Manufacturers of medical devices or of pharmaceuticals or biologics know that establishing a cleaning validation protocol is a challenge. Combination devices that combine traditional device substrates with an active drug delivery system present unique regulatory and assembly challenges. There are critical considerations in customizing cleaning validation protocols and in both defining and maintaining appropriate surface quality.
REGULATION OF DEVICES AND DRUGS
As with any medical device or pharmaceutical product, quality must be carefully controlled and is regulated. A challenge for combination devices is that the quality regulations for medical devices and drugs must be met simultaneously. In the United States, different portions of Federal regulations govern pharmaceuticals and medical devices. Pharmaceuticals are regulated through 21CFR210/ 211. If the drug is a biologic, derived from living organisms, it is regulated through 21CFR610. Medical devices are regulated through 21CFR820. Pharmaceutical manufacturing must use and document current good manufacturing processes (cGMPs).1 Medical device manufacturing requires a quality management system (QMS).2 With cGMP, the “how-to” of the process is specified; with QMS, the emphasis is on “how do we know that it is correct.”
FDA is required by Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assign a lead center that will have primary jurisdiction for pre-market review and regulation of a combination product. The FDA has addressed the area of combination devices and has established the Office of Combination Products (OCP). The OCP neither reviews nor specifies any methods to validate the cleanliness or safety of a combination device. The OCP is primarily a steering organization, designed to determine which branch of the FDA should have primary jurisdiction over a new device. The OCP performs this assignment by determining the primary mode of action (PMOA).3 That is, it determines whether the primary mechanism for the device is pharmaceutical (e.g., delivering a drug) or a medical device (e.g., keeping an artery open). It also determines which of these mechanisms poses the greatest challenge to demonstrating safety and considers several other factors. Based on these determinations, the OCP assigns an application to the FDA division most suited to review it.
The PMOA may not always provide a good basis for selecting which of the requirements stated in the drug, biologics, and device regulations should apply to a particular combination product in specific circumstances. Whichever FDA division reviews the application, for the product to be manufactured successfully and reliably, the device fabricator must be exquisitely concerned with the surfaces and with contamination control.
IS IT CLEAN ENOUGH?
The answer may be yes for classic implantable devices. The question needs to be rephrased: is it clean enough now that a biologic or pharmaceutical is present? Issues arise as to how the combination of biologic and classic materials impacts the cleaning process and also how cleaning impacts the interaction of the drug and product with each other. Related issues include when to clean, how to clean, and how to minimize contamination during assembly.
Proximal to the biologic or pharmaceutical
One area involves preparing the surfaces immediately proximal to the biologic or pharmaceutical. In general, surface residue must be minimized to a level that assures that the biologic or pharmaceutical will not be compromised. This may make a difference in the activity of the medicine due to local or possibly systemic immune responses the body may have to the medical device portion of the combination device.
Materials compatibility must also be reconsidered. Any cleaning or manufacturing process has the potential to react with or to modify the surface. The challenge for combination devices, as well as for other newer medical devices, is to define what the surface ought to look like. Perhaps a limited, controlled level of surface modification or controlled incompatibility is called for. For example, trace amounts of residue are often removed by plasma cleaning immediately prior to application of a specific engineered coating. Plasma cleaning might be the appropriate surface pre-treatment prior to application of certain pharmaceuticals or biologics. Plasma also has the potential for surface modification; this attribute is often used advantageously as a sort of controlled incompatibility. Chemical cleaners containing caustics, corrosives, or chlorine often modify the surface of devices that may positively or negatively impact the system as a whole. Some surface modification may make implantation easier in one example but weaken the device in another. Also, this change may alter the interaction the drug has with the device. It likely becomes a more complex issue to select cleaners when they are being used on combination products. An MSDS alone may not contain all the relevant information needed to determine the impact of a cleaner on the device. Therefore, being able to partner with a knowledgeable supplier becomes more important.4
In essence, for classic devices determining appropriate surface qualities or attributes has in part involved historical, pragmatic performance. Testing has often been for general levels of contamination, for example, total organic carbon and non-volatile residue. In contrast, for combination devices, it is important to understand and document the appropriate surface proximal to the pharmaceutical. Documenting the appropriate surface will involve more specific analytical characterization and metrics.
Corrosion is a natural process. It cannot be prevented, only forestalled. Corrosion and corrosive products have the potential to negatively impact combination devices. In combination devices, corrosive products can interfere with functionality. Corrosive products are perhaps most productively thought of as contaminants or as an undesirable surface modification. Control of corrosive product means detection at the micro-level5 along with appropriate protection of the surface. Any cleaner or disinfectant used with iron containing alloys should not contain chlorine.
When the variable of a drug delivery system is added, it is appropriate to reassess the approach to validation of the cleaning process. Specifically, the level of surface residue, the location of surface residue, the chemical nature of the residue, and the potential for interaction with the pharmaceutical must be determined. Given the large number of variables involved in cleaning, validations for combination devices are best accomplished through a risk-based approach.
Minimizing thin-film residue is of increased importance with implantable devices. Residues from detergents, organic solvents, and from other process chemicals that might be insignificant in classic implantables must be reassessed in terms of the potential to alter or to inactivate the biologic or pharmaceutical. This is especially true when dealing with biopharmaceuticals and the issue of bio-films that may form as a result of contamination from water lines.
Particles can interfere physically with drug delivery systems; they can also interfere chemically. Defining and maintaining a low level of particles in the cleanroom is important but will not necessarily assure the absence of particles on the surface.
Plastics, elastomers, and epoxies can adsorb alcohol and other solvents. The release of such solvents is often assessed for many classic devices. For combination devices, determination of residual adsorbed solvent will become even more important to assure that the pharmaceutical is not inadvertently altered.
