FDA/Industry Container Closure Guidance Training Session

October 26, 1999

GUIDANCE OVERVIEW
Donald N. Klein, Ph.D. CDER

Outline
Introduction Definitions References in the Guidance Websites Table 1: Examples of Packaging Concerns for Common Classes of Drug Products Table 2: Typical Suitability Considerations for Common Classes of Drug Product

Outline (contd)
Table 3: Information that should be Submitted Table 5: AAO Recommended Color Coding of Caps and Labels for Topical Ophthalmic Medications Comparison Table 4: Injectable or Ophthalmic Drugs Table 6: Liquid-Based Oral, Topical Drugs, and for Topical Drug Delivery Systems Table 7: Solid Oral Drugs and Powders Summary
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Packaging Guidance, May, 1999

Represents the Agencys current thinking on container closure systems for the packaging of human drugs and biological products; Does not create or confer any rights for or on any person and does not operate to bind FDA or the public; An alternative approach may be used if such approach satisfies the requirements of the applicable statue, regulations, or both.
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Definitions
Materials of Construction Container Closure System Packaging Component Primary Packaging Component Secondary Packaging Component Associated Component Quality Extraction Profile
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Definitions
Materials of Construction
refers to the substances, e.g., glass, HDPE, metal, used to manufacture a packaging component

Container Closure System

refers to the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components
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Definitions
Packaging Component
any single part of a container closure system

Primary Packaging Component

a packaging component that is or may be in direct contact with the dosage form
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Container Closure System

Primary Component
ampules closure liners desiccant container filler(cotton, rayon) dosing dropper closures (plastic, metal) syringes bottles(glass, HDPE) flexible bags tube with/without liner pouch innerseal blister packaging bulk containers
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Definitions
Secondary Packaging Component
a packaging component that is not or will not be in direct contact with the dosage form

Container Closure System

Secondary Component
overwraps cartons labels on cartons

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Definitions
Associated Component
intended to deliver the dosage form to the patient but not stored in contact with the dosage form dosing cup calibrated spoon syringe dropper

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Definitions
Quality
refers to the physical, chemical, microbiological, biological, bioavailability, and stability attributes that a drug product should maintain

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Definitions
Extraction Profile
refers to the analysis, usually by chromatographic means, of extracts obtained from a packaging component y USP <661>, characterization test on plastics y USP<381>, characterization tests on elastomers y USP <87> & <88>, Biological Reactivity Tests
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References in the Packaging Guidance

The United States Pharmacopeia Guidance for Phase 1 IND Studies of Drugs (Nov., 1995) Guidance for INDs for Phase 2 and 3 Studies(draft, April, 1999) Guidance for Stability Testing of Drug Substances and Drug Products(draft, June, 1998) Guideline for Drug Master Files(Sept., 1989) Guidance for Vaccine or Related Products(Jan., 1999)
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References in the Packaging Guidance

Guidance for Sterilization Process Validation in Applications for Human and Veterinary Drug Products(Nov., 1994) Guidance for Biological In Vitro Diagnostic Product(March, 1999) Guidance for Metered Dose Inhaler and Dry Powder Inhaler(draft, Nov., 1998) Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products(draft, May, 1999)
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Websites
CENTER FOR DRUG EVALUATION AND RESEARCH

http://www.fda.gov/cder/guidance/index.htm
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

http://www.fda.gov/cber/guidelines.htm
Compliance Policy Guides

www.fda.gov/ora
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Table 1: Examples of Packaging Concerns for Common Classes of Drug Products

y illustrates the correlation between the degree of concern regarding the route of administration with the likelihood of packaging component-dosage form interactions for the listed drug products

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Table 1: Examples of Packaging Concerns for Common Classes of Drug Products

y Degree of Concern associated with the Route of Administration - Highest; High; or Low y Likelihood of Packaging Component-Dosage Form Interaction - High; Medium; or Low

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Table 1: Examples of Packaging Concerns for Common Classes of Drug Products

y Injections: y Highest(degree of concern) with High(interaction) y Inhalation Powders: Highest(degree of concern) with Medium(interaction) y Oral Capsules: Low (degree of concern) with Low(interaction)

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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y summarizes typical packaging suitability considerations for common classes of drug products y Route of Administration/Dosage Form versus y Suitability
y y y y

Protection Compatibility Safety Performance/Drug Delivery

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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Protection: 5 categories y L: protects from light y S: protects from solvent loss/leakage y M: protects sterile products y W: protects from water vapor y G: protects from reactive gases

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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Compatibility: 3 cases y Case 1c: liquid based dosage form y could interact with container closure system y Case 2c: solid dosage form until reconstituted y possible interaction after reconstituted y Case 3c: solid dosage form y low likelihood of interacting
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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Safety: 5 cases y Case 1s: USP Biological Reactivity Test and extraction/toxicological evaluation y Case 2s: USP Biological Reactivity Test and possibly extraction/toxicological evaluation y Case 3s: Indirect food additive regulations for aqueous-based, but additional suitability information for non-aqueous based drugs

