Quality By Design for Packaging Development

By Saurav Anand

+91-8511773466Packaging Development, IIP, MBA

Quality By Design approach of Packaging Development Definition A systematic approach to development that begins with predefined objectives

and emphasizes product and process understanding, as well as process control, which are based on sound science and quality risk management.

Component Critical Quality Attributes (CQAs) are physical, chemical, biological or

microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Critical Process Parameter (CPP) is a process parameter whose variability has an impact on the CQA. The CPP should be monitored and controlled to ensure that the process produces products with desired quality specifications.

Quality By Design approach of Packaging Development

Design space is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within this design space is not considered a change.

Quality Target Product Profile (QTPP) is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality. QTPP also takes into account safety and efficacy of the drug product.

Packaging aspects must be considered during the development of product. The packaging process parameters may affect the final product quality. During the development of packaging for products, it is important to understand the impact of material attributes and process parameters on CQAs. It is essential to identify and control the sources of variability. It is also critical to continue to monitor these throughout the lifecycle of the product.

Fundamentals of Container Closure System (CCS)

ContainersA containers for Pharmaceutical use is an article which holds or is intended to contain andprotect a drug and is or may be in direct contact with it. The closure is a part of thecontainer. The container and its closure must not interact physically or chemically with thesubstance within in any way that would alter its quality.USP Tamper-Evident Packaging Light-Resistant Container Well-Closed ContainerTight ContainerHermetic ContainerSingle-Unit Container Single-Dose ContainerUnit-Dose Containers Unit-of-Use ContainersMultiple-Unit Containers Multiple-dose Containers

Fundamentals of Container Closure System (CCS)

Packaging material Any material employed in the packaging of a medicinal products,

excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according

to whether or not they are intended to be in direct contact with the product.

Any single part of a container closure system. Typical components areContainers , Container liners Closures, Closure linersStopper overseals, Container inner seals Administration portsoverwrapsAdministration accessories Container labels

Fundamentals of Container Closure System (CCS)Primary packaging componentPackaging component that is or may be in direct contact with the dosage

form.

Secondary packaging componentPackaging component that is not and will not be in direct contact with the

dosage form.

Container closure systemThe sum of packaging components that together contain and protect the

dosage form. This includes primary packaging components & secondary packaging

components, if the latter are intended to provide additional protection to the drug product.

Packaging system is equivalent to a container closure system

Type of Packaging by Route of AdministrationRoute of Administration Type of Packaging

Key Selection Criteria – Packaging Films

Choosing the most appropriate pack Shelf life enhancement. Material options – Barrier & Type ( Halogenated & Non-Halogenated) . Comply Quality by Design (QbD) Regional regulatory requirements.(e.g. CR/SF features). Anti-Counterfeit protection. Enable branding. Machine-packaging material interface – to improve productivity. Cost optimization.

Additional drivers & future challenges: Moisture sensitive drugs increasing barrier requirements Novel delivery systems Emphasis on speed to market Control of R&D Expenditure/resource - number of stability studies required Global - Regional - Local packs Anti-counterfeiting, illegal cross-border trading Pharmacogenomics - Personalised medicines Demographic change - Ageing population

Quality By Design (QBD) approach for Packaging DevelopmentOverview 1) Concept developmenta) Voice –of the-customer-resulted in established the QTPPs (Quality target product profile)b) Establish CQAs (Critical quality attributes)c) Concept and prototype selectionsd) Design of experiment and data analysis

2) Product Developmenta) Design verificationb) Validationc) Stabilityd) Real time process controls to ensure qualityf) Risk based change strategy

3) Industrializationa) Design transferb) Market introduction

Quality By Design (QBD) approach for Packaging Development

1) Concept Developmenta) Voice –of the-customer-resulted in established the QTPPs

(Quality target product profile)

b) Establish CQAs (Critical quality attributes)

c) Concept and prototype selections

d) Design of experiment and data analysis

1) Concept developmenta) QTPPs (Quality target product profile) Voice –of the-customer-resulted in established The quality

target product profile(QTPP) relates to quality, safety and efficacy.

Suitability – tests and studies and accepted for the initial qualification of

a component or a container closure system for its intend use.

Protection Safety Compatibility Performance & Dose delivery.

