Ensur­ing com­pli­ance with ISO 11607 is imper­at­ive in the field of pack­aging for ter­min­ally ster­il­ized med­ic­al devices. The inter­na­tion­ally har­mon­ized stand­ard is sep­ar­ated into two parts:

• ISO 11607 – 2 cov­ers the require­ments for the pro­cesses of form­ing, assembly and seal­ing of the pack­aging. The pro­cesses involved are known as a (pack­aging) pro­cess val­id­a­tion.

• ISO 11607 – 1 focuses on the require­ments for the mater­i­als, sterile bar­ri­er sys­tem and pack­aging sys­tem. One of the main aspects of to be con­sidered are the pack­aging system’s per­form­ance and sta­bil­ity. The pro­cesses involved are gen­er­ally known as a pack­aging sys­tem design val­id­a­tion or simply pack­aging val­id­a­tion.

ISO 11607 – 2 – Pro­cess Validation

A pro­cess val­id­a­tion at a min­im­um must con­sti­tute of an install­a­tion qual­i­fic­a­tion (IQ), an oper­a­tion­al qual­i­fic­a­tion (OQ) and a per­form­ance qual­i­fic­a­tion (PQ). The gen­er­al goal is to make sure that the equip­ment oper­ates as inten­ded and that the pack­aging can be pro­duced as con­sist­ently, repeat­ably and reli­ably as expected.

Let’s take a closer look at the qual­i­fic­a­tion phases:

• IQ – Install­a­tion Qualification

The pur­pose of Install­a­tion Qual­i­fic­a­tion is to ensure that equip­ment, sys­tems, and facil­it­ies are prop­erly installed and meet the spe­cified design criteria.

• OQ – Oper­a­tion­al Qualification

OQ focuses on veri­fy­ing and doc­u­ment­ing that the equip­ment or sys­tem oper­ates accord­ing to its oper­a­tion­al spe­cific­a­tions under nor­mal oper­at­ing con­di­tions. For seal­ing pro­cesses this includes the determ­in­a­tion of the lower pro­cess lim­its (LPL) and upper pro­cess lim­its (UPL) for crit­ic­al pro­cess para­met­ers like seal­ing tem­per­at­ure, time and pressure.

• PQ – Per­form­ance Qualification

This phase focuses on demon­strat­ing that the equip­ment or sys­tem con­sist­ently per­forms accord­ing to its spe­cified design and oper­a­tion­al require­ments in the inten­ded oper­at­ing envir­on­ment. For seal­ing pro­cesses, pack­aging which were sealed at nom­in­al pro­cess lim­its (NPL) are checked.

Dur­ing the OQ and PQ, it is cru­cial to assess the effect­ive­ness of the seal­ing through seal integ­rity test­ing, seal strength meas­ure­ments and oth­er pack­aging tests. See below for fur­ther inform­a­tion on a selec­tion of these tests.

ISO 11607 – 1 – Mater­i­al testing

Major parts of ISO 11607 – 1 focus on require­ments for the mater­i­als used for the pack­aging sys­tem and sterile bar­ri­er sys­tems, as well as for the pack­aging sys­tem and sterile bar­ri­er sys­tem themselves.

A selec­tion of some of the most import­ant require­ments is lis­ted in the following:

• Micro­bi­al bar­ri­er properties

Ensur­ing a micro­bi­al bar­ri­er is crit­ic­al for ensur­ing integ­rity once ster­il­ized, as it pre­vents the ingress of microorganisms.

• Biocom­pat­ib­il­ity

Biocom­pat­ib­il­ity should show that there are no crit­ic­al sub­stances that could migrate from the pack­aging mater­i­al to the med­ic­al device and cause any harm for patients. Test­ing can involve cyto­tox­icity, non­volat­ile residue etc.

