放弃或豁免生物学评价的报告2009.5

INTERNATIONAL CONCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USEICH HARMONISED GUIDELINEB IOPHARMACEUTICSC LASSIFICATION S YSTEM-BASEDB IOWAIVERSM9Draft v ersionEndorsed on 7 June 2018Currently under public consultationAt Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities of the ICH regions for internal and external consultation, according to national or regional procedures.M9Document HistoryCode History Date7 June 2018M9 Endorsement by the Members of the ICHAssembly under Step 2and release for publicconsultation(document dated 6 June 2018).Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided.The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document.The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.ICH H ARMONISED G UIDELINEB IOPHARMACEUTICSC LASSIFICATION S YSTEM-BASEDB IOWAIVERSM9ICH Consensus GuidelineT ABLE OF C ONTENTS1. Introduction (1)1.1.Background and Objective (1)1.2 Scope (1)2. Biopharmaceutics classification of the drug substance (2)2.1. Solubility (2)2.2. Permeability (3)3. Support of the eligibility of a drug product for a BCS-based biowaiver (4)3.1. Excipients (4)3.2. In vitro dissolution (6)4. Documentation (8)5. Glossary (9)INTRODUCTION11.1.Background and Objective2Two drug products containing the same active substance are considered bioequivalent if their 3bioavailabilities (rate and extent of drug absorption) after administration in the same molar 4dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo 5performance, i.e., similarity in terms of safety and efficacy. In in vivo bioequivalence studies, 6the pivotal pharmacokinetic parameters AUC (the area under the concentration time curve), 7and C max(the maximum concentration), are generally used to assess the rate and extent of 8drug absorption.9The BCS (Biopharmaceutics Classification System)-based biowaiver approach is intended to 10reduce the need for in vivo bioequivalence studies i.e., it can provide a surrogate for in vivo 11bioequivalence. In vivo bioequivalence studies may be exempted if an assumption of 12equivalence in in vivo performance can be justified by satisfactory in vitro data. The BCS is a 13scientific approach based on the aqueous solubility and intestinal permeability characteristics 14of the drug substance. The BCS categorizes drug substances into one of four BCS classes as 15follows:16Class I: high solubility, high permeability17Class II: low solubility, high permeability18Class III: high solubility, low permeability19Class IV: low solubility, low permeability20This guidance will provide recommendations to support the biopharmaceutics classification of 21drug substances and the BCS-based biowaiver of bioequivalence studies for drug products.221.2 Scope23BCS-based biowaivers may be used to demonstrate bioequivalence for example between 24products used in early clinical development through commercialization, for line extensions of 25the same pharmaceutical form of innovator products, in applications for generic drug products, 26and post-approval changes that would otherwise require in vivo bioequivalence evaluation, in 27accordance with regional regulations.28The BCS-based biowaiver is only applicable to immediate release, solid orally administered 29dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug 30products having a narrow therapeutic index are excluded from consideration for a BCS-based 31biowaiver in this guidance. Fixed-dose combination (FDC) products are eligible for a 32BCS-based biowaiver when all drug substances contained in the combination drug product 33meet the criteria as defined in sections 2 and 3 of this guidance.34352.BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE36BCS-based biowaivers are applicable to drug products where the drug substance exhibits high 37solubility and, either high permeability (BCS Class I) or low permeability (BCS Class III).3839A biowaiver is only applicable when the drug substance(s) in test and reference products are40identical. For example, a biowaiver is not applicable when the drug substance in the test 41product is a different salt, ester, isomer, or mixture of isomers from that in the reference 42product. Pro-drugs may be considered for a BCS-based biowaiver when absorbed as the 43pro-drug.44452.1.Solubility46A drug substance is classified as highly soluble if the highest single therapeutic dose is47completely soluble in 250 ml or less of aqueous media over the pH range of 1.2 – 6.8 at 37 ± 481°C. In cases where the highest single therapeutic dose does not meet this criterion but the 49highest strength of the reference product is soluble under the aforementioned conditions, 50additional data should be submitted to justify the BCS-based biowaiver approach.5152The applicant is expected to establish experimentally the equilibrium saturated solubility of 53the drug substance over the pH range of 1.2 – 6.8 at 37 ± 1ºC using a shake-flask technique or 54an alternative method, if justified. At least three buffers within this range, including buffers at 55pH 1.2, 4.5 and 6.8, should be evaluated. In addition, solubility at the pKa of the drug 56substance should be evaluated if it is within the specified pH range. The pH for each test 57solution should be measured after the addition of the drug substance and at the end of the 58equilibrium solubility study to ensure the solubility measurement is conducted under the 59specified pH. The pH should be adjusted if necessary. The lowest measured solubility over the 60pH range of 1.2 – 6.8 will be used to classify the drug substance.6162A minimum of three replicate determinations at each solubility condition/pH is necessary to63demonstrate solubility using a validated stability-indicating method, with appropriate 64compendial references for the media employed.6566In addition, adequate stability of the drug substance in the solubility media should be 67demonstrated. In cases where the drug substance is not stable with >10% degradation over 68the extent of the solubility assessment, solubility cannot be adequately determined and thus 69the drug substance cannot be classified. In this case a BCS-based biowaiver cannot be applied.70In addition to experimental data, literature data may be provided to substantiate and support 71solubility determinations, keeping in mind that peer reviewed articles may not contain the 72necessary