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

Adeline Siew, PhD

The increasing prevalence and high cost of medication errors have prompted regulators and manufacturers to look into the role of product design in ensuring the safe and correct use of medicines. Experts share insights on how product appearance such as size, shape, color, and imprint can make a difference in reducing medication errors.

Articles

Experts share insights on how product appearance such as size, shape, color, and imprint can make a difference in reducing medication errors.

Safety by Design—Mitigating the Risk of Medication Errors Through Product Design

While the success and potential of combination products in advancing patient care and making treatments safer and more effective have contributed to its rapid market growth, the regulatory framework for combination products can raise a variety of challenges for the industry. The diversity in the types of combination products means there is no “one-size-fits-all” approach. 

interviews Mark D. Kramer, former director of FDAs Office of Combination Products, and currently, president of the consulting firm, Regulatory Strategies Inc. (email: 

), about the regulatory requirements for combination products and the implications of FDA’s final rule on manufacturers of combination products.  

What is the regulatory definition of a combination product?

 (e), a combination product is defined as a combination of different types of regulated products (i.e., a drug and a device; a drug and a biological product; a device and a biological product; or a combination of a drug, device, and biological product) (1, 2). 

FDA recognizes three different ways that the components (called ‘constituent parts’) of the combination product may be combined to meet the combination product definition:

Physically/chemically combined (‘single-entity’ combination product). Examples include antimicrobial-coated catheter; drug-eluting stent; syringe or injector pen prefilled with a drug or biological product. 

Packaged together (‘co-packaged’ combination product). Examples include drug vial packaged with an empty syringe or injector pen; convenience kit containing a catheter, gloves, and anesthetic or antimicrobial jelly.

Labeled specifically for use together (‘cross-labeled’ combination product). These are separate products that are neither physically combined nor packaged together, but brought together or ‘combined’ only through their labeling in that each product label individually specifies the use of the other product. The United States is unique in recognizing cross-labeled constituent parts to be combination products. Cross-labeled products sometimes raise challenging regulatory issues, particularly where different companies are involved in the development of the respective constituent parts. Examples include drug cartridge and separately provided, dedicated injector pen; photodynamic therapy drug and activating light source.
  

Unlike the EU, in the US, the order of the terms typically has no meaning in describing the primacy of the drug or device constituent part. The term ‘drug/device combination product’ is typically used to describe a combination product comprised of a drug and a device even when the primary or principal mode of action is provided by the device constituent part. 

What are the key drivers for the development of combination products? 

Combination products have the potential to enhance the safety and/or effectiveness of either product used alone. The use of a drug coating on a device may help make the device more effective, or less likely to cause adverse events, than the device itself. For example, the drug coating on a stent is helpful in preventing the restenosis that may occur after stent implantation, and thus, can help reduce the need for additional surgery. The use of a novel device for local drug delivery may allow a drug to reach local concentrations that would be difficult to achieve as safely if the drug were to be administered systemically. The use of a companion diagnostic device may allow a drug to be targeted to patients most likely to benefit from it or least likely to experience the drug’s side effects.

While the above are examples where the use of the ‘other product’ can enhance the safety or effectiveness of the first product, there are also situations where the ‘other product’ is required. An example in this category is the light source used for photodynamic therapy or photodynamic diagnostic drug products. Without the light source (typically a laser or LED light source) to activate the drug or to illuminate the drug for diagnostic purposes, the drug product provides no therapeutic or diagnostic effect.

Another driver for the development of a combination product is to obtain a regulatory benefit that may help provide a competitive advantage. For example, an additional new drug product exclusivity period may be potentially achieved through the development of a novel method of drug delivery if clinical studies are required to support the new approval. In addition, if a new combination product becomes the standard of care because of the recognized safety or effectiveness benefits, the developer can enjoy a competitive advantage until other companies complete the required studies to support marketing authorization of their products. 

 What challenges do combination products present to manufacturers? 

Hopefully the benefits of combination product development for manufacturers, healthcare providers, and patients will outweigh the challenges, but it’s clear that combination products raise some unique challenges not presented by conventional drugs and devices. 

