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【原文題目】

Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms

作者：Anil Kane

Oral solid-dosage forms (typically, tablets and capsules) are manufactured using conventional manufacturing processes such as direct blending or granulation techniqueswet granulation, dry granulation/roller compaction, or fluid bed granulation followed by fluid bed drying, milling, compression, and coating. It is important to understand the critical processing parameters (CPPs) that impact critical quality attributes(CQA). The CQAs that impact the final outcome (i.e., the therapeutic efficacy of the drug product) usually are parameters such as in-vitro dissolution and drug product stability. In-vitro dissolution of the drug can influence the rate and extent of drug absorption. Drug substance properties such as particle size, morphology, dosage strength, and drug loading have a big impact on the blending process and can influence the homogeneity of the drug substance in the blend. Blending is a critical process that needs to be optimized and is considered a CPP that can impact the potency of the finished product. Similarly, each of the granulation techniques has a processing step that could cause variability and has the potential of impacting the CQAs. Key parameters that need to be optimized (see Table I) will depend on the API properties, its stability, dose, drug loading, and other factors.

口服固體制劑（例如片劑和膠囊劑）都可以采用傳統(tǒng)的制造工藝如直接混合造粒技術(shù)、濕法造粒技術(shù)、干法造粒技術(shù)、流化床造粒/干燥技術(shù)，包括粉碎、壓片、包衣等工序。理解影響關(guān)鍵質(zhì)量屬性（CQA）的關(guān)鍵工藝參數(shù)（CPPS）很重要。CQA是那些影響藥物最終結(jié)果（如療效）的因素，如體外溶出和藥物的穩(wěn)定性。藥物的體外溶出可以影響藥物吸收的速度和程度。藥物的性質(zhì)如粒徑大小、形態(tài)、劑量和載藥量對混合過程有很大影響，并會影響藥物的混合均勻性?；旌鲜且粋€(gè)需要進(jìn)行優(yōu)化的關(guān)鍵，它可以影響成品的含量。每一種制粒技術(shù)都包括一個(gè)可能引起變異和對CQAs有潛在影響的工序。表1中列出了需要優(yōu)化的關(guān)鍵參數(shù)，這取決于原料藥（API）的性質(zhì)、穩(wěn)定性、劑量、載藥量及其他因素。

Table I: Process and critical process parameters that require optimization.

表1. 需要優(yōu)化的工序和關(guān)鍵工藝參數(shù)

A typical process optimization methodology includes a systematic identification of CQAs, CPPs, and a risk assessment to identify the critical selection of key parameters. A plan can then be drawn up, using a statistical design of experiments (DOE), which can be a full- or partial-factorial design, based on the availability of API and the number of runs that can be manufactured. The DOE experiments involve running parameters at high, medium, and low values, as well as running a defined number of control runs at target parameters. By analyzing the data from the DOE runs, a design space can be identified. Knowledge of the design space enables a control strategy to be defined for the manufacture of the product.

一個(gè)典型的工藝優(yōu)化方法包括系統(tǒng)辨識CQAs、CPPs、對關(guān)鍵參數(shù)進(jìn)行風(fēng)險(xiǎn)評估。然后起草一個(gè)方案，可以采用實(shí)驗(yàn)設(shè)計(jì)（DOE）進(jìn)行一個(gè)完全或部分析因設(shè)計(jì)，這要基于原料藥（API）的可獲得性和可以生產(chǎn)使用的次數(shù)。DOE包括在高、中、低值中進(jìn)行試驗(yàn)，并在目標(biāo)參數(shù)上進(jìn)行一定數(shù)量的控制試驗(yàn)。通過對DOE數(shù)據(jù)的分析，可確定設(shè)計(jì)空間。對設(shè)計(jì)空間的了解后，則可以對產(chǎn)品的生產(chǎn)制定一個(gè)控制策略。

A similar approach is taken for formulation optimization, in which critical functional formulation excipients are evaluated with high, medium, and low levels, and the impact of these variables is studied on output parameters of that functionality (e.g., disintegrant levels studies can be done with the rate of disintegration of tablets as the output).