details of the testing to make a judgement regarding the quality of the studies.73742.2.Permeability75The assessment of permeability should preferentially be based on the extent of absorption 76derived from human pharmacokinetic studies, e.g., absolute bioavailability or mass balance.7778High permeability can be concluded when the absolute bioavailability is ≥85%. High 79permeability can also be concluded if ≥ 85% of the administered dose is recovered in urine as 80unchanged (parent drug), or as the sum of parent drug, Phase 1 oxidative and Phase 2 81conjugative metabolites. Regarding metabolites in feces only oxidative and conjugative 82metabolites can be considered. Metabolites produced through reduction or hydrolysis should 83not be included, unless it can be demonstrated that they are not produced by microbial action 84within the gastrointestinal tract. Unchanged drug in feces cannot be counted toward the extent 85of absorption, unless appropriate data supports that the amount of parent drug in feces to be 86accounted for absorbed drug material is from biliary excretion, intestinal secretion or 87originates from an unstable metabolite, e.g., glucuronide, sulphate, N-oxide that has been 88converted back to the parent by the action of microbial organisms.8990Human in vivo data derived from published literature (for example, product knowledge and 91previously published bioavailability studies) may be acceptable, keeping in mind that peer 92reviewed articles may not contain the necessary details of the testing to make a judgement 93regarding the quality of the results.9495Permeability can be also assessed by validated and standardized in vitro methods using 96Caco-2 cells(see Annex I). The results from Caco-2 permeability assays should be discussed 97in the context of available data on human pharmacokinetics. In vitro cell permeability assays 98(Caco-2) used in support of high permeability should be appropriately validated and 99standardized as outlined in Annex 1. If high permeability is inferred by means of an in vitro 100cell system, permeability independent of active transport should be proven as outlined in 101Annex I, “Assay Considerations”.102103If high permeability is not demonstrated, the drug substance is considered to have low 104permeability (e.g. BCS class III).105106Instability in the Gastrointestinal Tract107If mass balance studies or in vitro Caco-2 studies are used to demonstrate high permeability, 108additional data to document the drug’s stability in the gastrointestinal tract should be provided, 109unless ≥ 85% of the dose is recovered as unchanged drug in urine. Stability in the 110gastrointestinal tract may be documented using compendial and simulated gastric and 111intestinal fluids or, with suitable justification, other relevant methods. Drug solutions should 112be incubated at 37ºC for a period that is representative of the in vivo contact of the drug 113substance with these fluids, i.e., one hour in gastric fluid and three hours in intestinal fluid. 114Drug concentrations should then be determined using a validated stability indicating assay 115method. Significant degradation (>10 percent) of a drug in this study could suggest potential 116instability.1171183.SUPPORT OF THE ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED 119BIOWAIVER120A drug product is eligible for a BCS-based biowaiver provided that the drug substance(s) 121satisfy the criteria regarding solubility and permeability (BCS Class I and III), the drug 122product is an immediate-release oral dosage form with systemic action, and the drug product 123is a dosage form that is pharmaceutically equivalent to the reference product. In cases where 124the highest single therapeutic dose does not meet the high solubility criterion but the highest 125strength of the reference product is soluble under the required conditions, BCS-based 126biowaivers can be supported based on additional data. An example of such additional data is 127demonstration of dose proportional pharmacokinetics (i.e. AUC and C max) over a dose range 128that includes the highest therapeutic dose.129130Drug products with buccal or sublingual absorption are not eligible for a BCS-based 131biowaiver application. As such, an orodispersible product is eligible for a biowaiver 132application only if there is no buccal or sublingual absorption and the product is labelled to be 133taken with water only.134135In order for a drug product to qualify for a BCS-based biowaiver, criteria with respect to the 136composition (excipients) and in vitro dissolution performance of the drug product should be 137satisfied. The drug product acceptance criteria are described in sections 3.1 and 3.2 below.1381393.1.Excipients140Excipient differences between the proposed test and the reference products should be assessed 141for their potential to affect in vivo absorption. This should include consideration of the drug 142substance properties as well as excipient effects. To be eligible for a BCS-based biowaiver, 143the applicant should justify why the proposed excipient differences will not affect the 144absorption profile of the drug substance under consideration, i.e., rate and extent of absorption, 145using a mechanistic and risk-based approach. The decision tree for performing such an 146assessment is outlined in Figures 1 and 2 in Annex II.147The possible effects of excipients on aspects of in vivo absorption such as solubility, 149gastrointestinal motility, transit time and intestinal permeability including transporter 150mechanisms, should be considered. Excipients that may affect absorption include 151sugar-alcohols, e.g., mannitol, sorbitol, and surfactants, e.g., sodium lauryl sulfate. The risk 152that a given excipient will affect the absorption of a drug substance should be assessed 153mechanistically by considering154•the amount of excipient used,155•the mechanism by which the excipient may affect absorption,156•absorption properties (rate, extent and mechanism of absorption) of the drug 157substance.158159The amount of excipients that may affect absorption in the test and reference formulations 160should be addressed during product development, such that excipient changes are kept to a 161minimum. Small amounts included in the tablet coating or levels below documented 162thresholds of effect for the specific drug