The Odd Couple – Part 5: Authoring the Container Closure Systems for Packaging of Drug Substance and Product Modules

The Odd Couple – Part 4: Authoring the Analytical Control and Analysis and Reference Standards Modules
July 14, 2020
The Odd Couple – Part 6: Authoring the Container Stability of Drug Substance and Product Modules
August 4, 2020

The Odd Couple – Part 5: Authoring the Container Closure Systems for Packaging of Drug Substance and Product Modules

This full Series follows our initial Primer blogs: Constructing the CTD Quality Module 3, and Quality Overall Summary: Reviewers Guide. For the purposes of this blog series, it will be necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

The CTD Module 3

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.  

CTD Module 3 is well defined containing both drug substance (active ingredient) and drug product sections, with each containing required presentations of drug technical information, processes and key parameters, and various justification supported by qualification and validation studies.

This data and these reports provide the detailed evidence that a drug’s characteristics are well defined and well controlled, such that one can assure that the next lot produced is essentially the same as the last lot. Drug manufacture control and reproducibility is the essential message that Module 3 must convey if Agency reviewers are to conclude that a new drug application merits approval.

Sponsors have latitude in how data are presented, and how important messages are formatted in the compilation of a CTD application.

Preparation of CTD submissions for various regulatory authorities should be geared toward meeting those unique regulatory standards.

Container closure systems refer to the 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. The packaging information in the chemistry, manufacturing, and controls section usually includes a description of the components, the assembled packaging system and any precautions needed to ensure the protection and preservation of the drug substance and drug product during their use.

Materials of construction refer to the substances (e.g., glass, high density polyethylene 6 (HDPE) resin, metal) used to manufacture a packaging component.

A packaging component means any single part of a container closure system. Typical components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube liners), closures (e.g., screw caps, stoppers), closure liners, stopper overseals, container inner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps, administration accessories, and container labels.

A primary packaging component means a packaging component that is or may be in direct contact with the dosage form. A secondary packaging component means a packaging component that is not and will not be in direct contact with the dosage form.

A container closure system refers to the 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.

The materials of construction used in the labeling are a concern from a packaging perspective if they affect the protection and/or safety of the drug product.

A package or market package refers to the container closure system and labeling, associated components (e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons or shrink wrap). A market package is the article provided to a pharmacist or retail customer upon purchase and does not include packaging used solely for the purpose of shipping such articles.

CONTROL OF DRUG SUBSTANCE

S.6. CONTAINER CLOSURE SYSTEM (PACKAGING MATERIAL)

A full description of the primary package used to store drug substance should be given. The potential for any incompatibility between the package and drug substance should be reviewed.

The chemical and physical reactivity of the drug substance will dictate the type of packaging needed. For example, hygroscopic drug substances may require the inclusion of desiccants in the primary package. For drug substances sensitive to environmental conditions, (e.g., heat, light, moisture), data on the qualification of the packaging component should be given.

Once the critical packaging parameters are identified, these parameters should be tested routinely upon receipt of the container prior to its use in the holding of drug substance.

A minimum of identification testing should be performed for the packaging material regardless of the sensitivity of the drug substance. Techniques such as FT-IR identity for Polyvinyl Chloride (PVC) films is commonly applied.

CONTROL OF DRUG PRODUCT

P.7. CONTAINER CLOSURE SYSTEM (PACKAGING MATERIAL)

P.7.1. Primary Packaging

A full description of the primary package of the drug product should be given. The potential for any incompatibility of the package and the drug product should be discussed.

The chemical and physical reactivity of the drug product will dictate the type of packaging needed. For example, a hygroscopic drug product may require the inclusion of desiccants in the package container. For a drug product sensitive to environmental conditions (e.g., heat, light, moisture), data on the qualification of the packaging component should be given.

Once the critical package parameters are identified, these parameters should be tested routinely on the incoming containers.

A minimum of identification testing should be performed for the packaging material regardless of the functionality of the packaging component. Techniques such as FTIR identity for polyvinyl chloride films commonly is applied.

Based upon the knowledge of the physical and chemical behavior of the drug product in preformulation and subsequent stability studies of model formulations, an appropriate package is selected.

For stable products with no sensitivity to environmental conditions (e.g., moisture or oxygen) the justification of the package requires data sufficient to show the acceptability of the drug product’s physicochemical attributes during storage.

For oxygen- or moisture sensitive products, a package that provides an effective barrier must be demonstrated. In addition, it may be necessary to demonstrate via headspace analysis that the packaging conditions provide an acceptable internal atmosphere or that the addition of some appropriate inert gas is necessary.