Manufacturers accustomed to dealing only with drugs or devices may need to broaden their in-house and consulting expertise to be able to sufficiently anticipate and address the scientific, technical, and regulatory issues that may emerge. Device companies, typically taking an engineering focus, may not have the requisite experience in dealing with issues frequently arising in pharmaceutical development. For example, device manufacturers that start out considering a drug coating to be like any other device component or coating, may be surprised at the rigor with which regulatory authorities will expect the drug’s dose, elution characteristics, and stability to be evaluated. Likewise, pharmaceutical companies well-versed in drug synthesis, pharmaceutical manufacturing, and quality control will likely find the device design control requirements under ISO 13485 or

or the need for human factors/usability studies to require rethinking of their product development process (3, 4). 

Scientific and technical challenges may arise regarding the compatibility of the device and drug. For example, new dose-ranging or pharmacokinetic studies may be necessary for approved drugs being delivered locally through the use of a device. The potential for extractables and leachables of the device materials into the drug substance or drug adhesion/absorption to the device materials affecting the delivered dose may need to be considered. Residues from device manufacture could have an impact on drug performance characteristics. Either component could affect the stability of the other. 

Regulatory challenges may also emerge. The US has different regulatory paradigms for devices, drugs, and biological products. When these products are combined, there is some flexibility in terms of how these varying requirements will be applied. That flexibility allows FDA to tailor the regulatory controls as appropriate to the combination product, but at the same time, may create uncertainty on the part of the manufacturer as well as FDA staff in terms of precisely how a given combination product will be regulated. Similar to the EU, the US uses a ‘primary mode of action’ (PMOA) approach when regulating combination products. In the US, however, PMOA directly influences only assignment to a lead-reviewing center, not the regulatory authorities to which the product will be subject. While most combination products in the US are regulated under a single marketing authorization application, in some cases, FDA may require separate marketing applications for the individual constituent parts of the combination product. There are also situations where FDA may permit the use of a single marketing application for the combination product, but manufacturers may prefer separate marketing applications for the constituent parts, often to derive some type of regulatory benefit from the separate approval/clearance of the constituent parts. Finally, there can be uncertainty in how post-market regulatory requirements, such as GMP requirements and vigilance reporting, will be handled.

 Can you tell us more about the current GMP requirements for combination products? What are the implications of FDA’s final rule on manufacturers of combination products? 

 There is more clarity about the current GMP requirements to which combination products are subject since the FDA’s publication of a final rule in January 2013. This rule, codified at 21

, went into effect in July 2013 and applies to all ‘single-entity’ and ‘co-packaged’ combination products (i.e., new products as well as legacy products already being manufactured prior to the rule’s effective date) (5).

The rule takes the position that a combination product comprised of both a drug and a device is subject to both sets of GMP requirements—

 for devices (4), regardless of how the product is regulated. In other words, a prefilled syringe regulated as a drug product and a drug-coated catheter regulated as a device are both subject to drug GMPs under 

Under the final rule, a manufacturer has two options for ensuring compliance. The first option is for the manufacturer to comply with both sets of regulations outright (i.e., implement a quality system that fully incorporates

). The rule, however, provides a creative option to compliance that recognizes the inherent similarities in the underlying GMP regulations and FDA’s determination that it should be unnecessary for companies to fully implement both sets of requirements to be compliant. Under FDA’s ‘streamlined approach’ permitted by the regulation, a manufacturer may elect to use either

 as their ‘umbrella’ current good manufacturing practice operating system, provided that they also incorporate specific key provisions of the ‘other set’ of regulations. In addition, combination products including biological products must incorporate relevant provisions of

For example, a pharmaceutical company making a single entity or co-packaged drug/device (or device/drug) combination product operating in compliance with 

 as their umbrella quality system provided they also incorporate the following six provisions from 

 (as applicable)—design controls; purchasing controls; corrective and preventive action (CAPA); management responsibility; installation; and servicing. 

The same company, making the same product, could choose to operate a quality system compliant with 

 provided that it also incorporates the following eight specified provisions of 

—calculation of yield; expiration dating; stability testing; testing and approval/rejection of components, drug product containers and closures; testing and release for distribution; special testing requirements; reserve samples; and tamper-evident packaging for over-the-counter products. 

