Current Good Manufacturing Practices (cGMPs) in the Commercial Development of Nanomaterials for Hyperthermia Applications

C H A P T E R

13 Current Good Manufacturing Practices (cGMPs) in the Commercial Development of Nanomaterials for Hyperthermia Applications Steven J. Oldenburg, Whitney N. Boehm, Karolina Sauerova, Thomas K. Darlington nanoComposix, San Diego, CA, United States

13.1 INTRODUCTION The commercialization of a regulated device or drug is a long and expensive process. It takes approximately 12 years on average for a drug to be brought from concept to commercialization, with costs that can exceed $1 billion [1]. Development costs for medical device products average over $20 million, with higher risk projects exceeding $90 million [2]. In some cases, more than 75% of these costs are allotted to tasks related to regulation. To minimize cost and reduce the time to market, it is essential that data generated during development and clinical trials is robust and reliable from both scientific and regulatory perspectives. Understanding what will be required in terms of planning, experimental design, manufacturing, and recording results is critical for successful commercialization. In this chapter, an outline of the process of bringing

Nanomaterials for Magnetic and Optical Hyperthermia Applications https://doi.org/10.1016/B978-0-12-813928-8.00013-2

nanomaterials from research and development (R&D) to commercial current good manufacturing practices (cGMP) manufacturing is presented to identify development activities that will reduce the cost and time required to bring a hyperthermia device or drug to the market.

13.2 GOOD MANUFACTURING PRACTICES It is the responsibility of the manufacturer to ensure that a product intended for market meets all applicable legal, safety, and facility regulatory requirements. The manufacturer is also responsible for ensuring that the product has medical significance and the benefits and risks of the product are clearly labeled and communicated to the end user. In the United States, the Food and Drug Administration (FDA) is

339

# 2019 Elsevier Inc. All rights reserved.

340

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

responsible for ensuring that regulated materials are made using cGMPs, which provide guidance for manufacturing, testing, and quality assurance, ensuring that a medical device or drug product is safe for human use by guaranteeing that: • Manufacturing facilities are clean and hygienic. • Processes are clearly defined and controlled. • Operators are trained. • Manufacturing records clearly define all steps to be performed. • Records of manufacture enable batch traceability. • Complaints about marketed products are examined and appropriate measures are taken to prevent defective products. Under the FDA, cGMPs apply to every approved medical drug or device, covering a broad spectrum of products. For pharmaceuticals, cGMPs are covered under 21 CFR 210 and 211; they cover regulations for the manufacture of drugs. For medical devices, the cGMP guidance is 21 CFR 820, which is known as quality system regulations; it contains general regulations for manufacture as well as specific requirements for device development known as design controls. Because these regulations are written to encompass all drugs and medical devices, they do not provide a step-by-step guide for the development and manufacture of each and every device, but rather outline a development framework to follow for each product. Outside of the United States, regulations for drug and device manufacturing are overseen by country-specific organizations that follow quality system standards similar to those required by the FDA. For example, ISO 13485:2016, published by the International Organization for Standardization (ISO), is the principal standard for medical device quality management systems (QMSs). Following the formation of the European Union (EU), the European Commission standardized the regulation

processes of the member countries to foster interstate commercial interests while maintaining national autonomy. For medical devices, Medical Device Directive 2017/745/EU [3] is the primary standard used to determine the class of the device and provide guidelines for the preparation of a Technical File. The Technical File, which provides critical information surrounding the medical device, is submitted to a notified body that has been accredited by European authorities to audit medical device companies and products. A CE Marking Certificate is generated for the device and an ISO 13485 certificate issued for the manufacturing facility. A Declaration of Conformity is prepared and the product affixed with a CE Mark for commercial use. Despite different regulations, the approval process within the EU is similar to the process in the United States for a regulated drug or device.

13.3 REGULATORY CLASSIFICATION OF NANOMATERIALS Nanomaterial regulation is addressed in much the same way as any regulated drug or device. Many nanomaterials exhibit unique properties resulting from their size and shape, and historically there has been concern that these properties may have unintended consequences for human health and the environment [4]. For over a decade, the field of nanotoxicology has investigated nanomaterials within biological systems to assess whether there are unexpected size-related phenomena that could pose an unexpected risk [5]. While toxicity tends to increase as the size per particle is reduced, this observed effect is often due to higher dissolution rates at smaller particle sizes and not a direct result of particle size or shape [5a]. A recent publication that reviewed the current state of nanotoxicology research found that no known human disease or serious environmental impact

