FEATUre FEATURE Product and Package Stability Studies: The Application of FDA Guidance

The United States and The challenge The United States Food and Drug Administration (FDA) expects “products labelled as Drug Administration sterile to be free of viable microbial contamination” throughout their .1 A major role of packaging is to maintain this sterility during shipping and storage. The challenge provides guidance on physi- is in demonstrating this and it is not an easy task. Microbial contamination in a pack may be impossible to detect visually and the majority of the tests (physical and microbial) cal tests to employ to demon- that are available for assessing pack quality are destructive. Furthermore, if a product has a claimed shelf life of five years, it is not commercially viable to wait for the full period strate that packaging main- before testing. Therefore, validation techniques are used to ensure that the packs are robust and the production processes reliable.2 Validation depends on establishing the pack tains the sterility of products performance during the “design outputs” phase of a project, followed by regular quality analysis (QA) and process monitoring on validated equipment to ensure that this per- throughout their shelf life. formance is maintained. The obvious way to check for sterility is to open a pack and perform a microbiological This article discusses what analysis of the contents. But this is an attempt to demonstrate a negative. Proving that this means in practice for something is not there is not easy in practice. Testing for sterility can produce false nega- tives and false positives. False negatives result from the possibility that although there may manufacturers. be a fault in the pack, the viable organism in the selected culture medium has not entered the pack. To overcome this, the outside of the pack can be sprayed with an aerosol (or dust) that contains known microbes and then the contents of the pack analysed for those M. Turner, known organisms. However, this presents a different problem. It is extremely difficult to Medical Engineering Technologies Ltd, access the pack contents without contaminating them, even if the outside of the pack is treated chemically following exposure and prior to opening. This method increases the Folkestone, UK likelihood of false positives caused by the transfer of microbes to the product when the First published in the Spring 2009 issue of pack is opened. The FDA guidance document discussed here, “ and Med-Tech Packaging News. System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products”1 helps to address this challenge by accepting physical testing in place of sterility testing.

Physical testing The guidance document provides a nonexhaustive list of possible integrity tests. These include ■ bubble tests (an integrity test that measures the minimum pressure required for gas to penetrate the pack membrane/media) ■ pressure/vacuum decay (an integrity test that measures flow driven by a pressure differential across the pack membrane) T LTD T ■ trace gas /leak tests (an integrity test that measures flow of a gas from the pack driven by diffusion) ■ dye penetration tests (an integrity test for seal areas) Image: ME ■ seal force tests (burst or tensile tests for seal strength)

