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首頁 > 技術文章 > EMA 角質層取樣(膠帶剝離術)深圳銳拓翻譯稿

EMA 角質層取樣(膠帶剝離術)深圳銳拓翻譯稿

更新時間:2023-03-06      點擊次數:419

This annex provides information for an in vivo stratum corneum sampling (or tape stripping (TS)) study for semi-solid formulations as a permeation kinetic method to show equivalence, in lieu of a therapeutic equivalence study.


The S.C. sampling study is a minimally invasive technique that involves sequential removal of the outermost skin layer (i.e., the stratum corneum (S.C.)) using adhesive tapes after application of a drug-containing formulation. The amount of drug in the S.C. depends on three main processes: drug partitioning from the formulation into the SC, drug diffusion across the S.C., and drug partitioning out of the S.C. into the viable tissues. A major advantage of TS is that the experiment is conducted in vivo with a fully functioning cutaneous microcirculation so that drug clearance from the skin is unimpeded.


TS data provide direct measurements and information on the local bioavailability of semi-solid drug products that act on or in the S.C. e.g. antifungal products. In cases when the target sites of action are beyond the S.C., TS data may provide a suitable surrogate to characterise the rate and extent of drug absorption to the underlying tissues.


In vivo TS studies are only applicable for products where drug diffusion into and through the SC takes place. Thus, TS should not be used for testing of drug products to be applied on significantly damaged skin (e.g. open wounds, burns) or skin of premature new-born. In addition, any products that contain volatile drugs or target primarily the cutaneous appendages (e.g. hair follicles, sebaceous glands) are also not suitable.


A TS study is not an automated process and careful consideration of the experimental design is vital. The experimental conditions of the pivotal study should be assessed individually for the concerned products and should be established by performing a pilot TS study. A summary of the development and optimisation of the TS method should be provided.


The following experimental conditions should be established and verified during the pilot study:


●TS study should be conducted on healthy, normal forearm (volar) skin areas with avdequate skin barrier function. The inclusion/exclusion criteria for skin conditions should be defined. Skin with tattoos, any signs of dermatological abnormality or exhibiting a significant density of terminal haivr should be excluded. The preparation and cleaning procedures prior to the experiment should be established and further, that the treatment sites are not damaged by these processes.



●Skin integrity should be determined before and after the experiment. This is normally performed by the measurement of Transepidermal Water Loss (TEWL), although other techniques may be applicable if appropriate. The acceptance criteria should be fully discussed and justified.


●Due to inter-subject variability, the products to be compared should be applied on the same subject. Additionally, a negative control that is non-equivalent to the comparator product should also be included to demonstrate the discriminatory power of the method. It is recommended to blind the investigator responsible for formulation application and tape stripping to minimise risk of bias.


●The dosing amount should be determined based on the SmPC. During the pilot study, the dosage and area of dose application should be verified to achieve a quantifiable mass of active substance in the SC. The dosing technique, blinding and randomisation procedures should also be established.


●A single dose approach should be followed, i.e. skin stripping is performed after a single application of the test and comparator products.


It is necessary that the products are compared at two time points (one uptake, one clearance) for each subject. The optimal uptake and clearance times depend on the characteristics of the drugs and products and should be determined during the pilot study. Ideally and when relevant, the uptake time should be sufficiently long for the drug to have attained the diffusional steady state. This can be established by testing at multiple uptake times and from which time the mass of drug recovered from the SC remains constant. The clearance time should be long enough to allow measurable transfer of drug from the SC into the viable skin (and beyond) but should not exceed 48 hours to avoid any skin desquamation effect. The clearance time providing at least a 25% decrease in the mass of drug recovered from the SC with respect to that at the uptake phase is preferred. In all cases, the sampling times should be carefully  considered and justified.


The drug product should be removed from the skin surface after the specified uptake time. The cleaning procedure should be established to ensure that the residual formulation is efficiently removed from the treatment sites before stripping.