C. FROM BENCH TO BEDSIDE

13.4 HYPERTHERMIA PRODUCTS IN VARIOUS STAGES OF DEVELOPMENT

has been directly correlated to engineered nanomaterials [4]. The methodology for determining the safety of a nanomaterial-based drug or device from a regulatory perspective remains unchanged and the development of nanomedical products operates under current regulatory frameworks [5b]. Nanoparticles as therapeutic compounds can function as a device, a drug, or a drug/device combination product. To effectively determine whether a product is a drug or device, the FDA has defined each of these classifications by a series of principles that rely on both the attributes of the product itself and its intended use. A drug, as defined in Section 201(g) of the FD&C Act [21 USC 321(g)], is a product “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” that also can “affect the structure or any function of the body of man or other animals.” A device is classified as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar related article” that is “intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, of prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” Nanomaterial-based hyperthermia products have the potential to be classified as a drug, a device, or a drug/device combination product depending on the details of the implementation and their country of use. For example, it is more likely that a hyperthermia product will be classified as a drug or drug/device combination product if the particle is functionalized with a targeting agent such as an antibody, rather than the particle being sterically passivated with a nontargeting agent (e.g., polyethylene glycol,

341

PEG). The core action of nanoparticles used for hyperthermia, namely the process of absorbing energy from light or a magnetic field and generating heat, is consistent with the definition of a medical device. Typically, the regulatory burden for a drug is greater than that for a device, so there may be advantages in terms of cost and development time if the hyperthermiabased product can be classified as a device. Nevertheless, hyperthermia treatments are typically administered as an in vivo injectable, which will require extensive safety and efficacy data regardless of classification.

13.4 HYPERTHERMIA PRODUCTS IN VARIOUS STAGES OF DEVELOPMENT 13.4.1 Plasmonic Nanoparticles for Hyperthermia Nanoparticles exhibit unique optical and thermal properties that provide new opportunities for the therapeutic manipulation of heat [6]. Plasmonic nanoparticles, typically silver or gold, have an optical absorbance and a distinct color that is a function of their size, shape, and composition (Fig. 13.1) [6a]. The strong coupling of plasmonic particles to incident light efficiently heats the particles and their surrounding environment. Plasmonic nanoparticles in therapeutic applications are typically concentrated to a high optical density and are either injected directly into the treatment site or introduced intravenously. After administration, the particles are illuminated with a high-intensity light source and the localized increase in temperature damages the surrounding tissue. Biological tissue is more transparent to incident light at infrared wavelengths, so for many hyperthermia applications, the size and shape of the particle is designed such that the particles strongly absorb in the infrared region of the spectrum (Fig. 13.2). This allows for particles to be injected

C. FROM BENCH TO BEDSIDE

342

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

FIG. 13.1 Solutions of gold and silver nanoparticles of various shapes and sizes. Spherical silver nanoparticles with diameters between 10 and 100 nm (left) appear yellow while spherical gold particles are purple or red (middle). Silver nanoplates with thicknesses of 10 nm and diameters between 50 and 150 nm have colors that vary among purple, blue, and green (right).

deeper into tissue and still convert the applied light into therapeutic heat.

13.4.2 Magnetic Nanoparticles for Hyperthermia Another class of nanoparticles commonly used in hyperthermia applications are magnetic nanoparticles [Fig. 13.3 (left)]. Exposure to an alternating magnetic field will heat these particles [7]. Magnetic nanoparticles are prepared either in water or in organic solvents, where a subsequent ligand exchange is performed to transfer the particles to an aqueous solution. Nanoparticles for magnetic hyperthermia can consist of individual magnetic nanoparticles or composites where a number of magnetic particles are encapsulated into a larger but still nanoscale colloid. The particles are responsive to magnetic stimuli and at the smallest sizes will display ferrofluid properties [Fig. 13.3 (right)]. Superparamagnetic and ferromagnetic particles with different coatings and targeting agents have been used within clinical cancer therapy both as a stand-alone therapy and as an adjuvant to conventional chemotherapy and radiation therapy

[8]. The magnetic particles can be injected directly into the area to be treated or be introduced intravenously where they can accumulate at the target. When exposed to an electromagnetic field, the particles heat and locally damage tissue providing a therapeutic effect [8].

13.4.3 Current Status of Clinical Trials Involving Nanoparticles for Hyperthermia There are a wide number of nanoparticle drugs and devices currently undergoing clinical trials [9]. The AuroLase cancer treatment currently in development by Nanospectra Biosciences (Houston, TX) is in clinical trials for primary/metastatic lung cancer and for prostate cancer (NCT00848042, NCT01679470, and NCT02680535). According to https:// clinicaltrials.gov, “the study is an open-label, multicenter single-dose study of AuroLase Therapy in the focal ablation of neoplastic prostate tissue via nanoparticle-directed irradiation.” The AuroLase technology utilizes gold nanoshells that are approximately 150 nm in diameter and have a peak absorption