The ‘streamlined approach’ is available when both the drug and device constituent parts ‘have arrived at’ or are being manufactured at the same facility. This means that if Facility A manufactures only the active pharmaceutical ingredient (API) used in a combination product, while Facility B manufactures both the API and device into the finished combination product, only Facility B can use the streamlined approach. Since Facility A manufactures only a drug product in this example, it must comply with

 is now in effect for ‘single entity’ and ‘co-packaged’ combination products. Since ‘cross-labeled’ combination products are by definition separately manufactured and provided, they are not subject to these requirements and instead, each constituent part is subject to its respective GMP requirements. 

FDA has begun inspecting manufacturers to these new requirements and it is important that companies have procedures in place to ensure compliance. For pharmaceutical companies with a modern quality system incorporating management responsibility, purchasing controls and CAPA, design controls are likely to be the main gap. Companies should be prepared to show that they understand the requirements and how they have implemented them at each facility involved in the combination product manufacture.

Manufacturers should also be aware that the final Unique Device Identifier (UDI) rule (9), published in September 2013 with compliance deadlines beginning in September 2014, applies to combination products as well. In addition, manufacturers should be on the lookout for an anticipated final rule on post-market vigilance reporting requirements for combination products; a proposed rule was published in 2009 and a final rule continues to be anticipated.

,  accessed Mar. 5, 2014. 
  2. 	Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), 

, accessed Mar. 5, 2014.
  3. 	ISO 13485:2003 Medical devices--Quality management systems--Requirements for regulatory purposes. 
  4. 	Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC) 

,  accessed Mar. 5, 2014.
  5. 	FDA, 21 CFR 4 “

Final Rule: Current Good Manufacturing Practice Requirements for Combination Products

,”  accessed Mar. 5, 2014.
  6. 	Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC) 

, accessed Mar. 5, 2014.
  7. 	Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC)

, accessed Mar. 5, 2014.
  8.	Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC)

, accessed Mar. 5, 2014.
9. 	The Federal Register, "


  Adeline Siew is the scientifc editor for 

Mark D. Kramer talks about combination products from a regulatory perspective and explains the implications of FDA's final rule on current GMP requirements for combination products.

Navigating the Regulatory Landscape of Combination Products

Developing fixed-dose combinations (FDCs) is becoming a popular lifecycle-management (LCM) strategy for pharmaceutical companies seeking to maximize the value of their products. “The development of FDCs is driven by factors, such as the patent expiry of major blockbuster drugs, stiffer competition from generic drugmakers, and a drought in the pharmaceutical R&D pipeline,” Anil Kane, PhD, executive director and global head of formulation sciences at Patheon, noted in an interview with 

 Reformulating and combining drugs that have been proven to be safe and effective into FDCs represents an essential strategy for drug-development companies to realize maximal commercial returns in a faster way than developing new molecular entities, which could be a lengthy, expensive, and high-risk endeavor. FDCs can benefit patients through the potential increase in efficacy, the synergistic effect of a potentially lower dose, and the convenience in terms of administration and compliance. Combination drugs also offer an opportunity for intellectual property and exclusivity. Kane spoke to 

 about the challenges in the development of FDCs and discussed how to integrate quality-by-design (QbD) in the manufacturing process of FDCs. 

PharmTech: What factors must formulation scientists consider when developing FDCs? 

 The main challenge usually involves product formulation and manufacturing issues. Two or more active ingredients in the FDCs have to be physically and chemically compatible along with their excipients. It is important to ensure that these active ingredients do not generate new impurities or raise new drug-drug interactions. 

Individual drug dose differential can pose formulation and processing challenges when combined in a single-unit dosage form. Physicochemical properties and stability of each of the drug in an FDC will define the formulation approaches to maintain stability during the shelflife of the combined drug product. For example, the hygroscopicity of one active drug substance can influence the stability of the other drug in the combination product unless they are completely separated by way of multiple techniques. 

The particle size distribution of a low-dose drug and the distribution of the second high-dose drug can affect the content uniformity of one and flow and processability of the other for a single two-layer tablet. If the active drugs are incompatible with each other, they would need to be formulated in a single pill using a number of different options, such as multilayer tablets, compression-coated tablet, multiparticulates in capsules, combinations of coated and uncoated beads, or pellets of one placed with a powder of another active. 

Innovative formulation strategies also require new analytical procedures to accurately assess product quality. Additionally, the packaging of an FDC product may need to be re-considered based on the criticality of the multiple actives and their stability profile in combination. 

PharmTech: Can you describe the manufacturing process of FDCs? 

