Combination products (see the “Definition” box) are experiencing steady growth in the pharmaceutical industry. According to one report, about 30% of products currently in development are combination products (1). Expanding interest in such products can be attributed to manufacturers’ need to generate new market value for current products that will soon lose patent, requirements for long-term patient care, pressure to reduce healthcare costs, and consumer interest in localized drug delivery with improved therapeutic effectiveness (2). During the 2008 fiscal year (the most recent performance report available) the US FDA’s Office of Combination Products (OCP) received 330 products for review. Regulatory flexibility and clarity, updated FDA guidances (e.g., see the “2009 Proposed Rule” box), and continued innovations in delivery mechanisms and formulations will continue to drive commercialization for combination products.

Center Designation and CGMPS

OCP does not regulate combination products but is responsible for designating an FDA Center (Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, or Center for Devices and Radiological Health) to provide premarket review and postmarket regulation. A product’s primary mode of action (PMA, defined by21 CFR 3) is used as the basis for that decision. The agency determines a product’s PMA, but manufacturers have the option of submitting a Request for Designation, providing information to support their products’ designation as a drug (CDER), biologic (CBER), or device (CDRH). Once a company knows the jurisdiction of its product, it can establish a CGMP program for manufacturing (as described in the “2009 Proposed Rule” box).

The FDA’s process was configured to provide some clarity about which CGMP requirements would be mandated and allow some regulatory flexibility. However, industry concerns remain. Conference presenters on this subject have expressed concern that designation using PM A does not take into account unique aspects of specialized products and worry that safety issues of constituent products will not be taken into consideration. Other manufacturers worry about overregulation. “The overarching issue is the delay in FDA approval,” says Steve Richter, PhD, president and scientific director at Microtest Laboratories. “If you are developing a product, your main concern is getting it to the market, and how you do that through FDA is something that can become a quagmire. We’ve experienced it a couple of times with regulatory submissions. They develop into major projects primarily because of FDA’s perceived requirements.”

International agencies may have requirements that differ from those of the FDA, including those for packaging, process validation, and product safety. Therefore, companies should establish manufacturing processes that comply with the strictest regulations for which they intend to seek approval. In some cases, companies should acquire certifications and accreditations that are relevant to their product’s technology category and in accordance with specific requirements in the region of their manufacture and distribution (e.g., ISO 13485 quality certification for medical devices in Europe) (3). Developing testing methodologies and procedures for each product is a collaborative effort among manufacturers, formulators, and device companies. “It’s a coordinated effort with us and our clients,” says Richter. “We work with the knowledge base and recommend testing requirements. We have to guide our clients in the validation of sterilization, whether it’s the traditional method or medical-device method, because some of the medical device methods are based on ISO documents that do not require end-product or end-lot sterility testing.”

Biologic–Device Combinations

Most biologic combination products are those that include a device for drug carry and release. Although an exhaustive examination of all biologic–device products is beyond the scope of this article, proven or promising technologies include prefilled injection systems, tissue engineering, and stents.

Prefilled syringe (PFS) and injector systems are the leading biologic-device combinations. Analog insulin prefilled devices are rapidly growing at 45% in the United States and 35% elsewhere (4). Current products offered in these formats include Simponi PFS or SmartJect autoinjector (subcutaneous injection of golimumab, Centocor Ortho Biotech, a subsidiary of Johnson & Johnson); Humira pen autoinjector (subcutaneous injection of adalimumab); Enbrel (etanercept); and Cimzia (certolizumab pegol, as a PFS only). The number of such products is expected to grow, especially in generic biologics. In July2010, fouryears after the original submission, the FDA approved the first generic biologic: Momenta Pharmaceutical ‘s M-Enoxaparin, a version of the blood thinner Lovenox (Sanofi-Aventis), which is offered as a PFS. It will be interesting to see whether this is just the beginning of a surge of similar products when more than $30 billion worth of brand-name drugs will lose patent protection in 2012. The composition, design, and manufacture of future primary packaging components for combination products will have a direct effect on the quality of such products as biotherapeutics.