C. FROM BENCH TO BEDSIDE

13.4 HYPERTHERMIA PRODUCTS IN VARIOUS STAGES OF DEVELOPMENT

343

FIG. 13.2 Normalized extinction spectra and corresponding transmission electron microscopy (TEM) images from solutions of gold nanorods with different aspect ratios. Nanorods with higher aspect ratios have extinction peaks at longer wavelengths.

wavelength at 800 nm (Fig. 13.4). When introduced intravenously, the particles preferentially accumulate at the tumor site, and when subsequently illuminated with infrared light cause heat damage to cancerous tissue. In a clinical trial study NCT02680535, a single intravenous infusion of AuroShell particles was administered 12–36 hours prior to laser irradiation using an FDA-approved laser and an interstitial optical fiber. Preliminary results from the clinical trial demonstrated a mean prostate-specific

antigen decrease of 40.9% 1 month after treatment. Additionally, the first patient to undergo comprehensive treatment had no detectable cancer 3 months following the treatment [10]. Another hyperthermia treatment that completed a Phase I/II clinical trial (NCT01270139) for the treatment of coronary atherosclerosis incorporated silica-gold nanoparticles within a bioengineered patch that was grafted onto the epicardial myocardium [11]. The silica-gold particles were irradiated with a near-infrared laser

C. FROM BENCH TO BEDSIDE

344

FIG. 13.3

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

TEM image of magnetite nanoparticles (left). A solution of magnetite particles under the influence of a magnetic

field (right).

FIG. 13.4

Gold nanoshells that consist of a 120-nm silica core encapsulated with a 15-nm-thick gold shell.

7 days after administration. The first human trials demonstrated high safety levels and an increased percentage of survivors without the occurrence of a major adverse cardiovascular

event (94.3% vs. 90.5% with a stent control) (NCT01270139 and [11]). There are a number of hyperthermia-based dermatology products currently in clinical trials.

C. FROM BENCH TO BEDSIDE

13.5 REGULATORY STRATEGY FOR HYPERTHERMIA PRODUCTS

Sebacia (Atlanta, GA) has demonstrated the ultrasonic delivery of silica-gold nanoshells approximately 150 nm in diameter for the photothermolysis of sebaceous glands in humans [12]. When exposed to an infrared laser, thermal injury to the sebaceous gland permanently reduces oil production leading to an acne cure. Sienna Biopharmaceuticals is also in clinical trials for the selective photothermolysis of the hair follicle for the removal of unwanted hair using silica-coated silver nanoplates with resonant wavelengths purposely aligned to the most common dermatologic lasers found in clinics. The novelty of this treatment is its added capability to treat light or mixed-pigmented hair, which cannot be removed using a laser alone since a dark pigment in the hair is necessary for the laser energy to be absorbed and converted to heat. Magnetic particles that can be heated in vivo have been investigated for a wide variety of cancer therapies [13–15]. NanoTherm is a magnetic nanoparticle-based cancer treatment from MagForce (Berlin, Germany) that consists of an aminosilane-coated iron oxide magnetite (Fe3O4) nanoparticle, approximately 12 nm in diameter [14]. A clinical study was conducted in Finland for patients with recurrent glioblastoma multiforme. A magnetic fluid (MFL AS1) at a concentration of 112 mg/mL was administered to a study population of 59. The magnetic fluid was introduced to the tumor site using neuronavigational control, a procedure similar to a brain needle biopsy. When treatment was combined with fractionated stereotactic radiotherapy, the average life expectancy following initial diagnosis was 13.4 months, significantly longer than life expectancies featured in other glioblastoma studies [16]. MagForce has a CE mark to treat brain tumors with NanoTherm therapies in the EU. In the United States, AMAG Pharmaceuticals has produced a suspension of superparamagnetic iron oxide nanoparticles coated with a low molecular weight semisynthetic carbohydrate known as Feraheme. Feraheme has been approved for

345

human use for anemic patients who have an adverse reaction or prove unresponsive to oral iron supplements [17]. It has also been used offlabel as a vascular and nodal metastasis contrast agent [18]. A Feraheme solution heats in response to an alternating magnetic field, demonstrating its future utility for hyperthermia applications [19]. Targeted therapies using magnetic iron oxide nanoparticles for hyperthermia applications are still undergoing extensive research, but show promise as a method of increasing the localization of nanoparticles after injection [20].