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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Safety: 5 cases y Case 4s: Indirect food additive regulations y Case 5s: Indirect food additive regulations and USP Biological Reactivity Test

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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Performance/Drug Delivery: 3 cases y Case 1d: Frequently a consideration y Case 2d: May be a consideration y Case 3d: Rarely a consideration
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Table 2: Typical Suitability Considerations for Common Classes of Drug Products

y Injections y Protection: Light(L); Solvent(S); Microbial(M); Reactive Gases(G) y Compatibility: Liquid dosage form(Case 1c) y Safety: typically provided are USP Biological Reactivity Test data(Case 2s) y Performance: may be a consideration(Case 2d)
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Table 3: Information that should be submitted in an Original Application for Any Drug Product
Description Suitability
Protection Safety Compatibility Performance
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Quality Control Stability

Table 3: Description
Overall general description of the container closure system For each packaging component: Name, product code, and manufacturer Materials of construction Description of any additional treatments

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Table 3: Suitability
Protection Safety Compatibility Performance
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Table 3: Suitability
Protection
A container closure system should provide the dosage form with adequate protection from factors that can cause a degradation in the quality of that dosage form over its shelf life.
exposure to light loss of solvent microbial contamination absorption of water vapor

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Table 3: Suitability
Safety
Packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances into the drug product.
chemical composition of all plastics, elastomers extractables USP testing reference to indirect food additive regulations
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Table 3: Suitability
Compatibility
Packaging components that are compatible with a dosage form will not interact sufficiently to cause unacceptable changes in the quality of either the dosage form or the packaging component.
component/dosage form interactions, USP methods are typically accepted stability studies may support compatibility
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Table 3: Suitability
Performance
Refers to the container closure systems ability to function in the manner for which it was designed. Functionality: improve ease of use prefilled syringe

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Table 3: Suitability
Performance
Drug delivery refers to the the ability of the packaging system to deliver the dosage form in the amount or at the rate described in the package insert calibrated dropper

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Table 3: Quality Control

For each packaging components received by the Applicant
Applicants tests and acceptance criteria Dimensional drawing and performance criteria Method to monitor consistency in composition
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Table 3: Quality Control

For each packaging component provided by the Supplier
Letter of Authorization for the DMF is needed Manufacturers acceptance criteria for release Description of manufacturing process
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Table 3: Stability
Stability testing of the drug product should be conducted using the container closure system in the application The package system used in each stability study should be clearly defined Refer to the Draft Stability Guidance, June, 1998 37

Table 5: AAO Recommended Color Coding Caps and Labels for Topical Ophthalmic Medications
American Academy of Ophthalmology recommended to the FDA that a uniform color coding system be established for the caps and labels of all topical ocular medications Approved by AAO in June, 1996 38

Table 5: AAO Recommended Color Coding Caps and Labels for Topical Ophthalmic Medications
Class Color Pantone Number Class: Anti-Infectives Color: Tan Pantone Number: 467
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Information that should be Submitted

Comparison:
Table 4: Injectable and Ophthalmic Drugs Table 6: Liquid-Based Oral, Topical Drugs and for Topical Drug Delivery Systems Table 7: Solid Oral Drugs and Powders
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Description of Additional Treatments

Injectable Drugs(Table 4)
sterilization of packaging components

Liquid-Based Oral Drugs(Table 6)

procedure for washing packaging components

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Suitability: Protection
Injectable Drugs(Table 4)
solvent loss(liquid base) sterility

Topical Drugs(Table 6)
seal integrity of tubes leak testing of tubes

Solid Oral Drugs(Table 7)

water vapor permeation
USP<661> and USP <671>
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Suitability: Safety
Injectable Drugs(Table 4)
elastomeric closures: USP testing plastic components: USP testing

Topical delivery systems(Table 6)

indirect food additive regulations

Solid Oral Drugs(Table 7)

desiccant container labels
inks; adhesives; lacquers; varnishes
indirect food additive regulations
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Suitability: Compatibility
Injectable Drugs(Table 4)
plastic components: USP testing

Topical delivery systems(Table 6)

glass components: USP testing

Solid Oral Drugs(Table 7)

plastic and glass components: USP testing

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Suitability: Performance
Table 4: Injectable and Ophthalmic Drugs
syringe; IV bag

Table 6: Liquid-Based Oral and Topical Drugs

dosing cup; calibrated dropper

Table 7: Solid Oral Drugs

calibrated spoon
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Summary
Definitions Table 1: Packaging Concerns Table 2: Suitability Considerations Table 3: Information Submitted
Description Suitability Quality Control Stability
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Summary (contd)
Table 5: Topical Ophthalmic Medications Comparison by information submitted or by specific example Table 4: Injectable or Ophthalmic Drug Products Table 6: Liquid-Based Oral, Topical Drug Products, and Topical Drug Delivery Systems 47 Table 7: Solid Oral Drug Products