substance are of less concern.163164By definition, BCS Class I drugs are highly absorbed, and have neither solubility nor 165permeability limited absorption. Therefore they generally represent a low risk group of 166compounds in terms of the potential for excipients to affect absorption, compared to other 167BCS classes. Consideration of excipient effects for BCS ClassI drug products should focus on 168potential changes in the rate or extent of absorption. For example, if it is known that the drug 169has high permeability due to active uptake, excipients that can inhibit uptake transporters are 170likely to be of concern. For BCS Class I drugs that exhibit slow absorption, the potential fora 171given excipient to increase absorption rate should also be considered.172173For BCS Class I drugs, qualitative and quantitative differences in excipients are permitted, 174except for excipients that may affect absorption, which should be qualitatively the same and 175quantitatively similar, i.e., within ± 10.0% of the amount of excipient in the reference product. 176177BCS Class III drug substances are considered to be more susceptible to the effects of 178excipients. These drugs are poorly permeable and may have site-specific absorption, so there 179are a greater number of mechanisms through which excipients can affect their absorption than 180for BCS Class I drugs. For BCS Class III drugs, all of the excipients should be qualitatively 181the same and quantitatively similar (except for film coating or capsule shell excipients). This 182is defined in Table 1. Examples of acceptable differences in excipients are shown in Annex II. 183184Table 1:Allowable differences in excipients for drug products containing BCS Class III 186drugs.187Excipient class Percent of the amount ofexcipient in the referencePercent difference relative tocore weight (w/w)Excipients which mayaffect absorption:± 10.0%All excipients:Filler ± 10.0%DisintegrantStarch ± 6.0%Other ± 2.0% Binder ± 1.0%LubricantCa or Mg stearate ± 0.5%Other ± 2.0% GlidantTalc ± 2.0%Other ± 0.2%Total % change permitted: 10.0% Note: Core does not include tablet film coat or capsule shell188189For FDC formulations containing only BCS Class I drugs, criteria regarding excipients should 190follow that for a BCS Class I drug. For FDC formulations containing only BCS Class III 191drugs, or BCS Class I and BCS Class III drugs, criteria regarding excipients should follow 192that for a BCS Class III drug. This is applicable to FDCs which are pharmaceutically 193equivalent.1941953.2.In vitro Dissolution196When applying the BCS based biowaiver approach, comparative in vitro dissolution tests 197should be conducted using one batch representative of the proposed commercial 198manufacturing process for the test product relative to one batch of the reference product. The 199test product should originate from a batch of at least 1/10 of production scale or 100,000 units, 200whichever is greater, unless otherwise justified. During a (clinical) development phase, 201smaller batch sizes may be acceptable, if justified. The comparative in vitro dissolution 202experiments should use compendial apparatuses and validated analytical methods.203204The following conditions should be employed in the comparative dissolution studies to 205characterize the dissolution profile of the product:206•Apparatus: paddle or basket207•V olume of dissolution medium: 900 ml or less (it is recommended to use the volume 208selected for the QC test)209•Temperature of the dissolution medium: 37 ± 1°C210•Agitation: paddle apparatus - 50 rpm211basket apparatus - 100 rpm212•At least 12 units of reference and test product should be used for each dissolution 213profile determination.214•Three buffers: pH 1.2, pH 4.5, and pH 6.8. Pharmacopoeial buffers should be 215employed. Additional investigation may be required at the pH of minimum solubility 216(if different from the buffers above). Purified water may be used as an additional 217dissolution medium in some regions.218•Organic solvents are not acceptable and no surfactants should be added.219•Samples should be filtered during collection220•For gelatin capsules or tablets with gelatin coatings where cross-linking has been 221demonstrated, the use of enzymes may be acceptable, if appropriately justified.222223When high variability or coning is observed in the paddle apparatus at 50 rpm, the use of the 224basket apparatus at 100 rpm is recommended. Additionally, use of sinkers in the paddle 225apparatus to overcome issues such as coning may be considered with justification.226227To qualify for a BCS-based biowaiver for BCS Class I drug substances both the test product 228and reference product should display either very rapid (≥85 for the mean percent dissolved in 229≤15 minutes) or rapid (≥85 for the mean percent dissolved in ≤30 minutes) and similar in vitro 230dissolution characteristics under all of the defined conditions. In cases where one product has 231rapid dissolution and the other has very rapid dissolution, statistical similarity of the profiles 232should be demonstrated as below.233234For the comparison of dissolution profiles, where applicable, the similarity factor f2 should be 235estimated by using the following formula:236237f2 = 50 • log {[1 + (1/n)Σt=1n (R t - T t)2]-0.5 • 100}238239In this equation f2 is the similarity factor, n is the number of time points, R(t) is the mean 240percent reference drug dissolved at time t after initiation of the study; T(t) is the mean percent 241test drug dissolved at time t after initiation of the study.242243The evaluation of the similarity factor is based on the following conditions:244• A minimum of three time points (zero excluded)245• The time points should be the same for the two products246• Mean of twelve individual values for every time point for each product.247• Not more than one mean value of ≥85% dissolved for any of the products.248• To allow the use of mean data, the coefficient of variation should not be more than 24920% at early time-points (up to 10 minutes), and should not be more than 10% at 250other time points.251252Two dissolution profiles are considered similar when the f2 value is ≥50. When both test and 253reference products demonstrate that ≥85% of the label amount of the drug is dissolved in 15 254minutes, comparison with an f2 test is unnecessary and