13.5 REGULATORY STRATEGY FOR HYPERTHERMIA PRODUCTS The regulatory route a medical device or drug/device combination must undertake is dictated by its risk class. Class I devices are considered low-risk and require minimal regulatory controls. Class II devices are a moderate risk and require regulatory controls to ensure safety and effectiveness to mitigate risk. Class III devices have the highest level of regulatory controls which are deemed essential to controlling risk. The treatments currently in clinical trials from Sebacia and Sienna Biopharmaceuticals are classified as Class II devices. Nanospectra’s AuroLase cancer therapy is currently pursuing a de novo submission process as a Class II device, which recognizes that there is not a direct predicate device already approved as a Class II device, but claims that this is the appropriate risk classification for the product. One advantage of the device regulatory framework is that it provides a process for product development, and this process is broadly applicable to any type of medical device. From the perspective of the group developing the technology, this framework provides both the structure to ensure all regulatory needs are met and the flexibility to tailor the details of the development to suit the specific device. Based on the current trend of

C. FROM BENCH TO BEDSIDE

346

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

hyperthermia products classified and regulated as devices, the guidance provided throughout the rest of this chapter focuses on the device regulatory framework.

13.6 QUALITY MANAGEMENT SYSTEMS To comply with FDA or ISO regulations, a robust QMS ensures that each product or process is properly developed and documented. The purpose of a QMS is to control processes and procedures to ensure that the product conforms to all applicable medical device regulations. In addition, an effective transfer of the design to formal manufacturing following a structured, traceable, and reproducible methodology is critical to guarantee that all components of the drug or device can be manufactured successfully. A typical QMS will include procedures for the following: • • • • • • • • • • • • • • • • • •

Document control Product development Design review Design history file (DHF) Device master record (DMR) / manufacturing master record (MMR) Test protocols and reports Receiving and receiving inspection Supplier qualification and monitoring Purchasing controls Manufacturing controls and records Control of nonconforming material Control of monitoring and measuring equipment Product ID, traceability, and inspection status Equipment preventive maintenance Product labeling and packaging Sales order process, shipping, and distribution records Training process Analysis of data and corrective active and preventive action

• Internal and external audits • Complaint handling

13.7 CGMP AND DESIGN CONTROLS AS A FRAMEWORK FOR PROJECT SUCCESS The goal of cGMPs is to ensure that the proposed product is safe and meets the intended user needs. For medical devices, the Design Control process is a series of steps that are an important component of cGMP regulations and cover traceability of product development, manufacturing and test methods, and sourcing of raw materials. For hyperthermia applications, critical product metrics typically include clinical efficacy, patient comfort, duration and frequency of treatment, acute and chronic toxicity, cost of the injectable and associated external heating devices, and requirements of practitioner training. Ideally, the formal product development process generates not only a robust recipe for manufacturing but also provides a foundation for product success in the marketplace. The various stages of developing a device for commercial manufacture under formal design controls to establish a cGMP compliant commercial process are outlined in Fig. 13.5 and described in detail below.

13.7.1 Concept: Is This an Important Idea? Can It be Done? Will It be Worth It? The concept phase defines a series of objectives and a viable pathway for the product to be successfully commercialized. Throughout the development process, it is important to revisit the initial premise for the idea and to ensure that the manufacturing plan is in alignment with the overall goal. For hyperthermia applications, it is important to evaluate whether the proposed nanomaterial and application method are meeting the intended user need,

C. FROM BENCH TO BEDSIDE

13.7 CGMP AND DESIGN CONTROLS AS A FRAMEWORK FOR PROJECT SUCCESS

FIG. 13.5

347

Stages of cGMP and design controls for the development and commercialization of a medical device.

whether the treatment method and any associated side effects will be deemed accepted by both the user and regulatory bodies, and whether the proposed manufacturing methods will generate a safe and reproducible product. Understanding the proposed treatment method at an early stage is important to determine future product needs, such as storage conditions and shelf life requirements. As the development progresses, more accurate cost estimates of manufacturing at scale are obtained, and it is important to review initial assumptions to ensure that the product will be economically viable.

13.7.2 Research and Development: Is the Product Technically Feasible? Under most circumstances, any hyperthermia project that is transitioning into cGMP manufacturing would have undergone many years of R&D. The project would have had positive initial results that attracted additional interest and funding. The next step is the development of more robust manufacturing protocols to support future clinical trials. One of the challenges of transferring to cGMP manufacturing is that the process itself uncovers fundamental discrepancies that may require additional R&D. For example, during initial evaluation of scale-up feasibility it may become apparent that certain parameters are more costly

or challenging to execute at larger scales. These can include necessary mixing homogeneity, heating or cooling rates, timing for critical process points, and more. Any resulting inconsistencies can cause unintended and unwanted changes to key characteristics of the particle, such as size, shape, surface chemistry, or agglomeration state. The goal of additional R&D at this stage is to finalize process methods and product specifications to ensure that risks associated with technical feasibility have been mitigated. While product specifications are often altered at multiple points throughout the transfer to manufacturing process, there is a risk that data obtained with a previous version of the product may not be acceptable for submission to the relevant regulatory body. This is especially true with any changes that have the potential to impact user safety. Even seemingly insignificant changes to formulation or release criteria can lead to product differences with potential clinical significance.