The adhesive tape chosen should meet the following requirements: a) does not lose mass when applied and rubbed against the skin surface; b) minimal weight loss and gain during storage; c) the drug is readily extracted from the SC adhered to the tape; d) the adhesive or other components of the tape do not interfere with the analytical quantification of the drug; and e) the adhesive power should be such that the majority of the SC is removed with a sufficiently low number of tapes (e.g. not more than 30 tapes).

選擇的膠帶應滿足以下要求:a)在應用和摩擦皮膚表面時不會失去質量;b) 儲存期間的最小化重量損失和(he)增加;c) 藥物容易從粘附在膠帶上的SC中提取;d) 膠帶的粘合劑或其他成分不干擾藥物的分析定量;以及e)粘合力應使得大部分SC用足夠低數量的膠帶(例如不超過30條膠帶)去除。

The TS procedure followed must ensure that most of the SC (≥75%) is sampled for each skin site. The minimum and maximum number of tapes should be established based on the TEWL (or other relevant) criteria, e.g. eight-fold increment over baseline value, safety stop value.


Most commonly, the drug is first extracted from the tapes then quantified in the extraction solvent(s). Alternative methods of extraction/quantification may be used if justified. Satisfactory efficiency should be demonstrated for the proposed extraction method.最常見的(de)是(shi),首先從膠(jiao)帶中提(ti)取藥物,然后(hou)在(zai)提(ti)取溶劑中定(ding)量。如果合理,可使用其他提(ti)取/定(ding)量方法(fa)。應證明(ming)所提(ti)出(chu)的(de)提(ti)取方法(fa)具有令人滿意的(de)效率(lv)。

Detailed standard operating procedures should be prepared for the conduct of TS studies to ensure precise control of dosing, cleaning, stripping, extraction, quantification and other study variables or potential sources of experimental bias. The inclusion/exclusion criteria should be pre-defined and clearly stated in the protocol.


The following study design is recommended for TS studies. The final protocol developed for each specific case should be justified.


Subjects – TS studies should be performed in healthy volunteers. The subjects should be screened for suitability in line with the principles of bioequivalence studies.


Treatment area –healthy skin of the volar forearm areas sufficient to accommodate at least six application sites per forearm. Skin integrity should be verified e.g. by TEWL measurement. The same number of application sites should be assigned to each forearm;


Number of subjects – the choice of the number of subjects should be justified based on the variability estimated from the pilot studies and demonstrated to be statistically relevant. A minimum of 12 subjects should be used to demonstrate equivalence;


Number of replicates – at least two application sites per product (test, comparator and a negative control) per forearm. One forearm should be used for uptake samples and the other for clearance;


The products should be applied at pre-determined doses (±5%) and spread evenly over the entire demarcated application sites. Blank samples should be collected from the adjacent areas to verify the absence of background levels of drug or other compounds that may interfere with the quantification of drug in the treated SC;


The application sites should be randomised to avoid bias. The application time should be staggered to allow time for S.C. sampling;


Un-occluded conditions, unless occlusion is recommended in the product information, or otherwise justified e.g. to prevent inadvertent removal of formulation.


The formulation should be removed from all treatment sites (uptake and clearance) at the end of the uptake phase. The total cleaning time should be minimised to avoid any artefacts due to further drug diffusion. Skin integrity of the treated area should be checked before stripping;


The ‘uptake’ sites should be tape-stripped immediately after formulation removal. The ‘clearance’ sites should be tape-stripped at the pre-defined clearance times;


The exact number of tapes required should be determined based on TEWL measurements of the stripped area and the stopping criteria established from the pilot study;


The mass of SC removed per tape should be determined using a gravimetric method by weighing the tapes strips before and after stripping. Alternative methods of quantification of the SC can be used if suitably described and justified;


All stripped tapes collected from each treatment site should be analysed. The first two tapes should be analysed separately from the remaining tapes, so their contribution to the total amount of drug recovered can be eva1uated. To enhance analytical detectability, the subsequent tapes can be combined in groups (e.g. each group containing the required minimum content of SC) for extraction. The total mass of drug in the SC should be calculated as the sum extracted from all tape strip samples. The mass balance, including the drug content removed from the surface by cleaning should be determined for each treatment site. The overall recovery of 90-110% would be acceptable without justification; larger variation should be fully explained.