A wide range of PFS and autoinjection systems are commercially available, and the market life of anyone of them lasts only as long as it keeps pace with patient needs. W hen working on a new delivery system or changing from a PFS to an autoinjector, manufacturers should focus on “ human-centered ” designs (ergonomic, patient comfort, and ease of use) and consider having the ability to both own and partner delivery device platforms to support their biologic portfolios (4,5). Properties of the drug formulation can also affect product design. High-concentration MAbs are more likely to aggregate in a PFS or autoinjector, and a formulation’s viscosity and stability should be taken into account when determining injection time and force, needle gauge, injector size (volume), and refrigeration time (4).

DEFINITION OF A COMBINATION PRODUCT

Combination products are defined in 21 CFR 3.2(e). The term combination product includes

• A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
• Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
• A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose
• Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
  So by definition, a drug–drug, biologic–biologic, or device–device does not constitute a combination product.

The traditional material for PFSs is Type I borosilicate glass. Alt
hough plastic was common in older (about 20years) devices, the type of plastic used did not provide the qualities (e.g., clarity) that manufacturers and patients demanded. However, newer plastic materials have since been developed that offer some advantages over traditional materials (e.g., BD’s Sterifill SCF, Baxter’s Clearshot, and West Pharmaceutical/Daikyo’s Crystal Zenith). In addition to being impact and breakage-resistant, most new plastic PFS devices are free of silicone oil, and (unlike some glass PFS devices) their processing includes no use of tungsten. Both silicone oil and tungsten have been shown to interact with sensitive formulations, leading to aggregation that can compromise a user’s immune system.

Silicone oil is used for lubricating glass PFS cartridges, barrels, and stoppers. Prolonged exposure of some protein formulations to silicone oil may cause aggregation and particle formation during storage and delivery or from contact of these surfaces (6) Silicone oil contamination of protein formulations has been studied for more than 20years (one of the first incidents involved “cloudy” insulin in plastic syringes) (7). However, researchers continue to seek an understanding of how the oil directly affects intermolecular interactions with protein surfaces (or indirectly through effects on formulation solvents). Studies have shown negative effects on protein and emulsion stability and loss of soluble protein (6,8). Aggregation of protein molecules can create product instability. Some people have suggested alternatives to silicone oil, but most proposed materials have also proven to cause MAb aggregation, the extent of which can vary with changes in agitation, temperature, and pH (8).

The effects of tungsten on PFS formulations have been attributed to tungsten oxide vapor deposits in a syringe funnel and shed from heated tungsten pins used to produce the channel through which a needle is mounted (9,10). Studies have shown that vacuum stopper placement processes can significantly affect the total amount of tungsten in solution. Researchers have also shown that levels of residual tungsten can be lowered with improved syringe barrel forming and washing (9).

Manufacturers of PFS components have developed methods to help reduce interaction between sensitive drug products and substances from stoppers, including “high-purity” formulations with low levels of extractables (e.g., Stelmi’s Ultrapure 6901 formulation). In addition, state-of-the-art process operations are incorporating online vacuum filling and stoppering (e.g., Hyaluron/AMRI’s Bubble-Free system) and high-speed vacuum filling within restricted access barriers (Althea Technologies’ Inova H3-5 filling line). Filling under a vacuum minimizes headspace in the chamber. Oxygen-sensitive products such as proteins exposed to oxygen in the headspace are at risk of stability and potency loss, discoloration, and changes in toxicity.