13.7.3 Product Development: How Is the Product Going to Be Manufactured and Characterized? Once a target formulation has been identified, there is a need for a more formalized product development plan, which includes intended optimization steps, strategies for scale-up, and other product planning activities.

C. FROM BENCH TO BEDSIDE

348

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

A key element of the product development plan is the generation of the product specifications, otherwise known as the design inputs. The design input regulations within 21 CFR 820 are as follows: Each manufacturer shall establish and maintain procedures to ensure that design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. The procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements. The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s). The approval, including the date and signature of the individual(s) approving the requirements, shall be documented. Department of Health and Human Services [21]

Similarly, ISO 13485:2016 states, Inputs relating to product requirements shall be determined and records maintained. These inputs shall include: a) functional, performance, and safety requirements, according to the intended use, b) applicable statutory and regulatory requirements, c) where applicable, information derived from previous similar designs, d) other requirements essential for design and development, and e) output(s) of risk management These inputs shall be reviewed and approved. Requirements shall be complete, unambiguous, and not in conflict with each other. International Organization for Standardization [22]

The product development stage is where the formal aspect of design control begins. This is arguably one of the lengthiest stages as well as one of the stages most critical to the overall success of a product. It has been reported that the length of time for drafting and determining product specifications can be as much as 30% of a project’s overall timeline, and the failure of a product postmarket has a high probability of deriving from insufficient product specifications [23].

Product specifications typically include the following components: • • • • • • • • •

Product overview and product requirements Design characteristics/functionality Physical properties Storage and stability requirements Packaging and labeling requirements Safety requirements Reproducibility requirements Regulatory requirements Shipping requirements

All product specifications must be measurable and traceable to user needs. For hyperthermia applications, the product typically consists of a suspension of nanoparticles in a carrier fluid. R&D activities will have to identify optimal size and shape distributions of the particles, surface coatings that are efficacious in vivo, and particle concentrations that are appropriate for administration. The product specification requires the developer to create an objective method to characterize each aspect of a product, and these techniques are critical to the success of the product. There are many methods of characterization that can be performed to measure the most relevant characteristics for a given nanoparticle-based product. A main component of the product development stage is to determine which measurements are useful for information only (to help development) and which measurements should have stringent parameters set and incorporated into the batch records as acceptance criteria to be met for final product release. Table 13.1 outlines common particle characteristics and characterization techniques used. Another aspect of the product development stage is the investigation of the stability requirements. A unique challenge for nanoparticle suspensions is that accelerated aging, which utilizes elevated storage temperatures to predict shelf life, is not well established as a method for accurately predicting long-term stability. Thus, it is important to begin well-documented stability

C. FROM BENCH TO BEDSIDE

13.7 CGMP AND DESIGN CONTROLS AS A FRAMEWORK FOR PROJECT SUCCESS

TABLE 13.1 Common Particle Characteristics and Characterization Techniques That Are Used for Hyperthermia Product Specifications Particle Characteristic

Characterization Technique

Size and shape

Electron microscopy

Surface charge, isoelectric point

Zeta potential

Aggregation state

Dynamic light scattering

Optical properties

UV-visible spectroscopy

Particle concentration and product purity

Inductively coupled plasma mass spectrometry

pH

pH meter

Magnetic susceptibility

Magnetometry

Specific absorption rate

Thermocouple

studies as soon as a candidate formulation has been identified. One of the most critical tasks in the product development stage is evaluating potential process changes necessary to scale manufacturing. Fundamental nanomaterial fabrication and handling processes such as sonication, heating, mixing, and centrifugation are commonly used to prepare materials, but each comes with potential obstacles when moving to larger volumes. Sonication at small volumes is typically performed in a bath sonicator, which often has nonuniform sonication strength at different positions within the bath. At larger volumes, it is challenging to ensure that the entire solution is subjected to the same sonication forces present at a small scale. In many cases, performing additional development that reduces the need for sonication by finding methods or surface coatings that prevent particle agglomeration are recommended. If no solution can be found, flow-through sonication processes where the nanoparticles are not directly in contact with the transducer are recommended. Another challenge at large scale is heating and cooling the nanoparticle solution. For volumes greater than

