Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

	Armin Gerhardt, associate professor of Pharmaceutical Science, Concordia University Wisconsin School of Pharmacy, discusses the effects of moisture on product quality and how to achieve good control of moisture during pharmaceutical manufacturing operations.
	

 What are the different sources of moisture in a solid dosage form? 
	

 The most common sources of water in a solid dosage form are 
	atmospheric moisture vapor; the manufacturing process; and the excipients. Many pharmaceutical facilities are located in geographical locations where periods of high heat and relative humidity are found. With atmospheric moisture vapor, it is possible for exposed solid-phase materials to sorb gas-phase water on their surface or within the particles. While the manufacturing and storage environment may be tightly controlled, there can be disruptions due to mechanical or human factors; for instance, a maintenance event of the air-handling system, or an operator error, that produces a temporary surge in atmospheric water content. 
	During the manufacturing process, the most obvious sources of water increase are when liquid-phase water is added during a granulation or coating unit operation. While both these operations are associated with a subsequent drying step, it is important to conduct an accurate water content assessment of the product. Granulation samples taken from the drying unit operation need to ensure the sample particle size distribution is identical to the bulk material. 
	Riffling or cone and quartering are two options for preparing samples of appropriate size, but pouring from a container frequently enriches the sample with larger particles, thus producing an inaccurate moisture assay result. Milling, an operation carried out to increase solid particle surface area, also increases the potential for sorption to occur. The kinetics of sorption can be quite rapid; a few minutes of uncontrolled exposure may produce significant increases of moisture. Also hold times between unit operations may increase the quantity of moisture sorption. 
	Excipients are a potential source of moisture. Many pharmaceutical materials arrive with various quantities of water distributed in them. Polymeric materials are prime examples: microcrystalline cellulose typically has 4.5-5.0% water content, hard-gelatin capsules typically have 13-16% water content, and this water may equilibrate within the dosage form and influence processing and performance.
	

 What are the effects of moisture on the physical and chemical properties of a drug product and the manufacturing process?
	

 Moisture content of the powder blend during compression is crucial to this unit operation and to product stability; however, moisture has 
	opposite effects in these two facets. During compression, it is generally preferred to have a relatively higher moisture content so that higher tablet hardness can be produced at lower compression force. There is a limit though, because higher moisture content tends to produce two detrimental results: 
	A reduction in powder flow rate increases moisture, which then increases powder particle adhesion, leading to erratic tablet weight uniformity
	An increase in sticking defects, which can be particularly challenging with embossed compression tooling because there are more pockets where powder may adhere. 
	Regarding chemical stability, a relatively lower moisture content is preferred to reduce the extent of drug degradation and make it more difficult for microbial growth to occur. Effervescent tablets, for example, are extremely sensitive to moisture content. The chemical reaction between the organic acid and inorganic base is autocatalytic and it yields gaseous carbon dioxide and water. A very low moisture content is, therefore, required to prevent the 
	reaction from starting, but once started, the water produced by it further promotes the reaction until the components are exhausted. 
	One further caution with effervescent tablets is that the high salt content necessary to achieve effervescence may be a health challenge to those on a restricted salt diet. The challenge during the development phase is to balance the contrasting water preferences of processing and stability, and define a moisture range where reasonable tablet hardness, weight uniformity, and chemical stability are achieved, and this part requires considerable effort and data generation.
	

 How do you achieve good control of moisture during the manufacturing of solid dosage forms?
	

 Start with the principles of quality by design. Select excipients after a thorough review of their properties, including moisture level and impurities. Characterize the drug substance for its potential to sorb moisture and sensitivity to degradation. The drug substance need not decompose by hydrolysis to be sensitive to moisture. Water can move within a dosage form from one material to another. Rather than forming an even distribution across all surfaces or within particles, water may accumulate in microscopic pockets. And when it does, the solid-phase material at its periphery may become more mobile as the glass transition temperature in these zones is lowered, which may then lead to increased chemical reactivity and drug degradation. 
	Anticipate the risks of all activities, equipment, and processes. Build on prior experience of all products and unit operations. Consider not just what happens 
	within the confines of the manufacturing facility, but expand the scope to include excipient vendor activities/upgrades/modifications and equipment vendor expertise. Probe the technical service personnel of equipment vendors for their perspective on recent challenges and solutions that others within our industry have generated. Be particularly sensitive to queries from regulators as they have an inside perspective of all the companies within our industry. While they can not divulge the source or details of these questions, it is reasonable to infer another firm had challenges that spurred the question, and it may provide an opportunity to be proactive prior to having a similar challenge.
	

