Felicity Thomas is the former Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Oral-solid dosage forms remain the most common drug formulation used within the pharmaceutical industry and, according to market research (1), should continue to experience market growth in the near future. However, a range of factors, such as an amassing focus on biologics, higher proportion of poorly soluble molecules in the development pipeline, and regulatory development pathways, are potentially set to shift the balance and raise the profile of newer, innovative dosage forms, increasing the requirement for expert skills.

	“Pharma’s development pipeline is being filled with more sophisticated, harder to make compounds that require complex delivery strategies to administer doses correctly,” notes Louis Weber, managing director, Bora Pharmaceuticals. “Demand for specialist expertise has soared, and drug developers are increasingly seeking outsourced solutions to commercialize products.”

	A major challenge currently impacting drug development is overcoming bioavailability issues, which is becoming more difficult as a result of the increasing number of complex and poorly soluble molecules entering the development pipeline. “Around 40% of all new chemical entities (NCEs) have low water solubility, meaning a strategy for improving poor bioavailability becomes mandatory,” emphasizes Manuel Leal, business development director, Idifarma. 

	“The ‘put it in a tablet’ dosage form approach that may have worked in the past is no longer effective as molecules require more complex and advanced drug delivery technologies that address insoluble compounds,” explains Robert Lee, president, Particle Sciences. “There are a range of technologies to increase bioavailability but for them to be viable, expertise and experience on how to apply them is required so formulations stand a better chance of being effective.” 

	Using solvents, such as isopropyl alcohol, ethanol, and acetone, is a practical way in which developers can improve solubility of most drug substances, notes Weber. “In addition, solvent methods for dispersing drug substances can also be useful to deal with poorly soluble compounds prevalent in today’s therapeutic compounds,” he says.

	For Leal, there is a need for innovative processes to advance the galenic formulation of finished products as the discovery of new drugs that improve existing therapies has slowed. “Using innovative technologies helps improve the therapeutic arsenal and reduces the reliance on finding new active molecules for the industry,” he says. Constant adoption of a variety of strategies that enable enhancement of a drug’s absorption is vital for formulation scientists, in Leal’s opinion.

	Adoption of an orthogonal approach and being open to a variety of methods, particularly during early development was also advised by Lee. “Good development practice starts with the client providing a clear target product profile (TPP), which describes an idealized drug product image, including route of administration, dose, form factor, pH, particle size distribution, and so on,” he continues. “Once there is an understanding of the TPP and the physicochemical characteristics of the active, it is possible to assemble potential drug delivery technologies that may achieve the TPP.” 

	“The key to success,” stresses Jeremy Drummond, senior vice-president business development, MedPharm, “is to use a holistic approach considering the overall requirements of any formulation; from the properties of the API (the only ingredient that cannot theoretically be left out) to the end-use market, patient requirement, and target indication.”

	Speeding up the development pathway has obvious benefits for drug developers. Not only can these accelerated routes help shorten the development timeline but can also offer significant cost reductions.

	Using the US FDA’s 505(b)(2) pathway as an example, Lee highlights that innovative drug dosage forms are being realized thanks to the opportunities afforded by the accelerated development route. “A key advantage of the pathway is the 505(b)(2) sponsor can use clinical data produced by other companies to seek FDA approval without performing all the work required with a traditional new drug application,” he says. “This pathway is being used to improve existing drug products with new dosage forms, indications, dosing regimens, and new routes of administration.”

	In agreement, Weber adds that through accelerated pathways, such as 505(b)(2), developers are managing to breathe new life into existing products in an economical way. “According to FDA, the pathway allows drug developers a faster route to improve existing drugs, including new dosage forms that are faster acting or that combine two active ingredients in a new way,” he comments. “This includes creating new administration routes that enhance therapeutic performance or dose adherence.”

	On a global scale, other regulatory bodies also offer accelerated route options, for example in Europe the European Medicines Agency (EMA) allows developers to submit applications via the hybrid procedure, which is considered to be roughly equivalent to 505(b)(2). “The appeal of accelerated pathways is leading drug innovators to rethink existing market medicines and reformulate them in ways that place a greater emphasis on patient centricity,” confirms Lee. “This is leading to innovations such as long-acting injectables that require a lower dosing regimen than before or improving the bioavailability of a drug so that it can be delivered via an alternative, more convenient route of administration.”

	“The patient or consumer must always be at the forefront of any development strategy,” stresses Drummond. “It should always be remembered that it is not a drug (i.e., an API) that you give to a patient, but a drug product. For a formulation to achieve a positive clinical outcome and be a commercial success for the developer, the patient must be happy to use it.”

	In fact, a patient-centric approach to dosage form can be particularly vital when considering specific patient populations. “Traditional dosage forms, particularly tablets, may not always be taken by a patient as prescribed, which can lead to a negative therapeutic outcome and render a course of treatment much less effective,” says Lee. “Pediatric and geriatric patient populations are particularly averse to swallowing large tablets and in these cases powders or liquids formation can provide a much more convenient method of administering a therapeutic.”

