Stability Protocols: Road Maps to Success

This article will define the purpose of stability protocols, explore their potential elements, help us understand the impact of poorly designed protocols and learn how Stability Review Boards can assure optimal study design and improve forecasting.

The main objectives of stability testing include selecting adequate (from the viewpoint of stability) formulations and container-closure systems, determine shelf-life and storage conditions, substantiate the claimed shelf-life and to verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product.

What is a Protocol? After 3 primary definitions, Webster gets to around to our application in definition #4: a detailed plan of a scientific or medical experiment, treatment, or procedure.

For our purposes, a Stability Protocol is a:

• Design of formal stability studies
• Executable plan and record for exposure conditions, tests, and intervals
• Record of process, product, and package

Reading through 21 CFR Part 211.166 Regulatory Requirements for Stability Studies helps frame our thinking about stability protocols:

(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:

(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained.

(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;

(2) Storage conditions for samples retained for testing;

(3) Reliable, meaningful, and specific test methods;

(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed;

(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.

Further details regarding protocols emerge in the Guidances:

ICH Q1A(R2) Stability Testing of New Drug Substances and Products {B. Drug Product (2.2) 1. General (2.2.1)}

The design of the formal stability studies for the drug product should be based on knowledge of the behavior and properties of the drug substance, results from stability studies on the drug substance, and experience gained from clinical formulation studies. The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated.

This reference to Rationale (and hence; Justifications) gives us a good opportunity to reflect on some of the more popular choices that work their way into our responses when questioned by regulatory authorities:

• We’ve always done it that way and never had a problem
• It’s an Industry Best Practice
• It’s a Regulation / Guidance requirement
• We have scientific data to demonstrate that this is the best method

I’m a fan of the last 3 in descending order. We need to remember that including or referencing rationale and justifications for the actions that we cite in our programs and policies are part of the expectations laid out in the Guidances.

The World Health Organization Stability Guidance – Finished Pharmaceutical Product (2.2.9 Evaluation) is the first to use the term “protocol” and then outlines details of stability reports, some of which can suitably reside in the stability protocol:

The primary stability program should be described in a written protocol and the results presented in a formal report as outlined in 2.2.13.

Stability studies should include testing of stability-indicating attributes of the Finished Product, (those that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy).

The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (antioxidant or antimicrobial preservatives) and functionality tests (for a dose delivery system).

A systematic approach should be adopted to the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including particular attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms).

Where appropriate, a summary of additional knowledge and an understanding of stability gained from supporting studies, modeling, predictive tools, etc., may be incorporated to support knowledge gained from the primary stability program.

ICH Annex 10 gets even more specific on Protocol content:

The protocol for an ongoing stability programme should… include, but not be limited to, the following parameters:

• number of batch(es) and different batch sizes, if applicable
• relevant physical, chemical, microbiological, and biological test parameters with acceptance criteria or reference to the attached specifications
• reference to test methods
• description of the container-closure system(s)
• testing frequency
• description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines, and consistent with the API labeling, should be used)
• other applicable parameters specific to the API

We’ll go deeper into what should or could be included in protocols after seeing how the industry is doing with Protocol-related compliance. Here is a list of Stability 483’s in 2019 & 2020. It’s obvious that any seeming “improvement” shown in 2020 and beyond are due to the pandemic-related reductions in regulatory inspections. The story told by the 2019 numbers is a sad reflection on our stability programs in general, and several of these categories could be improved specifically through a more diligent effort with our protocols.

Some specific Stability Study Protocols citations:

• The generation, review and approval of stability protocols are not controlled by procedure.
• The modification or revision of protocols is not governed through the Change Control procedures of the company.
• The written stability program for drug products does not describe the storage conditions for samples retained for testing.
• Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans/test procedures designed to assure that [components, containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.
• No testing performed at 12 and 18 month time points to establish a shelf life of 30 months.

The impact of poorly designed or under-attended protocols opens a Pandora’s Box of quality and business problems:

• Disconnects to “the story” of your product
• Ambiguity of process and package (minor details omitted>loss of control)
• Limited scope of design may produce a Zone-challenged study
• Missing input from support disciplines open the door to late study surprises
• Revised test methods may not trigger a revised protocol
• Late-addition CROs may not be tracked

Some of us can remember single page protocol documents containing only Product & Package descriptions, Storage Conditions and Test Intervals.