• Phys­ic­al and chem­ic­al prop­er­ties

Con­form­ing to a vari­ety of phys­ic­al and chem­ic­al prop­er­ties ensures that the mater­i­als are suit­able for the inten­ded pur­pose of ensur­ing the over­all product safety and espe­cially ensur­ing the integ­rity even under phys­ic­al stress dur­ing dis­tri­bu­tion. Test­ing for phys­ic­al and chem­ic­al prop­er­ties can for example involve burst test­ing, clean­li­ness, print­ing & coat­ing, tensile prop­er­ties, thick­ness etc. and have to con­form to estab­lished prop­er­ties and/​or values.

• Ster­il­iz­a­tion compatibility

The mater­i­als used for the pack­aging sys­tem have to be com­pat­ible with the inten­ded ster­il­iz­a­tion meth­od (e.g., Gamma-ray, X‑Ray, EtO). Com­pat­ib­il­ity can for example be sup­por­ted by test­ing of per­meance, biocom­pat­ib­il­ity, seal strength and burst test­ing after expos­ure to the ster­il­iz­a­tion agent. 

ISO 11607 – 1 – Pack­aging Validation

The main goal of a pack­aging val­id­a­tion is to estab­lish evid­ence that the pack­aging sys­tem offers suf­fi­cient pro­tec­tion of the product, and, most import­antly, that the sterile bar­ri­er sys­tem is cap­able of uphold­ing its integ­rity after ster­il­iz­a­tion, dis­tri­bu­tion and storage.

A pack­aging sys­tem sub­jug­ated to a pack­aging val­id­a­tion should be man­u­fac­tured under stand­ard oper­at­ing pro­ced­ures using fully qual­i­fied equip­ment & seal­ing pro­cesses and ster­il­ized using a val­id­ated ster­il­iz­a­tion pro­cess. In every aspect pos­sible the worst-case scen­ario should be considered.

This includes:

• Worst-case med­ic­al device

If it is inten­ded to use the same pack­aging sys­tem for a med­ic­al device product fam­ily (i.e., med­ic­al devices that are sim­il­ar but not identic­al) the worst-case con­fig­ur­a­tion out of this product fam­ily should be used. This can for example be the heav­iest, bulki­est and/​or sharpest con­fig­ur­a­tion which poses the most stress on the pack­aging system.

• Worst-case seal­ing

Sterile bar­ri­er sys­tem (SBS) for the pack­aging val­id­a­tion should be sealed at LPL, which imposes the highest risk for com­prom­ising the integ­rity of the SBS.

• Worst-case ster­il­iz­a­tion

The samples for the pack­aging val­id­a­tion should be ster­il­ized in a way to impose a high­er chal­lenge com­pared to the routine ster­il­iz­a­tion para­met­ers. This for example can entitle a double-dose and/​or a double-cycle ster­il­iz­a­tion.

A com­pre­hens­ive pack­aging val­id­a­tion involves per­form­ance and sta­bil­ity test­ing. While it is not strictly pro­hib­ited to com­bine these two test­ing fields, it is recom­men­ded that they are kept sep­ar­ate from each other.

Pack­aging Val­id­a­tion – Per­form­ance Testing

Pack­aging per­form­ance test­ing involves a series of sim­u­la­tions and eval­u­ations to ensure that the pack­aging sys­tem can with­stand the chal­lenges encountered dur­ing the expec­ted hand­ling and dis­tri­bu­tion.

Some import­ant aspects to consider:

• Does the product ship as an indi­vidu­al box and/​or as an unit­ized load on a pallet?
• Will the product ship as full truck­load (FTL) or Less-Than-Truck­load (LTL)
• In what cli­mat­ic zones of the world will the product ship? What are the expec­ted cli­mat­ic con­di­tions which could be encountered dur­ing transit?
• Will the product be shipped by boat, truck, rail and/​or air?

Based on this inform­a­tion, it should be con­sidered what the most appro­pri­ate con­sensus stand­ard is that best aligns with the indi­vidu­al requirements.