	Another way of improving the patient experience and ultimately medication adherence in pediatric patients is through the use of modified-release formulations as they have a narrow therapeutic index and can support dose compliance strategies, confirms Weber. “Most patient groups respond well to taking medications that require fewer doses to be effective (and for longer periods) and reduced side effects from dose fluctuation for example,” he notes. “In addition, fixed-dose combination products with multiple APIs and different modified-release profiles can deliver more therapeutic value and better outcomes for both pediatric and geriatric patients.”

	Adherence issues are also found within patient groups suffering from chronic conditions, specifies Leal. “One answer for chronic disease therapies is to improve the solubility and bioavailability to allow for oral administration, which can improve comfort for the patients and allow them to take the drugs at home,” he adds. “A further way of supporting patient-centric approaches to drug dosage forms is through taste masking. Overcoming this issue can also directly impact the comfort of the patient taking the product and improve therapeutic compliance.”

	According to Weber, patient-centric principles are being applied in a variety of ways in pharmaceutical development. “Genetic profiling and advanced analytical techniques for example are assisting the personalized/precision medicine approach by providing deep insight into different patient populations and the pharmacokinetic and pharmacodynamic effects of drugs,” he says. “Therefore, patients can be more selective in their choice of pharmaceutical products, taking into consideration their efficacy in certain subsets of the populations.”

Gaining unique access through outsourcing

	As a result of cost-efficiency and patient compliance being major considerations for primary healthcare providers and payors, solid-dosage forms are still a preferred option for many pharmaceutical products, Leal specifies. “Demand for contract manufacturing of solid forms is, therefore, still strong,” he says. “However, there have been vast therapeutic improvements witnessed in smaller patient populations with unmet medical needs, such as in the field of oncology.”

	Oncology treatments tend to require smaller manufacturing volumes and require a higher degree of expertise, such as containment capabilities and agile manufacturing methods, Leal continues. “For traditional contract development and manufacturing organizations (CDMOs), who manage large volumes, these specialist products are very complicated to handle,” he emphasizes. “Hence, made-to-measure services can be better provided by smaller independent CDMOs.”

	In agreement, Lee adds that working with an outsourcing partner for formulation and development can be particularly relevant for non-conventional dose forms. “Dosage forms, such as nasal and ophthalmic, as well as implantable devices and depots, can have additional complexity and regulatory issues for developers to consider,” he notes. “Through an outsourcing partner, developers can access expertise and technologies that they do not possess in-house.”

	A further benefit for Lee is that an outsourcing partner can also provide an extension to a developer’s available resources. “If there is a backlog or lack of available resources with the client, they can use an outsourcing partner as an extension of their internal development teams,” he says.

	Flexibility and being able to adapt to any changes that may occur during formulation development is critical to drug development success, stresses Weber. “By partnering with organizations that have experience in commercialization and technical expertise in complex dosage forms such as modified release or fixed-dose combinations, companies will be able to overcome project challenges in an agile and efficient way,” he confirms.

	“Specialism is key in the pharma industry. If our clients were to make the investment into their own manufacturing facilities, they would have to dedicate huge amounts of resource and capital,” states Leal. “Outsourcing gives a drug developer access to unique skills and support within the supply chain, which means other benefits such an increased speed to market and reduced cost in the long run can be achieved.”

	In Lee’s opinion, routes of drug administration that have been previously overlooked, such as nasal dosage forms, will experience growth in the near future. “Nasal delivery can offer an ideal route and increased bioavailability for several drug types, particularly those indicated to treat the central nervous system,” he explains. “This route of administration may also be suitable for non-conventional APIs, such as biologics.”

	For Leal, the increasing prevalence of high-potency ingredients being developed is leading to more growth in demand for outsourcing partners that can effectively manage the associated containment issues. “High potency facilities are capital intensive and containment requirements are stringent,” he says. “Therefore, it will be more economical and practical for pharmaceutical companies to work alongside outsourcing partners to develop and manufacture their products in a more efficient manner.”

	A further trend that Leal believes will be important in the near future is that of value-added medicines that are based on well-known molecules with new applications, indications, finished-dosage forms, or strengths. “These drugs are an improvement on the traditional generics, which means more cost, but they remain more economical to develop than medicines based on new chemical entities,” he adds. 

	Currently, there is a trend happening in the industry to use artificial intelligence to mine for APIs to hit relevant newly discovered biochemical pathways, according to Drummond. “A major trend going forward will be the alignment of formulation with information technology and any relevant devices with a focus on making it simple and easy, and even attractive, for the patient to be compliant,” he comments.

	Ultimately, however, keeping the patient in mind when looking at drug development is and will remain to be of critical importance, emphasizes Lee. “If a patient does not like the dosage form then they are unlikely to take the drug, leading to negative therapeutic outcomes,” he concludes. “Dosage forms should appeal, not repel, the target audience.”

	1. Future Market Insights, “Oral solid Dosage Pharmaceutical Formulation Market: Emerging Markets of Latin America, APEJ, and MEA to Collectively Hold Over 45% Market Value Share: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” 


	Vol. 43, No. 10
	October 2019
	Pages: 16–20

	When referring to this article, please cite it as F. Thomas, “The Demands of the Perfect Dose,” 

Articles

As the development pipeline becomes more saturated with complex molecules and patient experience becomes more important, developers are looking to outsourcing partners to provide more specialized expertise and solutions.