the dissolution profiles are considered 255similar. In case the coefficient of variation is too high, f2 calculation is considered not 256accurate and reliable and a conclusion on similarity in dissolution cannot be made.257258To qualify for a BCS-based biowaiver for BCS Class III drug substances both the test product 259and reference product should display very rapid (≥85 for the mean percent dissolved in ≤15 260minutes) in vitro dissolution characteristics under the defined conditions.261262For FDC formulations, dissolution profiles should meet the criteria for all drug substances in 263the FDC to be considered. For FDC formulations containing only BCS I drugs, criteria 264regarding dissolution should follow that for a BCS Class I drug. For FDC formulations 265containing only BCS Class III drugs, criteria regarding dissolution should follow that for a 266BCS Class III drug. For FDCs containing both BCS Class I and BCS Class III drugs the 267dissolution criteria for the applicable BCS class for each component should be applied.268269For products with more than one strength the BCS approach should be applied for each 270strength, i.e., it is expected that test and reference product dissolution profiles are compared at 271each strength.2722734.DOCUMENTATION274The applicant should provide complete information on the critical quality attributes of the test 275drug substance and drug product and as much information as possible for the reference 276product, including, but not limited to: polymorphic form and enantiomeric purity; and any 277information on bioavailability or bioequivalence problems with the drug substance or drug 278product, including literature surveys and applicant derived studies. All study protocols 279including standards, quality assurance and testing methods should be appropriately detailed 280and validated according to current regulatory guidance’s and policies.281The reporting format should include tabular and graphical presentations showing individual 282and mean results and summary statistics. The tabular presentation should include standard 283deviation and coefficient of variation.284The report should include all excipients, their qualitative and, if possible, quantitative 285differences between the test and reference products.286A full description of the analytical methods employed, including validation, e.g. method 287linearity, accuracy and precision, should be provided. A detailed description of all test 288methods andmedia, including test and reference batch information [unit dose (milligram 289and %), batch number, manufacturing date and batch size where known, expiry date, and any 290comments] should also be provided. The dissolution report should include a thorough 291description of experimental settings and analytical methods, including information on the 292dissolution conditions such as apparatus, de-aeration, filtration during sampling, volume, etc. 293In addition, complete information with full description of the methods applied should be 294provided for the Caco-2 cell permeability assay method, if applicable (see Annex I).2952965.GLOSSARY297AUC: Area under the concentration versus time curve298BCS: Biopharmaceutics Classification System299C max: Maximum concentration300FDC: Fixed-dose combination301Pharmaceutically equivalent: Medicinal products containing the same amount of the same 302active substance(s) in the same dosage forms.303pKa: Acid dissociation constant at logarithmic scale304rpm: rotation per minute305306ANNEX I: Caco-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONS 307Permeability assays employing cultured Caco-2 epithelial cell monolayers derived from a 308human colon adenocarcinoma cell line are widely used to estimate intestinal drug absorption 309in humans. Caco-2 cells undergo spontaneous morphological and biochemical enterocytic 310differentiation, and express cell polarity with an apical brush border, tight intercellular 311junctions, and several active transporters as in the small intestine. Due to a potential for low 312or absent expression of efflux (e.g., P-gp, BCRP, MRP2) and uptake (e.g., PepT1, OATP2B1, 313MCT1) transporters, the use of Caco-2 cell assays in support of high permeability for BCS 314classification is limited to passively transported drugs (for definition see Assay 315Considerations).316317Method validation318The suitability of the Caco-2 cell assays for BCS permeability determination should be 319demonstrated by establishing a rank-order relationship between experimental permeability 320values and the extent of drug absorption in human subjects using zero, low (<50%), moderate 321(50 – 84%), and high (≥85%) permeability model drugs. A sufficient number of model drugs 322are recommended for the validation to characterize the full permeability range (a minimum 5 323for each permeability category, high, moderate and low is recommended; examples are 324provided in Table 1). Further, a sufficient number (minimum of 3) of cell assay replicates 325should be employed to provide a reliable estimate of drug permeability. The established 326relationship should permit differentiation between low, moderate and high permeability drugs. 327328Caco-2 cell monolayer integrity should be confirmed by comparing transepithelial electrical 329resistance (TEER) measures and/or other suitable indicators, prior to and after an experiment. 330In addition, cell monolayer integrity should be demonstrated by means of compounds with 331proven zero permeability.332333Reporting of the method validation should include a list of the selected model drugs along 334with data on extent of absorption in humans (mean, standard deviation, coefficient of 335variation) used to establish suitability of the method, permeability values for each model drug 336(mean, standard deviation, coefficient of variation), permeability class of each model drug, 337and a plot of the extent of absorption as a function of permeability (mean ± standard deviation 338or 95 percent confidence interval) with identification of the high permeability class boundary 339and selected high permeability internal standard used to classify the test drug substance.340341In addition, a description of the study method, drug concentrations in the donor fluid,342description of the analytical method, equation used to calculate permeability, and where343。