The selection of the packaging components for liquid formulations is determined during preformulation development. The selection of a product package for liquids is linked intrinsically to the formulation and should be part of the multivariate analysis in the design of formulation development and optimization studies.

The selection of rubber stoppers for parenteral liquids typically entails the examination of extractables from the stopper in contact with the parenteral base formulation. Techniques for the selection of stoppers for parenteral powders include a dynamic headspace technique that models the absorption of rubber volatile components by the drug product.

P.7.2. Secondary Packaging

Any secondary package used for the drug product should be described (e.g., cardboard box). If the secondary packaging material provides protection to the product, test results of stability studies with and without the secondary package should demonstrate the adequacy of the secondary package.

Based upon the knowledge of the physical and chemical behavior of the drug product in preformulation and subsequent stability studies of model formulations, an appropriate package is selected.

For stable products with no sensitivity to environmental conditions (e.g., moisture or oxygen) the justification of the package requires data sufficient to show the acceptability of the drug product’s physicochemical attributes during storage.

For oxygen- or moisture sensitive products, a package that provides an effective barrier must be demonstrated. In addition, it may be necessary to demonstrate via headspace analysis that the packaging conditions provide an acceptable internal atmosphere or that the addition of some appropriate inert gas is necessary.

The selection of the packaging components for liquid formulations is determined during preformulation development. The selection of a product package for liquids is linked intrinsically to the formulation and should be part of the multivariate analysis in the design of formulation development and optimization studies.

The selection of rubber stoppers for parenteral liquids typically entails the examination of extractables from the stopper in contact with the parenteral base formulation. Techniques for the selection of stoppers for parenteral powders include a dynamic headspace technique that models the absorption of rubber volatile components by the drug product.

Common Technical Document SectionRecommendations per Guidance(GMP) Source Documents Electronic Y/N
3.2.S Drug Substance 

3.2.S.6 Container Closure System A description of the container closure systems, including the identity of materials of construction of each primary packaging component, and their specifications Specifications should include description and identification (and critical dimensions with drawings, where appropriate).  Noncompendial methods (with validation) should be included, where appropriate. For nonfunctional secondary packaging components (e.g., those that do not provide additional protection), only a brief description should be provided For functional secondary packaging components, additional information should be provided. Suitability should be discussed with respect to, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance, including sorption to container and leaching, and/or safety of materials of construction.Packaging Components Packaging Monograph PMIS Packaging Component Specification Packaging Component BOM PID (Packaging Instructions Document) Packaging Ticket Labeling Instructions Label Specifications CMC (Registration/Filing) Specifications, Diagrams (component, container closures) Container Closure Specifications Container Closure Diagrams Container Closure Certificates of Analysis
3.2.P Drug Product

3.2.P.2.4 Container Closure System suitability of the container closure system (described in 3.2.P.7) for the storage, transportation (shipping), and use of the drug product should be discussed discussion should consider, for example, choice of materials, protection from moisture and light, compatibility of the materials of construction with the dosage form (including sorption to container and leaching), safety of materials of construction, and performance (such as reproducibility of the dose delivery from the device when presented as part of the drug product).Packaging Components Suitability studies (Extractables/Leachables)
Container Closure Specifications Container Closure Diagrams Container Closure Certificates of Analysis
3.2.P.7 Container Closure SystemA description of the container closure systems should be provided, including the identity of materials of construction of each primary packaging component and its specification. The specifications should include description and identification (and critical dimensions, with drawings where appropriate). Noncompendial methods (with validation) should be included Where appropriate. For nonfunctional secondary packaging components (e.g., those that neither provide additional protection nor serve to deliver the product), only a brief description should be provided.  For functional secondary packaging components, additional information should be provided. Suitability information should be located in 3.2.P.2.Packaging Components Packaging Monograph PMIS Packaging Component Specification Packaging Component BOM PID (Packaging Instructions Document) Packaging Ticket Labeling Instructions Label Specifications CMC (Registration/Filing) Specifications, Diagrams (component, container closures) Carton and Vial Label Sets Container Closure Specifications Container Closure Diagrams Container Closure Certificates of Analysis

For the purposes of this blog series, it will be necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.

Ultimately, the timeliness of an Agency’s review and approval status of a drug’s Quality section is best served by preparation of a well-designed Quality Module. Insights and recommendations from the past fifteen years are provided here to help maximize the potential for a successful outcome.

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