The Demands of the Perfect Dose

	Supply chain security is of crucial importance in the pharmaceutical industry. Should counterfeit or falsified drug products enter distribution channels and end up with a patient, not only is the reputation of the drug company at stake but also the health, and even in severe cases the life, of the end user.

	To combat counterfeiting within the pharma industry, regulatory authorities have been putting various measures in place. One example is the Falsified Medicines Directive (FMD), which was implemented in Europe on 9 February 2019. 

	Compliance with the new FMD regulation means that pharmaceutical companies must ensure all drug products have safety features placed on the packaging, comprising a unique identifier and an anti-tampering device. These safety features will then be used by medicines suppliers to verify and authenticate the products prior to distribution to the public.

	Radio-frequency identification (RFID) technology has been identified as a potentially useful tool to track items in the pharmaceutical supply chain. “RFID is the transmission of, at minimum, a unique identification (UID) between a transmitter and a reader using radio waves,” explains Gillian Ewers, vice-president of marketing at PragmatIC, a company that specializes in flexible electronics.

	“The transmitter could be a package that includes an RFID tag,” she says. “A tag (which is sometimes referred to as an inlay, as they are inlaid behind labels or inside packages) in this case is usually simply an integrated circuit (IC) mounted on a substrate (paper or film) that also has an antenna either etched or printed on to it. This is the simplest form of a tag, called a passive tag, as it contains no batteries and needs the reader to provide it with the energy to wake up and send the signal to the reader.”

	It has been reported that RFID is a more reliable technology than two-dimensional barcoding and is more difficult to counterfeit. However, uptake of the technology as a tracking and identification solution has been limited in the pharmaceutical industry, despite it becoming more affordable as the technology has matured over time. 

	Ewers details some of the main applications of RFID technology in pharma. “For supply chain management, RFID technology can not only help companies to manage inventory, control stock, and, as such, manage costs effectively, but can also help in grey market prevention-where products are bought in a low-priced country and sold for a higher price in a different country,” she says.

	Through assigning an invisible unique identifier (UID) to each product, it is possible to audit complete stock at the point of sale, or anywhere along the supply chain, Ewers explains. “Key to this is it being invisible, so machine readable barcodes are no good (plus require digital printing to be truly unique), custom solutions that are not readable by commercially available RFID readers would be ideal,” she adds. “The UID can be assigned to a specific end retailer at POS.”

	As mentioned earlier, authentication is an obvious application of RFID. The technology can be used to track and trace various materials and products throughout the supply chain and, hence, reduce the likelihood of counterfeit or falsified products entering distribution channels. “Furthermore, it is possible to use RFID technology to provide consumers with information about the medicine through near-field communication enabled devices and tags,” Ewers continues. 

	The ability to connect the patient to the drug manufacturer through smart packaging has been forecasted as an area of growth in pharma (1). Through smart packaging, companies are offered additional benefits, such as improved patient adherence, which inevitably leads to higher rates of therapeutic success. 

	“Non-adherence is a significant problem across the world,” asserts Ewers. “One estimate puts the cost per year in the United States at $290 billion (2) in ‘otherwise avoidable medical spending’.” Reasons behind non-adherence are numerous, with the simplest being that patients forget to take the dose. There is an easy solution to remedy this issue, which is a reminder on the patient’s smartphone or wearable device, for example, Ewers notes. 

	“Another reason for non-adherence is failure to re-order in time, which again can be automated, either purely by time or by the packaging,” she says. “Other possibilities are regulating dosages, providing better information and reporting to remove the fear of taking a medicine and its potential side effects. There is also talk of using technology to motivate people to take medicine (3), especially in the case of ones given to reduce the probability of an event occurring.”

	“In terms of FMD compliance, RFID can be used to assign a digital UID to each medical product, which means the technology can be used in combination with an appropriate software platform for serialization,” she continues. “When the technology is integrated onto packaging, it needs to be read, and so an appropriate software package is required to ensure that the UID is actually unique and to enable reporting of any exceptions to the appropriate data controllers.”

	“RFID tags require an additional step in the production of labels and packages to insert the tags,” notes Ewers. “There are many packaging suppliers that are already able to perform this step and so pharma companies, without in-house capabilities, should be looking to partner with relevant label manufacturers and packaging converters.” 

	PragmatIC offers a technology platform that features flexible integrated circuits (FlexICs). As the flexible options are thin and low-cost compared with traditional RFID systems, they are ideally suited for pharma applications, reveals Ewers. “The first ConnectIC product family, which is aimed at RFID applications, was announced in February 2019,” she says. “Additionally, there is a range available for closed RFID systems, which when coupled with a low-cost custom reader can provide a cost-effective solution for covert tagging of products to monitor grey market division, for example.”