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■ electrical conductivity and capacitance commonly performed according to ASTM Standard for Nondestructive tests (integrity tests that look for anomalies D4169-05 Standard Practice for Perform- Detection of Leaks in Packages by Vacuum in materials). ance Testing of Shipping and Decay Method. In this test, packages are The guidance document stresses that Systems. This testing can incorporate initial placed in a chamber that closely fits their these tests do not replace initial sterilisa- manual handling (ASTM D 5276-98 A), profile. The chamber is subjected to a tion validation or sterility release tests vehicle stacking (ASTM D 642-00 C), loose vacuum and leakage from the pack into the during manufacturing. They are, however, load vibration (ASTM D 999-01 F), vehicle vacuum is measured as a pressure increase. relevant to a stability evaluation pro- vibration (ASTM D 4728-01 E), and final This is similar to pressure decay testing, gramme or a shelf life test programme. It manual handling (ASTM D 5276-98 A). where a positive pressure is applied inside is also stated that the tests require proper the product or pack. It delivers accurate validation. Validation methods vary accord- Testing package and product quantitative results. ing to the tests used and pack types. To identify precisely what testing is A variety of gases may be used for tracer The physical tests outlined here should required, a risk analysis should be per- gas testing. Hydrogen (5% in nitrogen), be combined with environmental and formed. Questions to consider include: carbon dioxide and helium are all pos- ageing factors to simulate the conditions ■ Does the product (or pack) deteriorate sibilities. For these tests, packages can be the product may be expected to encounter with time? sealed in an environment rich in the tracer during transit and storage. ■ Is the product (or pack) labile at raised gas; or the gas can be introduced after or lowered or even normal welding by the storage of the packages in Ageing temperatures? an atmosphere of the tracer gas at elevated Real time ageing is often not a realistic ■ Is the product or pack sensitive to pressure; a probe is then used to locate option, especially for a new product or moisture? and quantify any leaks. Validation for both packaging system. Ageing can be acceler- ■ What environment may the product be methods can be performed using pack ated for most medical devices and pack- stored and transported in? perforations of a known size. For practical ages by following the Arrhenius equation,3 ■ What are the environmental conditions reasons the minimum hole that can be which states that a rise of in the hold of a plane or ship and on the made is usually 12.5 microns in diameter. 10 °C will double the rate of a reaction. dockside? The validation is achieved by comparing Hence, storage at 55 °C delivers one year ■ Does the product put pressure on the packs with perforations with packs known of equivalent ageing in less than six weeks, pack seals or materials? to be intact. An integral pack can be tested as stated in ASTM F1980-07 Standard ■ What is the mass of the product and how and shown to pass a test. The same pack Guide for Accelerated Aging of Sterile much can it move around in the pack? can then be perforated and used to chal- Barrier Systems for Medical Devices.4 The lenge the test method. guidance indicates that testing should be Medical device manufacturers often conducted at 12 month intervals up to the Products are usually tested against their question the “hole” size used for the vali- claimed shelf life. normal QA specifications following age- dation of these test methods. There are cer- ing and conditioning. The risk analysis tainly some extremely small bacteria. For Environmental conditions and failure modes and effects analysis may example, Brevundimonas (Pseudomonas) Prior to transport, simulation packages indicate additional areas of testing that do diminuta (ATCC19146) has a diameter of may require conditioning according to not appear in the normal QA routine. An 0.3 microns and a length of 0.8 microns. the environments they will encounter example may be additional tensile test- Viruses can be even smaller than this (typi- in practice. Conditions are described in ing on joints or volume verification for cally in the nanometre range).6 However, International Electrotechnical Commission products containing volatile fluids, both of filtration of airborne particles is not just a standards; US Defense standards, often which may be influenced by temperature sieving process. There are a variety of other termed MIL specs; and in ASTM D4332-01 fluctuations. Package testing is dependent mechanisms that entrap particles7 such (2006) Standard Practice for Conditioning on package design and materials. as diffusion (Brownian motion) inertial Containers, Packages, or Packaging Com- impaction and electrostatic attraction. ponents for Testing.5 Typically, these are Nonporous packs Hence, although a hole may appear large, ■ Tropical: temperature 38 °C, relative A wide choice of testing options is avail- the filtration efficiency may be greater than humidity 85% able for hermetically sealed packs. Pressure initially expected. This is one of the rea- ■ Desert: temperature 50 °C, relative (vacuum) decay or tracer gas tests can sons why porous packaging materials are humidity low be used to determine the integrity of the effective at keeping products sterile. ■ Frozen: temperature –20 °C, relative entire package; they allow confirmation of humidity low the web material and weld integrity. One Porous packs ■ Temperate: temperature 23 °C, relative option is a method described in ASTM Different methods are required for testing humidity 50%. F2095-07e1, Standard Test Methods for medical device packages that have at least Pressure Decay Leak Test for Flexible Pack- one porous element, for example or Shipping ages With and Without Restraining Plates. A . Pressure decay and tracer gas tests are Transport simulation for medical devices is better alternative can be, ASTM F2338-05, not suitable. Integrity testing for these packs

