Gap analysis and Impact assessment on packaging development for

pharmaceutical use, due to change in USP 39

By Saurav Anand+91-8511773466Mylan, Packaging Technologist, B.Pharma, IIP, MBA

USP Chapter for Packaging MaterialUSP Chapters related to packaging : <87>,<88> Biological reactivity <381> Rubber stopper► <660> Containers – Glass► <661> Containers – Plastics <661.1> Plastic materials of construction. <661.2> Plastic packaging system for pharmaceutical use. ► <670> Containers – Auxiliary Packaging Components ► <671> Containers – Performance Testing► <681> Repackaging► <755> Minimum Fill► <1136> Packaging – Unit of Use► <1146> Packaging Practices► <1177> Good Packaging Practices► <1178> Good Repackaging Practices► <1265> Written Prescription Drug Information► <1083> Good distribution Practices—Supply Chain Integrity PF 37 (6)► <1660> Evaluation of Inner Surface Durability of Glass Containers► <1663> Extractables Testing for Pharmaceutical Packaging Systems► <1664> Dosage Forms: Leachables Threshold

Gap analysis and Impact assessment on plastic packaging material for pharmaceutical use in USP 39

Changes in USP 39Following are the chapters have some modification, addition & Changes Chapter <661> Containers plastics name changed as <661>

Plastic packaging system and their material of construction-- Currently subdivided in to two parts.

<661.1> Plastic materials of construction.

<661.2> Plastic packaging system for pharmaceutical use.

USP <1661>- Evaluation of plastic packaging system and their materials of construction with respective to their user safety impact.

<670> Auxiliary packaging components – Desiccant added.

<661> Containers – Plastics as per USP38Introduction This chapter to provide standards for plastic materials and components used to package medical

articles (pharmaceuticals, biologics, dietary supplements, and devices). Plastic components used for products of high risk, such as those intended for inhalation,

parenteral preparation, and ophthalmics are tested using the Biological Tests in the section Test Methods.**

Plastic containers intended for packaging products prepared for parenteral use meet the requirements for Biological Tests and Physicochemical Tests## in the section Test Methods. Standards are also provided for polyethylene containers used to package dry oral dosage forms that are not meant for constitution into solution.

Include Polyrthylene (LDPE & HDPE) containers, Polypropylene containers, PET, PET G

Test Required Infrared Spectroscopy Differential Scanning Calorimetry Heavy Metals & Non volatile Residue Biological Tests** Physicochemical##

<661> Plastic packaging system and their material of construction

Plastic packaging system and their material of construction

Plastic packaging systems for therapeutic products involves multiple tests and testing procedures, as briefly outlined below:

Material screening: Characterization facilitates the identification of materials that are suitable for use in packaging systems.

Controlled extraction (simulation) study: Study to determine the extent to which extractables may become probable leachables (Assessment of Extractables associated with pharmaceutical packaging/deliverys systems <1663>).

Product assessment: Study to determine packaged drug product/delivery system for leachables. (Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems <1664>).

<661> Plastic packaging system and their material of construction<661.1> Plastic materials of construction (MOC): Individual base resins either are materials of construction themselves or may be combined with additional additives and processing aids to form a plastic material of construction. Testing of these plastic moc to be established in <661.1>.

<661.2> Plastic packaging system for pharmaceutical use: The packaging system is completed by assembling its various components into its final form. Testing of packaging systems to established in <661.2>.

Test to be performed:Biological reactivity testIdentification Physico-chemical testExtractable metals Plastic additives (Plastic material other than solid & topical dosages form) Ref 21 CFR 174–186 for solid & topical

Test to be performed:Biological reactivity testPhysico-chemical testSafety Assessement (Extractables /for leachables)

Impact on packaging development due <661> Plastic packaging system and their material of construction

This chapter give initial background to perform study related to plastic material of construction and packaging system, type of testing & its methods mentioned in sub chapter of <661> i.e. <661.1> & <661.2>

Test performed on plastic packaging material of construction as given in <661.1> will first screening of material to be safe for use in pharmaceutical product

Test performed on packaging system as given in <661.2> will give final assessment of packaging system for pharmaceutical use.

