The Odd Couple – Part 6: Authoring the Container Stability of Drug Substance and Product Modules

The Odd Couple – Part 5: Authoring the Container Closure Systems for Packaging of Drug Substance and Product Modules
July 23, 2020
The Odd Couple – Part 7: Authoring the Composition and Pharmaceutical Development Modules
August 13, 2020

The Odd Couple – Part 6: Authoring the Container Stability 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.

How to Know when to Toss your Prescription Drug or Refrigerate it? Stability Studies Provide the Answer!

Check the label on any prescription you fill, and chances are it will have a label with an expiration date, as well as instructions on whether to keep your drug out of sunlight, refrigerated or another instruction.

This information is designed to provide you with a date for when to discard your medication, as well to keep your prescription safe and effective.

In our Blog Series Part 5 we discussed the Container Closure Systems that contain and protect the dosage form.

According to the ICH guideline Q1A(R2) adopted by the FDA and EMA, the goal of stability testing is to demonstrate “how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity and light.

There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.

To support a stability study, analytical methods using HPLC, LC/MS and GC are generally used to test for degradation products apart from tests to determine the sterility of the substance and whether the container or packaging of the final commercial product is compromised.

Understandably, the FDA and other regulatory agencies require this data as part of a registration application for the drug substance or product. Usually, sponsors begin stability studies during Sponsors arrive at optimum storage conditions and the expiration date of a drug substance or drug product which can be seen commonly on drug labels after collecting stability data over months to years.

This data includes the effects of environmental conditions which can significantly alter the physicochemical characteristics, biological activity and other attributes of the drug substance or product.

The ICH Q1A(R2) is a good place to begin since it recommends factors and tests to be considered for a stability data package and draws upon other guidance documents such as “Photostability Testing of New Drug Substances and Products” specific to different aspects of a stability program.

In addition, monitoring the effects of environmental conditions on the quality of a drug product, substance, and in some cases the raw material is important to ascertain if is suitable for use by consumers or in manufacturing.

The information and instructions provided on these labels don’t come easily, but involve rigorous testing early in the drug manufacturing process through stability testing.

Stability testing is an important part of the drug development and approval process, determining the safety and integrity of the drug and also its shelf life and storage conditions. Contract Manufacturing Organizations (CMOs) and their sponsoring partner companies invest significant time and effort into stability testing.

What is Stability Testing?

Stability testing assesses how the quality of a drug substance or drug product, and it’s packaging, varies with time under the influence of environmental factors, including temperature, humidity and light. The process determines whether any physical, chemical or microbiological changes affect the efficiency and integrity of the final product.

This ensures that a pharmaceutical product is safe and effective, regardless of where in the world it will be supplied. Stability testing establishes the shelf life and recommended storage conditions of a finished pharmaceutical product and the retest periods for a drug substance.

What Role Does the FDA Play? The FDA provides recommended guidelines in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), which outlines the frequency and types of conditions that should be performed on any drug entity wishing to apply for FDA approval. A key recommendation is to perform stress testing of the drug substance, which can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures used.

How is Stability Testing Conducted?

The most suitable approach to gathering data to determine product stability and the stability of its packaging is to conduct real-time stability studies. However, since this approach is time-dependent, forced degradation studies are conducted to determine product stability over time.

These studies not only provide vital information about the product, but they also determine if the analytical method is a stability-indicating one.

Drug Substance and Drug Products are typically studied under at least two different storage conditions: long-term ambient storage and accelerated conditions.

Each stability program is conducted based on an approved protocol, and testing includes the product’s physical and chemical characteristics which may be susceptible to change during its storage, potentially impacting its strength, quality, purity, and ultimately, safety.

Each protocol describes the packaging, storage conditions and the tests that will be performed, along with stability test dates, test durations, etc. Stability tests are conducted using the same container closure system and packaging materials that are intended for the final product.

How much of the product should be tested?

Typically, three validation batches of a product are placed under a formal stability study, and it’s recommended that an informal study be conducted on development batches before initiating the formal study, so you can design a better packaging configuration for the product.

Batches manufactured for additional validation, such as process scale-up, are also often added to the stability study, and typically one batch per year is added to demonstrate ongoing material stability.

The purpose is to provide evidence about the quality of materials over time under the influence of various environmental factors.

Control of Drug Substance

S.7. Stability

Batches Tested

A review of all stability batches is performed. Special attention is given to any increase in impurities or appearance of a new degradation product. The amount of variability seen between batches in the level of degradation products may be indicative of the robustness of the process.

The appearance of new impurities or changes in impurity levels are consistent with poorly controlled processes. The degradation pathway for the drug substance and any critical intermediate should be elucidated.