生物等效性豁免那些事儿作者：陈亭亭（丽珠研究院副院长）来自：蒲公英一致性评价的工作正在国内掀起一场席卷全行业的风暴，是对历史的修正，也是行业的大洗牌，其结果会如何，还有待时间的考证。

时间，是一个很奇妙的东西，会掩藏过去，淡化曾经，也能抹平现在和未来的伤痛。

制药同行们，如同青春期叛逆而迷茫的少年，翘首以盼监管部门能给出更多、更明确的指示，而事实上，路得自己走、墙得自己撞，是否头破血流、是否灰飞烟灭，还是否飞黄腾达，都在一念之间。

当我们踌躇满志，且行且珍惜的时候，国家局在2015年5月18日发布了一则《人体生物等效性试验豁免指导原则的通告（2016年第87号）》，让众多迷茫的同行们看到一丝丝“加快进度、节省开支”的希望。

曾经闲暇之时对这一份具有历史意义的《指导原则》进行过详细的研究和比对（可参见蒲公英之前发布的四份连载文章），不是本文想要论述的重点。

既然FDA、WHO、FIP和CFDA都发布了类似的指导原则，为企业申请生物等效性豁免（Biowaiver）提供指导和依据，那么我们在开展一致性评价工作中，是否“有机可乘”，让我们能够“不费那么多钱，不花那么多时间，不投入那么大的人力”，轻松实现一部分品种的“一致性”呢？接下来，本文作者试图从FDA、WHO、FIP的豁免现状，“旁敲侧击”可能性。

