduct Biopharmaceutical Facilities

Packaging is no longer selected in the last stages of drug development and commercialization. A recognition that the appropriate choice of packaging can impact not only the marketability of a drug, but also aid in theft-prevention and patient compliance, has led to the consideration of packaging as an integral component of final formulated biotherapeutics. At the same time, advances in packaging technologies are creating opportunities for greater product differentiation and better management of products across the value chain, according to an analyst from market research firm, MarketsandMarkets. 


  The demand for pharmaceutical packaging is expected to increase as biologics manufacturers seek new methods for protecting and promoting their products, increasing patient compliance, and meeting new regulations. MarketsandMarkets estimates that the global pharmaceutical packaging market will grow at a compound annual growth rate (CAGR) of 6.7% from 2013 to 2018, reaching a value of $78.8 billion (1). 

It should be noted that this value includes drug delivery systems that are also considered to be product packaging. This sector of the packaging market is growing at an even faster CAGR of 9.1% due to increasing demand for delivery/packaging solutions as numerous small-molecule and biologic drugs come off-patent in the coming years, according to MarketsandMarkets.

Specifically for biopharmaceuticals, the fastest growing packaging types are prefillable syringes and parenteral vials, which are required to meet the packaging and delivery needs of new biologic drugs that must be injected. Other areas of the pharmaceutical packaging market seeing the greatest growth include labels and accessories, blister packs, temperature-controlled medicines packaging, and select niche products. 

MarketsandMarkets cautions, however, that both biopharmaceutical manufacturers and packaging suppliers must be aware of raw material availability,  price volatility issues, and changing health regulations that may impact the industry. In addition, pharmaceutical packaging must increasingly be designed such that it is appropriate for use in many different geographical markets and reflects a consideration of sustainability  (2). Furthermore, according to MarketsandMarkets, biologics companies should also note that consolidation among global pharmaceutical packaging suppliers has enabled leading firms to strengthen their presence, particularly in emerging markets.
  
  


  A packaging technology attracting growing attention for parenteral products is blow-fill-seal (BFS) technology, in which plastic vials (or other containers) are formed, filled, and then sealed in one continuous process. Aseptic BFS systems fill sterile product and are performed in a controlled, sterile environment. BFS systems are attractive for many biopharmaceuticals because they not only offer both low-cost packaging and sterility assurance with minimal human intervention, they are also suitable for biologics that cannot withstand the high temperatures required for terminal sterilization  (2). 

The increasing interest in BFS technology parallels the increasing demand for prefilled syringes, which provide both ease of use and convenience along with increased safety and reduced drug overfill, which can occur when administering a product using a vial and syringe. Prefilled syringes are, in fact, being used for both new products and to switch the delivery mechanism for products already on the market  (2). Separately, increasing numbers of patients in hospitals and nursing homes are receiving their medication in unit-dose vials that provide a single dose in a disposable package. One advantage of these vials is that any unused doses can be returned to the pharmacy  (2).

For products that must be maintained in a hermetically sealed ampoule to prevent exposure to air and/or moisture, there have been advances in ampoule technology that increase their safety, including ampoule that break more readily and with greater control, and devices that can be used to break the ampoules and keep humans hands from being exposed to a risk of injury  (2). 


Other new packaging technologies attracting interest have been developed to prevent counterfeiting of drug products. Tamper-evident packaging systems include specially designed film wrappers, shrink seals and bands, caps that must be broken to access an internal seal, and sealed tubes that require puncturing  (2). For parenteral formulations, with two-in-one prefilled vials, which have the water and active ingredient in separate chambers designed to allow mixing prior to use, it’s easy to detect tampering  (2). 

Some companies may use hidden features on labels, such as fluorescing fibers or chemical reagents as encrypted text visible only under special light, while others choose to use watermarks or metallic threads as an optically variable device with images that flip or transition. Radio frequency identification (RFID) tags are also used to track drug products  (2). 
  Functional security labels are also finding increasing use, including holographic labels, specially cut paper labels that only tear off, labels made of cellulose acetate or vinyl films that fragment when removed, and self-adhesive labels that, when removed, exhibit the word VOID (or another word) in the adhesive and the removed film  (2).