1) Concept development a) QTPPs (Quality target product profile) Examples of Packaging Concerns for Common Classes of Drug

ProductsDegree of Concern Associated with the Route of Administration

Likelihood of Packaging Component-Dosage Form Interaction

High Medium Low

Highest Inhalation Aerosols & Solutions;Injection & Injectable Suspension

Sterile Powders & Powders for Injection; Inhalation Powders

High Ophthalmic Solutions & Suspension; Transdermal Ointments & Patches; Nasal Aerosol & Sprays

Low Topical Solutions & Suspensions; Topical & Lingual Aerosols; Oral Solutions & Suspension

Topical Powders; Oral Powder

Oral Tablets & Oral (Hard & Soft Gelatin) Capsules

a) QTPPs(Quality

target product profile)

Overall general description 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

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 OtherSafety: (for each material of construction, as appropriate) Chemical composition of all plastics, elastomers, adhesives, etc.Extractables, as appropriate for the material Extraction/toxicological evaluation studies, as appropriate Appropriate USP testing Appropriate reference to the indirect food additive regulations (21 CFR174-186)Other studies as appropriateCompatibility: (for each component and/or the packaging system, as appropriate) Component/dosage form interaction, USP methods are typically acceptedMay also be addressed in post-approval stability studiesPerformance: (for the assembled packaging system) Functionality and/or drug delivery, as appropriate

For Each Packaging Component Received by the Applicant:Applicant's tests and acceptance criteriacDimensional (drawing) and performance criteriaMethod to monitor consistency in composition, as appropriateFor Each Packaging Component Provided by the Supplier:Manufacturer's acceptance criteria for release, as appropriateBrief description of the manufacturing process

Stability - As per ICH Guidelines

1) Concept developmenta)QTPPs Quality target product profile)

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1) Concept developmenta) QTPPs Quality target product profileRoute of Administration/

Dosage FormSuitability

Protection Compatibility Safety Performance/Drug Delivery

Inhalation Aerosols and Solutions, Nasal Sprays

L, S, M, W, G Case 1c Case 1s Case 1d

Inhalation Powders L, M, W Case 3c Case 5s Case 1d

Injections, Injectable Suspensions L, S, M, G Case 1c Case 2s Case 2d

Sterile Powders and Powders for Injection

L, M, W Case 2c Case 2s Case 2d

Ophthalmic Solutions & Suspensions L, S, M, G Case 1c Case 2s Case 2d

Topical Delivery Systems L, S Case 1c Case 3s Case 1d

Topical Solutions & Suspensions, andTopical and Lingual Aerosols

L, S, M, Case 1c Case 3s Case 2d

Topical Powders L, M, W Case 3c Case 4s Case 3d

Oral Solutions and Suspensions L, S, M Case 1c Case 3s Case 2d

Oral Powders L,W Case 2c Case 3s Case 3d

Oral Tablets and Oral (Hard and Soft Gelatin)

L, W Case 3c Case 4s Case 3d

1) Concept development b) Critical quality attributes (CQA)Quality control packaging material testing typically used and accepted to established the criticalquality attributes, and performed test give qualification of packaging component andcontainer closure system continue to passes the characteristics test established under CQA,it is essential for quality of product.

It can be controlled and studies (QC)- Physical & Chemical characteristic :Quality Control of Packaging Components Physical Characteristics Dimensional criteria. Physical parameters critical to the consistent manufacture of the packaging component Performance characteristics.

Chemical Characteristics May affect the safety, compatibility, functional characteristics or protective properties of a packaging components.

1) Concept development b) Parameter to established Critical quality

attributes (CQA) Dimension study USP/EP test USP 660, 671,661,381,87 88 , EP 32 etcESCR test Leak test IR StudyOTR/MVTR StudyDSC test Spray pattern studyDose delivery studyLacquer uniformity study Sterility testE/L study

1) Concept development Interrelationship between QTPP Vs CQA Attributes Concerns and Interaction Proposed Methods

ProtectionExposure to light, moisture, microbial ingress, and oxidation from presence of oxygen

USP<661>Light Transmission and Water Vapor Permeation, Container Integrity (Microbial ingress, Dye Penetration, Helium Leak)

CompatibilityLeachable induced degradation, absorption or adsorption of drug, precipitation, changes in pH, discoloration, brittleness of packaging materials