Today, the Stability Protocol should be the defining document for a study and the penultimate description of all elements, including Product, Package, Process, Site, Suppliers, Conditions, Tests, Schedule, and Links to all other pertinent information.

We can find Protocols in the form of Single Extensive Document, Centralized Index , as an element of LIMS or as a Comprehensive Report within a Digitized System.

In the 21’st Century, the age of stringent Good Documentation Practices and digitized systems, it would be counterproductive to miss the opportunity to make your protocol system electronic and integrated with your other Stability systems. That would speed planning, the creation of templates, review & approval and change control as well as assuring data integrity, accurate submissions, and overall quality.

Returning to protocol content, the Study Design Segment might include

• Why the study is being conducted
• What previous studies/data/supportive data* have led to this study
• How this study is related to other studies in the registration plan
• (ex. Batch 1 of 3 for this Product/Container Closure/etc. configuration)
• Table/Schematic for all studies in the project
• Deliverables (Reports)

*Any available studies carried out on the drug product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively.

At a recent Pharmaceutical Stability Discussion Group Meeting, a poll was taken of the attendees with the question: What’s In Your Protocol?

While not everyone had all of the elements listed below, there was a staggering array of information gleaned about their practices. Here are the responses organized by category. What would you add in your shop?

Product

• Specific Product (name, dosage form, strength)
• Formula & materials/component references
• API & source
• Suppliers and Part/Component numbers
• Type of Batch
• Batch size
• Lot number
• Date of Manufacturing
• Site of Manufacturing
• Processes Used
• Equipment Scale
• Special Treatments

Package

• Container
• Closure
• Count/Fill quantity
• Secondary Packaging
• Desiccants
• Component suppliers
• Blanket gas
• Sterilization if any
• Site of Packaging
• Site of further processing (over-packaging, sterilization, , etc.)
• Date of Packaging

Study

• Study Purpose
• Phase of Study
• Date of Study Start
• Sample Orientation
• Special Handling Requirements
• Storage Conditions
• Special in-process storage instructions/restrictions
• Hold/Reserve Quantities
• Intermediate Condition
• Storage Space Requirements
• Study Sample Quantities per condition/location
• Pull quantities
• Pull intervals
• Pull dates

Previous Developmental Studies

• Foundational API/Intermediate Studies
• Formula/Package/Other selection
• Reconstitution Studies
• Cycling Studies
• Shipping Studies
• In-Use Studies
• Photostability Studies

Tests

• List of Tests
• Test Methods & Specifications
• Test Method Version Code
• Sample Test Quantities
• Specific Test Lab designations where Tests are performed

Chambers

• Storage locations/Chamber Identification Code
• Measurement of Uncertainty of Chamber Outputs
• Back-up Chamber Plan
• Monitoring System & Back-up

Results

• Test data acceptance criteria
• Statistical Methods References
• Rounding Rules
• Reports required

Other

• Partners/CROs Involved
• Updates/Change Control
• Change Control Reference Numbers
• SOP(s) governing stability protocols/product/etc.
• Justifications for all significant actions
• Protocol Approval Chain

The WHO Annex 2 (ICH-A10) on Secondary Packaging helps address a sticky question: Should/Must every study be conducted in the secondary packaging? Several guidances stipulate studies in the final marketed package, yet in actual practice, not all companies conduct their studies in the final pack (there are often slight changes late in the cycle and questions could arise about repeating studies. The WHO Guidance provides a reasonable rationale for when to include the secondary packaging:

2.2.4 Container-Closure System

Stability testing should be conducted on the dosage form packaged in the primary container-closure systems proposed for marketing. If the secondary container-closure system has protective properties, and labeling clearly indicates that the product is to be stored in the primary and secondary packaging (e.g. “store tablets in blisters in the provided cartons”), or if the product is packaged in a semi-permeable container where components from the secondary packaging can migrate into the product, the secondary packaging may also form part of the packaging system for stability samples.