2009 PROPOSED RULE ON CGMPs FOR COMBINATION PRODUCTS

The FDA’s proposed rule on CGMPs for single-entity and copackaged combination products was drafted to establish a “transparent and streamlined” framework for their manufacture (currently no separate set of regulations) (29). The draft guidance was completed in 2004. However, instead of proceeding to a final guidance, the agency created a proposed rule in 2009 that would create a new 21 CFR Part 4 that would determine which regulations would apply. Each part of a product (drug, device, biologic) retains its individual regulatory status, and the requirements for each apply when that constituent is part of the combination product. So for a biologic–device combination, a manufacturer would comply with both the CGMPs for the biologic (21 CFR Parts 600 to 680) and the quality system preparation (QSR) for the device. In addition, the combination product as its own identity is subject to regulation overview.

To help prevent duplicate compliance efforts, the FDA allows manufacturers to elect a “streamlined approach.” They must demonstrate that its operating system is in “primary compliance” with either the CGMPs for the drug or the QSR for the device plus compliance with “selected provisions” (specified in the proposed rule) from the other regulation. However, if a constituent is manufactured in a separate facility, then the compliance requirement for that constituent applies and the streamlined approach does not apply. The proposed rule states that “an HCT/P that is a constituent part of a combination product will be regulated as a drug, device, and/or biological product. Further, because all biological product constituent parts meet the definition of drug or device, all HCT/P constituent parts of a combination product regulated as a biological product also meet the definition of a drug or device.”

Tissue engineering is a newer opportunity for combining biologics and devices to achieve localized delivery. Growing and expanding tissues in vitro from donor cells requires four components: (stem) cells, a matrix (scaffold made of collagen or polymers), a bioreactor, and cytokines (polypeptides that bind cell-specific receptors in cell membranes of target cells to trigger a response) (11). The process involves loading a biodegradable scaffold with cells and cytokines and expanding these in a bioreactor. The loaded scaffold is then aseptically processed, preserved, and packaged, and the final product is implanted in or applied on a patient.

The OCP has worked to clarify designation of allogeneic and autologous products as well as define their classification as human cells, tissues, and cellular-or tissue-based products (HCT/Ps). During the past decade, there has been some debate about the PMA of HCT/Ps. If the PMA of a matrix-cell combination is cellular, some researchers have argued that its designation should be CBER, whereas if the primary action is the matrix, then the designation should be with CDR H (12).

HCT/P combination product categories include

• demineralized bone combined with handling agents (e.g., glycerol, sodium hyaluronate, calcium sulfate, gelatin, collagen
• bone–suture–tendon allografts
• cultured cells (e.g., fibroblasts/keratinocytes/nerve/ligament/bone marrow) on synthetic membranes or combined with collagen
• encapsulated pancreatic islet cells.

Manufacturers of HCT/Ps have sought guidance about whether their specific products would be regulated as drugs, devices, or biologics — or whether they would be regulated under section 361 of the US Public Health Service Act (and applicable regulations in 21 CFR Part 1271). To this end, the FDA established criteria for an HCT/P to be regulated solely under the PHS Act Section 361. Such a product must

• be minimally manipulated (defined in a 2006 jurisdictional update) (13)
• be intended for homologous use only (as reflected in the labeling, advertising, or other indications of the manufacturer’s objective intent)
• not be combined with a drug or device (except for water; crystalloids; or a sterilizing, preserving, or storage agent — provided that such addition does not raise new clinical safety concerns with respect to the HCT/P)
• not have a systemic effect or be dependent on the metabolic activity of living cells for its primary function except if for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use.

The agency also clarified jurisdiction of devices used to process HCT/Ps (14). According to the the FDA, “Devices intended to process HCT/Ps ex v
ivo to create a therapeutic article, that is, products where the intended therapeutic effect is mediated by the biologic output of the device, have been assigned to CBER.” Such devices include cell sorters used at the point of care to isolate or concentrate autologous stem cells or hematopoietic progenitor cells for in vivo use. In its 2009 proposed rule, the FDA described requirements for combination products that include an HCT/P (see the “2009 Proposed Rule” box). In addition, representatives of the Office of Cellular, Tissue, and Gene Therapies (part of CBER) have given presentations about the regulation in regenerative medicine combination products, including cell-scaffold elements (15).