	The flexible tech is currently manufactured in the United Kingdom on a specific production system, FlexLogIC, which is an automated and scalable manufacturing model for FlexIC production. “As adoption of the technology is happening globally,” Ewers adds, “we envisage FlexLogIC systems being implemented around the world for the manufacture of FlexICs close to where they will be integrated.”

,” Report, March 18, 2016.
	2. HealthPrize Technologies, “

Medication Adherence: Pharma’s $637 Billion Opportunity

, [accessed July 8, 2019].
	3. Harvard Chan School, “

Increasing Cholesterol Medication Adherence with Financial Incentives May be Cost-Effective

Radio-frequency identification on packages aid drug supply-chain security.

Safe and Sound with RFID

	Recent figures from the United Kingdom’s government have demonstrated that graduates stand to earn £10,000 more than their peers who did not attend university (1). However, other factors have a significant role to play in future financial success, such as the subject chosen, university attended, or even gender!

	According to statistics, released by the Department for Education (DFE), graduates of pharmacology, toxicology, and pharmacy, ranked highly in terms of proportion of those going onto to further education or full-time employment, and for average earnings (2). Medicine and dentistry ranked the highest of the all the subjects that were assessed, and creative arts degrees were ranked lowest.

	Despite there being more female graduates in further study, or full-time employment at all time points examined, male graduates were still found to achieve higher median earnings than their female peers (2). Additionally, the findings from the DFE revealed that the gap in earnings between male and female graduates has actually increased over time.

	In light of this gender pay disparity-and the fact that science, technology, engineering, and mathematics (STEM) subjects comprised the majority of the top 10 highest earning subjects for graduates in the DFE’s analysis-the news that female students are now outnumbering male counterparts in A-level science subjects is surely welcome (3). If the trend of female students undertaking STEM subjects continues to rise perhaps the gender gap will start to reduce.

	Other disparities in employment rates and pay were found as a result of ethnicity, institution type, social background, family circumstances, prior qualification attainment, and age at the start of the course. Looking at international students, however, DFE’s analysis revealed that international graduates had greater yearly earnings, on average, than their UK peers.

Importance of attracting talent to pharma

	Obviously, the pharmaceutical industry, an industry that requires highly skilled employees, looks to attract graduates year-on-year to grow the talent pool and advance the sector. In a 2019 report, the Association of the British Pharmaceutical Industry (ABPI) outlined the needs of the biopharmaceutical industry and the importance of nurturing talent within life science disciplines (4).

	As stated in the report: “Just under half of undergraduates study STEM subjects-a proportion that has remained reasonably constant over many years […] Over the last decade, the number of UK undergraduates studying STEM subjects increased by 16% (compared to an overall increase across all subjects of 13%). By comparison, undergraduate numbers for (non-UK) [European Union] EU and non-EU students increased by 52% and 63% respectively over the same period […] It is also important that the pharmaceutical industry continues to be proactive in attracting STEM graduates.”

	The report also emphasized that university is not the only route through which the pharma industry can increase its talent pool. In fact, much work has been done within the industry to improve access through vocational pathways and the number of apprenticeships has risen since 2013 (4).

	“UK science and academia are the envy of the world and the we are vying to be Europe’s premier biotech cluster and second only to the United States,” said Sheuli Porkess, deputy chief scientific officer of ABPI, in a news release (5). “But we are seeing a decline in R&D investment. If we don’t address the skills shortages our status as a world-leading R&D hub we may see even more research-and with it highly skilled jobs-move abroad. This would be bad news for NHS [National Health Service] patients and the UK economy.” 

	1. DFE, “Graduates Continue to Benefit with Higher Earnings,” 

, 25 April 2019.
	2. DFE, “Graduate Outcomes (LEO): Employment and Earnings Outcomes of Higher Education Graduates by Subject Studied and Graduate Characteristics in 2016/2017,” 

, 28 March 2019.
	3. The Guardian, “Female Students Outnumber Males in A-Level Science Entries,” 

, 15 August 2019.
	4. ABPI, “Bridging the Skills Gap in the Biopharmaceutical Industry: Maintaining the UK’s Leading Position in Life Sciences,” 

, January 2019.
	5. ABPI, “Addressing Skills Shortages Critical to the Future of UK Science,” News Release, 


	Vol. 31, No. 9
	September 2019
	Page: 5

	When referring to this article, please cite it as F. Thomas, “Pharma’s Got Talent?” 

Government statistics show that pharma can be an illustrious career for graduates, which must be taken advantage of by industry to avoid skills shortages.


Pharma’s Got Talent?

As the pharmaceutical sector is one of the United Kingdom’s most productive industries (1), extensive investigations into the potential impact Brexit may have on the sector and significant work into contingency planning for a ‘no-deal’ scenario have been made. Contingency measures to avoid disruption to the supply of medicines, such as stockpiling of medicines, changing supply routes, duplicating drug testing, and transference of medicine licences, are underway by the pharmaceutical industry, according to the Association of the British Pharmaceutical Industry (ABPI) (2).

