Post-marketing changes to topical semi-solid formulations:
IVRT and IVPT testing regulations and implementation guidelines
I. Legal Background and Guiding Framework
Topical semi-solid formulations (including creams, ointments, gels, lotions, etc.) belong to multiphase complex formulation systems. The release rate and bioavailability of the active ingredients in these formulations are highly dependent on the interfacial tension between the internal and external phases, the grain size distribution, rheological properties (viscosity and shear stress), and the partition coefficient.
According to the "Guidelines for Post-Market Changes of Topical Semi-Solid Preparations" promulgated by the Food and Drug Administration (TFDA) of the Ministry of Health and Welfare in January 2025, and in accordance with the superior regulation "Guidelines for Verification of Equivalence of Therapeutic Effects of Topical Preparations":
In vitro release testing (IVRT):
It is mainly used to objectively evaluate the consistency of the release rate of the main component of topical semi-solid preparations before and after "minor changes" and "major changes in manufacturing location".
In vitro percutaneous penetration testing (IVPT) and in vivo bioequivalence (BE):
When changes involve "major alterations" (such as changes in excipients exceeding the specifications, changes in the crystal form of suspended main components), or when a product was initially approved for marketing based on in vitro bioequivalence (In Vitro BE: Q1/Q2/Q3 microstructure + IVRT + IVPT) during the initial inspection and registration, it must demonstrate that the product has the same clinical efficacy and safety before and after the change through percutaneous transdermal absorption (IVPT) or in vivo bioequivalence tests.
II. Changes in classification after listing and the legal basis for "required tests"
Based on the comparison standards in Sections 3 to 6 of the guidelines and Annex 1, the required tests for each change are classified as follows:
1. Changes in ingredients and composition (Section 3 of the guidelines)
Not major or minor changes (exempt from verification):
Any single excipient change is less than 5%, and the cumulative change of all excipients is less than 5%; or the source of a single excipient with a purity of 95% or higher is changed.
Secondary changes (legally required to be submitted: in vitro release test IVRT):
Any single adjuvant change is between 5% and 10%.
The cumulative change for all adjuvants ranges from 5% to 10%.
The source of the structural admixture has changed, or its technical grade has changed.
The particle size distribution (PSD) of the suspended principal component changes.
Major changes (legally required to be submitted: in vivo bioequivalence test or percutaneous absorption test):
The extent of the adjuvant change exceeds the scope of minor changes (single or cumulative changes exceeding 10%).
The polymorphism of the suspended main component changes.
2. Changes in manufacturing processes and equipment (Section 4 of the guidelines)
Not major or minor changes (exempt from verification):
Manual processes are transformed into automated or mechanized equipment; or replaced with alternative equipment of the same design and operating principle.
Secondary changes (legally required to be submitted: in vitro release test IVRT):
Replace it with process equipment of different design or different operating principle.
Change of mixing equipment type (e.g., from low-shear mixing equipment to high-shear emulsification equipment).
The mixing rate, mixing time, cooling rate, or process waiting time exceeds the originally approved range.
The process for mixing and adding the various phases (oil phase and water phase) has changed.
3. Batch scaling up or down changes (Section 5 of the guide)
Not major or minor changes (exempt from verification):
Batch scaling up or down by up to 10 times, using equipment with the same operating principle and following the same SOP.
Secondary changes (legally required to be submitted: in vitro release test IVRT):
Batch scaling up or down by more than 10 times.
4. Changes in manufacturing location (Section 6 of the guidelines)
Not major or minor changes (exempt from verification):
Minor adjustments to the location within the same factory area or facility.
Secondary changes (meeting specific prerequisites):
The facilities were relocated to adjacent factory areas or neighboring neighborhoods, and the equipment, processes, and standard operating procedures were exactly the same.
Key changes (mandatory submission: in vitro release test, IVRT):
Relocated to a different factory area (a brand new factory site in a non-adjacent neighborhood).
Adding or changing the contract manufacturing organization (CMO). Although this is a major change in the manufacturing location, under the premise that the equipment, processes and products are the same, the guidelines specify that IVRT release test data from both before and after the change should be submitted to prove that the quality is consistent.
III. Legal Operating Procedures and Statistical Judgment Criteria for In Vitro Release Testing (IVRT) (Section VII of the Guidelines)
1. Theoretical basis and calculation of release rate
The release of topical semi-solid formulations follows the Higuchi diffusion kinetics principle. The experiment plots the cumulative release per unit area (micrograms per square centimeter) of the main component in the drug delivery chamber against the square root of time. The slope of the straight line is defined as the "in vitro release rate".
2. Experimental equipment and parameter setting standards
Diffusion cell type: standard Franz vertical diffusion cell (Franz Diffusion Cell), standard opening diameter is 15 mm (orifice area is approximately 1.77 square centimeters).
Synthetic membrane selection: Use inert synthetic microporous membranes with a pore size of about 70 micrometers (such as polysulfone, cellulose ester MCE or polytetrafluoroethylene PTFE). The membrane material should not adsorb the active main components, nor should it become a rate limiting obstacle to drug diffusion and release.