Current tissue engineering and regenerative medicine products (in various stages of development) include

• Dermagraft (Advanced BioHealing) treatment for diabetic foot ulcers; a bioengineered skin substitute composed of human fibroblast cells embedded in a bioabsorbable mesh; currently regulated as a medical device under CDR H (3)
• Infuse (Medtronic) for multiple treatments such as spine fusion and open tibia fractures; a bone graft consisting of recombinant BMP-2(rhBMP-2) protein and a collagen sponge–based carrier; currently regulated as medical devices under CDR H
• Apligraf (Organogenesis) cultured fibroblasts and keratinocytes on bovine collagen
• OP-1 Implant (Stryker Biotech) rhBMP-7 regulated by CDRH
• GEM 21S(rhPDGF) (Biomimetics), a regenerative orthobiologics product for musculoskeletal injuries and diseases; based on a synthetic form of PDGF
• Epicel (Genzyme Biosurgery) cultured epidermal autograft using a patient’s own keratinocytes; skin cells are grown on irradiated mouse cells (the first enotransplantation classified product to be approved in the United States), approved in 2007 and regulated as a device.

Stents for gene delivery and transfer are in early stages of research but show some promise as possible combination systems. Drug-eluting stents for small molecules have been successful combination products. Gene-eluting stents and catheters have been assessed in animal-model studies investigating treatments for coronary artery disease. They have been used to deliver transgenes to inflammatory cells, adenoviruses, and plasmid DNA. Endovascular stents provide localized, prolonged, and controlled release of vascular gene therapeutics into blood vessels. Critical attributes of a stent include its retention of axial and radial mechanical strength; drug load capability; biocompatible coatings (e.g., PLGA, collagen, polyurethane), which must have the ideal binding properties; release kinetics; and vector capacity. Researchers have modified the surface of stents using polyethylene oxide to improve hydrophilicity and water uptake as well as facilitate functionality as drug carriers (e.g., intravascular stents for carrying recombinant adenovirus vectors to the vessel wall (16,17).

A nasal drug delivery system consists of a biologic and a nasal-spray device. Benefits of nasal delivery can include ease of administration, delivery to a large surface area with a large lymphatic and vascular network, and bypass of first-pass (presystemic) metabolism. Nasal epithelial tissue allows permeability of large molecules. Two major limitations to nasal delivery for proteins and peptides are mucosal irritation and low bioavailability(18). Biological products/candidates for nasal delivery include

• calcitonin (brand name Fortical, Miacalcin) for brittle bone disease
• oxytocin hormone (brand name Syntocinon) recently found to help autistic patients (19)
• luteinizing-hormone–releasing hormone (LHRH) agonists deslorelin, buserelin, and nafarelin; a 2009 study explored the use of “surface-functionalized ” deslorelin polystyrene nanoparticles to enhance the transport of macromolecules (>3.5 kDa) across the nasal epithelium (20,21).
• CP024 nasal spray of human growth hormone developed with an absorption promoter (Critical Pharmaceuticals); in November 2010, the company announced positive preclinical results
• nasal sprays for beta interferons (beta-1a tradename Rebif and beta-1b tradenames Betaseron and Betaferon) from Nerveda and Aegis Therapeutics; in January2009, the companies announced positive preclinical results for the treatment of multiple sclerosis (22).

Microneedle delivery patches for both insulin and vaccines are being developed as possible alternatives to PFS and autoinjectors. Microneedles have been shown to successfully deliver insulin in animal-model studies. Emory University started a clinical trial in September 2008 (scheduled for completion in early2011) to determine whether microneedles can “effectively and painlessly” deliver insulin to children and young adults with type 1 diabetes (bolus delivery to a depth of 23). In separate study, Emory University and Georgia Institute of Technology scientists completed a proof of concept on two adults with type 1 diabetes showing that microneedles inserted 1 mm within the skin “ led to rapid insulin absorption” and reduced glucose levels and postprandial glucose levels (24).