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is often divided into two areas: one test for Table I: Standard test methods for assessing the materials used in porous packaging for terminally the materials prior to sealing and a second sterilised medical devices include: test for seals in completed packs. Raw material tests on packaging webs ■ ISO 11607-1:2006 Packaging for Terminally Sterilised Medical Devices, Part 1: Requirements for Materials, Sterile Barrier Systems and Packaging Systems are usually performed by the ■ and manufacturers of these items. These ASTM F2638 07 Standard Test Method for Using Aerosol Filtration for Measuring the Performance of Porous Packaging Materials as a Surrogate Microbial Barrier tests include bubble point and electrical ■ ASTM F1608 00(2004) Standard Test Method for Microbial Ranking of Porous Packaging Materials (Exposure tests. One method for examining com- Chamber Method) plete packs is described in ASTM F2228- ■ EN868-1, Packaging Materials and Systems for Medical Devices which Are to Be Sterilised 02(2007) Standard Test Method for Non-Destructive Detection of Leaks in Medical Packaging which Incorporates vacuum is drawn above the fluid, which Evaluation and Research, Food and Drug 9 Porous Barrier Material by CO2 Tracer Gas in turn draws bubbles from the pack. Administration, 22 February 2008, Method. Dye penetration testing is a simple An alternative for large packs is to pres- www.fda.gov/cber/gdlns/contain.htm alternative for assessing seal integrity. It surise the packs internally as described in 2. M. Turner, “How to Validate a Packaging is described in ASTM F1929-98 (2004), ASTM F2096-04.8 Both of these tests will Process,” Medical Device Technology, 15, 3, 20–23 (2004). Standard Test Method for Detecting Seal only detect gross leaks of more than 250 3. M. Turner, “How to Simulate Shelf Life for Leaks in Porous Medical Packaging by microns wide. Ageing Trials,” Medical Device Technology, 13, 1, Dye Penetration. In this test, a dye and Electrical conductivity and capaci- 90 (2002). surfactant are introduced into the pack and tance tests. These tests are often mployed 4. ASTM F1980-07 Standard Guide for channels through the seals are searched on web materials. They look for perfora- Accelerated Aging of Sterile Barrier Systems for Medical Devices. for visually. The validation method for tions using charged plates either side of 5. ASTM D4332-01(2006) Standard Practice this test is also described in the standard. the web. An imperfection in the web will for Conditioning Containers, Packages, or It involves placing fine wires across the allow transmission of current or cause a Packaging Components for Testing. seal prior to welding. These wires are then change in capacitance. 6. http://en.wikipedia.org/wiki/ removed and tests are performed on the Seal force tests. Seal strengths can Virus#Structure 7. www.devicelink.com/mddi/ channels that remain. be analysed using a tensile peel test or archive/08/06/004.html Standard test methods exist for assessing a burst test. The burst test is superior, 8. ASTM F2096-04 Standard Test Method for the materials used in porous packaging for because it is quicker and tests the entire Detecting Gross Leaks in Medical Packaging terminally sterilised medical devices, see seal line of a package. It is described in by Internal Pressurisation (Bubble Test). Table I. ASTM F1140-07 Standard Test Methods for 9. ASTM D3078-02 (2008) Standard Test Method for Determination of Leaks in Internal Pressurisation Failure Resistance Flexible Packaging by Bubble Emission. Other tests of Unrestrained Packages. A tensile test is Bubble test web material. Bubble described in ASTM F88-07a Standard Test emission testing involves applying pressure Method for Seal Strength of Flexible Bar- Further reading to the lower side of a web material whilst rier Materials. ASTM F2097-08 Standard Guide for a liquid is placed on the upper surface Design and Evaluation of Primary Flexible (it is captured horizontally). As the air/ Reliable testing Packaging for Medical Products. PN gas pressure is increased underneath, the The FDA guidance document referred to fluid contact surface is monitored. The in this article seeks to clarify how device Mark Turner pressure at which a bubble first appears is manufacturers can demonstrate the sta- is Sales Director at Medical Engineering recorded. The test is often applied at goods bility of their product and packaging Technologies Ltd, 41 Seabrook Road, inwards before web materials are accepted. and substantiate shelf life claims without Hythe CT21 5LX, UK, tel. +44 845 458 8924, ASTM F2096-04 Standard Test Method for resorting to unreliable microbiological e-mail: [email protected] Detecting Gross Leaks in Medical Packag- and sterility test methods. For practical www.met.uk.com ing by Internal Pressurisation (Bubble Test) application, pressure decay, tracer gas, dye describes a method for finding holes with penetration and burst pressure tests are a diameter greater than 250 microns in often used at the point of packaging and First published in the Spring 2009 issue of spun bonded polyolefin and nonporous in stability studies, whereas electrical and Med-Tech Packaging News. packs.8 bubble tests are most applicable to mate- Bubble test impermeable packs. There rial manufacturers and goods inwards is also a bubble test, ASTM D3078-02 testing. (2008) Standard Test Method for Deter- mination of Leaks in Flexible Packaging References by Bubble Emission, that involves placing 1. Container and Closure System Integrity packs in a vacuum transparent chamber. Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for The pack is immersed in fluid and a Sterile Products, Center for Biologics

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