USP <661.1> - Plastic materials of construction Introduction: A plastic material of construction is deemed to be well characterized for its intended use if the

following characteristics have been adequately established:

Scope : This chapter solely applies to individual plastic materials and should not be applied to packaging

systems or components consisting of multiple individual plastic materials. The testing and qualification of plastic packaging systems and components for pharmaceutical use are covered in Plastic Packaging Systems for Pharmaceutical Use <661.2>

The scope of <661.1> is materials of construction and of <661.2> is packaging systems. A third type of test article, components, is not directly considered in the scope of either chapter. Since a component is constructed from materials and is part of a system, if component testing is deemed to be necessary, the relevant testing and specifications for the component are contained within <661.2>. The provisions in <661.2> for packaging systems must be met for components whose testing has been deemed to be necessary. The component must be constructed from materials that meet the requirements of <661.1>and the component must be tested by the methods, and meet the specifications, contained in <661.2>.

<661.1> (Plastic Materials of Characterization) Biological Reactivity Test - USP <87> & <88> Identification - IR & DSC Physico-chemical test - Provide general view of extracted substances Extractable Metals – Potential sources of Elemental impurities. Plastic Additives - Potential organic extractable

USP <661.1> - Plastic materials of construction

Biological reactivity Tests Chemical tests

Perform Biological Reactivity Tests, In Vitro <87>• Materials that meet the requirements of this test are not required to undergo testing as described in Biological Reactivity Tests, In Vivo <88>• Materials that do not meet the requirements of the in vitro test are not suitable for these dosage forms

• Perform Identification, Physicochemical, and Extractable Metals tests• Provide appropriate reference to the Indirect Food Additive regulations in 21 CFR 174–186, specifically those addressing the purity criteria and limitations pertaining to use• Materials that do not meet these requirements are not suitable for packaging for these dosage forms unless the materials are established to be suitable by other means that have been approved by an appropriate regulatory authority.

Table 1. Guidelines for Application of Tests for Oral and Topical Dosage Forms

Biological reactivity tests Chemical tests

• Perform Biological Reactivity Tests, In Vitro <87>• Perform Biological Reactivity Tests, In Vivo <88> to obtain the appropriate Classification of Plastics• Materials that do not meet the requirements of the in vivo or the in vitro tests are not suitable for containers for these dosage forms

• Perform Identification, Physicochemical, Extractable Metals, and Plastic Additives tests• Materials that do not meet these requirements are not suitable for containers for these dosage forms unless the materials are established to be suitable by other means that have been approved by an appropriate regulatory authority.

Table 2. Guidelines for Application of Tests for All Other Dosage Forms

USP <661.1> - Plastic materials of constructionTest required for <661.1>Plastic material of construction

Test to be performed/Plastic Polyethylene (LDPE/HDPE) Cyclic Olefines Polypropylene PET & PET G Plastic (PVC) 1) Biological Reactivity Test √ √ √ √ √ 2) Identification : IR √ √ √ √ √DSC √ √ √ √ √3) Physicochemical tests :Absorbance √ √ √ √ √Acidity or alkalinity √ √ √ √ √Total organic carbon √ √ √ √ √4) Extractable Metals Aluminum √ √ √ √ XArsenic √ √ √ √ √Cadmium √ √ √ √ √lead √ √ √ √ √Mercury √ √ √ √ √Cobalt √ √ √ √ √Nickel √ √ √ √ √Chromium √ X √ X XTitanium √ √ √ √ XVanadium √ √ √ √ √Zinc √ √ √ √ √Zirconium √ X X X XAntimony X X X √ XBarium X X X √ √Germanium X X X √ XManganese X X X √ XCalcium X X X X √Tin X X X X √Plastic AdditivesPhenolic Antioxidants √ √ √ X XNonphenolic Antioxidants √ √ √ X XCopolymer of Dimethyl Succinate √ √ X X X(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-YL) Ethanol

√ √ XX X

Amides √ √ √ X XStearates √ √ √ X XDi (2-ethylhexyl)phthalate,N' N" –Diacylethylenediamines,,Epoxidized soya oil, Epoxidized linseed oil,Vinyl chloride only for PVC

Impact on packaging development dueon packaging development due to to <661.1> Plastic material of constructionPlastic Material of construction

Impact on plastic material of construction for Packaging

Gap analysis and test required to perform

Compliance to USP 39

Polyethylene (LDPE & HDPE)

1) Poly bag2) HDPE Bottle, 3) Tri laminate*,4) Cap with PE based Wad*, 5) Alu Alu with Desiccant lidding foil and forming foil*

Except IR, other test required to perform either in house or some lab or confirm from Vendor .

For oral & topical dosages plastic additives not required and other than this it may required.