類似方法還可以進(jìn)行制劑處方的優(yōu)化，包括對關(guān)鍵功能性輔料進(jìn)行高、中、低水平的評價(jià)，并通過對輸出參數(shù)的研究來評估這些變量的影響（例如，考察崩解劑的量可以通過對片劑的崩解情況作為輸出變量來研究）。

A systematic DOE to optimize the formulation composition in an oralsolid-dosage form is important for two main purposes:

一個(gè)系統(tǒng)的DOE可以優(yōu)化口服固體制劑的處方組成，其中兩個(gè)重要的目的是：

（1）To ensure the optimum level of a functional excipient in the formulation. In an immediate-release tablet formulation, excipient levels of binder, disintegrant, and lubricant can be varied and the functionality challenged. A partial or full factorial DOE can evaluate multiple excipients at different levels of the excipient. For an extended-release tablet formulation based on a hydrophilicgel matrix, polymer levels will affect the release rate of the drug from the tablet. Hence, the level of polymer is selected based on the specifications or the target release profile.

（1）確定處方中功能性輔料的最佳用量。在一個(gè)速釋片劑中，粘合劑、崩解劑、潤滑劑的用量和功能是可變的。部分或全因子DOE可在不同水平上評估多種輔料。對于基于親水性凝膠基質(zhì)的緩釋片劑，聚合物水平會影響片劑的釋放速率，因此，聚合物的水平是根據(jù)質(zhì)量標(biāo)準(zhǔn)或目標(biāo)釋放曲線來選擇的。

（2）To optimize the drug load in a formulation to reduce the pill burden, especially for a large dose drug product. Many oral solid-dose products need tobe formulated in doses above 100 mg per unit tablet or capsule. There are quite a few new chemical entities that need a much higher dose up to a 500 or 750 mg per unit dose. Fixed-dose combination therapies are becoming more popular, due to synergistic therapeutic effects and as a lifecycle management strategy. The number of actives and the dose per unit tablet are increasing. Thus, there is a need to formulate such products in a way that the tablet size is reasonable to swallow, especially for geriatric patients. It is important, therefore, to optimize the formulation so that the drug load in a tablet is as high aspossible, which also means that there is little room for inert excipients. Selecting the right functional excipient in the right quantity thus becomes more crucial.

（2）優(yōu)化處方中的載藥量以減少服藥負(fù)擔(dān)，尤其是大劑量藥物。許多口服固體制劑產(chǎn)品（片或膠囊）的規(guī)格大于100mg。有相當(dāng)多的新化合物，需更更高規(guī)格如500mg或750mg。由于協(xié)同治療效果且作為一個(gè)生命周期管理策略，固定劑量聯(lián)合療法正變得越來越流行。這種治療的治療次數(shù)和服用數(shù)量正在增加，因此，有必要制定這樣的產(chǎn)品，其片劑的大小是可以合理吞咽的，尤其對老年患者。因此，優(yōu)化處方使片劑的載藥量應(yīng)盡可能高，這也就意味賦形劑的量會用得很少。正確選擇功能性輔料從而變得更加重要。

Products with multiple doses use a “dose weight proportional” strategy-using the same formulation composition (drug to excipient ratio) and compressing the larger dose into a larger tablet size. This strategy has the benefit of avoiding a separate stability study as the drug to excipient ratiois the same; however, the disadvantage is that the higher dose becomes a large tablet, which may present “patient compliance” issues because of difficulty in swallowing. The limited time available for developing clinical trial formulations often makes optimization of drug load and tablet size a low priority.

多規(guī)格的產(chǎn)品使用“劑量-重量成比例”的策略，即采用相同的處方組成（藥物與賦形劑的比例），較大的劑量會壓成較大的藥片。這種策略有利于避免進(jìn)行單獨(dú)的穩(wěn)定性研究，因?yàn)樗幬锱c賦形劑的比例是相同的；然而，缺點(diǎn)是高規(guī)格藥物是一個(gè)大藥片，病人吞咽困難，這可能會引起“病人依從性”的問題。由于開發(fā)臨床試驗(yàn)處方的時(shí)間是有限的，這常常使藥物載藥量的研究、片劑大小的研究降低優(yōu)先級。

During this stage, however, it is important that the choice ofexcipients, level of excipients, the drug load, and reduction of pill size and burden are optimized. Polypharmacy is a huge problem, and patients would benefit greatly if better drug products that are easier to swallow can be developed. Optimizing the formulation at the right stage in the development program by increasing the drug load per unit tablet or capsule, thereby, reducing the pill burden, would be beneficial.

然而，在這一階段，重要的是輔料的選擇，輔料的水平、載藥量、降低藥片大小和服藥負(fù)擔(dān)是需要優(yōu)化的。多重用藥是一個(gè)巨大的問題，如果開發(fā)的藥物使患者更容易服用，那么患者將大大受益。在開發(fā)的適當(dāng)階段，通過優(yōu)化處方，增加每單位片劑或膠囊中的載藥量，從而減少服藥負(fù)擔(dān)將是有益的。