一、FDA生物等效性豁免现状在追溯FDA生物等效性豁免历史情况时，着实费了一些功夫。

首先，有在美国长期从事仿制药开发的华人科学家提示，在美国的橙皮书（Orange Book）中，有大量的AA类产品，这类产品都是不需要开展生物等效性试验，直接批准上市。

寻着这条线索，查看了一部分AA类产品之后，有些失望。

AA类产品大致存在几个特征：1、以液体制剂居多，口服固体制剂较少；2、口服固体制剂大多数是具有长期临床使用数据积累，安全性、有效性等均经过实践证明，豁免生物等效性试验之后对临床使用没有太多安全性问题的品种；3、豁免并不是基于BCS分类。

关于申请要求临床豁免的报告省药品食品监督管理局：我厂生产的“一次性使用真空采血管”，现在国内已有很多家企业生产，产品的生产工艺和质量管理均已成熟。

产品的结构、标识颜色、添加剂使用均已按该产品的行业标准YY0314—1999标准中技术要求执行。

一、产品的生产过程及结构：我们依据参考文献大连市临床检验中心王永安执笔的真空采血管系列生产工艺过程及质量控制一文的要求组织生产，确保了产品完全符合临床检验要求。

二、产品用途及临床应用和评价真空采血管的临床用途是减少临床检验一次性用品对环境的污染，有利于血清分离临床检验以及添加剂的应用环节，保证检验的准确性，其临床应用文献有：1.《真空采血管系列生产工艺过程及质量控制》摘自（大连市临床检验中心王永安执笔）2.《从采血到检查测定值变动的原因》摘自（医学检查V ol.53 No.9 2004）3.《使用真空采血管的问题点》摘自(日本医学检查石泽修二等Vol.53 No.5 2004)4.《关于真空采血管的安全性的讨论》摘自（医学检查V ol.53 No.5 2004）5.《影响真空采血管测定变动的各种因素》摘自(检验医学与临床2005年4月第2卷第2期)6.《含分离的样本原管冻存血清的可行性初探》摘自(国外医学临床生物化学与检验学分册2005年12月第25卷第12期)7.《7种真空促凝采血管对15种生化指标检测结果的影响》摘自(检验医学2005年第20卷第4期)三、申请要求豁免的依据及理由1．要求豁免的依据是医疗器械产品注册的有关资料。

2．理由是我厂生产的真空采血管产品为成熟产品，现国内已有很多企业在生产该产品，产品的结构、使用方法、预期预期用途均相同，产品技术要求各企业均按YY0314—1999行业标准规定执行。

最关键的是该产品在国内相关文献中均对该产品的应用评价和安全性评价作了阐述。

为此我厂特此向省局提出要求予以准许临床豁免为盼。

医用器材厂2006．3。

ISO 10993-1生物学评价及化学表征常见问题及答案总结ISO 10993-1和提交FDA审评文件区别？美国FDA于2016年06月正式公布了生物学评估标准“ISO 10993-1标准的使用《医疗器械生物学评估—第1部分：风险管理过程中的评价与试验指南》Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" 。

FDA升级的法规，对于部分测试评估及萃取要求和ISO 10993-1内容有差异，尤其是高风险可降解植入物产品需观察植入后样品降解的短、中、长期时间对于生物体的影响，和对于植入物或贴有无热源（non-pyrogen）产品的热原及内毒素试验质控有新要求。

另外，FDA不承认ISO 17025体系，要求生物相容性测试必须在正规的GLP生物学实验室完成。

因此要申请美国FDA注册的医疗器械生产厂家，务必要委托具有GLP资质的实验室，按照FDA生物学评价标准完成有关的生物学试验。

FDA 法规原文节录如下：Any in vitro or in vivo biological safety experiments or tests should be conducted in accordance with recognized Good Laboratory Practice (GLP) regulations including, but not limited to, the assignment of competent trained staff in the conduct of biocompatibility testing.材料的可沥滤物和降解产物有区别吗？可滤出物指的是产品（材料、组件或器械）通过溶剂浸提后释放出来的物质；降解产物是由原始材料在生物体内化学裂解而产生的颗粒或者化学物质，可见两者定义是不相同的。