 What about the packaging of the drug product? What materials are typically used for moisture-sensitive formulations?
	

 Typically the unit dose container-closure systems are the most 
	challenging for stability. Composites with a layer of aluminum foil are routinely considered a very robust option for moisture-sensitive drug products. 
	A quick survey of the over-the-counter effervescent products in a community pharmacy can be helpful during the development process. Data are available to compare the moisture vapor transmission rate of a wide range of materials. In addition, the seal between layers is an important consideration because this aspect is a frequent source for barrier failure. Also with unit-dose materials, the shape of the cavity containing the tablet or capsule is a factor. During the process of heating the flat sheet stock to form the cavities, there is significant stretching and thinning of the polymeric material. The thickness reduction can be as much as 50% or more where there are bends, and it is these thin portions where the most risk occurs for moisture ingress. With multiple dosage unit containers, comparison of the moisture vapor transmission rate for packaging resins is recommended. The head space and the quantity of potential moisture that could be added to the drug product needs inclusion, hence the requirement for controlling air quality during packaging. One additional option is to include a desiccant packet or canister. 
	During early stages of development, it should be a top priority to initiate stability studies using a range of potential container-closure systems. Data from 12-, 18-, 24-month, or longer storage at the final storage temperature/relative humidity combination are very valuable.


	When referring to this article, please cite it as A. Siew, "Tackling Moisture Challenges in Solid Dosage Manufacturing," Sidebar to "A QbD Method Development Approach for a Generic pMDI" 

Articles

Armin Gerhardt, associate professor of Pharmaceutical Science, Concordia University Wisconsin School of Pharmacy, discusses the effects of moisture on product quality and how to achieve good control of moisture during pharmaceutical manufacturing operations.

Tackling Moisture Challenges in Solid Dosage Manufacturing

	Patients should be pharma’s top priority; after all, they are the reason for the industry’s existence. Of course pharma understands the importance of patient centricity, but the problem is the gap between intent and action. It’s the same with transparency and integrity, where the real challenge lies in putting theory into practice. 
	Nonetheless, pharma is making progress in restoring its reputation. The latest reputation survey by PatientView recorded the best ever results since 2011, when the first study was conducted (1). Of the 1075 respondent patient groups surveyed, 28% noted that the pharmaceutical industry’s corporate reputation improved in 2015. In fact, approximately 45% of those polled considered pharma to have an “excellent” or “good” reputation in 2015, compared with 34% in 2012, which marked the lowest score. 

	PatientView defines corporate reputation as the extent to which pharmaceutical companies are meeting the expectations of patients and patient groups. Interestingly, high-quality products were cited as the key contributor to the industry’s improved reputation, with 72% rating pharma’s products as “excellent” or “good.”
	Respondents, however, had reservations about drug pricing. Survey results showed that only 15% felt that pharma’s pricing practices were fair, while 45% rated pharma as “poor” in this area, particularly in the pricing of drugs for hepatitis, HIV/AIDS, and rare diseases, which was deemed unfair. 

	So here’s the bottom line, pharma still has a long way to go in proving that it puts patients before profits. If pharmaceutical companies can emphasize more on the number of lives saved or improved instead of their share prices, perhaps only then will the industry be regarded as a true catalyst in advancing healthcare. Patient centricity is, after all, believed to be the best route to profitability, and players who make patients the core of their efforts will reap the rewards in due time. 


	1. PatientView, “The Corporate Reputation of the Pharmaceutical Industry in 2015,” Press Release, 10 March 2016.


	When referring to this article, please cite it as S. Siew "Can Pharma Shake Off that Tainted Image?" 

Pharma understands the importance of patient centricity, but the problem is the gap between intent and action.

Can Pharma Shake Off that Tainted Image?