We must not neglect the orientation of samples as they are stored at the study conditions. ICH Annex 10 addresses this consideration:

The orientation of the product during storage, i.e., upright, on the side or inverted, as well as the rationale for the orientation, may need to be included in a protocol where contact of the product with the closure system may be expected to affect the stability of the products contained (e.g. liquids and semisolids), or where there has been a change in the container-closure system.

Stability protocols can be useful for forecasting, space planning and resource utilization. By applying the nature and number of tests that will be required to be performed during a study interval to the number of available analysts dealing with all studies, we can see where resource crunches will occur. Furthermore, at the planning stage, quantities of samples planned for each storage condition will provide a forecast of shelf space required at the start of the study and show the rate at which space is freed-up as samples are consumed. If protocols can be linked directly to planning systems, these calculations could be automated.

In preparing stability protocols we have some critical definitions to make.

What exactly defines our date of manufacture and what is our justification? How do other aspects of our process such as packaging, labelling and sterilization impact our dates of manufacturing and date of release? Have we decided if and when Release data will count as Time Zero study data? In some industries, Time Zero for study condition 1 is not the same as Time Zero for study condition 2. Much can depend on our corporate clocks, calendars, culture, and previous regulatory success. Will we need to include some interim testing or releases to avoid any questions? Are we starting a study on the date of manufacture, date of release, date of Time Zero testing or date in the chamber?

Well-founded debate occurs as to date of study start, and scientific data is a good factor to have in supporting your decision. In general, a study begins on the date in chamber (related not only to starting at the condition, but also to the level of control of the study’s parameters), while the shelf life clock starts on the date of manufacture [taking into consideration, that a study-generated shelf life is calculated at labelled storage conditions while conditions (including level of control) that a product experiences right after manufacture may not necessarily be the same as those in the stability study]

Definitions for Sample Pull date, Pull Windows and Date of Test are equally important. Each should be specific and justified. Is the Pull date the same as the Due date? Is the date of testing when testing began, finished, or was reviewed and approved? Do you cite Test date for each test, or for the entire slate of tests? Have you defined an acceptable range for completion of each of these parameters, again, with justification?

Protocol Templates

ICH Q1A R2 Stability Testing …Drug Substances Section 8 declares that “The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified”. To transfer uniformity within stability projects, utilize controlled templates. We can gain template input from a variety of sources, including CFR, ICH, WHO and EU GMP for Medical Products; Human and Veterinary Vol 4 Chapter 6 Section 6.3.0. In the end, your protocol template is up to you and should be well-conceived and well-controlled

Other Studies / Supportive Information

Any available studies carried out on the drug product outside its immediate container or in other packaging materials can form a useful part of the stress testing of the dosage form or can be considered as supporting information, respectively. Product Development Reports inform the design of our stability studies, providing rationale as well as justification. Within these reports, we can mine the results of compatibility and packaging studies, information about degradation, extractables & leachables, photostability, bulk hold times, freeze-thaw and cycling studies, and a multitude of others.

Cite them if related to your specific study protocol, BUT only reference previous work such as stress testing, compatibility studies, etc. for the purpose of justifying the current protocol.

When designing Stability protocols consider presentation formats of tables. Customize your protocol with the format that best illustrates your program. Here are two examples:

Condition Based

Test Based

Change Control

Change Control is a critical quality system that must not be neglected. Approved changes can be summarized in a table or footnoted in the protocol section to which they are related. There should be a brief understandable description of the change with a cross-reference/link to the Change Control document that was processed by the organization. Changes noted may include:

• Tests added, removed, or suspended
• Changes in Test Method
• Changes in Specifications
• Tests Condition added, removed, or suspended
• Test Intervals added, removed, or suspended
• Changes in Storage Site
• Changes in Test Site
• Quantities of samples changed
• Changes in Statistical applications
• Defined Report changes
• Any change deemed significant in your local Change Control Procedure

Build Phase-appropriate Protocols by considering the stability objectives of each phase:

Toxicology

• “Quick and Dirty”
• Labeled Storage plus 1 or 2 accelerated conditions
• Often less than 6 month protocol
• Standard Tox-convenient robust package (ex. glass)
• Active Pharmaceutical Ingredients