浅谈世界卫生组织的药品生物等效性豁免王玲;陈泽【期刊名称】《药学与临床研究》【年(卷),期】2012(20)6【摘要】介绍世界卫生组织(WHO)有关药品生物等效性实验豁免(以下简称生物豁免)的政策指南,使国内制药行业对其有所了解.就WHO的生物豁免政策而言,更多的药品可以避免进行体内生物等效性研究,这对于以仿制药为主的药品研发更具节约时间和开发成本的效益,也为国内的有关生物等效性豁免提供借鉴.%This article introduces medicine biowaiver guidelines of World Health Organization (WHO) to let Chinese pharmaceutical industry gain some understanding. According to the policy of WHO, bioequivalence in vivo can be avoided for more medicines, which can bring more economic benefits for the development and research of multi-source (generic) medicines. It provides reference for domestic biowaiver.【总页数】3页(P560-562)【作者】王玲;陈泽【作者单位】南京白敬宇制药有限责任公司,南京210038;南京柯菲平盛辉制药有限公司,南京211200【正文语种】中文【中图分类】R951【相关文献】1.食药监总局发布人体生物等效性试验豁免指导原则 [J],2.仿制药一致性评价中人体生物等效性试验豁免的风险分析与管理 [J], 廖萍;张景辰;李帅;龚前飞;陈桂良3.仿制药一致性评价中人体生物等效性试验豁免申请的进展及辅料影响考量点 [J], 廖萍;朱嘉;张景辰;吴浩;姜红4.国家药监局药品审评中心征求《生物利用度和生物等效性试验用药品的处理和保存要求技术指导原则》意见 [J],5.药审中心公开征求ICH指导原则《M9:基于生物药剂学分类系统的生物等效性豁免》意见 [J],因版权原因，仅展示原文概要，查看原文内容请购买。

关于印发医疗器械生物学评价和审查指南的通知国食药监械[2007]345号各省、自治区、直辖市食品药品监督管理局（药品监督管理局）：为规范医疗器械生物学评价和审查工作，我局组织制定了《医疗器械生物学评价和审查指南》。

现印发给你们，请参照执行，并将有关事项通知如下：一、申请涉及生物学评价的产品注册的企业，可提供生物学评价报告（含支持性文件）代替产品注册检验报告中的生物学试验部分，或进行全项生物学试验。

二、国外企业提供的医疗器械生物学评价报告中含有生物学试验报告的，企业应提供生物学试验室所在国的GLP证明。

附件：1．医疗器械生物学评价和审查指南2．《医疗器械生物学评价报告》的出具与审查要点国家食品药品监督管理局二○○七年六月十五日附件1：医疗器械生物学评价和审查指南一、目的与范围为使GB/T 16886－ISO 10993系列标准能够正确而有效地实施，特制定本指南。

本指南为医疗器械评价者提供了生物学评价指南，为医疗器械的审查提供了生物安全性审查指南。

注：本指南不涉及微生物污染、灭菌（如“无菌”、“细菌内毒素”）、除菌和动物源性医疗器械的病毒去除与控制等方面的生物安全性。

二、术语（一）医疗器械：同《医疗器械管理管理条例》。

（二）制造者：医疗器械制造者或商标持有人/单位。

（三）评价者：医疗器械制造者或受其委托的专家。

注：医疗器械制造者对生物安全性评价负责。

（四）审查者：对医疗器械管理负有职责的行政管理部门或受其委托负责医疗器械审查的机构。

三、医疗器械/材料首次生物安全性评价（一）评价依据GB/T 16886－ISO 10993《医疗器械生物学评价》系列标准。

（二）评价者应当经过培训并在医疗器械生物学评价方面具有长期实践经验。

（三）评价要求1．出于保护人类的目的，需要进行生物学评价的医疗器械，生物学评价（特别是必要的动物试验）未开展之前不得进入临床试验。

2．对医疗器械开展生物学评价时，应当按照GB/T 16886.1－ISO 10993.1给出的评价流程图开展。

人体生物等效性试验豁免指导原则集团文件版本号：（M928-T898-M248-WU2669-I2896-DQ586-M1988）附件人体生物等效性试验豁免指导原则本指导原则适用于仿制药质量和疗效一致性评价中口服固体常释制剂申请生物等效性（Bioequivalence）豁免。