The compatibility of a biologic formulation with its primary packaging and container closure system is key to maintaining the stability of drug product and preserving its safety and efficacy.

 spoke to subject matter experts from Pfizer CentreOne about the importance of choosing the right container and container closure system for biologics formulations and understanding the impact of primary packaging materials on the drug product. Pfizer CentreOne, a global contract manufacturing organization, was formed by the union of CMOs Pfizer CentreSource and Hospira One 2 One.

	Experts include Lisa Cherry, R&D manager; Martin Gonzalez, PhD, senior group leader, R&D; and Shen Chen, PhD, director, Pharmaceutical R&D, all three from Pfizer CentreOne; and Kerry Mulvaney, senior scientist, MS&T, Global Technology Services, Pfizer Inc.

 Why is it important to select the right container and container closure system for biologic formulations?

 Maintaining stability of a large molecule is of utmost importance and has to be considered at every step of the manufacturing and packaging process. Metal ions, pH, salts, silicone, gases, and leachables can all affect the stability in a container closure system. If a biomolecule becomes unstable, resulting in structural damage of the protein, it will lead to a propensity for aggregation of the drug product. Aggregation is a safety and efficacy issue that can lead to an immunogenic response within a patient. This means that the patient’s immune system could generate antibodies to attack the drug product, which can lead to drug clearance or neutralization. The bottom line is that choosing the wrong container and container closure system may put patients in jeopardy, especially if they are taking medication for a serious condition.

 What are the causes of incompatibility between a biologic formulation and its container?

 Incompatibility can occur by not fully understanding the material surface properties of the container. Some characteristics to consider include the container surface chemistry, surface wettability, dimensional consistency, and surface roughness. Protein may also adsorb to silicone oil, which is often used in prefilled syringe and cartridge systems. In other words, we need to consider any material characteristics that may lead to protein adsorption because adsorption can lead to protein aggregation.

	Another source for incompatibility would be with the rubber formulation for the stopper, plunger, or seal. Rubber components often contain additives and fillers to help strengthen the components. These additives and fillers, however, may contain trace metals that could leach into the drug product over time. This type of contamination may lead to protein damage.

 Can you talk about the components of the primary packaging materials and their impact on a biologic formulation?

 Typical containers for drug product biologics are made of glass or plastic and include vials, prefilled syringes, and cartridges. Each has a different set of closures: rubber stoppers for vials; plunger, needle, and needle shield (or luer tip and cap) for prefilled syringes; and plunger and seal for cartridges.

	All three container systems carry risk of interactions. We need to consider potential rubber-component leachables, as well as protein-silicone interactions. In particular, non-uniform silicone coating of containers is a real concern for protein stability over time. Tungsten may also be a problem. Prefilled syringes may be manufactured using a tungsten pin to shape the syringe tip. Residual tungsten in the syringe is a concern for biologics; it may become oxidized, cause a pH shift in the drug product solution, and lead to induction of protein aggregation. Prefilled syringe manufacturers are aware of this concern and are now marketing low-tungsten-containing syringes.

 So what are the key considerations when selecting a container and container closure system for a biologic drug product?

 The key consideration for initial container selection should be to choose components that maintain product stability by minimizing protein adsorption, extractables/leachables, oxidation, and pH changes. Another is the intended route of administration. Container selection for a liquid medicine, for example, requires different considerations than a lyophilized one. For instance, evaluating protein interaction with silicone in a prefilled syringe or cartridge system is more important for a liquid than a lyophilized medicine. Components must also meet functional requirements to ensure safety at the point of administration and to protect the purity of the drug product throughout its shelf life. Finally, to expedite medications that meet unmet medical needs so that patients get them more quickly, choosing a reliable, tried-and-true container closure system such as a vial may facilitate market approval. More novel container closure systems could follow according to lifecycle management strategy.

 Which is better for biologics, glass or plastic? How do you decide which to use?

 This is really molecule- and formulation-dependent. Knowing the molecule’s sensitivities is imperative. For example, if a biomolecule is sensitive to oxygen, a semi-permeable plastic container may not be optimal. However, if a biomolecule formulation leads to delamination in glass and does not exhibit oxygen sensitivity, a plastic container may be ideal. Certain types of glass and plastics can also cause wider variations in the drug product solution’s pH; again, pH changes can affect product stability, leading to potential protein aggregation.

	In addition, we need to evaluate end-user requirements. A medication in one container closure system may be better suited for an emergency-care setting rather than for self-administration. Human-factor studies provide valuable information for assessing an appropriate container closure system from a patient usability perspective.