Dosage (Infinite Dose): Approximately 300 mg of semi-solid sample should be uniformly coated on the membrane surface, and the receiving end and the delivery end should be kept sealed to prevent volatilization and matrix concentration.
Drug carrier solution and sampling: The drug carrier solution must have appropriate solubility to maintain the sink condition, and the temperature should be controlled at 32 degrees or 37 degrees. The total test time is usually 6 hours, and includes at least 5 sampling time points. After each sampling, an equal volume and temperature of fresh drug carrier solution must be immediately replenished, and there should be no air bubbles remaining under the diffusion membrane.
3. Legally mandated two-stage statistical criteria for determining the absence of a parent figure (90% confidence interval)
The guidelines require that the test be conducted by placing samples before the change (control batch R) and after the change (test batch T) simultaneously in a diffusion chamber for parallel comparison. The evaluation criterion is the 90% confidence interval of the median release rate ratio (T/R ratio), which must fall entirely within the acceptable range of 75.00% to 133.33%.
Stage 1:
Six samples from each of the test batch and the control batch were taken and two independent tests were conducted (a total of six release slopes were obtained for each batch). All possible ratios of the slopes of the test batch and the control batch were calculated, resulting in a total of 36 T/R ratios.
Sort the 36 ratios from smallest to largest.
The 8th position in the sorting is used as the lower limit of the 90% confidence interval, and the 29th position is used as the upper limit.
If this range falls between 75.00% and 133.33%, the test is considered passed. If it does not fall within this range, proceed to the second stage.
Stage 2:
Four additional trials were performed (each batch adding 12 slopes, bringing the cumulative number of slopes to 18). The 18 test batch slopes were cross-divided by the 18 control batch slopes, resulting in a total of 324 T/R ratios.
Sort the 324 ratios from smallest to largest.
The 110th position in the sorted sequence is used as the lower limit of the 90% confidence interval, and the 215th position is used as the upper limit.
If this interval falls entirely within the range of 75.00% to 133.33%, the in vitro release rates of the two are considered equal; otherwise, they are considered unequal.
IV. Relationship and Regulatory Basis of In Vitro Percutaneous Transcutaneous Testing (IVPT)
According to the connection explanation in Section 1 and Section 8 of the guidelines:
Continuity of changes to products approved for in vitro bioequivalence:
If a drug was exempted from clinical trials during its initial application for marketing authorization, based on the "Guidelines for Verification of Equivalence of Therapeutic Effects of Topical Preparations" and using an in vitro testing route (proving that Q1 is the same, Q2 is the same composition ratio, and Q3 is the same microrheological structure, with IVRT and IVPT as supporting evidence), then when significant changes occur after its market launch, the same technical framework must be maintained, and data from IVPT penetration tests performed on human or mammalian ex vivo skin samples must be submitted, comparing the maximum penetration flux (Jmax), cumulative penetration (AUC), and lag time.
Alternative assessments for Major Changes:
If the prescription undergoes significant changes (such as an excipient change exceeding 10% or a change in crystal form), the drug cannot rely solely on IVRT to prove its quality uniformity. In accordance with current international regulatory trends, pharmaceutical companies, in addition to conducting traditional human clinical efficacy trials or vasoconstriction and skin pallor tests, can also seek consultation from regulatory authorities to adopt rigorous transdermal absorption studies (such as compliant IVPT or skin microdialysis techniques) as evidence of bioequivalence.
V. Key Technical Points for Pharmaceutical Companies to Conduct IVRT/IVPT Experiments
To meet the stringent audit requirements of this guideline regarding sample cross-matching, sampling time accuracy, elimination of bubble interference, isothermal backfilling, and data integrity, the following key aspects of experimental setup are recommended:
Bubble-free flow path and automatic tilting exhaust:
Page 11 of the guidelines specifically states that the presence of bubbles beneath the diffusion membrane will obstruct the drug delivery surface and cause extreme data deviations. It is recommended to use the Franz diffusion channel system, which features a lateral bubble-free guide arm or an automatic tilting venting mechanism, to completely eliminate bubble retention.
High-precision micro-sampling and isothermal and isovolume replenishment:
IVRT requires intensive sampling within 6 hours, and the volume deviation and replenishment temperature of each sample must be strictly controlled. A multi-channel push-pull precision syringe pump sampling station ensures complete synchronization of each sampling point and maintains the liquid level and constant temperature of the receiving tank (within 0.5 degrees Celsius or 37 degrees Celsius) to avoid changes in diffusion-driven pressure differential.
Solvent pre-degassing procedure:
When the drug-coated medium is heated and stirred, it is very easy to precipitate fine dissolved bubbles, which can interfere with the contact surface of the microporous membrane. Pretreatment with a high-vacuum degassing device before sample injection is an important standard procedure to ensure experimental reproducibility and pass inspection and audit.
Data integrity and audit tracking (21 CFR Part 11):
All sampling time, temperature records, speed control, and sample dispensing procedures should be electronically recorded and have an tamper-proof audit trail to ensure compliance with international ALCOA principles and the data integrity requirements for TFDA inspection and registration.
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