该指导原则是基于国际公认的生物药剂学分类系统（Biopharmaceutics Classification System，以下简称BCS）起草。

一、药物BCS分类BCS系统是按照药物的水溶性和肠道渗透性对其进行分类的一个科学架构。

当涉及到口服固体常释制剂中活性药物成分（Active Pharmaceutical Ingredient，以下简称API）在体内吸收速度和程度时，BCS系统主要考虑以下三个关键因素，即：药物溶解性（Solubility）、肠道渗透性（Intestinal permeability）和制剂溶出度（Dissolution）。

（一）溶解性溶解性分类根据申请生物等效豁免制剂的最高剂量而界定。

当单次给药的最高剂量对应的API在体积为250ml（或更少）、pH值在1.0—6.8范围内的水溶性介质中完全溶解，则可认为该药物为高溶解性。

250ml的量来源于标准的生物等效性研究中受试者用于服药的一杯水的量。

（二）渗透性渗透性分类与API在人体内的吸收程度间接相关（指吸收剂量的分数，而不是全身的生物利用度），与API在人体肠道膜间质量转移速率直接相关，或者也可以考虑其他可以用来预测药物在体内吸收程度的非人体系统（如使用原位动物、体外上皮细胞培养等方法）对渗透性进行分类。

当一个口服药物采用质量平衡测定的结果或是相对于静脉注射的参照剂量，显示在体内的吸收程度≥85%以上（并且有证据证明药物在胃肠道稳定性良好），则可说明该药物具有高渗透性。

（三）溶出度口服固体常释制剂具有快速溶出的定义是：采用中国药典2015版附录通则（0931）方法1 （篮法），转速为每分钟100转,或是方法2（桨法），转速为每分钟50或75转，溶出介质体积为500ml（或更少），在溶出介质：（1）0.1mol/L HCl或是不含酶的模拟胃液；（2）pH4.5缓冲介质；（3）pH6.8缓冲介质或是不含酶的模拟肠液中，30分钟内API的溶出均能达到标示量的85%以上。

生物等效性豁免指南中英对照GUIDANCE FOR INDUSTRY1Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System基于生物制剂分类系统的速释固体口服制剂体内生物利用度和生物等效性研究豁免指南I. INTRODUCTION 引言 (3)II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM 生物制剂分类系统 (3)A. Solubility 溶解 (4)B. Permeability 渗透 (4)C. Dissolution 分解 (5)III. METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT 药物分类和制剂溶解特性测定方法 (5)A. Determining Drug Substance Solubility Class 判定原料药的溶解度分类 (5)B. Determining Drug Substance Permeability Class 判定原料药渗透性分类 (6)1. Pharmacokinetic Studies in Humans 人体内药代动力学研究(7)2. Intestinal Permeability Methods 肠道通透性检测方法 (7)3. Instability in the Gastrointestinal Tract 胃肠道稳定性研究 (10)C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity 测定药物的溶解特性和溶解相似性 (11)IV. ADDITIONAL CONSIDERATIONS FOR REQUESTING ABIOWAIVER 生物豁免请求其他注意事项 (12)A. Excipients 辅料 (12)B. Prodrugs 药物前体 (13)C. Exceptions 不适用情况 (13)1. Narrow Therapeutic Range Drugs 治疗范围狭窄的药品 (13)2. Products Designed to be Absorbed in the Oral Cavity 口腔吸收制剂 (13)V. REGULATORY APPLICATIONS OF THE BCS BCS的申请 (13)A. INDs/NDAs (13)B. ANDAs (14)C. Postapproval Changes 批准后变更 (14)VI. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS 生物豁免请求支持数据 (15)A. Data Supporting High Solubility 支持高溶解度的数据 (15)B. Data Supporting High Permeability 高渗透性支持数据 (15)C. Data Supporting Rapid and Similar Dissolution 快速及相似溶出支持数据 (16)D. Additional Information 其他信息 (17)ATTACHMENT A 附录A (18)I. INTRODUCTION 引言This guidance provides recommendations for sponsors of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications who wish to request a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies for immediate release (IR) solid oral dosage forms. These waivers are intended to apply to (1) subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period, and (2) in vivo BE studies of IR dosage forms in ANDAs. Regulations at 21 CFRpart 320 address the requirements for bioavailability (BA) and BE data for approval of drug applications and supplemental applications. Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22. This guidance explains when biowaivers can be requested for IR solid oral dosage forms based on an approach termed the Biopharmaceutics Classification System (BCS).本指南给INDs、MDAs、ANDAs和增补申请主办方为速释固体口服制剂请求获得生物利用度和/或生物等效性研究豁免提供建议。