1. Manufacturing Process of Drug Product: Container closure system Compatibility
Ratiya KUKHETPITAKWONG
27 April 2016

2. Container Closure System
คำจำกัดความ (Definition)
Material of construction
อ้างถึงสาร (substances)
Packaging component
ส่วนของระบบปิดของภาชนะบรรจุ
Primary packaging component - ภาชนะบรรจุปฐมภูมิ
Secondary packaging component - ภาชนะบรรจุทุติยภูมิ
Container closure system (Packaging system)
ระบบปิดของภาชนะบรรจุ
Package (Market package)

3. Quiz
ภาชนะบรรจุทุติยภูมิ
ภาชนะบรรจุปฐมภูมิ

4. Containers http://www.hexpoltpe.com/getfile.php?
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5. คุณสมบัติของ Packaging Component
A packaging system found acceptable for one drug product is not automatically assumed to be appropriate for another.
Information depend on
Dosage form
Route of administration

6. Packaging Component-Dosage Form Interaction
Risk-base approach
Degree of Concern Associated with the Route of Administration
Likelihood of
Packaging Component-Dosage Form Interaction
High
Medium
Low
Highest
Inhalation Aerosols & Solutions; Injections & Injectable suspensions
Sterile Powders & Powders for Injection; Inhalation Powders
Ophthalmic Solutions & Suspensions; Transdermal Ointments & Patches; Nasal Aerosols & Sprays
Topical Solutions Suspensions; Topical & Lingual Aerosols; Oral Solutions & Suspensions
Topical Powders; Oral Powders
Oral Tablets & Oral (Hard & Soft Gelatin) Capsules

7. Information that should be submitted for any drug product (1/2)
Description
Overall general descriptions of the container closure system, plus:
For each Packaging Component:
Name, Product code, manufacturer, physical description
Materials of construction (for each, name, manufacturer, product code)
Description of any additional treatments or preparations
Suitability
Protection: (By each component and/or the container closure system, as appropriate)
Light exposure
Reactive gases (e.g., oxygen)
Moisture permeation
Solvent loss or leakage
Microbial contamination (sterility/container integrity, increased bioburden, microbial limits)
Filth
Other
Safety: (for each material of construction, as appropriate)
Chemical composition of all plastics, elastomers, adhesives, etc.
Extractables, as appropriate for the material
Other studies as appropriate
Compatibility: (for each component and/or the packaging system, as appropriate)
Component/dosage form interaction
May also be addressed in post-approval stability studies
Performance: (for the assembled packaging system)
Functionality &/or drug delivery, as appropriate

8. Information that should be submitted for any drug product (2/2)
Quality control
For each packaging component received by the applicant:
Applicant’s tests & acceptance criteria
Dimensional (drawing) & performance criteria
Method to monitor consistency in composition, as appropriate
For each packaging component provided by the supplier:
Stability
Guidance for industry Q1A(R2) Stability testing of new drug substances and products

9. Potential effects of Packaging component/dosage form interactions
Hemolytic effect
Pyrogenic effect
Potency of drug product or concentration of antimicrobial preservatives

10. ข้อควรพิจารณา Suitability for intended use
Quality control of Packaging Components
Associated components
Packaging components which are typically intended to deliver to dosage form to the patient but are not stored in contact with the dosage form for its entire shelf life.
Secondary packaging components
Packaging components which are not intended to make contact with the dosage form.

11. Suitability for intended use (1/2)
Protection
Light exposure
Moisture permeation
Seal integrity or leak test
Compatibility
<661> Containers-Plastics
Polyethylene (PE) containers: HDPE, LDPE
Polypropylene (PP) containers:
PE terephthalate (PET) bottles and PET G containers
Physicochemical tests: IR, DSC, Heavy metals & nonvolatile residue, & component used in contact with oral liquid
<381> Elastomeric closures for Injections

12. Suitability for intended use (2/2)
Safety
<87> Biological reactivity test, in vitro
<88> Biological reactivity test, in vivo
Performance
<671> Containers-Performance testing
Moisture permeation
Light transmission

13. Quality control of packaging components
Physical characteristics
Dimension criteria
Physical parameters critical to the consistent manufacture of a packaging component
Performance characteristics
Chemical composition
New materials of packaging component may result in new substances being extracted into the dosage form or a change in the amount of known extractables.

