Originally Published
MDT March/April 2009
MATERIALS
Use of Polymeric Materials in Orally Inhaled and Nasal Drug Products
To maintain a high standard of quality in the materials and components used in the container systems of orally inhaled and nasal drug products, manufacturers need to collaborate closely with all those in the supply chain. Best practices in information sharing, particularly in relation to change control, are outlined here.
D.M. Dohmeier, D.L. Norwood, G. Reckzuegel, C.L.M. Stults and L.M. Nagao International Pharmaceutical Aerosol Consortium on Regulation and Science, Washington, District of Columbia, USA.
Critical considerations
Orally inhaled and nasal drug products (OINDPs) are used to treat local lung and nasal conditions such as asthma, chronic obstructive pulmonary disease and chronic rhinitis, and systemic conditions such as diabetes. Types of OINDPs include metered dose inhalers (MDIs) (see Figure 1), dry powder inhalers, nasal sprays and solutions or suspensions for inhalation through nebulisers or other devices. OINDPs consist of a formulation containing the active drug and excipients together with a carrier or propellant, and a container closure system/device (CCS).
 |
Figure 1: Schematic of an MDI. The valve is made up of a
number of components, including elastomeric gaskets, a plastic
stem and a metal spring. The actuator is typically moulded
plastic and the canister is metal, which can include an interior
organic coating. The propellant is an organic solvent such as
chlorofluorocarbon or hydrofluoroalkane.
(click image to enlarge)
|
Careful design and development of the CCS is critical to ensuring the overall quality, safety and efficacy of an OINDP. The systems consist of a variety of polymeric, elastomeric and metal components, some of which are in direct contact with the drug formulation during storage and use of the product, and most are integral and necessary to the product’s proper functioning. OINDP manufacturers must therefore maintain a high standard of quality in the materials and components used, and need to be aware of the best way to maintain that quality throughout the materials/ components supply chain.
Regulatory agencies have emphasised the importance of the CCS for OINDPs.1–4 Container closure related issues for OINDPs are considered high risk.1 The United States (US) Food and Drug Administration (FDA) has also provided detailed regulatory guidance on extractables and leachables from OINDP components.5,6 In addition, industry, FDA and academic scientists collaboratively developed best practices and safety thresholds for OINDP extractables/leachables.7 This article discusses the technical and quality management expectations relevant to materials selection for CCSs and throughout the OINDP lifecycle. Communication and collaboration between OINDP manufacturers and their materials/component suppliers is necessary to realising these expectations, thus strong partnerships among these entities are essential.
Challenges in materials selection
Materials used to fabricate CCSs must meet multiple criteria. First and foremost, they must have the appropriate physical properties to meet the functional and mechanical characteristics required for the CCS. For example, plastics must have sufficient strength, rigidity and chemical resistance to allow repeated accurate dosing of the drug. Elastomeric materials must have the required modulus, hardness and compression set to function properly throughout the life of the OINDP. Materials must be readily moulded or processed into the required shape.
The next critical criterion is compatibility with the formulated drug. Because the materials of the CCS are in direct contact with the drug formulation, the chemical composition of the materials may affect its stability and vice versa. Uptake of the drug or excipients by the materials through sorption may adversely affect accurate dose delivery or the stability of the formulation and must be avoided. Moisture ingress into the drug product from the external environment must also be prevented. In addition, the materials must be resistant to changes in physical properties caused by contact with the drug; the materials cannot become brittle or swell to such a degree that they impede the proper functioning of the CCS.
The third criterion is the potential for compounds from the material to leach into the drug product. Leachable compounds such as plasticisers, release agents and/or antioxidants can result not only from the base polymer, but from additives and processing aids used to provide the required physical properties and/or manufacturability. Any compounds that leach into the drug product will be inhaled by the patient. Leachable compounds may also affect the stability of the drug. Care must, therefore, be taken when choosing materials for OINDPs to minimise the possibility of leachable compounds. For this reason, OINDP developers and suppliers perform exhaustive extraction studies on materials and components to develop a qualitative and quantitative profile of potential leachables. Toxicological bioassessment studies are then performed to evaluate the potential safety implications of patient exposure to leachables from the drug product.
Importance of materials information
 |
Figure 2: Generic example of the plastics component supply chain. Types of additives
typically included at each stage are also noted. Entities in the supply chain are termed
N (OINDP manufacturer); N-1 (component manufacturer) and so on. The authors thank
Michael Ruberto, Ciba Expert Services, for input on this figure.
(click image to enlarge)
|
Understanding the composition of the materials used for CCSs and the potential risks associated with leachables is critical. It is best that this information is generated and maintained by suppliers of the component materials. The supply chain for these materials is complex as shown in Figure 2, which provides a generic example of a plastics component supply chain.