349

5 L, the heating rate from a standard hot plate is much slower than what can be achieved at smaller scales, which can be detrimental to the synthesis. Insulation and heating mantles are a potential solution for medium-scale volumes, but if larger volume heating is necessary then specialized equipment such as double wall reactors, where a heat transfer fluid is pumped through the exterior chamber surrounding the reaction mixture, is necessary to achieve the correct temperature profile. For large-scale mixing, stir-bar mixing is often replaced with overhead stirrers, which must be carefully engineered to match the mixing elements with the dimensions of the container. A simple vortex is not an effective mixing method, so the mixing system should be designed to generate turbulent flow, which allows for any additives to be rapidly and effectively mixed [24]. For wash steps or concentration, centrifugation is often used at the bench scale. However, due to the limited volume capacity of most centrifuges and the time it takes to decant and resuspend pelleted nanoparticles, continuous flow filtration systems are preferred for larger volumes [25]. Hollow tubebased tangential flow filters are very effective at both concentrating and washing nanoparticle solutions. By varying parameters such as filter surface area, filter pore size, shear rates, and pressure, a wide variety of nanoparticle solutions can be effectively processed with low losses and minimal aggregation. The effect of these process changes should be evaluated as early as possible in the development process. For hyperthermia applications, sterility is also an issue, as the product will typically be designed for injection. If all components of the particle solution are less than 200 nm, terminal filtration with a 0.2 μm or less pore size filter is the most straightforward method to ensure that the material is sterilized. Alternatively, the solution can be autoclaved or gamma irradiated, however, depending on the type of particle and the particle surface, both methods can alter the particle characteristics. Chemical washes

C. FROM BENCH TO BEDSIDE

350

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

with ethanol and/or hydrogen peroxide, UV irradiation, and ethylene oxide or formaldehyde fumes are other potential methods for sterilization. Once sterilized, the nanoparticle solutions need to be packaged for delivery. This is typically performed in a clean room rated for aseptic handling. The easiest method to bring the material into the clean room is through a double pass filter. If this is not possible, then part of the synthesis and/or sterilization process may need to be performed within the cleanroom, adding to the complexity and cost of the synthesis.

13.7.4 Design and Development: What Is the Process to Reproducibly Manufacture the Product at Scale? At this stage of the development process, the manufacturing procedures and product specifications should be well defined. Subsequent tasks involve the identification of critical process points, implementation of a design freeze, and identification of failure modes and their effect on the product. One of the challenges of nanoparticle synthesis in particular is that seemly innocuous details such as glassware cleaning methods, addition rates, heating ramps, and reagent storage and handling can be critical for maintaining reproducibility; special consideration should be given to these items which may not be nearly so important in other chemical manufacturing processes. An approved suppliers list should be generated and secondary sources for reagents validated. Multiple lots of the scaled-up product are to be produced and lot-to-lot variability assessed. Robustness experiments are conducted to evaluate each step in the nanoparticle synthesis and formulation to determine which processing variables are most critical to achieving reproducible particle characteristics. Identifying which steps in the process are most sensitive will minimize potential manufacturing losses when fabricating at scale. Once a reproducible method has been identified, final product documentation

is drafted. Documentation should be written such that a reproducible and reliable product is produced each time, and all important parameters are recorded. Finally, a verification test plan should be developed that identifies standards and regulatory guidance documents that the product must abide by.

13.7.5 Verification: Did I Make This Product Correctly? Verification confirms that the developed fabrication methods result in a product that meets the product specifications. During the verification phase, the manufacturing process is repeated multiple times with different operators following controlled manufacturing methods with different sets of reagents. Included in the verification stage are reproducibility testing, cleaning validations, packaging and labeling verification, preproduction lots, the finalization of product specifications, final product storage, and stability and sterility testing protocols. This is also the stage in a product life cycle where regulatory submissions are typically initiated, a process that is complex and requires significant time to complete.

13.7.6 Validation: Did I Make the Correct Product? Validation is confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. Validation and verification are often intertwined but are sometimes incorrectly considered to be interchangeable terms. While both phases of development rely on similar processes, they produce separate results that meet separate expectations and regulations. Verification ensures that the product that has been developed meets the initial product specifications. Validation ensures that the product meets user needs. In other words,

C. FROM BENCH TO BEDSIDE

351

13.8 CONCLUSION

verification is “Did I make the product that I initially set out to make?,” while validation is “Did I make a product that meets the user needs I set out to fulfill?” There are two types of validation that need to be addressed for any given product. Process validation is the determination “by objective evidence that a process consistently produces a result or product meeting its predetermined specifications,” while design validation is the determination “by objective evidence that device specifications conform with user needs and intended use(s)” [21]. In other words, process validation ensures that the processes associated with a product are working, and design validation ensures that the product is achieving its designated purpose and meets the user needs identified earlier in the process. The resulting data from the validation stage is analyzed primarily to ensure that the product meets the product requirements, that is, the user needs. It also provides information on how effectively the process causes the product to consistently meet the product requirements, and what levels of variability cause the product to not meet the product requirements. For hyperthermia applications, validation activities will typically include clinical feedback, reports on risk management, confirmation that all the design inputs are being met in the final product, and a finalization of all associated documentation.