	However, despite preparative works and planning for every potential outcome of Brexit come 31 October 2019, there are a number of factors that remain outside of the control of industry. Additionally, ‘unpicking’ the intricacies of the relationship between the UK and European Union for medicines regulation and trade, a relationship that has been forged over decades, will undoubtedly give rise to challenges for pharmaceutical companies, both in the European region and around the world.

An integrated framework and disruption of ‘no-deal’

	“The pharmaceutical industry shares a regulatory framework with the EU,” explains Munira Wilson, corporate affairs director, Merck UK & Ireland. “It relies on integrated supply chains, an internationally diverse workforce, and a pan-European approach to research collaboration. All these aspects of the pharma business will be impacted by Brexit, regardless of whether the UK departs from the EU with or without a deal.”

	Despite the benefits for the UK to leave the EU with a deal in place, such as the transition period that would afford the industry, regulatory bodies, ports, and governments time to prepare for the potential new relationship between the UK and EU, it is looking ever more likely that the Brexit scenario will be that of ‘no-deal’. “A no-deal Brexit could potentially lead to significant short-term disruption, particularly at ports,” asserts Wilson. 

	Former Prime Minister Theresa May’s three attempts to pass a Brexit deal-that was agreed upon with the EU-in the UK parliament were to no avail and she resigned in June 2019 (3). May’s successor, Boris Johnson, is well-known to be insistent on the UK leaving the EU by 31 October 2019, be that with or without a deal (4). So, in light of the increased probability of a ‘no-deal’ scenario, preparations are becoming more important, with both the UK and EU set to experience disruptions.

	“In terms of public health, an ongoing close and collaborative relationship on systems and processes is particularly important,” stressed Wilson. “For example, collaboration is paramount on EU pharmacovigilance systems and databases, the European Databank on Medical Devices (EUDAMED), EudraVigilance, and the European Centre for Disease Prevention and Control.”

Avoiding a disorderly exit and preparations

	“Like all businesses, we hope that a disorderly Brexit will not happen,” continues Wilson. “However, not preparing for such an outcome would be negligent, because ensuring that patients get the medicines they need is a top priority.” A sentiment vehemently supported by industry bodies within the UK, such as the ABPI and the UK BioIndustry Association (5).

	Both the pharmaceutical supply chain and regulatory environment are set to be affected as a result of Brexit, Wilson explains, although the extent to which these areas are impacted depends on the nature of the future economic partnership that is agreed upon between the UK and the EU. In terms of an area that may experience a significant amount of disruption, she states that the regulatory environment within the UK could be detrimentally affected. “This impact will probably be seen due to the fact that the rest of the EU will continue to regulate medicines through the European Medicines Agency, which has relocated to Amsterdam, whereas the UK will likely end up with ‘third country’ status,” Wilson says. “However, the pharma industry is very clear that the UK government’s stated position of seeking associate membership of the EMA is the preferred regulatory position post Brexit.” 

	Many pharmaceutical companies are well underway in terms of preparing for Brexit, albeit with negative undertones in some instances where manufacturing investments have been frozen for example. However, for a lot of companies, preparations have included stockpiling and putting transportation arrangements in place. As reported by 

, a third of manufacturers affiliated with the British Generics Manufacturers Association have booked additional ferry capacity to ensure their medicines will be transported between the UK and EU should there be a ‘no-deal’ outcome (6).

	“Like many others, Merck has built up its contingency stock and is planning for re-routing of supply if necessary, in the event of a noâdeal Brexit, which could lead to significant disruption at ports,” Wilson adds. “The Department of Health & Social Care has issued a lot of guidance on this matter and is in regular contact with most (if not all) companies.”

	“Merck certainly respects the outcome of the referendum,” Wilson asserts. “However, at the same time, it is important for patients and for our business that Brexit takes place in an orderly fashion.” 

	Regarding transition arrangements, Wilson explains that ideally any government plans should be put in place as soon as possible, so that sufficient time is allowed for all parties involved to prepare for whatever future partnership is subsequently negotiated. “Obviously, the number one priority for all involved should be to mitigate against any disruption of supply of medicines to patients,” she concludes.

	1. House of Commons Business, Energy, and Industrial Strategy Committee, “The Impact of Brexit on the Pharmaceutical Sector,” Report, 

, 8 May 2019.
	2. ABPI, “‘No-Deal’ Brexit,” Information Page, 

[Accessed 16 Aug. 2019].
	3. The Guardian, “Theresa May Announces She Will Resign on 7 June,” 

, 24 May 2019.
	4. BBC, “Boris Johnson: What is His Brexit Plan?” 

, 23 July 2019.
	5. PharmTech, “Industry Responds to UK Government Planning for ‘No-Deal’ Brexit,” 

, 28 June 2019.
	6. C. Wickware, “One in Three Generic Manufacturers Opt to Arrange their Own No-Deal Brexit Ferry Transport,” 


	Vol. 31, No. 9
	September 2019
	Pages: 46–47

	When referring to this article, please cite it as F. Thomas, “The Big Deal Behind the ‘No-Deal’ Scenario,” 

As a potential ‘no-deal’ Brexit looms, pharma companies and industry bodies are preparing for the worst-case scenario but hoping that the UK won’t end up with a disorderly exit from the EU.