Cleaning the skin surface at the end of the application period prior to tape-stripping is important and must be capable of removing excess formulation (i.e. unabsorbed drug) efficiently without inadvertently ‘driving’ the drug into the barrier. The cleaning procedure usually involves quickly and gently wiping the skin with dry/wet tissue, cotton swabs and/or fresh alcohol wipes. The cleaning components should be known not to influence drug diffusion into and through the SC. A careful eva1uation and validation of an efficient skin cleaning procedure should be performed prior to the pivotal study, e.g. by demonstrating satisfactory recovery (>90%) of the drug formulation removed from the skin surface and the negligible drug content (<10%) recovered by stripping the cleaned skin immediately after application. Other ways of validation may be used if suitably justified.



The bioanalytical method employed for drug quantification in the tape strips should be validated. The efficiency of the extraction procedures (including extraction of tape strips in groups) should be established and demonstrated as consistent prior to the pivotal study.


The discriminatory power of the TS method should be demonstrated for batches with different quality attributes (a negative control), such as a drug formulation with ±50% of the proposed product strength, that is shown to be statistically different and non-equivalent to the test and comparator products. The analytical methods for determining the content of active substance in the tape-stripped SC should be validated according to the Guideline on Bioanalytical Method Validation.


Data from all subjects should be reported and the validity and variability of the results should be discussed. All treated subjects and application sites should be included in the statistical analysis. The permitted reasons for exclusion must be pre-specified in the protocol. Data exclusion based on statistical analysis or for kinetic reasons alone is not acceptable.


For each product, the thickness of SC removed, the number of tapes used and final TEWL value measured at both uptake and clearance times should be reported. Any differences in these parameters between the test and comparator products should be discussed with respect to equivalence.


A plot of drug content profile in the SC should be presented for each application site, e.g. the drug content of each SC tape strip (single or grouped) versus SC depth.


The duplicated measurements for each product in each subject should be averaged (population geometric mean) prior to analysis.


For the comparison of products, the equivalence parameters: mass of drug recovered from the uptake (Muptake) and clearance (Mclearance) sites, should be statistically compared, according to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ).

對于產品的比較,應根據《生物等效性研究指南》(CPMP/EWP/QWP/1401/98 Rev.1/Corr)對等效參數:從吸收Muptake)和(he)清除(chu)(Mclearance)部位回收的藥物質量進行統計比較。

The acceptance criteria for equivalence parameters (Muptake) and (Mclearance) are:

The 90% confidence interval for the ratio of means of the test and comparator products should be contained within the acceptance interval of 80.00- 125.00%, unless justified.


Wider 90% confidence interval limits, to a maximum of 69.84 – 143.19, may be accepted in the case of high variability observed with low strength and limited diffusion drug products, and if clinically justified. The procedure in the Guideline on Investigation of Bioequivalence,  “Section 4.1.10 Highly variable drugs or drug products” should be followed.


In addition, for the test to be valid:


The acceptance criteria for equivalence parameters (Muptake) and (Mclearance)


The 90% confidence interval for the ratio of means of the test and negative control products should be entirely outside the interval of 80.00- 125.00%.

試驗和陰性對照產品平均值比率的90%置信區間應完全超出80.00-125.00%的區間。The 90% confidence interval for the ratio of means of the comparator and negative control products should be entirely outside the interval of 80.00- 125.00%.對照產品和陰性對照品平均值之比的90%置信區間應完全超出80.00-125.00%的區間。The 90% confidence interval for the ratio of means of the test product clearance (Mclearance) and (Muptake) comparator products should be entirely below 1.0.試驗(yan)產(chan)品清除率(Mclearance)與(yu)對(dui)照產品(Muptake)平均值(zhi)之比(bi)的90%置信區間應完全低于1.0。

The 90% confidence interval for the ratio of means of the comparator product clearance (Mclearance) and (Muptake) comparator products should be entirely below 1.0.


The overall conclusions of the study should be provided. This should be supported by a sound scientific discussion and interpretation of the TS data.






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