Researchers at Georgia Institute of Technology are also developing a microneedle patch for influenza vaccine delivery. Their goal is to help increase the number of those vaccinated and improve immunogenicity. They achieved promising results both using metal microneedles coated with the H1N1 virus vaccine and with dissolving polymer microneedles that encapsulated the H1N1 virus vaccine (25). Similar results were found with seasonal influenza B and H3N2; virus-like particles against H1, H5 (avian), and H1N1; and DNA vaccines against H1 and H5 influenza.

Nanotechnology-generated biologic–device combinations maybe future delivery vehicles that incorporate microelectronics, microsensors, biomarkers, and bioinformatics. Researchers have begun discussiing these tools for the treatment of cancer (26). The US National Science Foundation has predicted that nanotechnology will produce half the pharmaceutical industry’s product line by2015 (27). The OCP participates in the Interagency Task Force on Nanotechnology and in its 20 08 Performance Report stated that the “FDA expects that many future nanotechnology products will be combination products. The OCP continues to provide assistance in development of policy for these innovative products through the Nanotechnology Task Force and other nanotechnology-related activities.”

Drug –Biologic Combinations

There are a few biologic-drug combinations offered either as one product or copackaged for the same intended use. Several research studies for possible products are focusing on cancer treatments. The FDA has expedited review of biologics when shown to be effective in combination therapies. For example, in 2004, the agency approved Erbitux (ImClone Systems) to treat colorectal cancer. The recombinant, human/mouse chimeric monoclonal antibody targets and binds to epidermal growth factor receptor (EGFr, expressed in >35% of all solid malignant tumors), there by inhibiting the binding of EGF and other ligands. The biologic was approved both as a monotherapy and as part of a combination therapy with the drug irinotecan. In 2002, Erbitux (then referred to as IMC-C225) proved to be effective when used in combination with iriniotecan (referred to as CP T-11) (28). In March 20 06, the FDA approved it (generic: cetuximab) as the first head and neck cancer treatment in 45years (combined with radiation therapy, reportedly
prolongs survival of patients with squamous cell cancer of the head and neck).

Future biologic–drug combinations may come from a wide range of current studies involving “ drug cocktails,” therapeutic combinations of several drugs to treat serious illnesses such as late-stage cancer. In December 2010, the FDA released a draft guideline for such multidrug treatments that may help accelerate development and streamline review of drug–biologic combination therapies. Companies currently developing such therapies include Roche, Pfizer, Merck & Co., AstraZeneca, Novartis, and GlaxoSmithKline Plc.

COMPANIES MENTIONED HEREIN

Microtest Laboratories (www.microtestlabs.com)
Centocor Ortho Biotech (www.centocororthobiotech.com)
Momenta Pharmaceuticals (www.momentapharma.com)
Sanofi-Aventis (www.sanofi-aventis.us)
BD (www.bd.com)
Baxter (www.baxter.com)
West Pharmaceutical Services (www.westpharma.com)
Stelmi (www.stelmi.com)
Hyaluron/AMRI (www.amriglobal.com)
Althea Technologies (www.altheatech.com)
Advanced BioHealing (www.abh.com)
Medtronic (www.medtronic.com)
Organogenesis (www.organogenesis.com)
Stryker Biotech (www.stryker.com)
Biomimetics (www.biomimetics.com)
Genzyme Biosurgery(www.genzyme.com/business/biosurgery/biosurg_home.asp)
Critical Pharmaceuticals (www.criticalpharmaceuticals.com)
Nerveda (private company)
Aegis Therapeutics (www.aegesthera.com)
ImClone Systems (www.imclone.com)

Author Details
Maribel Rios is managing editor of BioProcess International, 1574 Coburg Rd. #242, Eugene, OR 97401; 1-646-957-8884; mrios@bioprocessintl.com.

REFERENCES