Here is a selec­tion of the most com­monly used stand­ards for pack­aging per­form­ance test­ing for med­ic­al device packaging:

• ASTM D4332

This stand­ard is often used as a basis for test­ing envir­on­ment­al cli­mat­ic con­di­tions encountered dur­ing trans­it. Depend­ing on which cli­mat­ic zones the product will be shipped, the tem­per­at­ure can for example range from ‑40 °C to 70 °C and 10 % — 95% rel­at­ive humid­ity. Know­ledge of the expec­ted cli­mat­ic con­di­tions dur­ing trans­it is essen­tial, as these con­di­tions should be tested in a series of sim­u­lated cli­mat­ic con­di­tion­ing steps which com­bined is known here at Früh as a cli­mat­ic cycle.

• ASTM D4169

This widely used stand­ard for trans­port sim­u­la­tions can be used as a basis to eval­u­ate the abil­ity of the pack­aging sys­tem to with­stand the dis­tri­bu­tion envir­on­ment with a focus on mech­an­ic­al haz­ards, such as drop­ping, stak­ing and vibra­tion. Depend­ing on the ship­ment con­fig­ur­a­tion (single box vs. unit­ized load on a pal­let) and expec­ted ship­ment meth­od (truck, rail, cargo ship and/​or plane) the user can choose from a vari­ety of dif­fer­ent test sequences known as dis­tri­bu­tion cycles (DC).

• ISTA 3A

This stand­ard shares many sim­il­ar­it­ies with ASTM D4169 and is there­fore anoth­er great option for trans­port sim­u­la­tions for med­ic­al device pack­aging. One import­ant dif­fer­ence is that test­ing accord­ing to ISTA 3A can only be done on single boxes inten­ded to be shipped via a par­cel sys­tem. In gen­er­al, test­ing accord­ing to this stand­ard is more chal­len­ging but less cus­tom­iz­able than its ASTM counterpart.

After per­form­ance test­ing, sterile bar­ri­er sys­tem integ­rity has to be proven through integ­rity test­ing. Seal strength meas­ure­ments and oth­er pack­aging tests can be included as well. See below for fur­ther inform­a­tion on a selec­tion of these tests.

Pack­aging Val­id­a­tion – Sta­bil­ity Testing

The primary object­ive of sta­bil­ity test­ing is to assess the abil­ity of the sterile bar­ri­er sys­tem to with­stand the risks which can occur through­out the claimed shelf-life. The data from accel­er­ated aging, which is aging con­duc­ted at elev­ated tem­per­at­ures, is per­miss­ible to use for ini­tial mar­ket launches, but the claimed shelf-life must be con­firmed through real-time aging. ASTM F1980 is the go-to stand­ard for estab­lish­ing accel­er­ated aging pro­to­cols for med­ic­al device pack­aging and gives guid­ance to cal­cu­late the time for the accel­er­ated aging based on the Arrhe­ni­us equa­tion.

Let’s take a look at an example:

An accel­er­ated aging tem­per­at­ure of 55 °C, an assumed real-time aging tem­per­at­ure of 25 °C and an Arrhe­ni­us aging factor of Q₁₀ = 2 allows for a reduc­tion of the real-time aging time by a factor of 8. There­fore, for example, accel­er­ated aging would shorten the time of 10 years real-time aging to 456.3 days (approx­im­ately 1.25 years).

After sta­bil­ity test­ing, sterile bar­ri­er sys­tem integ­rity has to be proven through integ­rity test­ing. Seal strength meas­ure­ments and oth­er pack­aging tests can be included as well. See below for fur­ther inform­a­tion on a selec­tion of these tests.

Integ­rity and oth­er pack­aging tests

Pack­aging sys­tems includ­ing all sterile bar­ri­er sys­tems have two very import­ant func­tions in the life cycle of a ter­min­ally ster­il­ized med­ic­al device:

• Pro­tec­tion of the med­ic­al device from dam­ages until the point of use
• Ensur­ing ster­il­ity of the med­ic­al device until the point of use

Wheth­er the pack­aging sys­tem is able to ful­fill these func­tions has to be tested after each step of the pack­aging validation.

For this pur­pose, ISO 11607 – 1 lists a mul­ti­tude of tests to choose from. Some of the most com­monly used tests are lis­ted below.