Early Project, selecting process, formula, package

• Side by side studies for comparison of candidates in several study categories.
• Protocols heavy on accelerated conditions with Real Time/Refrig. baseline
• Caution: avoid so many variables that source of failure cannot be identified
• Iso-Conversion principles can be appropriate

Proving the process and components selected

• Comprehensive Longer-term protocol, all conditions
• If no changes anticipated, conduct cycling, in-use, photostability testing, etc.
• Use this phase to prove current multiple sources

Registration Batches

• Highly Collaborative protocols with Regulatory Affairs
• Planning Meeting with FDA/Regulatory Bodies
• Suppliers/Components/Procedures/Methods Locked
• Trending all results frequently
• “Out of’s” communicated quickly throughout organization
• Investigations given priority

Post Approval Commitments

• Regulatory-negotiated protocols, Check SUPAC Regs
• May contain new conditions, test methods, test points
• Some special accelerated protocols may be requested
• Suppliers/Components/Procedures/Methods Locked
• Trending all results frequently
• “Out of’s” communicated quickly throughout organization
• Investigations given priority

Annual Commercial Batch / Package / Site

• Strong Regulatory input
• Labeled Storage condition plus early accelerated
• Cover all sites, configurations
• Potentially negotiate bracketing/matrixing if very close numerous variations exist
• Carefully monitor production and plan target batches
• Intense preparation required for updating annual reports

How many annual commercial studies should be placed on stability?

One lot per year, per configuration, per site, per any other differences or changes. Additional lots for batch anomalies or significant changes. Internal Regulatory negotiates Post Approval Commitments and any additions or reductions in studies for slight differences in product/configuration

When adding Sites, Contractors, and Partners:

• Mirror previous studies for comparison
• Make use of Comparative tactics, statistics, etc.
• (A=B, C=B, therefore C=A) inform Regulators
• Pay particular attention to unanticipated differences in the “target’s” practices, sources, procedures, methods, etc.

Changing out or adding alternate suppliers

• Maximize Liaison contact with alternates to cover expectations and minimize variables and surprises
• Mirror previous studies for comparison
• Make use of Comparative tactics, statistics, etc.
• (A=B, C=B, therefore C=A) inform Regulators
• Pay particular attention to unanticipated differences in the target’s practices, sources, procedures, methods, etc.

Line extensions, Changes to components

• Maximize Liaison contact with alternates to cover expectations and minimize variables and surprises
• Mirror previous studies for comparison
• Make use of Comparative tactics, statistics, etc.
• (A=B, C=B, therefore C=A) inform Regulators
• Pay particular attention to unanticipated changes in practices, sources, procedures, methods, etc.

The Stability Review Board: Building Science, Quality, and Compliance into Stability Protocols

A Stability Review Board can assure that science, regulatory, quality, and administrative considerations are represented. Administered correctly, it assures broad participation, timeliness & quality. Administered incorrectly, it can become a bureaucratic nightmare of delay and confusion.

Consider the input needed to/from these Stakeholders Influencing Stability:

Consider the input needed to/from these Stakeholders Influencing Stability. These include: HVACs, Metrologists, Informatics, LIMS Team, Custodial, Facilities, Security, Formulators, Toxicology, Packaging, Analysts, Microbiologists, Quality Control, Reference Standards, Method Development, Change Control, Stability Operations, Warehouse, Shipping, Regulatory Affairs, Technical Writing, Quality Assurance, Budget Office, Validation Team, Data Reviewers, Statisticians, CRO Liaisons, Risk Management, Project Team, Manufacturing Schedulers, and many more members of the Stability community!

The Stability Review Board should represent those stakeholders that are critical to the elements of quality, compliance, and science in the protocol. For example:

Chairperson, Administrator, Stability Operations, QC Laboratory, Method Development, Microbiology, Packaging, Statistician, Regulatory Affairs, Product Development (aka Pharmaceutical Sciences), Product Manager / CRO Liaisons, Manufacturing, Quality Assurance, Supply Chain Representative, Shipping / Cold Chain Representative, and more!

