A separate Office of Combination Products (OCP) was established in 2002 to develop regulatory guidelines and compliance systems for products that combine two or more product types.
It can take hundreds of millions of dollars of research and development, significant funding for clinical trials, and an extensive amount of time to even reach the stage of seeking FDA approval. The regulatory process itself can also be time-consuming as the FDA reviews the volumes of materials and data a company submits in support of its application for approval
This addresses moisture gain or loss in the package, evaluating extractables and leachables from and to the package, providing full chemical composition of the materials via Drug Master Files (DMF), and a completely different set of product stability requirements. All these requirements may be found in CBER Guidance for Container Closure Systems for Packaging Human Drugs and Biologics, CDER Guidance for Stability Testing of Drug Substances and Drug Products, and USP 661,” a characterization test on plastics. Typically, stability testing on three different batches of packaging materials is performed.” Packaging materials are involved in some instances because some of these products need to be sterile, so how does that have an impact? Previously, maybe you put a device in a package and sterilized the whole thing. Maybe now you’re not able to do that because it has a drug.”
What is a Drug Eluting Stent? <ul><li>A drug-eluting stent (DES) is a coronary stent (a scaffold) placed into narrowed, diseased coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots (thrombus), could otherwise block the stented artery, a process called restenosis. The stent is usually placed within the coronary artery by an Interventional Cardiologist during an angioplasty procedure. </li></ul>
DES and Bare Metal Stents <ul><li>Drug-eluting stents in current clinical use were approved by the FDA after clinical trials showed they were statistically superior to bare-metal stents (BMS) for the treatment of native coronary artery narrowings, having lower rates of major adverse cardiac events (MACE) (usually defined as a composite clinical endpoint of death + myocardial infarction + repeat intervention because of restenosis) </li></ul>
Restenosis <ul><li>Historically, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth. To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall. While initial efforts were unsuccessful, it was shown in 2001 that the release (elution) of drugs with certain specific physicochemical properties from the stent can achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects. As currently used in clinical practice, "drug-eluting" stents refers to metal stents which elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent restenosis. </li></ul>
Drug Eluting Stents <ul><li>Stents have 3 components: </li></ul><ul><ul><li>Stent </li></ul></ul><ul><ul><li>Drug Delivery Vehicle </li></ul></ul><ul><ul><li>Drug </li></ul></ul>
History <ul><li>The first successful trials were of sirolimus-eluting stents. A clinical trial in 2002 led to approval of the sirolimus-eluting Cypher stent in Europe in 2002. After a larger pivotal trial (one designed for the purpose of achieving FDA approval), published in 2003, the device received FDA approval and was released in the U.S. in 2003. Soon thereafter, a series of trials of paclitaxel-eluting stents led to FDA approval of the Taxus stent in 2004.The Xience V everolimus eluting stent was approved by the FDA in July 2008 and has been available in Europe and other international markets since late 2006. It is an investigational device in Japan. </li></ul><ul><li>Stents quickly became the fastest-selling medical devices in recent history after their introduction in 2003. However, questions about the devices' safety compared with bare-metal stents slowed growth beginning in 2006. </li></ul>
A Brief History on Stenting <ul><li>The concept of the stent grew directly out of interventional cardiologists' experience with angioplasty balloons in the first decade of use (1977-87). </li></ul><ul><li>Sometimes the wall of the coronary artery became weakened after balloon dilatation. Although the artery would be opened successfully using a balloon, in a small percentage of cases, the artery would collapse after the balloon was deflated -- sometimes this might not happen until the patient had been moved to the recovery room. </li></ul><ul><li>Since there was no interventional "fix" available, the only option for this patient was emergency bypass graft surgery to repair the problem. </li></ul>
The Challenges of Packaging Combination Devices & the Effect of Balloon Material Property on the Life of the Drug Eluting Coronary Stent (DECS) Structure
Packaging Combination Devices <ul><li>The role of medical packaging is to deliver a clean, sterile, protected medical device to the point of use and to allow aseptic presentation. </li></ul><ul><li>The package not only has to meet the needs of the stent, but also the needs of the drug incorporated into its polymer coating. </li></ul><ul><li>The package has to allow the transfer of ethylene oxide gas for sterilization, but when in storage, must provide a barrier to keep out moisture and oxygen. </li></ul>
Packing Combination Devices <ul><li>For combination products, the fundamentals of medical packaging still apply, but there are new challenges facing the packaging designer involving not only protecting the device , but also maintaining the safety and effectiveness of the drug or biologic. </li></ul><ul><li>The designer must consider what affects there may be on the drug/biologic internal environment: </li></ul><ul><li>+ Biocompatibility </li></ul><ul><li>+ Photostability </li></ul><ul><li>+ Moisture sensitivity (hydrolysis) </li></ul><ul><li>+ Reaction to gases (oxygen) </li></ul><ul><li>to prevent from Oxidation </li></ul><ul><li>+ Temperature stability and its </li></ul><ul><li>effect on the safety and effectiveness </li></ul><ul><li>of the drug product </li></ul>
DES Packing Protection & Stability Testing <ul><li>The packaging MUST be compatible with the method of sterilization and should protect the device during handling, distribution and storage. </li></ul><ul><li>The purpose of stability testing is to provide evidence on how the quality of a drug product varies with time under the influence of a variety of environmental factors, to establish a retest period for the drug substance, and/or a shelf life for the drug product and recommended storage conditions . </li></ul>
Study of Effect of Balloon and Stent-Balloon Friction <ul><li>The presence of balloon in the delivery system creates the partial loading of the stent. </li></ul><ul><li>Balloon used to deploy cardiovascular stent is actually folded inside the crimped stent before its deployment. </li></ul><ul><li>Stents are mounted over a balloon at the tip of the catheter before deployment. </li></ul><ul><li>Pressure is applied internally to inflate the balloon as well as the stent. </li></ul><ul><li>The balloon is removed and the stent is implanted in the vessel </li></ul>How is the Coronary Stent Implanted?
