Dr Steven Richter, president and cso of Microtest Laboratories Inc, looks at the regulatory and validation challenges posed by combination drug and medical device products.
The market for combination products – medical devices embedded with pharmaceutical or biologics components – is moving forward with a new direction and emphasis regarding product safety and FDA requirements. Navigant Consulting estimated the market at US$5.9bn (€4.7bn) in 2004 and forecast a 10% compound annual growth rate that will see the market reach $9.5bn (€7.5bn) in 2009.
The FDA received 275 combination product submissions in 2005; according to one survey, an estimated 30% of new devices under development are “combo” products. At the forefront is a new crop of experimental heart stents that have been filed with the FDA. The Abbott Labs “absorb” product represents a significant change to existing drug eluting stent technology. Along with new breakthrough technologies like absorb, FDA regulatory centres are struggling with the changes and challenges that these new technologies pose.
For manufacturers, the convergence of drugs/biologics and devices also brings a host of regulatory challenges. One such challenge focuses on the struggle to address a host of testing guidelines, practices and regulations unique to the development and production of combination products. A pharmaceutical article recognised in the official USP, NF, or any supplement is intended to diagnose, cure, mitigate, treat or prevent disease in man or other animals. It also is intended to affect the structure or any function of the body of man or other animals and is intended to be used as a component of any articles specified above but not including devices.
A device is defined as: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar article which is recognised in the USP/NF, intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment or prevention of disease in man or other animals or intended to affect the structure of any function of the body of man or other animals.
A biological product means any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of disease or injuries of man. A combination product has a drug/biologic component and medical device component. An example of this product is the drug-coated stent used for coronary angioplasty (Boston Scientific, Abbott or Johnson and Johnson). In this case, there are actually two medical device components. One is the balloon delivery system that creates the pressure to push the plaque in coronary arteries out to the edges to increase blood flow. There is also the stent, or a wire mesh tube, that is designed to keep that plaque from collapsing back into the artery. Impregnated in the stent is the drug component that is designed to inhibit plaque formation.
Interest in combination products is surging among both medical device and pharmaceutical manufacturers as the industry and the medical community mature. There is a growing realisation among both groups of the therapeutic benefits of putting a drug into a medical device and providing it as a combination unit – and using the resulting product to deliver drugs directly to certain areas of the body, often with dramatic results.
For example, many pharmaceutical companies are evaluating the potential of single dose types of devices. In the case of the syringe dosing market, a physician can grab a pre-filled unit dose syringe and use it, rather than wasting time with preloading. In addition, the loading procedure may give rise to bacteria entering and contaminating the patient.
The dynamics of combination products offer several advantages. They include safety or quality in terms of controlling the dosage – which might otherwise vary if loaded individually by physicians. There is greater peace of mind for the patients, who will see they are getting a self-contained sterile dose rather than something taken or mixed from a larger supply. There is an added efficiency for the physician and hospital in terms of labour, dispensing, inventory control and billing. And there is a corresponding element of economics. With these benefits, the pharma-ceutical companies are eagerly opening a new market.
In the US, the FDA’s Office of Combination Products (OCP) will determine the primary mode of action (PMOA) for the product. Generally, if the device is for drug delivery, then the Center for Drug Evaluation and Research (CDER) will be the governing centre. If the device is used to open vessels, but has a drug coating to impart some secondary preventive action, then it is governed by the Center for Devices and Radiological Health (CDRH).
The Center for Biological Evaluation and Research (CBER) would be involved with a device component/biologic that is also some sort of drug delivery system (implantable encapsulated tissue constructs). All have a responsibility to determine scientifically if the manufacturer has proven beyond a doubt that the product is safe and efficacious. Mike Treadway at The Tech Group, a division of West Pharmaceuticals, Scottsdale, Arizona, spoke about the challenges of combination products in a recent report. He noted that because this is a combination device, one of the biggest challenges is making sure that the quality systems are in place and compliant with regulatory requirements. The Tech Group is manufacturing the insulin multidose inhaler, Exubera, for Pfizer.