New ink jet coding, laser coding, and metal electrolytic etching technologies are also being employed as anti-counterfeiting measures because they enable rapid, flexible, online coding at reasonable cost, particularly due to the use of digital printing techniques  (2). Color-shifting inks (formulated with special pigments) that appear to change color with the viewing angle are increasingly being used in security seals due to the ability to control the details of the color change. Pharmaceutical packaging companies also offer anti-counterfeiting technologies based on forensic markers, such as trace chemicals and biological compounds that can only be detected when using specially designed test kits or in the laboratory  (2).

Drug Delivery Technologies Market – Global Forecasts to 2017

, Markets and Markets, April 2013.
2. N. Zadbuke et al, 

Once an afterthought, packaging has now become an essential component of biopharmaceutical product development and marketing.

Packaging Becomes Enabler for Biopharmaceuticals

Solid dosage forms are preferred for the delivery of APIs, but many therapeutic agents do not readily form stable crystalline materials or the crystals have poor solubility. Cocrystals alter the physical properties of APIs without chemical modification while maintaining the benefits of a crystalline solid form, and thus may provide a viable solution for some of these difficult APIs. Cocrystals can also be synthesized using numerous different methods, some of which use little solvent or are solvent-free and have the potential to provide real cost advantages. As a result, the potential for cocrystals is significant.

This potential is tempered, however, by the industry’s reaction to FDA’s classification of pharmaceutical cocrystals as “drug product intermediates” (DPIs) rather than APIs in its April 2013 regulatory guidance on cocrystals (1). This decision is generating significant discussion within the industry about the risks associated with the practical development of cocrystals. Based on the public comments on the draft guidance, manufacturers would prefer cocrystals to be considered drug substances rather than drug product intermediates. As the industry moves toward adopting the FDA guidance, the risk associated with developing cocrystal-based products appears to be increasing rather than decreasing. There are questions, for example, about expiration dates for drug products that incorporate cocrystals manufactured using processes that are consistent with API (drug substance) materials but regulated as DPIs. In addition, FDA is the only agency to date to formally define a regulatory scheme for cocrystals. If other agencies around the world take a different approach, it could become difficult for companies to develop cocrystal-based products that satisfy global regulatory requirements. The European Medicines Agency (EMA), for example, could consider cocrystals to be drug substances rather than DPIs.


“The selection of a specific crystal form for a given API is a profoundly important step from clinical, legal, and regulatory perspectives: the dissolution rate and intrinsic solubility of different crystal forms is variable and can strongly influence bioavailability; stability to temperature and humidity are critically dependent upon crystal packing; and the unpredictability (i.e., lack of obviousness) of crystal structures and physical properties means that there are legal issues and challenges in terms of obtaining and maintaining patent protection for an API,” says Ning Shan, director of preclinical development at Thar Pharmaceuticals. 

Highly lipophilic APIs have dissolution problems that may be overcome using a cocrystal because the new crystalline lattice being formed often has different dissolution properties compared to those of the crystals of the API alone, according to Chris Frampton, chief scientific officer of SAFC Pharmorphix. The formation of a new crystal lattice with a pharmaceutically acceptable coformer can overcome development hurdles, such as compaction problems and difficulties with hygroscopicity. In addition, for non-ionizable APIs, for which it is not possible to make a salt, the option to form a cocrystal can be advantageous over exploring exotic formulation methods or changing the API molecular structure to include the acid or base functionality required for salt formation, which can have an impact on the activity of the API. There is also the potential to use cocrystals as a lifecycle management tool, because their use can delay or divert generic competition.


Defining cocrystals as drug product intermediates, in which the coformer is treated as an excipient and the cocrystal is effectively considered to be a formulated material, has several consequences. A potential advantage could be in the area of cocrystal synthesis. Traditionally, APIs are crystallized from an organic solution, and such processes often require the use of large quantities of solvent. Utilization of solvent is common in drug substance manufacturing plants, but not in drug-product manufacturing facilities where DPIs are manufactured. Because cocrystals can be produced using solventless solid-to-solid or slurry conversion processes that are well documented in the literature, they are ideally suited for production in DPI facilities, according to Scott L. Childs, president and CSO of Renovo Research. “These novel synthesis techniques have been used to scale up cocrystals at gram scales and for screening purposes for many years. Now that cocrystals are classified as drug product intermediates, it is possible to consider these methods for cocrystal synthesis on the commercial scale,” he explains.  “The ability to prepare cocrystals using solventless synthesis methods in drug-product manufacturing facilities, which is where amorphous dispersions and other enabling formulations are manufactured, provides the opportunity to use ‘greener’ production methods and realize better manufacturing economics and reduced development times,” Childs adds.