Development of DES Packaging Material <ul><li>The foil material is a white multilayer structure consisting of biaxially oriented polyamide, aluminum foil and a peelable sealant. </li></ul><ul><li>DES packing employs TWO separate pouches: </li></ul><ul><li>+ Primary Sterile Pouch (nylon): </li></ul><ul><li> - allows ethylene oxide sterilization (EtO) which has a porous membrane to allow gas flow during the sterilization cycle. </li></ul><ul><li>+ Secondary Non-sterile High Barrier Pouch (aluminum foil): </li></ul><ul><li> - have excellent barrier properties that protects the stent’s drug coating from oxygen and moisture during its packaged shelf life. </li></ul><ul><li>Packing Steps: </li></ul><ul><li>+ After sterilization, the primary pouch containing the DES is placed inside the secondary pouch, which is gas flushed with a nonreactive gas such as nitrogen, and then sealed. To sequester any residual oxygen and moisture, a desiccant/oxygen scavenger may be used. </li></ul><ul><li>Aseptic Presentation & Easy Opening </li></ul><ul><li>To allow easy access to the DES, the foil has a peelable sealant and a “corner opening” feature is designed into the seal profile. </li></ul>Seal Configuration Opening Feature
Challenges: Risk Free Supply <ul><li>Apart from the obvious and serious requirements that medical packaging should ensure absolute safety, there is also financial risk because of the high cost of the device. One DES costs approximately US$3000 compared with US$1000 for a bare metal stent. </li></ul><ul><li>It is estimated that in the sterilization </li></ul>chamber there could be as much as US$10 million worth of stents. If for some reason the packaging fails, the DESs cannot be re-sterilized . It is therefore important that the pouch is produced using the highest possible “ risk free” manufacturing standards.
References <ul><li>http://www.mayoclinic.com/health/drug-eluting-stents/HB00090 </li></ul><ul><li>http://www.americanheart.org/presenter.jhtml?identifier=3043941 </li></ul><ul><li>http://www.devicelink.com/mddi/archive/08/10/002.html </li></ul><ul><li>http://www.ptca.org/news/2008/0702_XIENCEV.html </li></ul><ul><li>http://www.persiabme.com/articles/view.asp?id=48 </li></ul><ul><li>***** We all should have only one references slide…I just listed them so we can include them in our final presentation </li></ul>
The Broad Medical Device Industry Medical Device Testing Electronic Components Metal Components Biomedical Engineering Plastics Components Research Packaging Post-processing
Different Regulatory Requirements <ul><li>Combination products present a difficult regulatory challenge: which regulations should apply? </li></ul><ul><li>A separate Office of Combination Products (OCP) 2002 </li></ul>
Packaging considerations <ul><li>When packaging a ESD manufacturers must consider: </li></ul><ul><li>Regulatory matters </li></ul><ul><li>Materials </li></ul><ul><li>Machinery </li></ul><ul><li>Sterilization methods </li></ul>
FDA Approval <ul><li>Developing and receiving FDA approval for a DES is: </li></ul><ul><ul><li>Difficult </li></ul></ul><ul><ul><li>Time-consuming </li></ul></ul><ul><ul><li>Expensive </li></ul></ul>
Regulation Issues <ul><li>Medical device packager must comply with a whole new set of packaging requirements and testing. </li></ul><ul><li>Is the container and closure system suitable for use with the drug? </li></ul><ul><li>drug product packaging requirements involve batch-to-batch uniformity of materials to ensure product safety and efficacy. </li></ul><ul><li>How is that drug going to interact with the materials used to make the stent? </li></ul>
Challenges <ul><li>Each device must be packaged to ensure that it is functional and that pharmacological or biologic properties are protected until the point of use. </li></ul><ul><li>The ever-changing regulatory environment- It is difficult to predict the requirements of a global marketplace. </li></ul><ul><li>Would a new product offering be viewed as a device or a drug with the device serving as the delivery system? </li></ul><ul><li>This may lead to companies developing such combination products to have to deal with the regulations of both agencies, which could potentially lead to dual sets of requirements. </li></ul>
Opportunities <ul><li>Combining a medical device with a pharmaceutical to create a drug delivery device is a great opportunity for both the device company and the pharmaceutical firm. </li></ul>