 What testing or characterization studies do you have to carry out to determine compatibility of the biologic formulation with the container and container closure system?

 The main objective for determining compatibility would be to ensure that the biomolecule is stable in its container closure system. A typically ‘happy’ protein will exhibit maximum biological potency and minimal aggregation, denaturation, and/or damage. Initially, we can perform material contact studies to examine adsorption of the molecule to relevant container closure materials as well as contact effects on the potency and other critical quality attributes of the drug product. This type of study could be used for screening materials (for example, glass with different coatings) as well.

	Once we choose a container closure system, filled drug product units should be tested under stress (temperature, humidity, light, and agitation) and normal storage conditions. For certain types of containers, functionality testing is extremely important. Prefilled syringe and cartridge systems require proper functionality to deliver the intended dose. Glide force and break-loose force are common tests to ensure the liquid drug product is delivered smoothly and accurately. These types of mechanical tests should be included with stability studies.

 What about the issue of extractables and leachables?

 Rubber components are a significant contributor to leachables because they contain additives and fillers including transition metals, which could leach into the drug product over time. This type of contamination may lead to protein damage, especially when the product is exposed to agitation (air-liquid interface exposure). Another source of recent concern would be leachables from the adhesive used to attach the needle to a prefilled syringe system.

	Stability testing of the drug product should monitor protein stability; changes in protein aggregation, oxidation, degradation, pH changes, and particulate matter can be indicators of compatibility. Stress studies, including agitation, can also provide key insights to compatibility.

 What recent trends do you see in primary packaging of biologic drugs?

 As patients are taking a more active role in their healthcare, we are seeing more and more packaging systems that provide greater ease of use. Glass vial presentations have been moving towards prefilled syringe systems, especially as part of a lifecycle management approach. Dual-chamber prefilled syringes, allowing for mixing of a drug product immediately prior to application, have developed interesting applications in the biopharmaceutical market. There is some movement towards the use of layered plastic containers, such as cyclic olefin copolymer and cyclic olefin polymer, which prevent gas transmission into the drug product. Specialty pens, patches, and containers for self-infusion pump devices are also popular.

When referring to this article, please cite it as A. Siew, “Container Selection for Biologic Formulations," 

	Editor's Note: The article was updated from its original version to reflect changes in the company's name.

Choosing the right container and container closure system is crucial for ensuring product quality, safety, and efficacy of a biologic formulation.

Container Selection for Biologic Formulations

	Pharma has huge responsibilities resting on its shoulders to deliver safe and effective medicine. As the push for transparency heightens, the industry finds itself increasingly being scrutinized in many areas, from drug pricing and the reporting of all clinical trial results to business ethics, sales and marketing activities, and quality control of manufacturing operations. But how well is Pharma managing regulatory compliance? A PwC report (1) in March 2016 noted a rise in the number of pharmaceutical companies being issued warning letters by the United States Food and Drug Administration for GMP violations related to data integrity deficiencies. The three most common data integrity issues cited by FDA for inspections from 2013 to 2015 were the lack of controls to prevent alterations of data by staff, failure to maintain records of accurate data, and delayed reporting of data.

	Data integrity is fundamental in pharmaceutical manufacturing. It enables traceability of a batch to its origin and, more importantly, ensures that drugs are made and tested according to the required quality standards. It is, therefore, crucial that data records are accurate, complete, legible, attributable, intact, and maintained within their original context, including their relationship to secondary data records. Non-compliance does not only result in revenue loss for the violator due to facility shutdown, product recalls, import bans, and delayed or denied drug approvals, but it also tarnishes the company’s reputation and provides competitors with an opportunity to increase their market share. In addition, warning letters divert the attention of workers from their daily activities to corrective and preventive actions, which cost significant time and money.  

	According to Ernst & Young (2), one the key root causes of data integrity issues is staff shortage combined with excessive workload that lead to inaccurate and incomplete documentation; the emphasis on quantity over quality forces workers to compromise on quality so that production targets and dispatch timelines can be met. The lack of awareness among employees and ineffective training are also known to result in data integrity problems.