SRB Responsibilities include:

• Evaluate proposed specific product stability study protocols for content, compliance and compatibility with procedures, resources, and calendar constraints
• Address stability issues, such as confirmed OOS and OOT and make recommendations toward resolution
• Recommend termination or holding of non-productive studies
• Jointly conduct the stability component of Annual Product Reviews
• Regularly review the relevance, compliance, and effectiveness of standard stability protocols
• Annually review forecasts and capacity to assure internal/external space and associated resources
• Quarterly review the overall Stability Metrics (# oos/oot/deviations/studies per product/etc.)
• Escalate metrics and issues to the Management Committee

SRB Meetings and roles of members:

Frequency: As business requires, weekly/monthly with ad hoc meetings added as necessary.

Chair: Prepare agenda, materials to be presented, and finalize meeting minutes.

Administrator: Schedule meetings, distribute agenda, record, and distribute meeting minutes

Members: Each representative is responsible for reviewing agenda items and where applicable, have recommendations prepared. When a member is unable to attend a meeting, their designee must attend in their place. Protocols and stability decisions are not delayed by human factors.

Stability Review Board Success Factors

• Protocol requirements are clear. Training, procedures, and templates guide the submitter to a satisfactory SRB submission
• SRB members and Protocol Submitters have back-ups and commit to on-time review and attendance. Electronic approvals may be accepted.
• Meetings are scheduled at frequent intervals and far in advance on the calendar (cancelled when no items are on the agenda)
• Any protocol submitted on time with a one week review period receives a decision in the meeting
• During the review period, reviewer and submitter are encouraged to negotiate any needed improvements and share the update with the SRB
• During the SRB Meeting, reviewers and submitter may negotiate any needed improvements. (SMEs, Quality, Regulatory, etc. are all present)
• Protocols can be conditionally approved with commitment to recommendations

Protocol Efficiency Strategies

ICH: Q 1 D: Bracketing and matrixing designs for stability testing of drug substances and drug products

2.3 Bracketing (High-Low)

As defined in the glossary to the parent guideline, bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design.

Example of a Bracketing Design

2.4 Matrixing (Sampling across studies)

Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

Example – One-Third Reduction Matrixing Design on Time Points for a Product with 2 Strengths

Leveraging (Similar enough to make deductions)

Leveraging is the use of previous data from similar materials / process to support a proposed claim for a new product. With prior Regulatory Authority approval, Leveraged study data can be cited in a submission. If a new Stability Protocol is constructed on the basis of leveraged data, the previous studies/data/supportive data and their impact on the current study should be discussed in the Protocol’s Introduction segment.

Comparability (Pre-defined proof of equivalence to bridge changes in product aspects such as methods, sites, equipment, suppliers, etc.)

Comparability Studies are a form of leveraging, but are meticulously planned with well-defined acceptance criteria to demonstrate that if stability of A=B and stability of B=C, then stability of A= stability of C. With prior Regulatory Authority approval, Comparability study data can be cited in a submission. If a new Stability Protocol is constructed on the basis of Comparability studies, their impact on the current study should be discussed in the Protocol’s Introduction segment.

Comparability Study Types

• Risk Assessment of the specific types is critical
• Side by Side Studies
• Historical Data
• Degradation / Stress

Summary

Stability Protocols:

• May be a Stabilitarian’s most useful record in each of the product development phases (Toxicology, R&D stages, Registration, Post Approval, Annual, Life Cycle Changes)
• Contain necessary unique identification, description of product and package
• List internal/external testing labs with address/contact information
• Set out sample, space, and resource requirements
• State study purpose and connectivity to other studies in the same project
• Benefit from a Stability Review Board bringing the eyes of many disciplines
• There are multiple avenues to conserve resources
• Ensure timeliness and coordination of all sample and test activities
• Are a template for corporate efficiency
• Alleviate many compliance issues through thorough preparation
• Connect all Aspects of a Stability Study

Therefore, make Stability Protocols a primary focus of your stability program. Benjamin Franklin said: “Keep your shop and your shop will keep you.” Stabilitarians may observe that if you keep your protocols, your protocols will keep you.