Integ­rity Tests:

• Bubble Emis­sion Test through intern­al pres­sur­iz­a­tion (ASTM F2096)

The pack­aging is placed under­wa­ter and sub­jec­ted to increased intern­al pres­sur­iz­a­tion. Con­stant bubble streams emer­ging from the pack­aging point to the exist­ence of leaks.

• Bubble Emis­sion Test – neg­at­ive pres­sure (ASTM F3078)

The pack­aging is placed under­wa­ter in a cham­ber. A cer­tain level of vacu­um is applied to the cham­ber, which causes a pres­sure dif­fer­en­tial between the inside and out­side of the pack­age. Con­stant bubble streams emer­ging from the pack­aging point to the exist­ence of leaks.

• Dye Pen­et­ra­tion Test – por­ous pack­aging (ASTM F1929)

A dye solu­tion is injec­ted into the pack­age, or, altern­at­ively, the edges of each side of the seal are dipped into the dye solu­tion. Each side of the seal seam is inspec­ted for channels.

• Dye Pen­et­ra­tion Test – non-por­ous pack­aging (ASTM F3039)

A dye solu­tion is injec­ted into the pack­age. Each side of seal seam is then inspec­ted for chan­nels. Under cer­tain con­di­tions, it is addi­tion­ally pos­sible to inspect the flat sur­faces of the pack­aging for leaks.

• Visu­al Inspec­tion of the seal­ing (ASTM F1886/F1886M)

This meth­od focuses on visu­ally detect­ing chan­nels and oth­er qual­ity rel­ev­ant seal char­ac­ter­ist­ic, such as under­seal­ing, over­seal­ing, folds etc.

Mater­i­al Tests:

• Tensile Strength and Elong­a­tion at Break (DIN EN ISO 527−1÷527−3)

Tensile strength and elong­a­tion at break are two import­ant mech­an­ic­al prop­er­ties used to char­ac­ter­ize the beha­vi­or of mater­i­als under ten­sion. Tensile strength is the max­im­um amount of tensile (stretch­ing) stress that a mater­i­al can with­stand before fail­ure or break­ing. Elong­a­tion at break meas­ures the extent to which a mater­i­al can stretch or deform before it breaks. Both val­ues are meas­ured by pulling apart a strip of the test material.

• Punc­ture Res­ist­ance (DIN EN 14477 or ASTM F1306)

Punc­ture res­ist­ance is a mech­an­ic­al prop­erty that meas­ures a mater­i­al’s abil­ity to with­stand the pen­et­ra­tion of sharp objects without tear­ing or punc­tur­ing. The test is per­formed by for­cing a probe into the mater­i­al until com­plete pen­et­ra­tion, res­ult­ing in the meas­ure­ment of the force and energy at break.

Oth­er pack­aging tests:

• Seal strength (ASTM F88/F88M)

The pur­pose of seal strength test­ing is to eval­u­ate the abil­ity of a seal to with­stand the stress and pres­sure encountered dur­ing trans­port­a­tion, hand­ling, and stor­age. For this test, a defined sec­tion of the seal seam is pulled apart until full sep­ar­a­tion, res­ult­ing in the meas­ure­ment of the seal strength.

• Visu­al inspec­tion of pack­aging (in-house method)

By visu­ally examin­ing pack­aging signs of dam­age, such as tears, punc­tures, or deform­a­tion, weak­nesses and vul­ner­ab­il­it­ies in the pack­aging sys­tem can be iden­ti­fied. Invest­ig­at­ing these issues helps to pre­vent product loss, con­tam­in­a­tion, or dam­age, ulti­mately safe­guard­ing the sterile bar­ri­er sys­tem and the pack­aged product. 

• Dimen­sion­al meas­ure­ments (ASTM F2203 or in-house method)

Dimen­sion­al meas­ure­ments can be taken from any part of the pack­aging. Most com­monly this test is used to meas­ure the seal width of the sterile bar­ri­er sys­tem either with a steel ruler (ASTM F2203) or with a digit­al cal­iper (in-house method).