	Regulators worldwide are increasingly focusing on data integrity in their enforcement efforts. Despite recent reports of Indian and Chinese companies receiving warning letters for data integrity violations, the problem is, in reality, a global one. The solution for the industry does not only involve changing its approach from reactive to proactive but embracing a culture of quality so that regulatory compliance becomes second nature in every company.


	1. PwC, Health Research Institute Regulatory Spotlight, 

Data Integrity Problems A Growing Risk to Global Pharma Companies 

(March 2016), accessed 1 Apr. 2016.
	2. Ernst & Young, 

When referring to this article, please cite as A. Siew “The Repercussions of Data Integrity Violations,” 

Pharma has huge responsibilities resting on its shoulders to deliver safe and effective medicine.

The Repercussions of Data Integrity Violations

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important mechanism of action through which monoclonal antibodies (mAbs) exert their therapeutic effect, particularly in cancer targeting. The ADCC activity of these antibodies is often assessed using 

 spoke to Catriona Thomson, PhD, director of R&D and Technical Services at Sartorius Stedim BioOutsource, about the challenges of developing and validating an ADCC methodology, including the difference between the classical ADCC assay and the reporter bioassay.

 What is the principle behind the classical ADCC assay?

 ADCC is an immune defense mechanism and is one of the ways in which the body can clear unwanted tissue composed of damaged, cancerous, or infected cells. Host antibodies are able to target these unwanted cells and recruit effector cells of the immune system to initiate a cell death process that ultimately lyses the target cells. Therapeutic antibodies can harness the ADCC activity of the immune system provided that their antigen is expressed on the surface of target cells, and this has been demonstrated with many different molecules.

environment. An antigen-expressing target cell line is selected and a dilution series of the antibody is added. An effector cell population is then added, and for the classical ADCC assay, many different options have been described. Natural killer cells are the predominant mediators and are most commonly applied within a mixed cell population called PBMCs (peripheral blood mononuclear cell) but may also be used as a purified fraction. The target cells, antibody, and effector cells are then incubated together, and target cell death is measured at the end of the assay.

The challenges and limitations of ADCC assays

 Bioassays are amongst the most challenging of analytical methods primarily due to the cells that are used in the ADCC assay. There are two cell types to deal with--the target and effector cells. Most assays use primary effector cells, and in this case, there are limited quantities of cells available from each donor. Designing an assay based upon the response of a single donor would be relatively straightforward, but establishing a robust method that works with different donors presents the biggest challenge. A common observation is that donors tend to provide an excellent response for one antibody but a poor response for another. Moreover, the response we get from cells obtained from repeat donations by the same donor can be influenced by any medication they are receiving or whether or not they have an infection.

 What are the problems or limitations associated with the classical ADCC assay?

 It is relatively easy to measure the ADCC activity of antibodies that are specifically designed to mediate it--those that possess the optimum glycan composition and have a ready abundance of target cell lines that express high levels of target antigen. The majority of problems arise when studying the activity of antibodies that are highly fucosylated with poor target cell lines because it is difficult to obtain a response of sufficient magnitude, and there is a poor level of signal to noise. When this problem occurs, it affects all aspects of assay performance and can result in high levels of variability. It is, therefore, important to optimize the method and screen for the optimum donors. The standard means of controlling method variability is to increase replication in the assay, but this approach is limited by the finite quantities of effector cells, which poses another challenge.

 Can you tell us more about the ADCC reporter bioassay, how does it work and how does it compare with the classical ADCC assay?

 The reporter assay uses an engineered cell line in place of effector cells: the cell line stably expresses a specific Fcγ receptor (eg FcγRIIIa (V158)) that, when bound to the Fc region of a target antibody, results in signal transduction and emission of a luminescent signal. The most significant difference is the availability of an unlimited supply of effector cells for the ADCC reporter bioassay, which provides several benefits. As a result, it can deliver a level of consistency that is difficult to achieve in the classical assay. Reporter assays can be developed with better definition of sample concentrations that will aid accuracy and make routine GMP performance far easier. Also, for antibodies that produce a low level of response in the classical assay, the signal can be amplified by increasing the concentrations of the effector cells without causing non-specific cytotoxicity as the endpoint is luminescence, rather than death. These advantages make the assay easier to perform in general and allow laboratories with limited capabilities to obtain primary effector cells to conduct ADCC assessments. The assay design can be simplified and, as a result, deliver greater levels of throughput while always using the same effector cells, thereby removing the consideration of donor bias when interpreting results. Although the reporter assay has a number of distinct advantages, its limitation centers on the fact it does not specifically measure cell death.