13.7.7 Design Transfer: Is My Product Ready to Be Introduced to the Market? Design transfer is the last step completed under design control, although it is initiated much earlier in the product development process. A key portion of design transfer is generating and transferring all documentation surrounding how to build and test the device— the Device Master Record (DMR)—from the development team to formal manufacturing. The preliminary version of the DMR is developed at design freeze and is updated as materials are

made for verification and validation. Design transfer is completed at the “final design review” which reassesses all the data gathered from the verification and validation stages to evaluate the established design and ensure that all problems encountered during these phases have been addressed. The Design History File and the Device Master Record are the primary components of the final design review that completes the design transfer. At this stage, the DHF will include the final product specification, all design verification and validation reports as well as risk management while the DMR will include Manufacturing Batch Records, Raw Material Specifications, Inspection and Test Instructions, Test Methods, Calibration Methods, Preventive Maintenance Instructions, Bill of Materials, and product documentation (Labeling, Instructions for Use, Safety Data Sheet, Certificate of Analysis, Certificate of Compliance). It is important that design transfer is conducted in parallel with other testing as well as through the various phases of clinical trials. At the completion of the final design review, the design transfer is concluded and the device is ready for commercial manufacture. After approval is obtained from all applicable regulatory bodies, the product will undergo postmarket surveillance, during which the product is monitored by the regulatory body after release into the market.

13.8 CONCLUSION The transfer of a nanomaterial to GMP manufacturing is a long series of steps that result in a robust, reliable manufacturing process that can consistently produce a device or drug that is efficacious while minimizing risk to the user. The production of nanoparticles for hyperthermia applications within the GMP and device control framework has unique challenges associated with the novel properties and behavior of nanoparticle formulations. The preparation of nanomaterials under GMP is, to date, a

C. FROM BENCH TO BEDSIDE

352

13. cGMPs IN DEVELOPMENT OF NANOMATERIALS FOR HYPERTHERMIA

relatively uncommon practice, so there is still much to learn about how GMPs are best applied to nanoparticle synthesis. While preparing a nanomaterial for manufacture under GMPs is a time-consuming and expensive process, that process ensures the developed hyperthermiabased treatment will safely and effectively provide a clear and substantial health benefit for the patient.

References [1] J. Mestre-Ferrandiz, J. Sussex, A. Towse, The R&D Cost of a New Medicine, Office of Health Economics Research Report, 2012. [2] J. Makower, A. Meer, L. Denend, FDA Impact on U.S. Medical Technology Innovation, Survey of 200 medical device companies, 2010. [3] European Parliament and Council of the European Union 2017 “Regulation (EU) 2017/745 of the European Parliament and of the Council”. [4] V. Grassian, A. Haes, I. Mudunkotuwa, P. Demokritou, A. Kane, C. Murphy, J. Hutchison, J. Isaacs, Y. Jun, B. Karn, S. Khondaker, S. Larsen, B. Lau, J. Pettibone, O. Sadik, N. Salehm, C. Teaguen, NanoEHS—defining fundamental science needs: no easy feat when the simple itself is complex, Environ. Sci.: Nano 3 (2016) 15–27. [5] N. Duran, S. Guterres, O. Alves, Nanotoxicology Materials Methodologies and Assessments, Springer, New York, NY, 2014. [5a] S.M. Hussain, L.K. Braydich-Stolle, A.M. Schrand, R.C. Murdock, K.O. Yu, D.M. Mattie, J.J. Schlager, M. Terrones, Toxicity evaluation for safe use of nanomaterials: recent achievements and technical challenges, Adv. Mater. 21 (16) (2009) 1549–1559. [5b] A.C. Eifler, C.S. Thaxton, Nanoparticle therapeutics: FDA approval, clinical trials, regulatory pathways, and case study. Methods Mol. Biol. 726 (2011) 325–338, https://doi.org/10.1007/978-1-61779-0522_21. [6] G. Baffou, Thermoplasmonics: heating metal nanoparticles using light, Cambridge University Press, Cambridge, 2017. [6a] S.J. Oldenburg, R.D. Averitt, S.L. Westcott, N.J. Halas, Nanoengineering of optical resonances, Chem. Phys. Lett. 288 (2–4) (1998) 243–247. [7] A. Giustini, A. Petryk, S. Cassim, J. Tate, I. Baker, P. Hoopes, Magnetic nanoparticle hyperthermia in cancer treatment, Nano Life 1 (2) (2010) 1–23. [8] C. Kumar, F. Mohammad, Magnetic nanomaterials for hyperthermia-based therapy and controlled drug delivery, Adv. Drug Deliv. Rev. 6399 (2011) 789–808.