14. Compatibility
<1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems.
Definition
Extractables - organic & inorganic chemical entities that can be released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction under laboratory conditions. Extractables themselves, or substances derived from extractables, have the potential to leach into a drug product under normal conditions of storage and use.
Leachables – organic or inorganic chemical entities that migrate from a packaging/delivery system, packaging component, or packaging material of construction into an associated drug product under normal conditions of storage and use or during accelerated drug product stability studies. Leachables are typically a subset of extractables or are derived from extractables

15. Studies on Extractables and Leachables
Extractables studies - the overall laboratory processes required in order to create extractables profile(s) of particular pharmaceutical packaging/delivery systems, packaging components, or materials of construction. Extraction studies are also referred to as Controlled Extraction Studies.
<1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems.
Leachables Studies - laboratory investigations into the qualitative and quantitative nature of a particular leachables profile(s) over the proposed shelf-life of a particular drug product.

16. Leachable study
เพื่อช่วยสรรหา packaging components & their materials of construction
Leachable characterization (for high-risk dosage form)
Trend identification in leachables accumulation levels
Individual leachable evaluation
Qualification of the leachables on a safety basis
การหาความสัมพันธ์ระหว่าง Leachables-Extractables
การพิจารณา specification & acceptance criteria ของ leachables

17. Decision tree for identification & qualification Q3B(R2)

18. Toxicological Evaluation
Safety Concern Threshold (SCT) – the threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and noncarcinogenic toxic effects
Qualification Threshold (QT) – the threshold below which a given non-carcinogenic leachable is not considered for safety qualification unless the leachable presents
Analytical Evaluation Threshold (AET) – the threshold at or above which a particular extractable &/or leachable should be identified, quantified, & reported for potential toxicological assessment

19. ข้อควรพิจารณาเพิ่มเติม
Submission of Investigational New Drug (IND)
Submission on packaging of a drug product by another firm
Contract packager
บริษัทที่รับจ้างบรรจุภัณฑ์ผลิตภัณฑ์ยา ผู้รับจ้างมีความรับผิดชอบต่อคุณภาพของผลิตภัณฑ์ระหว่างขนส่ง (Shipping) การเก็บรักษา (Storage) และการบรรจุภัณฑ์ (Packaging)
Repackager
บริษัทที่ซื้อผลิตภัณฑ์ยาจากผู้ผลิตหรือผูกระจายยาและทำการบรรจุภํณฑ์ใหม่เพื่อขายภายใต้การติดฉลากที่แตกต่างไปจากผู้ผลิต ซึ่งบริษัทผู้ซื้อต้องรับผิดชอบต่อคุณภาพและความคงสภาพของผลิตภัณฑ์ยาที่บรรจุภัณฑ์ใหม่นั้น

20. Examples of the items that have been submitted
Descriptive information:
General description of the component and the address of the manufacturing site
Description of the manufacturing process for a packaging component and operations performed after manufacture, but prior to shipment (washing, coating, sterilization or depyrogenation)
Description of the acceptance, in-process, and release controls for materials of construction, the manufacturing process, and the finished product (component or assembled component)
Characterization of the key properties
Information about suitability:
Protection provided by the component
Safety information on the materials of construction or the finished component
Compatibility of the materials of construction or the finished component with the specific dosage form, the specific drug product, or equivalent materials
Information about quality control:
Dimensional (an engineering drawing) & performance criteria for the component
A description of the quality control measures used to maintain consistency in the physical and chemical characteristics of packaging components
A summary of the quality assurance/quality control criteria when release of the component is based on statistical process control

21. เอกสารอ้างอิง
Guidance for industry: Container closure systems for packaging human drugs & biologics (May, 1999)
ICH Impurities in New Drug Products Q3B(R2) (June 2006)
PDA J Pharm Sci and Tech 2013, 67:
USP

22. Thank you for your attention