Conducting Release and Stability Studies for Blinded Comparators

Due to the limited guidance available for release and stability testing of comparators, strategies are left to the discretion of individual pharmaceutical companies. The release and stability testing philosophy is to assess the impact blinding has on the commercial product. This article discusses Pfizer’s approach to these subjects.

A comparative agent is a commercially available drug product manufactured and released by a competitor company that will be used in a clinical study. Comparative agents can be used in clinical studies in their commercial presentation or in a blinded fashion. Comparative agents are blinded to minimize false positive or false negative bias in clinical study results. Hence, the patient and the investigator are unaware of the specific drug product being administered. The commercial drug products involved have been fully tested and released by the manufacturer prior to any blinding activities taking place. Testing of the blinded product is subject to the interpretation of industry guidance on the subject of blinding qualification, release and stability for modified commercial dosage forms. Pfizer’s approach is to test on those parameters that have the potential to be impacted by the blinding process.

Qualification testing is performed to determine whether the blinding strategy impacts the integrity of the commercial dosage form. This qualification work supports abbreviated testing for release and stability for individual clinical lots.

Table 1 - Blinding Options and Their Associated Risks

The philosophy behind the release and stability testing pattern is based upon the blinding option required to blind the commercial product and industry guidance documents [1-5]. Many of the industry guidance cited pertain to commercial or marketed products. However, Pfizer applies the strategies in these guidance to blinded comparative agents. Each blinding option imparts a potential risk to the commercial product. The extent has been categorized, based upon SUPAC guidance on components and composition, into three levels; negligible, minor and major. A negligible change is defined as a change that is unlikely to have any detectable impact on formulation quality and performance. A minor change could have a significant impact on formulation quality or performance and a major change is likely to have a significant impact on formulation quality or performance [1-2]. The information in Table 1 assumes primary packaging (the packaging in direct contact with the drug product) is equal to or more protective, and storage conditions and restrictions are equivalent, to commercial packaging.

Table 2 - Release and Stability Testing Requirements Based on Blinding Strategy

Release testing involves evaluating only criteria with the potential of being impacted by the blinding process. Stability testing involves evaluating criteria that may change over time, assuming an equal or more protective primary package is utilized, allowing the focus to be on potential changes due to blinding. The tests included in Table 2 are those that are potentially impacted by the blinding strategy.

The testing listed in Table 2 is performed at release and/or stability. The most common tests performed include: appearance, identification, dissolution, water, assay and purity. Analytical methods are developed and validated to assess the performance of the blinded product against the commercial product. The commercial product in its original packaging is used as a control for release, stability and investigational purposes.

Appearance for release is a test highlighting the visible features of the blinded product in its clinical presentation. Appearance for stability is an inspection of a drug product for visual defects or anomalies such as: change in color, change in odor or other physical characteristics.

Identification testing comprises both quantitative and qualitative testing. Quantitative identification testing is required when the potency of a commercial product being blinded can not be distinguished from other strengths of the same product. In cases where quantitative testing is not required, the qualitative identification testing is sufficient.

Dissolution is most commonly performed on over-encapsulated products on stability rather than release. Comparative dissolution is performed on blinded and commercial products during blinding qualification. Release and stability testing requires only the blinded product to be tested. The commercial product in its commercial packaging is stored in the stability chambers as a contingency sample for investigational purposes.

Moisture monitoring is only performed on over-encapsulated intact moisture-sensitive products and over-encapsulated split or ground tablets. The commercial product, in its original packaging, is compared against blinded samples, in their clinical packaging configuration.

Assay is performed when the risk to the integrity of the commercial dosage form is considered to be moderate/high, such as products that are reprocessed (i.e., split or ground tablets). Assay is not performed on blinded intact dosage forms since the stability risk is considered to be either negligible or low.

Similar to moisture monitoring, the commercial product is used as a control for comparison purposes for purity testing. The need to test purity is evaluated on a case-by- case basis. It is not a common test on release or stability. Purity may be performed for a variety of reasons. The most common reasons include: using an excipient in the backfill that is not present in the commercial formulation or blinding via moderate/high stability risk techniques.

Table 3 - Acceptance Criteria for Release and Stability Tests

The Acceptance Criteria for release and stability testing are listed in Table 3. The rationale for setting the acceptance criteria is based upon Pfizer’s interpretation of industry guidance [6-9].