From an OINDP manufacturer’s perspective, it is highly beneficial for all supply chain entities to share with each other and with the drug product maker all available information on component composition and processing. This facilitates quality and risk assessment and materials selection, reduces redundant quality control testing, enhances communication between suppliers and their customers on issues such as method development for extractables testing and establishing appropriate acceptance criteria, and most importantly helps to ensure the long term safety and quality of the final drug product for patients. Qualitative and quantitative composition information should include
- the identity of the elastomeric/polymeric base material
- the identity and amounts of all additives, for example, antioxidants, acid scavengers and if possible, related impurities and reaction/degradation products of individual additives.
Sources of known potent carcinogens or mutagens should be avoided or minimised. Examples of these include polynuclear aromatic hydrocarbons in carbon black filler, and N-nitrosamines and mercaptobenzothiozole in sulphur-cured elastomers.
It is also desirable for suppliers to convey information related to a manufacturing process that could result in any chemical modification of additives or the polymer such as
- the polymerisation process and associated polymerisation/curing agents
- the fabrication process, including any processing aids and process parameters such as temperature
- cleaning/washing processes for finished components, including the cleaning agents
- the storage/shipping environment for the components.
Suppliers should also provide extractables profiles because these help to identify potential extractables (and therefore potential leachables) other than those already known from composition information. These types of compounds may include oligomers and additive degradation products.
Finally, medical or pharmaceutical grade materials should also comply with a number of regulations and pharmacopoeias. Therefore, it is important for suppliers to provide OINDP manufacturers with compliance statements; these statements include
- compliance with food contact regulations and regulations for specific compounds such as phthalates or materials generally recognised as safe8,9
- reference to US, European and Japanese pharmacopoeias
- biocompatibility of materials10–13
- measures to minimise the risk of transmitting transmissible spongiform encephalopathy (TSE including BSE) via drug products or medical devices for the use of tallow derived or other animal-sourced products,14,15
- compliance with medical device legislation.16,17
Quality management
The overall quality of CCSs is governed by quality systems for which Current Good Manufacturing Practices (cGMPs) provide a standard. In general, OINDP manufacturers expect component suppliers to follow cGMPs and to use and be aware of various guidelines and standards.18–21 Of primary importance among these is the International Pharmaceutical Aerosol Consortium on Regulation and Science GMP guideline.21 This notes the importance of strong quality systems as well as issues of critical importance to OINDP such as change control, an understanding of extractables and development of sound quality agreements with customers. It encourages the establishment of a strong partnership between component (N-1) suppliers and the OINDP manufacturer, and recommends that N-1 suppliers likewise develop strong relationships with their suppliers to help ensure that quality and especially change control is managed throughout the supply chain.
Change control
As discussed, the quality of materials and the level of control over the processes used to manufacture CCSs can have a significant affect on the quality and ultimately the safety profile of the OINDP. There are several regulations that apply specifically to controlling changes to those materials or processes.22–24
According to the FDA 21 Code of Federal Regulations Part 820.30(i) Design Controls, each manufacturer is required to, “establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review and approval of design changes before their implementation.” The ISO language is similar. It is a common misconception that this type of control applies only after verification/ validation is complete. In reality it is expected that changes will be controlled during development and throughout the product lifecycle.
The significant point is that a change is expected to be evaluated prior to implementation, not after the fact. This becomes a complex matter for most inhalation devices because the supply chain is often three or four layers deep, as shown in Figure 2.
Pharmaceutical manufacturers may or may not have any direct relationship with the design of the CCS and thus control over it. However, they are responsible for the safety profile of the product, which includes the drug formulation, packaging and the CCS. To resolve this inherent disconnection, pharmaceutical manufacturers will typically have a notification of change requirement with their N-1 suppliers. After being made aware of a change, its impact is evaluated and an implementation plan is created. The impact evaluation must include performance, compatibility and a safety assessment that may be partially based on extractables or leachables information.
Often, changes that seem to be minor considerations to an N-1 supplier and therefore not worthy of notification may have a significant effect on leachable substances and thus the safety profile. In other cases, the N-1 supplier may not be notified that a change has been implemented by an N-2 or N-3 supplier. Examples of those types of changes may include
- new equipment or site of manufacture
- changes in raw materials: composition, processing or technical grade
- tooling or processing changes for container-closure components
- changes in assembly or handling of components and/or devices.
A supplier directly responsible for a change may be operating under a formal change control system wherein the steps of identification, documentation, validation, review/approval and implementation are accomplished. However, the documentation and validation steps may only include risk analysis and testing that consider mechanical/functional attributes, but not the safety of the end user. For example, the producer of a low density polyethylene bag may choose to add powdered magnesium silicate, referred to as talc, as a processing aid, not realising that this bag is used to package an inhalation device; the talc will now be transferred to an OINDP and potentially inhaled by a patient, which could result in toxic effects. This illustrates the importance of communication between upstream and downstream suppliers and highlights the issue of responsibility and proper risk analysis. Establishing connectivity between supplier change control systems minimises the impact of change to patient safety and may in some cases reduce the need for extractables/leachables testing and/or additional compatibility evaluations.