The FDA guidance generally creates the opportunity for the application of non-traditional synthesis techniques to the preparation of cocrystals. There are processes being developed that have potential for application to the industrial-scale manufacture of cocrystals, such as methods using hot melt extrusion, continuous oscillatory baffled crystallizers, and resonant acoustic mixing techniques (2-4). Some solventless methods rely on various grinding techniques and melting approaches, according to Marcel Hoffmann, chief science officer with Crystallics. “Gaining an understanding of cocrystal formation and their interactions at the molecular, particle, powder, and product level is necessary in order to improve the manufacturing processes for this type of drug,” he adds. If the industry embraces the FDA guidance with respect to the manufacture of cocrystals in drug-product manufacturing facilities, there could be a significant shift in cocrystal manufacturing away from solvent-based processes and towards solventless processes, according to Childs.


Defining cocrystals as drug product intermediates has also created significant concerns. According to Hoffmann, depending only on differences in pKa, the same counter ion would form a salt with one API and a cocrystal with another API, and the two substances would be treated differently from a regulatory perspective. “In addition,” he notes, “this definition opens the door for generic companies to develop cocrystals and follow a 505(b)(2), or even bioequivalence route, rather than a more costly new chemical entity route.” 

Shan does point out, though, that a cocrystal still has the same active moiety as the original drug. “Even so, under the patent protection of the original drug, a cocrystal version of the same drug cannot circumvent the original patent,” he notes. “However, a cocrystal with desired properties can be patented, IP protected, and marketed, as mentioned previously in the context of life-cycle management.”

The FDA approach may not be consistent with the approach that other world regulatory agencies adopt for cocrystals, according to Childs. “If novel cocrystal manufacturing is enabled via the FDA guidance, but the same manufacturing approach causes a regulatory problem in other world markets, then that creates risk,” Childs observes. “There is currently no clear answer regarding how the FDA approach will fit in with the rest of the world, which is making it difficult to get buy-in and investment into this new technology from a very risk-averse industry,” he adds.

Shan further notes that the requirement in the FDA guidance that the developer of a cocrystal drug product must provide “assurance that complete dissociation of the API from its excipient occurs prior to reaching the site of action for pharmacological activity” could be a real challenge. 


At SAFC Pharmorphix, the ability to perform crystal structure analyses on really small crystals has been advantageous. “Knowing the crystal structure makes it possible to see how the two materials come together to form a supramolecular complex. Then we can go back to our list of potential coformers, tune them slightly, and follow an iterative process to develop the optimum cocrystal,” observes Frampton.

Renovo, meanwhile, has developed a new approach to formulating cocrystals that uses the improved cocrystal solubility more effectively. Traditionally, as is commonly done with salts, cocrystals are used in 

 preclinical studies as “neat” material (pure crystalline powder), according to Childs. This approach is not optimal, because cocrystals are highly susceptible to solvent-mediated transformation into the poorly soluble form of the API when dosed as neat material.  

“We have developed a new approach, demonstrated with a danazol cocrystal, that utilizes solubilizing excipients and precipitation inhibitors to create an optimal supersaturation level and controlled dissolution event,” Childs explains.  The model system achieved a 10X increase in the area under the concentration time curve (AUC) in animal studies using the formulated cocrystal, compared to only a 1.7X increase in the AUC using the neat cocrystal solid.  “The results of this study suggest that the appropriate formulation of cocrystals can be an important part of the cocrystal development process,” he says. Childs believes that the concepts outlined in this study present a viable roadmap for moving cocrystals forward because it suggests that formulated cocrystals can directly compete with more established drug-delivery technologies such as amorphous dispersions and lipid-based solubilizing formulations.  


Despite these significant regulatoryconcerns, interest remains in cocrystals. “Looking at the ratio between salt formation and cocrystal studies that Crystallics carries out on behalf of its customers, it is clear that the pharmaceutical industry is still hesitant to make cocrystals their final marketed products,” notes Hoffmann. He does, however, point to Esteve’s cocrystal of Tramadol and Celecoxib as one example of a cocrystal that is progressing towards a new drug approval. There is hope that a successful application of this cocrystal will pave the way for others. Crystallics is in fact seeing a renewed interest in the development of cocrystals, with most projects focused on tuning the physicochemical properties of the API, particularly solubility and dissolution rate. 