1) Confirmation from vendor for availability of data2) Confirmation for In house testing capability 3) Confirmation for FDA approved testing lab to do these testing

Polypropylene 1) PP CRC Cap, 2) PP NonCRC cap

PVC 1) PVC2) PVC-PVdC 3) PVC Aclar3) Lidding foil (VMCH coating), 4) Alu-Alu forming film

Cyclic olefins 1) COC Vials2) COC forming film

PET & PET G 1) PET Bottle

USP <661.2> - Plastic packaging system for pharmaceutical use

Introduction: The term “plastic packaging system” refers to the sum of packaging components that together contain the

pharmaceutical product, including closures. This sum of packaging components includes: 1) primary packaging components, which are those that directly contact the pharmaceutical product at some time during the product's manufacturing, distribution, storage, or use; and 2) secondary packaging components, which are those that may interact with the pharmaceutical product during the product's manufacturing, distribution, storage, and use, although the component does not directly contact the pharmaceutical product.

Scope: A packaging system is chemically suited for its intended use with respect to safety if:

1) The packaging system is constructed from well-characterized materials that have been intentionally chosen for use as established by testing according to Plastic Materials of Construction <661.1>.

2) The packaging system's general physicochemical properties have been established.

3) The packaging system's biocompatibility (biological reactivity) has been appropriately established.

4) The packaging system has been established to be safe by means of the appropriate chemical testing, such as extractables or leachables profiling, and toxicological assessment of the test data. This combination of chemical testing and toxicological assessment is termed “chemical safety assessment”.

<661.2> Plastic packaging system for pharmaceutical use Biological Reactivity Test - USP <87> & <88> Physico-chemical test - Provide general view of extracted substances Safety Assessement (Extractables/ Leachables)- E/L study and its toxicological assessment

Impact on packaging development due to on packaging development due to <661.2> Plastic packaging system for pharmaceutical useTest required

Impact on Packaging system

Gap analysis and test required to perform

Compliance to USP 39Conf. from Vendor for availability of data

Conf. for In house testing capability

Conf. for FDA approved testing lab to do these testing

1) Biological Reactivity Test :

1) Bottle pack 2) Blister pack 3) Injectable vial (USP type I vial, Rubber stopper &

flip off seal)4) Pet Bottle for oral liquid5) Inhalation /nasal pump

devices 6) Ophthalmic dosages form Currently there were not a

system to perform these test for in-house packaging system, In some cases of injectables/ophthalmic there is chemical assessment study from out side lab, other test may not performed on packaging system study

Need to define and discussed to perform these testing on packaging system

May not able to provide as these testing required on packaging

system only. Can provide

potential extractable for

individual component ,

Extractable on packaging

system need to perform

Need to define and discussed to develop capability perform these testing on packaging system

Indentify FDA Approved Lab to perform these test

on packaging system

2) Physicochemical tests :Appearance of SolutionAbsorbanceAcidity or alkalinityTotal organic carbonEthylene Glycol in PET & PET G packaging systemTotal terephthaloyl moieties in PET & PET G 3) Chemical safety assessment : Assessment of E/L Associated with Pharmaceutical Packaging/Delivery Systems (E- <1663> & L - <1664>)

USP <1661>- Evaluation of plastic packaging system and their materials of construction with respective to their user safety impact

Introduction:

The potential patient safety impact of interactions between a drug product and its packaging is assessed and established via the appropriate testing of the packaging systems and its materials and components of construction. Plastic packaging systems and their materials of construction <661> establishes the tests and specifications that are necessary and appropriate for ensuring that such systems are suitable for use, specifically safe for use. Chapter <661> consists of two sub-chapters, plastic materials of construction <661.1> and plastic packaging systems for pharmaceutical use <661.2>.

Scope:

The purpose of this chapter is to communicate the key concepts behind <661> and its related sub-chapters, <661.1> and <661.2>, and to provide additional information and guidance regarding the application and applicability of this set of chapters. Given the large and diverse nature of the pharmaceutical marketplace, the proper use and application of the <661> suite of chapters may not be intuitive to some stakeholders. Impact on packaging development due to <1661> Plastic packaging system and their

material of construction :

This chapter give better understanding to perform test mentioned in <661.1> and <661.2> as sub chapter of <661>, hence test performed on plastic packaging material of construction and packaging system as given in <661.1> and <661.2>, will be sufficient for suitability & safe use of packaging material/system for pharmaceutical use

USP <670> Auxiliary packaging component

Introduction:

Auxiliary packaging components are articles that are used to support or enhance container–closure systems. These Articles include, but are not limited to, pharmaceutical coil ▲and desiccants▲USP39 for containers. The components Covered in this chapter must meet the applicable requirements provided and the additional applicable requirements provided in other specified chapters.

