FDA container closure system & drug stability saurav anand 23 iip

1. FDA GUIDELINES OF CONTAINER
CLOSURE SYSTEM FOR
PACKAGING
&
DRUG STABILITY
Saurav Anand
(+091-9974564659,89800775590)
Alembic Research Center
PGDPT,IIP

2. FDA GUIDELINES OF
CONTAINER CLOSURE SYSTEM
FOR PACKAGING

3. 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

4. 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.

5. 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 Requirements
ii) General test and assay section of the USP.

6. CGMP[CODE OF FEDERAL REGULATIONS (CFR)]
 21 CFR 211.80 - 211.94 - Control of Components and Drug
Product Containers and Closures
a) 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

7. U.S.P./NATIONAL FORMULARY
FOR 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 Injections
Biological Test Procedures
Physicochemical Test Procedures
<601> Aerosols
<661> Containers
<671> Containers - Permeation
Multiple-Unit Containers for Capsules and Tablets
Single-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

8. 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.

9. 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)

12. INFORMATION TO BE SUBMITTED TO FDA
 DESCRIPTION
 SUITABILITY FOR THE INTENDED USE
a) Protection
b) Compatibility
c) Safety
d) Performance
i) Container Closure System Functionality
ii) Drug Delivery
 QUALITY CONTROL(section III.C.3)
a) Physical Characteristics
b) Chemical Composition
 Associated Components (sections III.B.1 and III.B.2)
 Secondary Packaging Components (sections III.B.1 and
III.B.2)
 STABILIYT

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

16. 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.

17. POSTAPPROVAL PACKAGING CHANGES
The 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 BLA
PACKAGING 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)

18. 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

19. DRUG STABILITY

20. 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.

21. DRUG STABILITY
There are five types of stability that must be
consider for each drug.

22. 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.

23. 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.

24. 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.

25. CLIMATIC ZONES & STABILITY CONDITION
STUDY CLIMATIC ZONE CLIMATIC ZONE
I & II III & IV
(US & EUROPE) (DOMESTIC &BRAZIL)
TEMP & % RH COND. TEMP & % RH COND.
LONG 25 + 2 C & 30 + 2 C &
60 + 5 % RH 65 + 5 % RH
INTERMEDIATE 30 + 2 C & ---
65 + 5 % RH
ACCELERATED 40 + 2 C & 40 +2 C &
75 + 5 % RH 75 + 5 % RH

26. CLIMATIC ZONES/STORAGE COND. (ICH)
DRUG PRODUCTS – GENERAL CASE
STUDY STORAGE CONDITION MIN. TIME PERIOD
COVERD BY DATA
AT SUBMISSION
LONG TERM 25°C ± 2°C / 60% ± 5% r.h. or 12 months
30°C ± 2°C / 65% ± 5% r.h.
INTERMEDIATE 30°C ± 2°C / 65% ± 5% r.h. 6 months
ACCELERATED 40°C ± 2°C / 75% ± 5% r.h. 6 months
DRUG PRODUCTS–PACKAGED IN SEMI-PERMEABLE CONTAINERS
STUDY STORAGE CONDITION MIN. TIME PERIOD
COVERD BY DATA
AT SUBMISSION
LONG TERM 25°C ± 2°C / 40% ± 5% r.h. or 12 months
30°C ± 2°C / 35% ± 5% r.h.
INTERMEDIATE 30°C ± 2°C / 65% ± 5% r.h. 6 months
ACCELERATED 30°C ± 2°C / 65% ± 5% r.h. 6 months

27. CLIMATIC ZONES/STORAGE CONDITIONS
DRUG SUBSTANCES –
INTENDED FOR STORAGE IN A REFRIGERATOR
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% 6 months
r.h.
DRUG SUBSTANCES/PRODUCTS –
INTENDED FOR STORAGE IN FREEZER
STUDY STORAGE CONDITION MIN. TIME PERIOD
COVERD BY DATA
AT SUBMISSION
LONG TERM -20°C ± 5°C 12 months

28. 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 study Minimum time for study
37°C 12 Months 6.4 Months
45°C 8.3 Months 2.9 Months
60°C 4.1 Months 3 Weeks
85°C 06 Weeks 2.5 Days