We adopt a decision tree for formulating two or more drugs as FDCs (see 

). Depending on the formulation strategy adopted, the manufacturing of an FDC can be as simple as mixing the two or more active drug substances (provided they are physically and chemically compatible and stable) with excipients required for encapsulation, or tableting and compression followed by coating or encapsulation.

The manufacturing process is more complex with bilayer, three-layer, or tablet-in-a-tablet manufacturing. This could involve multiple granulations and compressing these layers using suitable multilayer tablet presses or a special press for tablet in a tablet. Minitablets can be manufactured using conventional tablet presses with specialized tooling and multiple minitablets containing different components of the FDC can be encapsulated in a capsule.

The manufacturing process of FDCs as multiparticulates could involve beads or pellets prepared using an extrusion spheronization process and a second active drug layering. An alternative is to have multiple layers loaded onto nonpareil sugar or cellulose beads. In general, if a high drug loading is required, an extrusion process is preferred to manufacture pellets and the second active drug can be layered using an active coating process. For low drug loading, layering onto sugar or cellulose beads is feasible. The beads or pellets of different population containing different active drug substances can then be filled into a hard-shell capsule.

PharmTech: How do you integrate QbD into the manufacturing process of FDCs? 

It is important to integrate principles of QbD into the development and manufacturing process for all products, especially the complex processes of FDCs. The critical quality attributes (CQAs) for FDCs will be similar to single-ingredient drug products. The only additional complexity will be impact of two or more active drug substances on the potency, impurities, dissolution of individual drugs, and content uniformity of each active especially where there is a big dose differential among the active drugs. The drug-drug interaction 

 are additional attributes to be considered for FDCs.

The critical process parameters (CPPs) are similar to individual single-drug products as well. The CPPs become more complex when the impact of physicochemical properties of multiple ingredients on the manufacturing unit process affects the processability and the quality parameters. Properties such as hygroscopicity and particle size distribution play a key role in the ability to process the FDC’s to meet the target product profile (TPP). Depending on the final identified target dosage form and the method of manufacture, the CPPs could be different (e.g., roller compacted granules of Drug A + a direct blend of Drug B with excipients compressed as a bilayer tablet). The formulator needs to understand the process by a systematic design of experiments conducted to evaluate the impact of processing parameters to meet the quality specifications. QbD in development of FDCs becomes more critical as it involves study of the impact of multiple actives and process understanding to formulate and manufacture a robust FDC product. 

Anil Kane from Patheon spoke to Pharmaceutical Technology about the challenges in the development of FDCs and discussed how to integrate quality-by-design (QbD) in the manufacturing process of FDCs.

Tackling challenges in the development of fixed-dose combinations

Current issues with Nanomedicines The global market for nanomedicines has been experiencing a strong growth and is expected to reach a value of $177.60 billion within the next five years according to a report by Transparency Market Research (1).
  Advances in nanotechnology have seen a number of nanomedicines successfully progress from the laboratory bench to the clinic with the majority of applications focused on drug delivery, such as solubility/ bioavailability enhancement and better drug targeting. Despite that, there are several issues in nanomedicine development and commercialization that remain unresolved, for example, imprecise patent classification, patent proliferation and the lack of a universal nano-nomenclature among others. To gain further insight on these interrelated issues, 

 spoke with Raj Bawa, PhD, patent agent at Bawa Biotech LLC (Ashburn, VA, USA), scientific advisor at Teva (Israel) and adjunct professor at Rensselaer Polytechnic Institute
  (Troy, NY, USA).

PharmTech: Can you talk about the current issues with nanomedicines primarily from a patent and regulatory perspective?

Securing valid, defensible patent protection from the US Patent & Trademark Office (PTO) along with clearer regulatory/ safety guidelines from FDA are crucial to the commercialization of nanomedicines. Since the early 1990s, in light of inadequate search systems and exploding ‘prior art,’ the PTO has issued duplicate nanotech patents and/or patents of questionable validity to entities often called ‘patent prospectors,’ and a kind of ‘nanopatent land grab’ has continued ever since. Another problem is that the PTO continues to classify US nanopatents into Class 977 where they currently number less than 10,000. These numbers and classification system, however, are clearly inadequate because they are based on the ill-conceived National Nanotechnology Initiative (NNI) definition of nanotechnology that limits all nanostructures and nanoproducts to a subnanometer range (i.e., 1–100 nm). The shortfalls with this definition, especially for nanomedicine, are well documented. As a result, these
numbers are an under-estimate and, therefore, miss the majority of patents (out of approximately 8 million US patents issued) that are nanotech-related. In fact, the confusion and ambiguity surrounding the definition of nanotechnology and nanomedicine continues to be one of the most significant problems shared by regulators, policymakers, researchers, and patent practitioners.