Leachability Study (Migration of chemicals into drug product) using LC/MS, GC/MS, ICP/AA, pH, appearance of drug and container, Thermal analysis (DSC, TGA), IR

SafetyNo leached harmful or undesirable amounts of substances to expose patients treated with drug

Extraction study (USP Physicochemical Tests-Plastics), USP Elastomeric Closures for Injections, Toxicological Evaluation, USP Biological Reactivity and complied with CFR additives and purity

PerformanceContainer closure system fuctionality, drug delivery

Functionality (improved patient compliance or use)Delivery (transfer dose in right amount or rate)

1) Concept Development

c) Concept and prototype selections Study of QTPP and CQA will help to established the concept and

prototype selection of container closure system. Concept and prototype selections of container closure system (ccs)

will determine the design space for specific formulation At each stage of the development cycle several factors influenced

the progression of new design. Uncertainty is reduced through statistical analysis.

Selection and development of container closure system (ccs) depends on the basis of product characteristic (drug product and drug substance),dosages form, route of administration container closure system will be determine.

For initial development stage various type of ccs will determine for to plan the stability study & experiment describe in CQA.

1) Concept Development

d) Design of experiment and data analysis After selection of prototype and design space of container closure

system for drug formulation we can design the experiment to validate and analyze our design space and selection of container closure system.

Design of experiment and data analysis will finally give an idea for selection of final container closure system for drug formulation quality. with effective depends on the selection of ccs, formulation dosages form and route administration.

Design of experiment at development stage will be high and maximum data analysis generate for risk assessment.

Maximum risk assessment at RnD level will reduce the risk at scale up range and increase product quality.

2) Product Packaging development

Design of experiment and data analysis will determine the final container closure for the formulation.

Final CCS further studied to verify and reduce the risk on drug formulation quality.

Following are the point of study to verify the CCS a) Design verificationb) Validationc) Stabilityd) Real time process controls to ensure qualityf) Risk based change strategy

3) Product Packaging Industrialization RnD Development study will be the basis of selection of

container closure system for drug formulation scale up batch at cGMP plant level.

Tech transfer is the process to transfer the RnD process or technology to plant level at plant level.

This is the process to understand and establish what are plant level equipment will required and also understand that plant scale up equipment will not impact product quality and efficacy.

Industrialization is the process to establish packaging line feasibility and operation at industrial level

a) Design transferb) Market introduction

3) Product Packaging Industrialization

a) Design transfer Industrialization comes with transfer of technology from RnD to Plant

(Operation level) Large scale equipment need to use to produce commercial

requirements. In packaging development there are two stage of design transfer pre

approval or submission (exhibit batch) design transfer that comes mainly primary packaging material selection, dummy unprinted carton and batch coding.

Some times submission batch has some manual operation. Machine details some time change at commercial scale. Product Post approval design transfer further require lots of activity

such as appropriate machine change part, automization, batch coding details, printed packaging material development, track and trace system, anti counterfeiting etc.

3) Product Packaging Industrialization

a) Design transferExample of Essentials of design transfer for “Integrated Blister Cartoning

Line” High Level of Automation (w/o Human intervention) Reliability Safety to Product High Operational Efficiencies Quick Change Over cGMP Norms Ease of Line Clearance Ease of Validation Flexibility to handle various Packaging films.

◦ Thermo Forming◦ Cold Forming

Flexibility to handle Multi Products in a Blister

3) Product Packaging Industrialization

a) Design transferExample of Essentials of design transfer for “Integrated Blister CartoningLine” Online Printing on Lidding Foils.

◦ Child Resistant Foil◦ Print Registration

Online Checks for Inserts and Cartons... Camera Systems for Products Pharma Code Readers 2 – D Matrix Code Pin Hole Detector for both Cold Forming & Lidding Reject Verification OCR / OCV 2 – D Matrix Code Track & Trace with Serialization / Random Online Check Weighing Online Bundler

3) Product Packaging Industrialization

b) Market introduction This is post approval commercial production of goods with printed

packaging material. Pharmaceutical product after primary secondary and tertiary

packaging it is safely reach to retail market with intact product quality.

Packaging material play very important role in safe and secure transportation of goods.

Labeling and dispensing instruction printed on packaging material for safe use of drugs

development of Trace and trace, bar code during packaging development help in patient as well as distributor end.

Without packaging development not a single product can be reached in to market.