“I am convinced that pharmaceutical cocrystals are here to stay,” Hoffmann asserts. “With increasing research, our understanding will rapidly grow and cocrystals, unlike other bi-component crystals, offer the possibility of crystal engineering. Predicting the physicochemical properties up front is the holy grail of drug development,” he comments.  Frampton points out, though, that the current lack of predictability of cocrystal formation is necessary to some degree. “As soon as it is possible to predict cocrystal structures, we have a problem. Patent applications for salt forms are already being questioned on the grounds that they are predictable and obvious due to the pKa of the API and the limited list of pharmaceutically acceptable salt formers. The lure of the cocrystal remains the questionable and unexpected successful outcome.”

Childs adds that although additional advancements are needed to help the field mature, the science does not appear to be the limiting factor in the uptake of cocrystals by the pharmaceutical industry, but rather it is the perceived risk associated with cocrystals that seems to be slowing progress with respect to their industrial application. “With the appropriate time, effort, and investment, cocrystals can be used to consistently create improved pharmaceutical products. In specific situations, cocrystals should be able to compete directly with amorphous dispersions in terms of efficacy, but offer a superior product because of the lower risk and improved stability of the crystalline state compared to the amorphous state,” he concludes. 

Guidance for Industry: Classification of Pharmaceutical Co-Crystals

 99(4), 1693-1696 (2010).
  3. L. Zhao et al., 

, 2014 Advance Article, DOI: 10.1039/C4CE00154K.
  4. 	D.J. am Ende et al., 


  Cynthia A. Challener is a contributing editor at 

Drug developers are taking a wait-and-see approach to the use of cocrystals.

Scientific Advances in Cocrystals are Offset by Regulatory Uncertainty

The majority of highly potent APIs (HPAPIs) to date have been developed for the treatment of cancer (cytotoxics and cytostatics), particularly tyrosine kinase inhibitors and derivatives. There are, however, other therapeutics, including hormones, narcotics, and retinoids, which are also highly potent. In addition, while HPAPIs are generally thought of as small-molecule drugs, many biopharmaceuticals have occupational exposure limits  (OELs) of 10 μg/m3·8 h or less, a general guideline for classifying APIs as highly potent, according to Srinivas Achanta, regulatory affairs manager with Hetero. Of particular interest are antibody drug conjugates (ADCs), drugs that include a small molecule, cytotoxic payload, and an antibody connected with a linker. These therapies are designed to deliver the highly potent payload to targeted cells, reducing the likelihood of harm to normal cells. The number of ADCs in development has grown in recent years, and this growth is a key driver of the HPAPI market. The increasing number of ADCs and HPAPIs in general is creating challenges with respect to the prevention of cross-contamination in large manufacturing facilities with multi-use equipment and maintaining containment during larger-scale purifications.


  Because ADCs enable the targeted delivery of HPAPIs to the specific cancer cells (or other problematic cells), they have attracted significant attention, and the number of ADCs in development has increased dramatically. “The toxin that is conjugated to the antibody in ADCs has been the fastest growing segment of the HPAPI market, with demand quickly increasing in recent years,” says Dave Bormett, director of operations for SAFC. With three components to manufacture and combine together under containment conditions, the production of ADCs can be a complex process, adds Achanta. In addition, Bormett notes that certain new types of ADC compounds, which may be considered the next generation of ADCs, are considered to be even more potent than existing products and are pushing the limits on current capabilities with respect to the handling of low OEL materials.


  Single-use manufacturing technologies are on the rise for small-scale highly potent products such as ADCs, according to Jeff Marcoux, technical business development manager at Novasep. “Another important trend is the widespread acceptance of portable dedicated equipment, including both single-use and permanent systems for small-scale production of very highly potent compounds such as ADC payloads, which often have OELs lower than 0.1 µg/m3·8 h,” he notes. “Dedication of equipment and the adoption of single-use technologies can play an important role in controlling cross-contamination and maximum carry-over limits after cleaning (MACO) when implemented as part of a risk-based approach,” adds Marcoux. 

At SAFC, on the other hand, single-use, disposable technologies have thus far been used in certain limited applications, but they are being considered for HPAPI manufacturing where they can improve containment, particularly for larger-scale manufacturing activities, according to Bormett.