The Big Deal Behind the ‘No-Deal’ Scenario

	Oral-solid dosage (OSD) forms remain a popular choice for both pharmaceutical companies and patients. Convenience, ease of manufacture and administration, increased stability, and simplicity for pack and transport-compared with alternative dosage forms-are some of the factors leading to the continued popularity of OSDs.

	According to market research, the global OSD formulation market is anticipated to grow by an annual compound rate of 6.5%, reaching a value of US$926.3 billion (EUR826 billion) by the end of 2027 (1). As tablets comprise a significant proportion of OSD forms, within the pharma industry, tools that can aid in formulation and manufacturing efficiencies are of critical importance.

	One such tool that finds use in tablet formulation and manufacture is near-infrared (NIR) spectroscopy. To learn more, 

discussed the technique and its uses in greater detail with Federica Giatti, compression technologist at IMA Active Process Development R&D Laboratory. 

Could you highlight the main uses of NIR specifically in tablet formulation and manufacture?

NIR spectroscopy can be used in every step of the tablet formulation and manufacturing processes. For example, NIR is useful in tasks such as raw material identification, blend homogeneity, tablet characterization, and end-points determination in manufacturing critical process parameters. 

	Thanks to the efficient and non-destructive method offered by NIR spectroscopy in the detection and quantification of physical and chemical characteristics of tablets, it is possible to quantify many tablet attributes, such as drug content, hardness, and dissolution, non-destructively from a single measurement. Additionally, NIR can be useful for in-line process control, where it can be used to monitor whether or not tableting is performed to the required quality level over time. The probe can deliver real-time data to prevent process deviations and stop the machine before powder has gone through the process area. Statistical post-process NIR analysis can be also implemented to verify, in a redundant way, the quality of tablets and compare with spectra acquired before. 

Why is it important to analyze materials to be used in tableting, and how is NIR beneficial for these purposes? 

Several variables should be taken into consideration in a common tableting process-variations in raw materials, deviations in granulation, or handling of all phases of formulation preparation could all affect the quality of the final blend.

	Although NIR spectroscopy cannot be the primary analytical method for characterizing raw materials, its sensitivity to certain raw material characteristics (e.g., moisture content) allows for verification of the consistency between each API or excipient batch. 

	In the granulation process stages, a process analytical technology (PAT) approach based on NIR sensors allows for the simultaneous determination of multiple parameters by measuring on-line residual moisture and particle enlargement during all phases of the granulation process by achieving the desired quality attribute phase-by-phase and not at a predetermined time. 

	Verification of blend homogeneity is another interesting feature of NIR technology because it can lead to the avoidance of issues caused by thief sampling used in traditional content uniformity testing of powder blends. The spectral information can provide data about qualitative features of the blend (possibility to predict mixing end-point) or quantitative characteristics (API content) for building a specific calibration model.

	Furthermore, NIR spectroscopy is useful when trying to keep process variations under control. A big advantage of the technique is real-time optimization of the process parameters by reducing the risk of batch rejection. This benefit is achievable as information about process or material properties can be obtained in a shorter period of time. 

Can NIR provide significant benefits in dissolution testing? 

NIR spectroscopy has been evaluated by numerous investigators for predicting dissolution profiles in a PAT approach. The major benefits provided by the technique are that it is a fast, non-destructive method allowing users to overcome the issues of a potentially long, drawn-out analysis as well as the small sample size that is commonplace in standard dissolution tests. 

	Moreover, dissolution can be predicted to a certain level of reliability through calibration model development (e.g., partial least squares) when API content is variable. In addition, as NIR spectroscopy can detect the physical characteristics of tablets or a powder blend, tablet hardness variation can be monitored with NIR spectra. It is well known that as strength increases, API release decreases, and so for this reason, if the NIR spectra are studied extensively, dissolution behavior can be accurately predicted.

In your opinion, what does the future hold in terms of NIR spectroscopy within tablet formulation and manufacture?

Regarding the future, particularly looking toward continuous manufacturing, NIR spectroscopy can help in the prediction of deviations from a quality gold standard using post-process chemometric algorithms. Through the acquisition of spectra continuously over time, pharmaceutical developers and manufacturers will be able to define specific areas or sections of the process when critical process parameters are under control, and also when out-of-specifications occur. For the latter situation, it could be possible to set up an alarm that can stop the machine and as a result avoid batch rejections.

	1. Future Market Insights, “Oral Solid Dosage Pharmaceutical Formulation Market: Emerging Markets of Latin America, APEJ, and MEA to Collectively Hold over 45% Market Value Share: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” 

In this interview, the main uses and benefits of NIR spectroscopy in tableting are discussed.


Putting NIR to Good Use in Tablet Formulation and Manufacture

A version of this article was published in 

APIs, Excipients, and Manufacturing 2019 Supplement

In recent years, regulatory bodies across the globe have been taking a more stringent approach to excipient quality. Within the European Union (EU) alone, regulatory guidance on the assessment of risk related to excipients was published in 2015 and required to be implemented by 2016 (1). However, these guidelines only offer a general framework from which pharmaceutical companies and excipient suppliers can look to develop their own appropriate ways of ensuring excipient quality.