The combination product regulatory framework requires a unique perspective on both medical devices and pharmaceutical/biologic. The dichotomy between Drug GMPs (21 CFR 210/211), Biologics Product Standards (21 CFR 610) and medical device QSRs (21 CFR 820) is immutable. A combination product manufacturer must have a robust pharmaceutical GMP system in place that addresses some of the issues with the device QSRs. The main regulatory foundation must be the drug GMPs. These regulations cover the following issues:
Batch records: • OOS/Excursions on filling operations • Environmental microbiology data • Microbiological contamination
QC drug release criteria • Emitted dose • Content uniformity • pH, colour and appearance • Particulate • Excipient concentration • Preservative concentration • Microbiological data (sterility, bioburden) • Container integrity • % label claims • Purity • Active concentration • Stability programmes (ICH Guidelines) • Storage and shipment
Biologics • PAT/DOE attributes • Cell-based therapeutics • Source material characterisation: cultures/animals etc. • Viral inactivation studies: orthogonal approach • Mycoplasma studies • Sterility • Surface markers • Secreted proteins • Scaffolding material characterisation and biocompatibility (tissue grafts) • Isoelectric focusing • Southern Blot testing • Ligand binding assays • Protein content and characterisation.
Manufacturers may be required to comply with foreign compendia methodology when harmonisation has not been successful. The EU requires a certification by a qualified person (QP) prior to clinical trial material (CTM) studies in the European Community.
Medical device regulations are concerned with design review and ISO documentation that may not be part of a drug GMP programme. The ISO certification may be required for shipment into the EU. The short list is as follows: • Design review • Quality systems requirements • ISO 13485 requirements •l ISO 9000 requirements
Drug regulations are shifting from product to process, according to the Process Analytical Technology (PAT) approach taken by CDER/CBER. The PAT approach is to test drug/biologics products in real time, inline, and effectively determine the acceptability of the lot prior to release testing. One can see the value in stopping a process that is inheritably OOS. The value in drug product manufacturing is multi-dimensional from a validation perspective. A large value is dependant upon the ability to validate a process and demonstrate its robustness and reproducibility over time. The PAT initiatives emphasising quality by design (QbD) and design of experiments (DOE) strategies are associated with FDA requirements. QbD is an important tool to identify the correct information needed to demonstrate robustness and process control. These analytical technologies will be the driving forces for validating critical process controls used in the manufacture of drug/biologic products.
The combination product manufacturer’s largest challenge will be during the scale-up process because additional quality control (QC) measures are required to determine process scale-up parameter shift. During scale-up, combination products should be under additional QC pressures along with a robust release testing programme. New technologies will require operations that are proven within acceptable ranges based on process scale-up and manufacturing limitation regarding device technology and delivery. Risk analysis tools and Failure Mode and Effect Analysis (FMEA) methods are required during scale-up and validation procedures. These tools help establish key critical risk factors that could create safety and quality issues during manufacturing. They can be an integral part of a robust PAT programme whereby the real-time decision to reject or salvage a valuable raw material can be determined.
Combination biologic products create new dichotomies in terms of scale-up and marriage downstream during manu-facturing. Scale-down processes are needed to determine if critical attributes are measured during the DOE phases of a robust quality attribute programme.
Cell-based therapeutics create unusual challenges for both the practitioner and the FDA. Characterisation of the source material is regarded as one important requirement for safety considerations due to the inherent variability in the source material.
Sterilisation of combination products can be problematic due to drug/biologic and sterilant incompatibilities. Radiation and ethylene oxide sterilisation cycles may degrade drug/biologic characterisation and potency. Impurities may increase due to these harsh process parameters. Aseptic processing (coating drug products) can be an alternative to final product sterilisation using radiation or ethylene oxide gas. A dry heat sterilisation process can be an option for most small molecule combination products. When it comes to developing robust analytic systems for combination products, the device manufacturer’s knowledge base will be challenged in their ability to manage a regulated drug product and follow CMC controls. While none currently exists, the FDA will issue guidelines specific to combination products and the result will be increased cGMP regulatory action that affects both laboratory and manufacturing.
We expect this guideline will incorporate both PAT and DOE requirements regarding both small molecule and large molecule process design and scale-up. The medical device component and molecular inter-actions regarding delivery or disease integration will be more important as biologics enter. Cell-based therapeutics and stem cell issues will create new challenges for both the manufacturer and the FDA.
Contact Steven Richter President and Chief Scientific Officer Microtest Laboratories Inc .(JavaScript must be enabled to view this email address) www.microtestlabs.com