Importance of sharing
Materials and components used for OINDP CCSs must be manufactured to a high standard of quality because they affect the safety and efficacy of the final drug product. This quality is dependent on strong partnerships between OINDP manufacturers and their suppliers, including, but not limited to, sharing of technical information relevant to extractables/leachables, compatibility, functionality and change control.
1. US FDA Guidance for Industry, “Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation,” May 1999, www.fda.gov/cder/guidance/1714fnl.pdf
2. “Guideline on Plastic Immediate Packaging Materials,” Committee for Medicinal Products for Human Use and Committee for Medicinal Products for Veterinary, www.emea.europa.eu/pdfs/human/qwp/435903en.pdf.
3. Committee for Medicinal Products for Human Use “Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products,” October 2006, www.emea.europa.eu/pdfs/human/qwp/4931305en.pdf
4. Health Canada Guidance for Industry, “Pharmaceutical Quality of Inhalation and Nasal Products,” 2006, www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/inhalationnas-eng.pdf
5. US FDA Draft Guidance for Industry, “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products, Chemistry, Manufacturing and Controls Documentation,” October 1998, www.fda.gov/cder/guidance/2180dft.pdf
6. US FDA Guidance for Industry, “Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products — Chemistry, Manufacturing and Controls Documentation,” July 2002, www.fda.gov/cder/guidance/4234fnl.pdf
7. Product Quality Research Institute report on “Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products,” 8 September 2006, www.pqri.org/pdfs/LE_Recommendations_to_FDA_09-29-06.pdf
8. Code of Federal Regulations (CFR), Title 21, Food and Drugs, parts 170–199. US Department of Health and Human Services. http://www.access.gpo.gov/nara/cfr/waisidx_08/21cfrv3_08.html
9. Commission Directive of 6 August 2002 relating to plastic materials and articles intended to come into contact with foodstuffs, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2002:220:0018:0058:EN:PDF
10. United States Pharmacopeia (USP) <87>, Biological Reactivity, In vitro.
11. USP <88>, Biological Reactivity, In vivo.
12. USP <1031>, Biocompatibility of Materials Used in Drug Containers, Medical Devices and Implants.
13. ISO 10993. Biological Evaluation of Medical Devices.
14. Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA 410/01 Rev. 2 -October 2003) adopted by CPMP and CVMP, www.emea.europa.eu/pdfs/human/bwp/TSE%20NFG%20410-rev2.pdf
15. ISO 22442:2007, Medical Devices Utilising Animal Tissues and Their Derivatives.
16. US FDA Food, Drug and Cosmetics Act, Section 510(k), as amended 31 December 2004, www.fda.gov/opacom/laws/fdcact/fdctoc.htm
17. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31993L0042:EN:HTML
18. ICH Harmonised Tripartite Guideline. “Pharmaceutical Quality System Q10,” Step 4, June 2008, www.ich.org/LOB/media/MEDIA3917.pdf
19. PS9000:2001, Pharmaceutical Packaging Materials. Pharmaceutical Quality Group, Institute of Quality Assurance, 2001. http://www.pqg.org/publications/psseries/index.php
20. ISO 15378:2006, Primary Packaging Materials for Medicinal Products — Particular Requirements for the Application of ISO 9001:2000 with Reference to Good Manufacturing Practice (GMP).
21. Good Manufacturing Practices Guideline for Suppliers of Components for Orally Inhaled and Nasal Drug Products, International Pharmaceutical Aerosol Consortium on Regulation and Science 2006.
22. US FDA, Quality System Regulation, Section 820.30, Design Controls, Subsection (i), Design Changes, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=820.30
23. ISO 13485:2003. Medical Devices. Quality Management Systems, Requirements for Regulatory Purposes, Section 7.3.7, Design Changes.
24. ISO 9001:2000, Quality Management Systems. Section 7.3.7, Design Changes.
In addition to their work at International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), in the OINDP Materials Working Group, Daniel M. Dohmeier is a Research Specialist at 3M Drug Delivery Systems, Daniel L. Norwood is Director Physical and Chemical Analysis at Boehringer Ingelheim Pharmaceuticals Inc., Gaby Reckzuegel is a Principal Scientist at Boehringer Ingelheim Pharma GmbH & Co. KG and Cheryl L.M. Stults is Senior Staff Scientist at Nektar Therapeutics. *Lee M. Nagao is a Senior Science Advisor and Secretariat for IPAC-RS, 1500 K Street, NW, Suite 1100, Washington, District of Columbia 20005, USA, tel. +1 202 230 5165, e-mail: lee.nagao@dbr.com, www.ipacrs.com
*To whom all correspondence should be sent.
Copyright ©2009 Medical Device Technology
)
)