	To learn more about the European regulatory guidance, its implementation, potential impact on workloads, and best practices for companies and excipient suppliers, 

spoke with Frithjof Holtz, advocacy and surveillance-life science regulatory management, Merck KGaA.

Could you elaborate on the EU regulations surrounding excipients and how these have developed over the years?

The critical role of excipients in drug production has come into focus over the past few years. This has meant shaking off the long prevailing perception of excipients being passive additions to APIs. Now, regulatory authorities are calling for more stringent quality management in excipient production and use, leading to new requirements for both excipient suppliers and pharmaceutical manufacturers.

	Regulating excipient quality, however, is no small task. More than 1000 different excipients are available, and only a small fraction is manufactured solely for pharmaceutical use. This heterogeneity and the resulting complexity have led to the European Commission’s (EC’s) approach to excipient quality. 

	In 2011, the EU’s Falsified Medicines Directive established that pharmaceutical manufacturers must perform a formalized risk assessment for each excipient they use and determine its appropriate good manufacturing practices (GMPs). It also stated that the EC would develop guidelines offering direction on the risk management process and the appropriate level of GMP for excipients. Based on this directive, the EU excipient risk assessment guidelines were drafted in 2013 and published in March 2015 after intense discussion.

	The guidelines apply not only to medicinal products produced in Europe but also for products manufactured outside Europe and intended for the European market. Since 21 March 2016, excipient users in the EU are legally mandated to implement GMP requirements, including comprehensive risk assessments for each excipient. 

	The EU excipient risk assessment guidelines capture both the intended use and source of the excipients. Its main topics are described in chapter two to four, covering the determination of appropriate GMP based on type and use of excipient, the determination of an excipient manufacturer’s risk profile, as well as confirmation of application of appropriate GMP.

	However, while regulations regarding GMP for APIs clearly define what is needed for compliance, the EU excipient risk assessment guidelines are-as the name suggests-not more than guidelines that offer tools and a framework but do not prescribe how to implement them. They neither provide detailed instructions nor a clear definition of appropriate GMP for excipients. This is the responsibility of the manufacturing authorization holder-and, evidently, no small task either. 

Why has the EC taken a riskâbased approach to excipient quality?

A risk-based approach is the most logical way of assessing excipient quality. Some excipients pose much greater risks than others. Risks vary depending on the route of administration and the function of the excipient. An excipient used as filler, for instance a binder or colorant, might pose a lower risk than one used as a stabilizer or a vehicle for controlled release. Hence, the risk-based approach focuses on the harm posed by microbiological, chemical, or physical hazards.

	Due to the risk excipients can pose to patients, robust excipient GMPs are needed. Increased attention to supply chains and more structured communication between excipient suppliers and drug manufacturers are essential in order to help reduce risks. Drug manufacturers should expect their suppliers to provide dossiers accompanying each excipient with information that, in turn, supports the drug manufacturer’s risk assessment. This can include data on production, testing, supply chain and quality systems, as well as information about alignment with regulatory guidelines.

Implications and potential aides for manufacturers

Are there significant workload implications for manufacturing authorization holders, and are there any solutions available to ease the workload? 

It is important to understand that the EU excipient risk assessment guidelines offer a general framework. Developing a compliant risk assessment process and defining appropriate GMPs for all excipients is clearly the responsibility of the medicinal product manufacturer. However, there is no need for manufacturers and users of excipients to develop their own GMPs. Several well-established, voluntary industry standards can be used for guidance, such as the International Pharmaceutical Excipients Council-Pharmaceutical Quality Group (IPEC-PQG) GMP Guide, 

) General Chapter <1078>, EXCiPACT, and NSF/IPEC/ANSI-363-2016. 

	Take the IPEC-PQG GMP Guide as an example, it provides an in-depth description of a voluntary GMP guide for pharmaceutical excipients. Together with the IPEC Europe ‘how-to’ document on 

EU Guidelines on Risk Assessment for Excipients

published in 2016, it gives a good initial guidance (2). The step-by-step document also offers a clearly arranged process overview of how to comply with the requirements outlined in the EU excipient risk assessment guidelines. In many cases, application of these standards is likely to be sufficient. However, a small number of excipients could potentially pose hazards to patients and require application of more thorough controls than those recommended in the voluntary standards.

	Unfortunately, manufacturers and users of excipients are often still at a loss as to how exactly they should perform their risk assessment. Given the abundancy of excipients, a formalized risk assessment might even seem unmanageable. Also, the sheer number of supporting documents can be overwhelming, as helpful as they might be. So yes, the more stringent regulations have increased the workload of all parties involved. Performing excipient risk assessment in a structured manner requires a lot of effort and has significantly changed the daily work of excipient users and manufacturers. 

	Although the voluntary industry standards are a great help, they are not binding, but based on best industry practices, offering guidance and facilitating implementation. As described before, excipient suppliers and pharmaceutical manufacturers are still facing the complicated task of putting these standards into practice.