“All high-potency APIs must be produced under conditions that not only protect the operators from exposure to the compounds, but also prevent contamination and the inadvertent carryover of a different product that was previously produced or is simultaneously being manufactured. While modern HPAPI facilities are meeting today’s requirements, there is a continual need to improve these technologies going forward. To accomplish this task, we need to focus on the development of production and handling methods including single-use systems and/or new technologies that can provide increased protection of the API from cross-contamination. Such protection systems must focus on the cleaning and removal steps,” observes Achanta. “The development of such new technologies is of increasing importance as the number of multiproduct facilities, which pose the greatest risk of contamination of HPAPIs, are growing around the world in order to meet the greater demand for these products,” he adds.


  ADC payloads are small molecules containing complex chemical structures. As such, the purification of these molecules is challenging from a safety, health, and environmental point of view, as well as with respect to the technological aspects, according to Marcoux. “The chemical structures of the impurities obtained from chemical processes used for the synthesis of ADC payloads are often closely related to the desired HPAPI. As a result, traditional purification processes, such as crystallization or low-pressure silica gel chromatography, are often inadequate or lead to unacceptable loss levels,” he explains.  Novasep has found that HPLC purification technologies are particularly well suited for this class of compounds, ensuring robust, scalable, and reproducible purification under contained operational conditions. 

Marcoux also notes that because tracking of impurities is a challenge at the ADC stage after conjugation of the payloads with the antibody, much of the purity control for ADCs occurs at the payload stage. Both conjugatable and non-conjugatable impurities are increasingly controlled at this stage of the manufacturing process.

Maintaining containment around large-scale purification steps, such as chromatography, can also be challenging, according to Bormett. “It is important, therefore, to implement appropriate facility and equipment controls to ensure that these operations are handled appropriately,” he comments.


  Appropriate process design is in fact crucial for the entire HPAPI production operation. “Most very highly potent APIs and ADC payloads require small clinical and commercial quantities, and the production of gram-scale GMP APIs and payloads can be challenging. The control of containment using flexible and small equipment, including glass equipment, is always a challenge and requires a tailored approach for each process and each unit operation,” Marcoux says.  The appropriate process design at the development scale is also necessary to ensure that the process will fit the equipment and capabilities of the facility upon scale-up, according to Bormett. “The technical issues that must be addressed for scale-up of a manufacturing process are the same for an HPAPI or non-HPAPI. The challenge is ensuring that the proper engineering controls are in place for the process upon scale-up, and ensuring any limitations are considered when developing the process,” he notes.

One of the biggest challenges at large scale is the handling of powders and solids, according to Achanta. “Up to a scale of a few kilos, it is relatively straightforward to manage solids, because bottles with alpha-beta split butterfly valve connectors can be used for charging reactors to maintain containment. On a larger scale, however, this approach is impractical,” he explains. 

Bormett also notes that appropriate cleaning methods must be implemented to achieve the required limits for residue levels in multi-use equipment. “The use of analytical methods that provide very low detection limits is necessary in order to confirm that the required residue levels have been achieved,” he says. Bormett further notes that there is certainly an interest in continually achieving lower detection limits when handling HPAPIs.

Finally, Achanta points to the ambiguity surrounding the classification of HAPAIs given that different pharmaceutical companies often use proprietary systems is an issue. In addition, he notes that because the classifications for new APIs are often unknown due to a lack of data, they must be carefully managed with appropriate process design and containment controls.


  There has been an increase in investment in HPAPI capacity by both contract manufacturing organizations and large pharmaceutical companies, particularly to support ADC development and manufacturing, according to Bormett. SAFC, for example, has two major expansion projects under way to support HPAPI manufacturing. At the company’s Verona, WI facility, three HPAPI-capable GMP manufacturing areas are being added, including a plant with 400 L and 800 L reactors. In addition, Bormett says that SAFC is building a commercial antibody drug conjugation facility in St. Louis, MO to meet growing market demand beyond the current clinical-scale facility. 

Novasep, meanwhile, recently invested $4 million to expand its HPAPI manufacturing capabilities at its site in Le Mans, France. In the expanded cGMP facility, which has been commissioned, the company manufactures highly potent compounds with OELs lower than 0.03 µg/m3·8 h at the kg-scale, according to Marcoux. The investment features cryogenic chemistry at -60°C in Hastelloy reactors, as well as large-scale HPLC chromatography and drying in contained areas to manufacture ADC payloads at commercial scale. 


Cynthia A. Challener is a contributing editor to 

Increasing potency and growing interest in antibody-drug conjugates are creating challenges for manufacturers of HPAPIs.