Another major issue is the lack of a universal nano-nomenclature whereby distinct terms frequently refer to identical or similar nanostructures or nanomaterials. As a result, in certain sectors of nanotech, ‘patent thickets’ exists today that could stifle commercialization efforts in future. It is time to seriously consider governmental action under the Bayh-Dole Act of 1980 whereby an imposition of compulsory licensing or exercise of march-in rights needs to be considered. Even the creation
  of an open-source type process to rectify the erroneous issuance of some of these basic, upstream nanopatents should be contemplated so that downstream development of nanomedical products is not stifled.

Advances in nanomedicine and the FDA system for governing nanomedicines are inevitably intertwined. The ‘baby steps’ that FDA has undertaken during the past decade have, however, led to regulatory uncertainty. At the moment, only draft FDA guidelines exist. Whether FDA eventually creates entirely new regulations or tweaks existing ones, the FDA Commissioner should officially announce that it will review nanomedical products on a sciencebased, case-by-case basis.

The toxicity of many nanoscale materials is not fully apparent. Premarket testing of nanomedicines will not detect all adverse reactions and it is crucial that long-term safety testing be conducted. Therefore, postmarket tracking or a surveillance system must be adopted to assist in recalls. Toxicity data specific to nanomaterial need to be collected and an effective risk research strategy devised. FDA should seriously contemplate nano ingredient labeling on a case-bycase basis since there are few to no reliable means for a consumer to identify marketed ‘nano-containing’ products. The agency has data on liposomal drugs that dates back to the 1950s. Perhaps data that pertains to ‘nanoliposomes’ can be compiled and released into the public domain as such data will be invaluable to a potential sponsor developing nanoliposomal medicines (which the majority of current nanomedicines are).

PharmTech: What is the future outlook for nanomedicines especially now that the pharmaceutical industry is moving away from the blockbuster model towards more targeted therapies such as personalized medicines?

 With the demise of pharma’s blockbuster model, in future, novel ‘multifunctional/ multicomponent’ nanomedicines will be designed as new generations of drug-delivery systems to target specific organs, specific tissues, or even specific organelles.
  As we rapidly enter the age of nanotheranostics, these novel ‘combination drugs’ will present additional challenges for FDA because the agency’s current ‘primary mode of action’ (PMOA) regulatory paradigm may prove ineffective. Furthermore, some
  of these complex nanomedicines can be classified as NBCDs (e.g., Copaxone), which could present additional issues for FDA as it reviews generic versions of these NBCDs. NBCD generics will almost always lack bioequivalence to their referenced NBCD, thereby, prompting submission of clinical data from the generic drug developer. In any case, as various manufacturing and toxicology bottlenecks are overcome, the long-term development of nanomedicines will hinge on effective nanogovernance
  and patent reforms requiring the full commitment of various governmental entities (e.g., FDA, Congress, PTO, EPA) as well as the regulated community (i.e., big pharma and the manufacturing sector).

Nanomedicine Market (Neurology, Cardiovascular, Anti-inflammatory, Anti-infective, and Oncology Applications)—Global Industry Analysis, Size, Share, Growth, Trends and Forecas

Despite the progress made in nanomedicine development, there are several issues that remain unresolved. Raj Bawa, PhD, provides insight.

Current issues with nanomedicines

While it is recognized that nanomedicines can offer promising benefits in the diagnosis and treatment of diseases, there are still concerns about the safety and quality of these therapeutics partly because of the lack of clear regulatory guidance. Scott McNeil, PhD, director of the Nanotechnology Characterization Laboratory (NCL), a collaboration among the National Cancer Institute (NCI), the National Institute of Standards and Technology (NIST), and FDA, spoke with 

FDA does not currently have specific guidance or require specific additional characterization for nanomedicines or products containing nanoscale materials beyond what is required for traditional products, McNeil notes. However, recommendations have been made to FDA to develop nanomedicine-specific guidances for industry, and FDA scientists have acknowledged areas of special focus for nanomedicines in public presentations.