	As a result of these complexities, Merck has developed the Emprove program (3). The intention of the program is to simplify processes and to help drug manufacturers master the challenges of timely information, structured communication, and ‘inspection-friendly’ documentation. Dossiers, which are available 24/7 online and backed by comprehensive support, cover the relevant EU guidelines, with constant reference to the respective chapters. Additional information, such as a quality self-assessment and detailed supply information, is also included in the dossiers. Regarding excipient risk assessment, the tools and information help to efficiently implement a compliant and sustainable risk assessment process, which makes pharmaceutical manufacturers optimally prepared for inspections.

Do you have any best practices for companies to successfully prepare for excipient risk assessment inspections?

Absolutely, a few months ago, we [at Merck] conducted a real-life case study to simplify the task and to enable effective learning through practical experience. We began by selecting medicinal products to identify all relevant excipients and their respective use. This selection resulted in a total of 24 excipients for inclusion in our investigation and assessment.

	Based on the EU guideline, we then compiled criteria for manufacturing and supply, as well as application. This led to the definition of five different quality areas: quality management system (QMS), manufacturing of excipients, supply chain, route of administration, and function of the excipient. Based on these initial considerations, we conducted the case study in four distinct steps.

	The first step focused on supplier qualification. The EU guidelines were translated into a supplier questionnaire. The incoming information was harmonized and bundled in a spreadsheet. 

	Next, we developed an excipient risk ranking template covering all elements of the EU guidelines. It provides a risk score (low, medium, and high) for each individual excipient for each criterion as well as the overall risk score. As recommended by the EU guidelines, we used International Council for Harmonization (ICH) Q9 Quality Risk Management as guidance for risk prioritization (4).

	Finding an appropriate procedure for risk prioritization of the responses was by far the greatest challenge. Here, suppliers can actively contribute to a good risk assessment process by following established guidelines, fulfilling information needs and providing timely documentation, ideally bundled in packages and transmitted electronically.

	Step three determined the supplier risk, based on the previous definition of minimum requirements derived from the IPEC-PQG GMP Guide and EXCiPACT. 

	Finally, a risk profile for each supplier was created based on a gap analysis. The goal was to find effective mitigation options, such as an update of the quality assurance agreement or intensified incoming goods control.

	All 24 excipients were classified as medium risk. It is important to note that this classification represents an overall ranking, as explicitly required by the guidelines. This means that excipients might show high single risks-which need to be closely looked into-but are still classified as medium risk overall. The high single risks showed that storage monitoring and packaging are important considerations regarding the excipient’s source, whereas dosage form, permanent intake, and function are predominant regarding the excipients’ use.

	The gap analysis at the supplier end resulted in 14 excipients classified as low, and 10 as medium risk. The identified gaps include a potential for microbiological or endotoxin/pyrogen contamination-with the mitigation option to perform additional quality control testing in the manufacturing authorization holder’s laboratory. Other identified gaps concerned environmental control and control of storage/transportation conditions including cold chain management and packaging integrity.

	One of the main challenges we recognized in conducting our analysis was in obtaining meaningful data. Supplier data input to our survey was sometimes incomplete, contradictory, not as requested or not delivered in a unified format. Also, data transfer and dealing with large spreadsheets was an error-prone and time-consuming task. More clearly defined instructions for suppliers might be able to solve this challenge. 

	Another major challenge we encountered is providing a sustainable risk assessment process that can be easily incorporated into daily business to keep it up to date. However, it is important to note that the risk assessment cannot replace regular audits, since the information provided by suppliers and manufacturers does not necessarily reflect the degree of compliance in daily work.

What do you believe the excipient suppliers and pharma manufacturers should anticipate in terms of regulatory guidance and required compliance for quality of excipients in the near future?

I see two important areas. The first is multicompendial compliance. Unfortunately, pharmacopeial harmonization has not led to the expected results. Manufacturers and users of excipients still need to cross-validate pharmacopeial standards, as long as the industry is lacking a standardized approach. The industry needs to develop a best practice that is accepted by regulatory authorities. This would enable companies to align their internal procedures for compliance with multiple compendia.

	Second, novel excipients are prevented from being introduced in the EU due to the absence of an excipient master file system. Major regulatory environments such as Japan, US, Canada, and China, have design master file-type systems in place and treat novel excipients as APIs, requiring comprehensive manufacturing, quality, and safety data. In Europe, however, there is no way to directly submit confidential information for an excipient in a centrally authorized product. A regulatory pathway that guarantees the protection of confidential manufacturing know-how for novel excipients would encourage innovation.

	1. EU, “Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use,” 

, 58 10–13 (2015).
	2. IPEC Europe, “‘How-To’ Document: Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use (OJ 2015/C 95/02),” Guide, 

(Brussels, 2016). 
	3. Merck, “The Emprove Program,” Regulatory Support Information, 

[Accessed 19 August 2019].
	4. ICH, Q9 Quality Risk Management (ICH, 9 November 2005). 

Regulatory bodies are taking a more stringent approach to excipient quality, but unlike guidance on GMP for APIs, those for excipients offer a framework only, meaning the onus lies with the manufacturer or supplier.