 How do you develop and validate an ADCC methodology?

 In general, the standard approach to bioassay development and validation would be adopted with the scope commensurate with the stage of the antibody’s development. The additional considerations for an ADCC assay are associated with the use of primary effector cells--it would be rare to find a method in which every single donor provides a response that would be appropriate for a GMP lot-release method. This variability could be considered as part of robustness, but it is likely that adoption of an extensive donor screening and qualification program with a specification assigned for acceptable donor polymorphisms would be appropriate.

	Both development and validation should be planned with foreknowledge of the antibody product’s variability in relation to the expected differences in the glycan composition to understand the performance capabilities of the method and establish the levels of sensitivity.

 Why is important to understand the method’s sensitivity?

 Without characterizing the method’s sensitivity, conclusions about whether or not the sample is within the specification cannot be drawn with any certainty. The sensitivity of an ADCC method specifically relates to the ability of the method to detect the biological impact of structural differences in the Fc domain--primarily glycans and aggregates--that affect the binding of the antibody to the effector cells. Take a biosimilar for example; if a test reveals no differences from the innovator, is it a true result? Or is the method that has been used insensitive? Conversely, if large differences between a biosimilar and innovator are observed, is the difference meaningful and does it translate to a biological difference, or is it the result of using a highly sensitive method that will detect even the smallest structural difference? Without understanding the sensitivity of the method, it is difficult to interpret the results that are obtained.

 What affects the performance of the assay--for example, how does polymorphism affect the results?

 It has been long established that polymorphisms in the effector cell population, where a point mutation in the CD16a receptor at amino acid 158 produces low (F/F), intermediate (V/F or F/V), or high (V/V) affinity variants, that impart differing levels of sensitivity to the assay. Here, the most sensitive assays are obtained using donors with the higher affinity polymorphisms. What is becoming increasingly clear is that the degree to which these different polymorphisms affect assay sensitivity is further influenced by the composition of the effector cell population, with purified natural killer cells providing the most sensitive classical assay formats. There is now a delicate balance between establishing assays that are both sensitive and retain the ability to be predictive of the in-vivo outcome.

 Can you provide an example of application of the ADCC reporter bioassay in characterizing a therapeutic antibody?

 In our experience, the ADCC reporter bioassay can provide one of the most sensitive ADCC assay formats and as such, its application is valuable at all stages of the development of a biosimilar, particularly at the earliest stages of development when clones, media, and processes are established and optimized. The assay’s throughput lends itself nicely to the large number of samples that require analysis at this stage. 

:
	When referring to this article, please cite it as A. Siew, “Assessing Antibody-Dependent Cell-Mediated Cytotoxicity," 

The reporter bioassay, used to evaluate ADCC activity of therapeutic antibodies, complements the classical ADCC assay.

Assessing Antibody-Dependent Cell-Mediated Cytotoxicity

Over the past decade, there has been an increasing number of high-potency APIs (HPAPIs) as drug-development activities continue to shift towards more targeted therapies. Although they form a relatively small portion of the API market, HPAPIs are thought to be one of the fastest growing segments in the pharmaceutical industry. The global HPAPI market is expected to hit $25.86 billion by 2022, with oncology being the primary driver for this increasing demand (1).

	HPAPIs are known for their ability to target diseases more selectively in smaller doses, hence, reducing the risk of unwanted side effects in patients. “As the patent cliff continues and blockbusters become less frequent, there is more focus on developing targeted treatments for smaller patient populations,” notes Aileen Ruff, vice-president, Business Unit Strategy and Marketing, Advanced Delivery Technologies, Catalent. “For example, the oncology market is expected to exceed $100 billion by 2020 (2), and anti-cancer development activity is trending upwards across all clinical phases. Many of these oncology drugs are considered highly potent or cytotoxic. Within and beyond the oncology space, antibody-drug conjugates (ADCs)--which consist of antibodies conjugated with a small-molecule toxin--are also on the rise for more targeted therapies, with the market estimated at $396 million in 2013 and to grow to nearly $2.8 billion by 2018, registering a five-year compound annual growth rate of 48.1% from 2013 to 2018 (3),” she says.

