FDA GUIDELINES OF CONTAINER CLOSURE SYSTEM FOR

PACKAGING&

DRUG STABILITY

Saurav Anand(+091-9974564659,89800775590)Alembic Research CenterPGDPT,IIP

FDA GUIDELINES OF CONTAINER CLOSURE SYSTEM

FOR PACKAGING

CONTAINER CLOSURE SYSTEM FOR PACKAGING HUMAN DRUGS & BIOLOGICS

CONTENTS: DEFINITION CGMP, CPSC AND USP REQUIREMENTS. QUALIFICATION AND QUALITY CONTROL OF PACKAGING

COMPONENTS. POSTAPPROVAL PACKAGING CHANGES. TYPE III DRUG MASTER FILES. BULK CONTAINERS. REGULATORY REQUIREMENTS. COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING. EXTRACTION STUDIES DRUG STBILITY

DEFINITION MATERIALS OF CONSTRUCTION- Substances (e.g., glass, Plastic

resin, metal) used to manufacture a packaging component. A PACKAGING COMPONENT- Any single part of a container closure

system.(e.g., ampules, vials, bottles), container liners (e.g., tube liners), closures (e.g., screw caps, stoppers),stopper overseals, inner seals, container labels etc.

A PRIMARY PACKAGING COMPONENT-Packaging component that is or may be in direct contact with the dosage form.

A SECONDARY PACKAGING COMPONENT-Packaging component that is not and will not be in direct contact with the dosage form.

A CONTAINER CLOSURE SYSTEM- Sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system.

CGMP, CPSC and USP REQUIREMENTS

Current good manufacturing practice (CGMP)CGMP– 21CFR 210 & 211.

Consumer Product Safety Commission (CPSC) The United States Pharmacopeial Convention has

established requirements for containers which are described in many of the drug product

monographs in The United States Pharmacopeia/National Formulary (USP/NF).

i) General Notices and Requirementsii) General test and assay section of the USP.

CGMP[CODE OF FEDERAL REGULATIONS (CFR)] 21 CFR 211.80 - 211.94 - Control of Components and Drug

Product Containers and Closuresa) Shall not be reactive, additive, or absorptive so as to alter

the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.

b) Adequate protection against foreseeable external factors in storage and use

c) sterilized and processed to remove pyrogenic properties to ensure for use also documented.

21 CFR 211.122 - 211.137 - Packaging and Labeling Control 16 CFR 1700-1702 - Special Packaging. Regulations issued

under the PPPA establish performance standards and test methods that determine if a packaging system is child-resistant and adult-use-effective (16 CFR 1700.15 and 16 CFR 1700.20, respectively).

The Poison Prevention Packaging Act of 1970 (PPPA). 21 CFR 174-186 - Indirect Food Additive Regulations

U.S.P./NATIONAL FORMULARYFOR PACKAGING COMPONENT General Notices - Preservation, Packaging, Storage, & Labeling. General Tests and Assays.<1> Injections<51> Antimicrobial Preservatives - Effectiveness<61> Microbial Limit Tests<71> Sterility Tests<87> Biological Reactivity Tests, in vitro<88> Biological Reactivity Tests, in vivo<161> Transfusion and Infusion Assemblies<381> Elastomeric Closures for InjectionsBiological Test ProceduresPhysicochemical Test Procedures<601> Aerosols<661> Containers<671> Containers - Permeation Multiple-Unit Containers for Capsules and TabletsSingle-Unit Containers and Unit-Dose Containers for Capsules and

Tablets<691> Cotton (or the monograph for Purified Rayon USP)<771> Ophthalmic Ointments<1041> Biologics<1151> Pharmaceutical Dosage Forms

QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS

CDER and CBER approve a container closure system to be used in the packaging of a human drug or biologic as part of the application (NDA, ANDA or BLA) for the drug or biologic.

The type and extent of information that should be provided in an application will depend on the dosage form and the route of administration.

TYPES OF DOSAGE FORMS

Inhalation Drug Products (section III.D) Drug Products for Injection and Ophthalmic Drug Products (Section III.E) Liquid-based Oral and Topical Drug Products and

Topical Delivery Systems (section III.F) Solid Oral Dosage Forms and Powders for

Reconstitution (section III.G) Other Dosage Forms (section III.H)

INFORMATION TO BE SUBMITTED TO FDA DESCRIPTION SUITABILITY FOR THE INTENDED USEa) Protectionb) Compatibilityc) Safetyd) Performance i) Container Closure System Functionalityii) Drug Delivery QUALITY CONTROL(section III.C.3)a) Physical Characteristicsb) Chemical Composition Associated Components (sections III.B.1 and

III.B.2) Secondary Packaging Components (sections III.B.1

and III.B.2) STABILIYT

INFORMATION TO BE SUBMITTED TO FDA Inhalation Drug Products (section III.D)i) Metered Dose Inhaler (MDI) and Dry Powder Inhaler

(DPI) Drug Productsii) Nasal Spray and Inhalation Solution, Suspension,

and Spray Drug Products; Chemistry, Manufacturing and Controls Documentation.

Drug Products for Injection and Ophthalmic Drug Products (section III.E)

Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems (section III.F)

Solid Oral Dosage Forms and Powders for Reconstitution (section III.G)

Other Dosage Forms (section III.H)

THE FEDERAL FOOD,DRUG,& COSMETIC ACT Section 501 -A drug or device shall be deemed to be

adulterated. Section 502 - A drug or device shall be deemed to be

misbranded.

EXTRACTION STUDIES Study of a packaging component typically involves exposing

a sample of the component, often subdivided into small pieces to increase surface area, to an appropriate solvent or preferred solvent would be the drug product or placebo vehicle system at elevated temperatures, followed by chemical analysis.