PharmTech: What characterization studies are required for nanomedicines? 

McNeil: At NCL, we evaluate nanomedicines in an assay cascade that has been developed specifically to tailor tests routinely used in the pharmaceutical industry to the unique properties of nanomaterials. As part of its assay cascade, NCL characterizes nanomedicines’ physical attributes, their in-vitro biological properties, and their in-vivo compatibility using animal models. NCL also looks at trends across nanoparticle platforms, parameters that are crucial to nanoparticle biocompatibility, and develops new assays to identify and address areas of potential safety risks. NCL has developed more than 40 protocols that rigorously characterize nanoparticle physicochemical properties, as well as in-vitro immunological and cytotoxic characteristics and administration, distribution, metabolism, and elimination (ADME)/toxicity profiles in animal models. These assays have undergone extensive in-house validation and are subjected to regular revision to ensure applicability to a variety of nanomaterials.

PharmTech: What are the challenges associated with the characterization of nanomedicines?

McNeil: Most of the challenges associated with testing nanomedicines arise from their complexity. Nanomedicines are complicated formulations that incorporate not only drugs, but also polymeric coatings, targeting ligands (such as antibodies), and imaging agents among others. Expertise is required to successfully develop these products, and bring them to clinic and onto the market. Not only must the developer understand the chemistry to synthesize the nanomedicine reproducibly, but they must also have the requisite knowledge to thoroughly test and understand its biodistribution, metabolism, pharmacokinetics, toxicological profile, and immunological consequences.

Some of the most common pitfalls encountered by the NCL are listed below. These challenges and others are described in detail in, ‘Common pitfalls in nanotechnology: lessons learned from NCI’s nanotechnology characterization laboratory’ by Crist et al. (1).

Sterility and endotoxin contamination should be addressed before you test your nanomedicine in animals. Endotoxin is a component of the cell wall of some bacteria, and tends to stick to nanoparticles, especially those that are positively charged. Contamination can cause misleading results in animal testing. Further complicating the issue, many nanomaterials interfere with traditional tests routinely used in the pharmaceutical industry to measure endotoxin. Therefore, it is important to include all appropriate controls when looking for endotoxin concentration in nanomedicines. 

Always thoroughly characterize a nanomaterial, and do so under biologically relevant conditions such as physiological temperature and pH. 

Consider the biological consequence of every component that is used in the manufacturing and purification process. If a non-biologically compatible component is required, develop a test to detect and quantify it in your nanomedicine.

Test the biocompatibility of every component, including linkers and components of the formulation. If nontoxic or more biocompatible components are available, use them.

Test batch-to-batch consistency at an early stage in the product development process. Poor batch-to-batch consistency may cause results on multiple batches of material to vary unpredictably.

Find an appropriate test to assess nanoparticle stability and drug release under physiologically relevant conditions.

PharmTech: What is the best way to accelerate the development of nanomedicines?

McNeil: Nanomedicines may be at a critical juncture as a handful of option deals between large pharmaceutical companies and small biotech companies developing nanomedicines seem to indicate interest and investment in this technology. Across the pharmaceutical industry, larger firms have focused on late-stage clinical validation and distribution, with less in-house early R&D. Instead of doing the early, risky studies themselves, large pharmaceutical companies have been acquiring small biotech companies with products already in clinical trials. Continued investment in nanotech from pharma will be crucial to the advancement of nanomedicines.

A globally unified approach to nanomedicine characterization and greater certainty in the regulatory pathway would greatly assist nanomedicine developers in advancing their technologies. Countries should work together to establish coordinated approaches to testing/characterization and regulation. Specifically, the EU and US, which are home to most of the big pharmaceutical companies, should make efforts to coordinate and harmonize their regulatory framework for nanomedicines.

Scale up and development of GMP for nanomaterials are critical vulnerabilities for many nanotech start ups. Such companies struggle to find contract manufacturing and research organizations with experience in the manufacture and testing of nanomaterials. They also face challenges in reproducible scale up to produce sufficient amounts of nanomedicine for large clinical trials. As previously mentioned, nanomedicines are often complicated formulations that may incorporate many components (e.g., the drug, 
polymeric coatings, targeting ligands such as antibodies, and imaging agents); supply chain issues in manufacturing, scale up, and testing can, therefore, overwhelm a small start up. Funding agencies should develop a coordinated strategy to provide assistance in this area.