	Ruff also points out that poorly soluble compounds, which now represent 70-90% of the development pipeline (4), are often classified as highly potent. “With this increase in potent compounds, there is a corresponding increase in emphasis on accurate potent classifications and containment strategies to protect manufacturing personnel and patients,” she adds.

	Ruff explains that compounds are typically classified for high-potency handling requirements based on an occupational exposure limit (OEL) that is assessed through various means such as toxicological data, risk phrases, pharmacological/dosage data, analogy, and in-silico modelling data.

	"Consulting firm, Safebridge Consultants, Inc., has been involved in developing these types of classification systems, but many companies also work with local toxicologists and consultants to design a customized system for their business,” she observes. “Catalent, in partnership with Safebridge, uses a four-band system, with Category 3 (potent) defined as an OEL between 1 and 10 μg/m3 and Category 4 (highly potent) as less than 1 μg/m3.” According to Ruff, if toxicology data are not available, a compound may default to potent status in one of these categories. “While these classifications provide initial guidance on containment requirements, each compound should be evaluated on a case-by-case basis,” she says. “For example, in some cases, such as hormones, a fully segregated facility or suite may be required.  In other cases, engineering controls, flexible containment, and/or personal protective equipment (PPE) may be sufficient.”

Formulation and processing considerations


	HPAPIs require specialized facilities and equipment to ensure that both personnel and the environment are protected from exposure. In terms of formulation and processing, there are several considerations in the development of a dosage form containing low concentrations of a highly potent drug substance, highlights Robert Harris, chief technical officer at Juniper Pharma Services. “The aim, first of all, is to make the unit dose as small as possible so that the ratio of drug to excipients in the formulation is maximized and more importantly, it helps achieve satisfactory drug uniformity and consistency of drug content.”

	For tablets containing 1-5 mg of active, Harris notes satisfactory content uniformity can be achieved by blending the powders followed by direct compression, or by serial dilution of the API with an excipient (i.e., trituration) and sieving the powder blend through a suitable mesh screen. He adds that the choice of excipients is also a crucial factor in the formulation and process development of a homogeneous and segregation-free, low-dose tablet. The use of partially pre-gelatinized starch as a filler, for example, has been shown to achieve better drug uniformity compared with other commonly used fillers, says Harris.  

	For tablets containing less than 1 mg of active, the preferred approach, according to Harris, is to pre-dissolve the required amount of API in a suitable solvent and spray the drug solution onto a carrier excipient such as lactose or microcrystalline cellulose, either using high-shear granulation or fluid-bed granulation. The high-shear granulators and single-pot processors, such as IMA Pharma’s Roto Cube, allow the entire granulation process--from loading of raw materials to discharge of dry granules--to be carried out in a single, contained bowl. “This approach is particularly suited to HPAPIs because contact between product, personnel, and the environment is eliminated. The spraying, granulating, and drying activities all take place within a single, contained bowl,” explains Harris. He recommends applying a coating to tablets containing HPAPI, adding that the coating will help prevent dust generation from attrition of the tablet cores during handling.


	Liquid formulations in hard-shell capsules or softgels are becoming a popular option for HPAPIs because of the advantages they offer. “These formulations have long been recognized as one of the most successful drug-delivery technologies for challenging compounds,” observes Kevin Li, product manager, Pharmaceutical Softgel, Catalent. “In addition, softgel technologies have a proven commercial record of bringing potent drugs to market, such as hormones, vitamin D analogues, and other cytotoxic compounds.”

	Unlike tablets and capsules that involve powder production, liquid formulations do not present issues such as dust generation, and the hazards of product cross-contamination are minimized. Moreover, the processing of liquid formulations is more convenient and does not require complex and expensive engineering controls. According to Harris, the highest risk is during the initial powder-handling stages (i.e., during dispensing of the drug and when it is being added to an aliquot of the vehicle). “These steps are typically performed in an isolator or containment hood,” he says.

:
	When referring to this article, please cite it as A. Siew, "Liquid Encapsulation for HPAPIs," 

Liquid formulations in hard-shell capsules or softgels are becoming a popular option for HPAPIs because of advantages such as improved safety and lower risk of potential exposure and product cross contamination.