[9] G. Pillai, Nanomedicines for cancer therapy: an update of FDA approved and those under various stages of development, SOJ Pharm. Pharm. Sci. 1 (2) (2014) 13. [10] J. Winoker, P. Shukla, M. Carrick, H. Anastos, C. Knauer, A. Tewari, B. Taouli, S. Lewis, J. Schwartz, J. Stern, S. Canfield, A. Rastinehad, Gold nano-particle directed focal laser ablation for prostate tumors using US and MR fusion technology, J. Urol. 197 (2017) 375–376. [11] A. Kharlamov, J. Feinstein, J. Cramer, J. Boothroyd, E. Shishkina, V. Shur, Plasmonic photothermal therapy of atherosclerosis with nanoparticles: long-term outcomes and safety in NANOM-FIM trial, Futur. Cardiol. 13 (4) (2017) 345–363. [12] D. Paithankar, F. Sakamoto, W. Farinelli, G. Kositratna, R. Blomgren, T. Meyer, L. Faupel, A. Kauvar, J. Lloyd, W. Cheung, W. Owczarek, A. Suwalska, K. Kochanska, A. Nawrocka, E. Paluchowska, K. Podolec, M. Pirowska, A. Wojas-Pelc, R. Anderson, Acne treatment based on selective photothermolysis of sebaceous follicles with topically delivered light-absorbing gold microparticles, J. Investig. Dermatol. 135 (7) (2015) 1727–1734. [13] M. Ban˜obre-Lo´pez, A. Teijeiro, J. Rivasa, Magnetic nanoparticle-based hyperthermia for cancer treatment, Rep. Pract. Oncol. Radiother. 18 (6) (2013) 397–400. [14] K. Maier-Hauff, F. Ulrich, D. Nestler, H. Niehoff, P. Wust, B. Thiesen, H. Orawa, V. Budach, A. Jordan, Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme, J. Neuro-Oncol. 103 (2) (2011) 317–324. [15] B. Thiesen, A. Jordan, Clinical applications of magnetic nanoparticles for hyperthermia, Int. J. Hyperth. 24 (2008) 467–474. [16] R. Stupp, M. Hegi, W. Mason, M. Van den Bent, M. Taphoorn, R. Janzer, S. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. Brandes, J. Gijtenbeek, C. Marosi, C. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J. Cairncross, R. Mirimanoff, Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol. 10 (2009) 459–466. [17] I. Macdougall, W. Strauss, J. McLaughlin, Z. Li, F. Dellanna, J. Hertel, A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency in anemia in patients with CKD, Clin. J. Am. Soc. Nephrol. 9 (2014) 705–712. [18] S. Vasanawala, K. Nguyen, D. Hope, M. Bridges, T. Hope, S. Reeder, M. Bashir, Safety and technique of ferumoxytol administration for MRI, Magn. Reson. Med. 75 (5) (2016) 2107–2111.

C. FROM BENCH TO BEDSIDE

FURTHER READING

[19] J. Bullivant, S. Zhao, B. Willenberg, B. Kozissnik, C. Batich, J. Dobson, Materials characterization of feraheme/ferumoxytol and preliminary evaluation of its potential for magnetic fluid hyperthermia, Int. J. Mol. Sci. 14 (9) (2013) 17501–17510. [20] A. Mukherjee, T. Darlington, R. Baldwin, C. Holz, S. Olson, P. Kulkarni, T. DeWeese, R. Getzenberg, R. Ivkov, S. Lupold, Development and screening of a series of antibody-conjugated and silica-coated iron oxide nanoparticles for targeting the prostate-specific membrane antigen, ChemMedChem 9 (7) (2014) 1356–1360. [21] Department of Health and Human Services, CFR— Code of Federal Regulations Title 21, (2017). Retrieved December 09, 2017, from www.accessdata.fda.gov. [22] International Organization for Standardization, ISO 13485:2016—Medical Devices—Quality Management Systems—Requirements for Regulatory Purposes, www.iso.org/standard/59752.html, 2016. [23] Speer, J. (2015). The Art of Defining Design Inputs and Design Outputs. Retrieved November 12, 2017, from https://blog.greenlight.guru/defining-design-inputsand-design-outputs.

353

[24] K. Myers, M. Reeder, J. Fasano, Optimize mixing by using the proper baffles, CEP Mag. 98 (2002) 42. [25] J. Robertson, L. Rizzello, M. Avila-Olias, J. Gaitzsch, C. Contini, M. Magon, S. Renshaw, G. Battaglia, Purification of nanoparticles by size and shape, Sci. Rep. 6 (2016) 27494.

Further Reading [26] L. Braydich-Stolle, E. Breitner, K. Comfort, J. Schlager, S. Hussain, Dynamic characteristics of silver nanoparticles in physiological fluids: toxicological implications, Langmuir 30 (50) (2014) 15309–15316. [27] G. Oberd€ orster, A. Maynard, K. Donaldson, V. Castranova, J. Fitzpatrick, K. Ausman, J. Carter, B. Karn, W. Kreyling, Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy, Part. Fibre Toxicol. 2 (8) (2005) 1–35.

C. FROM BENCH TO BEDSIDE