Purposes: To perform USP characterization tests on plastics (USP

<661>) or elastomers (USP <381>) To perform USP Biological Reactivity Tests (USP <87> and

<88>) on plastics or elastomers To obtain qualitative & quantitative extraction profiles of

plastics or elastomers To evaluate whether the FDA indirect food additive

regulations provide an adequate indicator of safety.

POSTAPPROVAL PACKAGING CHANGESThe safety or effectiveness of the product depends on the

identity, strength, quality, purity, or potency of a product as they may

vary when making a change to or in the container closure system.THE CONTAINER CLOSURE SYSTEM i) Interaction between the packaging component and the dosage

form.ii) Performance. 21 CFR 314.70 for an NDA or ANDA 21 CFR 601.12 for BLAPACKAGING CHANGES Major Changes (Prior Approval Supplement) Moderate Changes (Supplement - Changes Being Effected) Minor Changes (Annual Report)LABELING CHANGES Major Changes (Prior Approval Supplement) Moderate Changes (Supplement - Changes Being Effected) Minor Changes (Annual Report)

TYPE III DRUG MASTER FILES The letter of authorization(LOA) is a letter from

the manufacturer(Vendor) to the applicant Descriptive Information Information About Suitability Information About Quality Control

BULK CONTAINERS Containers for Bulk Drug Substances Containers for Bulk Drug Products

DRUG STABILITY

DRUG STABILITY Container/closure system in which Formulation is remain

within its physical, chemical, microbiological therapeutic and toxicological specification.

The USP definition:“extent to which a product retains within specified limits” and throughout its period of storage and use (i.e. its shelf life) the same properties and characteristics that it possessed at the time of its manufacturer’’.

Assurance of drug stability come from an accumulation of valid data on the drug in its commercial package. These data involves selected parameters that taken together from the stability profile. Pharmaceutical products are expected to meet their specification for identifying purity, quality and strength throughout their defined storage period at specific storage condition.

DRUG STABILITYThere are five types of stability that must be

consider for each drug.

ROLE OF STABILITY TESTING

Provides evidence on how the drug substance or product quality varies with time under environmental conditions during distribution.

Helps to recommend storage conditions including establishment of shelf life, expiry date or retest period

Key assurance of quality of pharmaceuticals.

INTERNATIONAL CONFERENCE ON HARMONIZATION (ICH)

ICH stands for International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use

OBJECTIVES OF ICH: Harmonization of registration applications within the three

regions of the EU, Japan and the United States.

ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines.

Tripartite guideline on stability testing of new drug substances and products (Q1A) in 1993, has become standard for stability evaluation in Japan, US, Europe.

TYPE, SIZE, NUMBER OF BATCHES

ICH/ WHO GUIDELINES:

At least 3 primary batches of drug product, should be of the same formulation, packaged in same container as proposed for marketing

2 out of 3 batches should be pilot scale batches.

Stability to be performed on each strength, container size.

CLIMATIC ZONES & STABILITY CONDITION

STUDY CLIMATIC ZONE I & II (US & EUROPE) TEMP & % RH COND.

CLIMATIC ZONE III & IV(DOMESTIC &BRAZIL) TEMP & % RH COND.

LONG 25 + 2°C & 60 + 5 % RH

30 + 2°C &65 + 5 % RH

INTERMEDIATE 30 + 2°C & 65 + 5 % RH

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ACCELERATED 40 + 2°C & 75 + 5 % RH

40 +2°C & 75 + 5 % RH

CLIMATIC ZONES/STORAGE COND. (ICH)

DRUG PRODUCTS–PACKAGED IN SEMI-PERMEABLE CONTAINERSSTUDY STORAGE CONDITION MIN. TIME PERIOD

COVERD BY DATA AT SUBMISSION

LONG TERM 25°C ± 2°C / 40% ± 5% r.h. or30°C ± 2°C / 35% ± 5% r.h.

12 months

INTERMEDIATE 30°C ± 2°C / 65% ± 5% r.h. 6 monthsACCELERATED 30°C ± 2°C / 65% ± 5% r.h. 6 months

STUDY STORAGE CONDITION MIN. TIME PERIOD COVERD BY DATA AT SUBMISSION

LONG TERM 25°C ± 2°C / 60% ± 5% r.h. or30°C ± 2°C / 65% ± 5% r.h.

12 months

INTERMEDIATE 30°C ± 2°C / 65% ± 5% r.h. 6 monthsACCELERATED 40°C ± 2°C / 75% ± 5% r.h. 6 months

DRUG PRODUCTS – GENERAL CASE

CLIMATIC ZONES/STORAGE CONDITIONS

STUDY STORAGE CONDITION MIN. TIME PERIOD COVERD BY DATA AT SUBMISSION

LONG TERM -20°C ± 5°C 12 months

STUDY STORAGE CONDITION MIN. TIME PERIOD COVERD BY DATA AT SUBMISSION

LONG TERM 5°C ± 3°C 12 months

ACCELERATED 25°C ± 2°C / 60% ± 5% r.h.

6 months

DRUG SUBSTANCES – INTENDED FOR STORAGE IN A REFRIGERATOR

DRUG SUBSTANCES/PRODUCTS – INTENDED FOR STORAGE IN FREEZER

SHELF LIFE

Maximum and Minimum time at which potency must be at least 90% of label claim at the temperature indicated in order to predict a shelf life of two years at Room Temperature.Temperature Maximum time for

studyMinimum time for study

37°C 12 Months 6.4 Months45°C 8.3 Months 2.9 Months60°C 4.1 Months 3 Weeks85°C 06 Weeks 2.5 Days