Table 4 - Clinical Packaging Options for Blinded Product

The clinical packaging options listed in Table 4 represent the most common packaging configurations for Pfizer clinical studies. The packaging options for the blinded clinical product are based on the commercial packaging presentation. These packaging options take into account an assessment of oxygen and moisture permeability, light protection and data supplied by packaging vendors.

The stability strategy is to assess only the effects of the blinding process steps over time. Hence, it is preferable to package in equal or more protective packaging than the commercial. No additional testing other than that outlined in Table 2 is required to support these packaging options. Alternate packaging options are available and are assessed on a case-by-case basis. The outcome of the assessment may indicate additional stability testing is necessary. An example of an alternate packaging presentation that may be requested for use in a clinical study but is not listed in Table 4 are clear laminate blisters. Clear laminate blisters may be used and the impact of this package on product stability must be evaluated for each case. If this packaging option is deemed viable, a stability program would be designed and executed to support its use.

Pfizer’s stability strategy is based on industry guidance [1-2], clinical product packaging, historical data from multiple dosage forms, blinding and stability strategies, and stability programs from a variety of products. If a product is packaged in multiple configurations, each configuration needs to be assessed to determine whether a stability program is warranted. This strategy has allowed Pfizer to maintain quality and streamline the amount of stability data generated, which has reduced the overall cost of method development, validation, and stability.

The overall stability strategy does not necessitate every lot being set up on stability. The first lot for each packaging configuration is considered a “Lead Lot” and set up on stability. The stability program will continue until one month past the commercial expiry of the ingoing commercial lot. The maximum expiry of the blinded product is equal to the expiry of the ingoing commercial product.

The Lead Lot is used to establish the initial “Use Period.” Use Period is defined as the duration of time from the date of blinding to the expiration date of the ingoing commercial lot. If a subsequent lot requires a Use Period longer than the Use Period set by the Lead Lot, then stability data would need to be generated to support the longer Use Period. Subsequent lots do not have to be setup on stability if the Use Period is less than or equal to the Use Period of any previously blinded lot, as this data will underwrite the Use Period.

The purpose of the stability program is to asses the impact of the reprocessing over time. The time points applied to lots on stability depend on the risk blinding might have on the ingoing commercial product. Low stability risk programs, as listed in Table 1, typically have time points at 6, 12, 18, 24 months and then annually until one month past commercial expiry. These programs do not require an initial time point. The blinding qualification has shown that the blinding strategy will have minimal impact on the integrity of the commercial product at the time of release. Moderate to high risk stability programs, as listed in Table 1, will have additional pull points at 3 and 9 months. An initial time point should be considered for moderate to high stability risk programs for trending purposes.

Solid oral products have typical stability storage condition of 25ºC/60% RH and are assigned an expiry equivalent to the ingoing commercial product. However, if a product is a high stability risk, then an accelerated storage condition may be added at 40ºC/ 75% RH and the expiry assignment is made based on real time stability data, up to the expiry of the in-going commercial product.

The philosophies and strategies that are outlined in this article have evolved based on years of experience with a wide variety of products, dosage forms and regulatory filings. The contents of this article reflect Pfizer’s current practices for release and stability of comparative agents and placebos. Practices for comparative agent release and stability will continue to evolve as the industry changes.

References

1. Immediate Release Solid Oral Dosage Forms, Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-IR) http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
   
2. Modified Release Solid Oral Dosage Forms, Scale-Up and Post approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-MR)http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
3. EMEA Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials http://www.ema.europa.eu/pdfs/human/qwp/18540104en.pdf
   
4. GMP Annex 13: Manufacture of Investigational Medicinal Products http://tern-quay.com/Orange_Guide/Annexs/EU-GMP-Vol4_Annex13.pdf
   
5. The Guideline for Good Clinical Practice, ICH E6 in the section on Manufacturing, Packaging, Labeling, and Coding Investigation Products http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
   
6. United States Pharmacopeia http://www.uspnf.com/uspnf
   
7. European Pharmacopeia http://www.online.edqm.eu
   
8. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf
   
9. Federation International Pharmaceutique (FIP) Guidelines for Dissolution Testing of Solid Oral Products http://www.fip.org
   

This article was printed in the September/October 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 5. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.