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

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)

Quiz ภาชนะบรรจุทุติยภูมิ ภาชนะบรรจุปฐมภูมิ

Containers http://www.hexpoltpe.com/getfile.php? type=banner_images&id=Syringe.jpg http://www.chinazfeng.com/Attachment/ 20127714191619.jpg http://www.greatbearhealthcare.co.uk/ wp-content/uploads/2012/10/gb3-280x300.jpg

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

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

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

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

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

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.

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

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

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.

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

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.

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

Decision tree for identification & qualification Q3B(R2)

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

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

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

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: 413-429. USP

Thank you for your attention