Nanomedicines can offer promising benefits in the diagnosis and treatment of diseases but there are still concerns about the safety and quality of these therapeutics partly because of the lack of clear regulatory guidance. Scott McNeil, PhD, director of the Nanotechnology Characterization Laboratory (NCL), spoke with Pharmaceutical Technology about nanomedicine characterization.

Characterization of nanomedicines

It first started with the generics for small-molecule drugs, followed by the biosimilars for biologic drugs. With nanomedicines on the rise, a new class of non-biological complex drugs (NBCDs), which include nanosimilars, has emerged. Once again, drug regulators are faced with the challenge of defining a framework to ensure the safe introduction of the follow-on nano-therapeutics. Stefan Muhlebach, scientific director of Vifor Pharma Ltd, Glattbrugg, Switzerland, professor of pharmacology and hospital pharmacy, Basel University, Switzerland, and chairman of the NBCD Working Group in the Netherlands, explains why NBCDs cannot be assessed using the standard generic or biosimilar approaches.

 NBCDs are complex macromolecular drug products from an elaborate synthetic manufacturing process. NBCDs contain non-homomolecular structures showing partly nanoparticular properties (nanosimilars). Examples include iron carbohydrates (such as iron sucrose), glatiramoids, and liposomal drugs.

PharmTech: Why are NBCDs considered different from generics and biosimilars?

 In contrast to generics, NBCDs cannot be fully characterized by physicochemical means, and the generic paradigm cannot be used for comparability testing. Biosimilars are also complex macromolecular drug products but they are biologics (i.e., manufactured by living organisms).

PharmTech: How do you determinecomparability of NBCD follow-on nanomedicines or nanosimilars?

A multiple step approach is indicated but not yet established: physicochemical comparability, in-vivo non-clinical evaluation (animal model for biodistribution and drug tissue targeting) and clinical head-to-head analysis in patients for therapeutic
equivalence (substitution and interchange).

PharmTech: Can you describe the regulatory framework if there is one?

 There are guidance for industry documents from FDA and reflection papers by EMA, such as the bioequivalence assessment of different IV iron products (FDA) (1) and reflection papers on data requirements for follow-on liposomal and nanoparticular IV iron preparations (EMA) (2).

PharmTech: What type of studies do regulators such as FDA and EMA require?

Muhlebach: In addition to assessment/quantification of nanoparticles (e.g., sizing and morphology with up-to-date analytics), there are non-clinical (EMA) and clinical studies to evaluate pharmacokinetic-pharmacodynamic bioequivalence (such as which
  compartment is most reliable for comparing) and data on therapeutic equivalence for substitution and interchange. There are still no defined regulatory documents at the moment.

PharmTech: What does the future hold for NBCDs and nanosimilars?

The appearance/awareness of NBCDs showed that these are complex drugs that can no longer be dealt with using the generic approach of demonstrating pharmaceutical equivalence and bioequivalence in volunteers. For NBCDs, a similarity approach and the totality of evidence demonstrated will indicate how similar the reference and test product have to be for therapeutic equivalence and full drug product characterization. The challenge is to know what clinically meaningful differences exist between two products to exclude patient efficacy and safety concerns.

It is difficult to define an abbreviated procedure for market authorization for NBCDs. There is a major concern to what extent such products could or should not be interchanged and how they perform after market approval. Nanomedicines represent an attractive field of drug innovation to change drug targeting and the fate of the products in the body with even established drugs to improve efficacy and safety. There are established NBCDs that have been introduced and used safely for a long time even though their nano-character is not fully known. It is, therefore, not clear if the data required by regulators would motivate marketing authorization applicants to go for an independent full new chemical entity submission or for a reference similar approach where the data requirements are high with no guarantee for a successful regulatory submission.

, (Rockville, MD, recommended Mar 2012; revised Nov 2013).
  2. EMA, “Guidelines and concept papers,” Press Release, Aug. 2, 2013.

With nanomedicines on the rise, a new class of non-biological complex drugs (NBCDs), which include nanosimilars, has emerged. As drug regulators are faced with the challenge of defining a framework to ensure the safe introduction of the follow-on nano-therapeutics, Stefan Muhlebach explains why NBCDs cannot be assessed using the standard generic or biosimilar approaches.