CLEANING PROCESS DESIGN
Initial cleaning process design is important to assure a reliable, consistent process. For example, minimizing outgassing involves selection of the appropriate cleaning agent. Many high boiling solvents are readily adsorbed into plastics. Even additives to aqueous cleaning agents have the potential to outgas. Determining the drying or bakeout time that is adequate to drive off residual cleaning agents and then allowing additional time as a safety measure can be helpful. However, heat can also modify the surface. Therefore, using cleaning agents where the ingredients are well defined and well supported by the manufacturer becomes increasingly important.
The cleaning process must be clearly defined. For large, classic medical devices, cleaning more and cleaning more forcefully may be a reasonable practice. For combination devices, and for other advanced, micro devices, over-cleaning may result in undesirable surface modification. Under-cleaning may leave interfering residue.
This takes us back to cleaning basics. Cleaning has three steps: washing, rinsing, and drying. The cleaning agent, the cleaning action or force, the temperature, and the elapsed time cannot necessarily be extrapolated from performance with classic devices. Instead, the process must be reevaluated for combination devices to assure that the surface is not compromised and that undesirable residue does not remain.
This includes the quality of water used. Issues of cleaning and the type of water used for medical device or pharmaceutical may be different than those in the combination product. The use of water for injection may be considered to cut down on water born biobur-den and/or endotoxins.
DESIGN FOR MANUFACTURABILITY
Classically, devices have been designed by one group and manufactured by another. The two groups (the product designers and the product manufacturers) worked independently, in isolation, and sometimes at odds with each other. A design may be functionally exquisite, but if manufacturability is not considered, the product may be a logistical nightmare in terms of assembly, cleaning, and contamination control. It is encouraging that the device designers and the manufacturing groups are meeting early on in product development. This is a desirable trend not only for combination devices but also for medical devices in general and for many other high-value products. When combining metals and plastics, moisture retention may be an issue partially due to different coefficients of thermal expansion that can cause varying gaps, allowing intrusion and trapping of water. This trapped moisture could then be a source of biocontamination.
For combination devices, cleaning cannot be an afterthought; and the same holds for sterilization. Selecting the appropriate method for sterilization for combination products can be a challenge. Steam may be an alternative to ethylene oxide in some instances.6 Changing the physical state of the bio-portion of the device, for example through lyophilization, may be an option in some instances.7 Given the diversity of materials in combination devices, it is reasonable to expect that customized sterilization regime will be developed and validated.
Radiation sterilization may be a more complex issue in combination devices. Radiation may not only alter the structure/activity of the drug (small or large molecule) but may affect the release of drug in certain cases. Radiation normally affects polymers in two basic manners, both resulting from excitation or ionization of atoms. The two mechanisms are chain scission, a random rupturing of bonds, which reduces the molecular weight (i.e., strength) of the polymer, and cross-linking of polymer molecules, which results in the formation of large three-dimensional molecular networks.8 Plastics that are absorbed must be checked for structural and chemical alteration after gamma sterilization. An example is the network structure formed after irradiation reduced significantly the OFdUrd (oxobutyl-5-fluoro-2-deoxyuri-dine, an antitumor agent) release from EVA [poly(ethylene-co-vinyl acetate)] films. In this manner, the radiation dose applied to the polymeric matrix modulated the release of OFdUrd, avoiding the high concentrations that may cause severe systemic toxicity.9
For combination devices, the specifics of the assembly process, the cleaning process, and the sterilization process must be coordinated early on in product development (Table 1). This holds true especially if manufacturing is to be out-sourced. It involves an understanding of the following:
- Materials compatibility
- Stability of biological materials
- Surface quality
- Critical cleaning
- Sources of contamination
- Approaches to minimizing contamination
In summary, remember that a combina tion device is a way of getting the best of two worlds, a medical device and an on board drug delivery system. However, get ting to those worlds involves understanding the contamination pathways that could affect either of those worlds and dealing with them in a way that does not compro mise the other. In addition, there can be pathways that are unique to the combina tion of these worlds and, therefore, would be new even to people who are well versed in both technologies separately.
- B. Kanegsberg and E. Kanegsberg, “Contamination Control and cGMP”, Controlled Environments Magazine, Feb. 2008.
- B. Kanegsberg and E. Kanegsberg, “Recent Developments in Medical Device Cleaning and Standards”, Controlled Environments Magazine, Jan. 2007.
- Federal Register: August 25, 2005 (Volume 70, Number 164) Pages 49848-49862
- B. Kanegsberg, “The Joyful Dawn of a New Era”, Process Cleaning Magazine, May/June 2007.
- B. Kanegsberg and E. Kanegsberg, “Must it Rust, Part II: Microbial Corrosion”, Controlled Environments Magazine, July 2006.
- V. Reitz, “The Best of All Worlds,” Medical Design, Sept, 2006. http://www.medicaldesign.com/articles/ID/13166.
- K. Hemmerich, “RADIATION STERILIZATION Polymer Materials Selection for Radiation-Sterilized Products”, MDDI, February, 2000. http://www.devicelink.com/mddi/archive/00/02/006.html.
- Alvaro A.A. de Queiroz, Gustavo A. Abraham, and Olga Zazuco Higa, “Controlled release of 5-fluorouridine from radiation-crosslinked poly(ethylene-co-vinyl acetate) films”, Acta Materialia Inc. Published by Elsevier Ltd, Volume 2, Issue 6, November 2006, Pages 641-650.
Jeff Phillips is a primary investor and Principal Consultant with Atzari Consulting.He has established and performed cleaning processes and procedures including cleaning validations in the pharmaceutical and medical device industries.He can be reached at firstname.lastname@example.org.