Summary of Forced Degradation Studies and Stability Studies Under Stress Conditions

Typically, as part of method development, forced degradation studies of the drug substance are performed. The treatment of drug substance with light, heat, moisture, acid/base, and peroxide enable the analyst to demonstrate that the analytical method to control the drug substance is indeed specific and stability indicating.

The data produced in accelerated studies also provide information to the assessment team regarding potential processing issues (e.g., light protection) that might be necessary in the manufacture of the drug product. Ideally, some level of degradation should be produced (-5-10%) during forced degradation studies in order to demonstrate the specificity of the method and provide information on the degradation pathways of the drug substance.

Therefore, depending upon the intrinsic stability of the molecule, it may be necessary to adjust the relative intensity of the degradation conditions. The Tables below provide a summary check list for review of items concerning elucidation of structure, impurities, control of drug substance, primary packaging, and stability.

Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided. Reference ICH Guidelines: Q1A and Q5C 3.2.S.7.3 Stability Data (name, manufacturer) Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included. Reference ICH Guidelines: Q1A, Q1B, Q2A, Q2B, and Q5C

Control of Drug Product

P.8. Stability

Batches Tested

A review of all stability batches is performed. Special attention should be given to any increase in impurities or appearance of a new degradation product. The amount of variability seen between batches in the level of degradation products may be indicative of the robustness of the drug product manufacturing process.

The appearance of new impurities or changes in impurity levels are consistent with poorly controlled processes. The degradation pathway for the drug product and any critical intermediate should be elucidated.

Summary of Forced Degradation Studies and Stability Studies Under Stress Conditions

Forced degradation studies are performed as part of the drug product method development. The treatment of the drug product with light, heat, moisture, acid/base, and peroxide provides a means to demonstrate that the analytical method to control the drug substance assay/impurity is indeed specific and stability-indicating.

The data produced in accelerated studies also provides information to the due diligence reviewer regarding potential processing issues (e.g., light protection) that might be necessary in the manufacture of the drug product. Ideally, some level of degradation should be produced (5–10%) during the forced degradation studies to demonstrate the specificity of the method and to provide information on the degradation pathways of the drug product.

Therefore, depending upon the intrinsic stability of the product, it may be necessary to adjust the relative intensity of the degradation conditions. The Tables below provide a checklist for review of the control of the drug product stability.

Post-approval Stability Protocol and Stability Commitment

The post-approval stability protocol and stability commitment should be provided. Reference ICH Guidelines: Q1A and Q5C 3.2.S.7.3 Stability Data (name, manufacturer) Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. Information on the analytical procedures used to generate the data and validation of these procedures should be included. Reference ICH Guidelines: Q1A, Q1B, Q2A, Q2B, and Q5C

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.

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

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusionstypes of studies conducted, protocols used, and the results of the studies should be summarized summary should include results, for example, from forced degradation studies and stress conditions, as well as conclusions regarding storage conditions and retest date or shelf life reference ICH guidances Q1A, Q1B, and Q5C.Packaging Components Stability Packaging Instructions/ Expiry Information CMC (Registration/Filing) Stability Study Data Summaries ID of degradation products
3.2.S.7.2 Stability Protocol and Stability CommitmentPost approval stability protocol and stability commitment should be provided. reference ICH guidances Q1A and Q5C.Stability API Stability Study Protocols

3.2.S.7.3 Stability Data Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphic, or narrative information on the analytical procedures used to generate the data and validation of these procedures should be included. Reference ICH guidances Q1A, Q1B, Q2A, Q2B, and Q5C.Stability Stability Data Reports CMC (Registration/Filing)
Stability (protocols, reports, spreadsheets, ICH  Stability Study Reports Forced Degradation and Stress Testing

3.2.P Drug Product

3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusion Information The types of studies conducted, protocols used, and the results of the studies should be summarized. The summary should include, for example, conclusions regarding storage conditions and shelf life, and, if applicable, in-use storage conditions and shelf life. Reference ICH guidances Q1A, Q1B, Q3B, Q5C, and Q6A.Stability Packaging Components Packaging Instructions/ Expiry Information CMC (Registration/Filing)
Stability Study Data Summaries ID of degradation products
3.2.P.8.2 Stability Protocol and Stability Commitment Stability protocol and stability commitment should be provided Reference ICH guidances Q1A and Q5C.Stability CMC (Registration/Filing) Drug Product Stability Study Protocols

3.2.P.8.3 Stability Data results of the stability studies should be presented in an appropriate format (e.g., tabular, graphic, narrative) Information on the analytical procedures used to generate the data and validation of these procedures should be included reference ICH guidances Q1A , Q1B, Q2A, Q2B, and Q5C.Stability  CMC (Registration/Filing) Stability (protocols, reports, spreadsheets, ICH  Stability Study Reports Forced Degradation and Stress Testing

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