Pharmaceutical Coil: Pharmaceutical coil is used as a filling material in multiple-unit containers for solid oral dosage

forms to prevent Breakage of tablets or capsules during shipment. The filling material should be discarded once the bottle is opened.

Desiccants: Desiccants are used to remove moisture from air in containers in order to protect drug products,

particularly solid oral dosage forms. They are supplied in a number of different packaging materials including cotton, Kraft paper, rayon and polyester cloth bags, perforated plastic, polymer films, polymer housings or Tyvek®. The most common types of Commercial desiccants are bentonite, calcium chloride, calcium oxide, molecular sieves, and silica gel. Other desiccants are subject to appropriate testing to ensure suitability for the intended application.

Where desiccants are incorporated directly into the wall or cap of packaging containers or bound by a carrier material, use unincorporated desiccant in the test methods. For desiccants that are loaded with a predetermined moisture content, perform the testing before the moisture has been loaded or after the desiccant has Been regenerated.

USP <670> Auxiliary packaging componentTest required for Pharmaceutical Coil (Ph. Coil)

Test to be performed/Ph. Coil Cotton Ph. Coil Rayon ph. coil Polyester ph. coilIdentification √ √ √ Acidity or Alkalinity √ √ √Florescence √ √ XResidual hydrogen peroxide conc. √ X XLoss on drying √ √ √Residual on Ignition √ √ √Water-soluble substances √ √ X Fatty matter √ √ X Dyes & Other Foreign matter √ √ X Acid-Insoluble Ash X √ XFinish on Fibers X X √

Test required for DesiccantsTest to be performed/Desiccants Bentonite Calcium Ch. Anh. Calcium Oxide Molecular Sieves Silica Gel Appearance √ X X X √Identification: Characterization of crystalline & partially crystalline solids by XRPD

√ X X

X X

Calcium X √ √ X XChloride X √ X X XIdentification A & B X X X √ √Precipitation √ X X X XAssay X √ √ X √Specific tests: pH √ √ X √ √Loss on drying √ X X √ √Loss on ignition X X √ X XMoisture Adso.cap. at 25/40 √ X X √ √Moisture Adso.cap. at 25/80 √ √ √ √ √Inorganic Impurities :Arsenic √ √ √ X XLead √ √ √ √ √Fluoride X √ √ X XMagnesium X √ √ X Xalkali salts X √ √ X XSoluble ionizable salts X X X X √Acid-insoluble substances X X √ X X

Impact on packaging development due to packaging development due to <670> Auxiliary packaging component

USP <670> - Auxiliary packaging componentsA) Pharmaceutical coil (Ph. coil)

A) Pharmaceutical coil (Ph. coil) Gap analysis/Impact assessment comments Cotton Ph. coil There is no change in USP, hence material should comply USP

testing requirement and specification or supplier can confirm that it meets all testing requirement.

Rayon ph. coil Same as abovePolyester ph. coil Same as above

B) DesiccantB) Desiccant Gap analysis/Impact assessment comments Silica Gel New inclusion of Auxiliary packaging component in USP 39 hence

these material should comply USP testing requirement and specification or supplier can confirm that it meets all testing requirement.

Molecular Sieves Same as aboveBentonite Same as aboveCalcium Ch.Anh. Same as aboveCalcium Oxide Same as above

Packaging development strategy for new projects with changes in USP 39

Three stage of packaging development and selection of their plastic materials of construction & packaging system

Packaging development strategy for new projects with changes in USP 39

Packaging system for pharmaceutical product required optimum testing procedure to identify the qualification and safety of plastic packaging material.

Before finalizing suitability of container closure system now it is essential to screen the plastic material of construction and packaging system through extensive testing.

Now packaging system will be come under USP testing, hence packaging system qualification is important for USA submission.

Plastic Materials of Characterization Biological Reactivity Test - USP <87> & <88>

Identification - IR & DSC Physico-chemical test - Provide general view of extracted substances

Extractable Metals – Potential sources of Elemental impurities. Plastic Additives - Potential organic extractable

Plastic packaging system for pharmaceutical use Biological Reactivity Test - USP <87> & <88> Physico-chemical test - Provide general view of extracted substances Safety Assessement (Extractables/ Leachables)- E/L study and its toxicological assessment

Packaging development strategy for new projects with changes in USP 39 A Universe of USP Chapters related to the chemical characterizations of system

and their materials of construction

Packaging development strategy for new projects with changes in USP 39

Well Characterized material

The five dimension that define a well-characterized material of construction

Packaging development strategy for new projects with changes in USP 39

Safe Packaging System

The five dimensions that define a packaging system that is suited for its intended use with respect to safety