一、關鍵質量屬性
A Critical Quality Attribute (CQA) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs can be associated with drug substances, drug products, excipients, intermediates (in-process materials), and container/closure components. At an early stage of process development, the information available on product attributes may be limited. For this reason, the first set of CQAs may come from prior knowledge obtained during early development and/or from similar products rather than from extensive product characterization. The degree of criticality assigned to quality attributes is derived using risk-based tools and the potential impact of the attributes on safety and efficacy. Following comprehensive assessments of scientific evidence and risk, quality attributes are ranked according to the degree of criticality, which may be a continuum that more accurately reflects the complexity of structure-function relationships and varying levels of uncertainty around attribute classification. Attributes not assigned as CQAs should also be considered in the development of the process.
關鍵質量屬性（CQA）是為了保證預期藥品質量需要保持在適宜的限度、範圍或分布範圍內的物理的、化學的、生物的或微生物的性質或特性。CQAs 可能與原料藥、製劑產品、輔料、中間產品（中間物料）和容器/密封系統有關。在工藝開發的早期可以限定為可用的產品屬性信息。為此，起初設定的關鍵質量屬性可能來自早期開發和/或類似產品獲取的先前的知識而不是大量的產品性質。質量屬性的關鍵程度來源於利用基於風險的工具和質量屬性對安全性與有效性的潛在影響。在對科學證據和風險進行了綜合評估之後，根據關鍵性程度對質量屬性排序，這樣可能更能反映結構-功能關係的複雜性和屬性分類不確定性的變化程度。與CQAs 無關的屬性在工藝開發中也應加以考慮。
CQAs are not synonymous with specifications. In addition, there is not necessarily a one-to-one relationship between CQAs and specifications. Specifications are a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. Several product attributes identified as CQAs may be detected by a single test method, and therefore, built into a single test specification (e.g., API solubility, hardness, porosity are CQAs evaluated using a single test: dissolution). Some CQAs may not be included in the specifications if they are very well-controlled and consistently achieved within the process (e.g., viral clearance is not tested for every batch), while some attributes not considered critical may be included in the specifications.
CQAs 與質量標準不是同義詞。另外，也沒有必要將CQAs 與質量標準一一對應。質量標準是檢驗、參照的分析程序和用數值限度、範圍描述的適當的可接受標準或描述的測試的其他標準的列表。被確定為CQAs 的幾個產品屬性可以用單一方法檢查，因此，可以建立單一的測試標準（例如：API 的溶解度、硬度、孔隙度是可以用一個試驗-溶出度來評價的CQAs）。有些在工藝過程中容易控制和達到的CQAs 可以不包含在質量標準中（如病毒清除不是每批檢查），而一些不是關鍵性的屬性也可能制定在質量標準中。
The identification of potential CQAs is an ongoing activity initiated early in product development. It makes use of general knowledge about the product and its application, as well as available clinical and non-clinical data. CQAs are subject to change in the early stages of product development, and thus require a quality risk management approach that evolves as knowledge about the product and process is generated (for discussion, see Section 6.1 「Application of Risk Management」). CQAs for commercial products should be defined prior to initiation of Stage 2 activities.
潛在CQAs 的確定是一個始於產品開發早期的持續性活動。它需要利用產品及其應用以及臨床和非臨床數據等一般知識。在產品開發的初期，CQAs 是易變的，所以需要質量風險管理方法來轉化產生的產品和工藝的知識（有關討論見6.1 節「風險管理的應用」）。商業產品的關鍵質量屬性應在第二階段活動開始前被定義。
二、新的工藝驗證第一階段需要輸出的文獻資料
下面的列表概括了在工藝驗證生命周期中從第一階段（工藝設計）到第二階段（性能確認）轉移所需的信息。本節詳細討論應轉移的資料並提供額外的參考信息。
• Quality Target Product Profile (QTPP) — This is done at the initiation of Stage 1
目標產品質量概況(QTPP)-第一階段開始就完成的。
• Critical Quality Attributes (CQAs) with corresponding Criticality Risk Assessment and desired confidence
關鍵質量屬性及對應的關鍵性風險評估和理想的置信度
• Manufacturing Process Design
生產工藝設計
• Process description showing process inputs, outputs, yields, in-process tests and controls, and process parameters (set points and ranges) for each unit operation
工藝描述：包括每個操作單元的工藝輸入、輸出、收率、中間檢測與控制和工藝參數（設定控制點和範圍）；
• Process solution formulas, raw materials, specifications
工藝溶液處方、原材料及規格；
• Batch Records and production data from laboratory or pilot scale production
批記錄和來自實驗室或中試生產規模的生產數據
• Analytical Methods (for product, intermediates, and raw materials)
分析方法（包括產品、中間產品和原材料）
• Quality Risk Assessment
質量風險評估
• Initial risk-based categorization of parameters prior to process characterization
工藝特性化前對參數進行基於風險的初步分類
• Criticality and Risk Assessments
關鍵性和風險評估
• Identification of Process Parameters with corresponding criticality and risk analysis
基於關鍵性和風險分析識別工藝參數
• Process Characterization
工藝表徵
• Process Characterization Plan and Protocols 工藝表徵計劃和方案
• Study Data Reports 研究數據報告；
• Process Control Strategy
工藝控制策略
• Release Specifications 放行標準；
• In-Process Controls and Limits 中間產品控制與限度；
• Process Parameter set points and ranges 工藝參數設定點和範圍；
• Routine Monitoring requirements (including in-process sampling and testing) 日常監控要求（包括中間品取樣和測試）；
• Storage and time limitations for intermediates, process solutions, and process steps 中間產品、加工溶液的貯藏和工藝步驟的時間限度；
• Raw Material/Component Specifications 原料/包裝材料的質量標準；
• Design Space (if applicable) 設計空間（如適用）
• Process Analytical Technology applications and algorithms (if PAT is used)
過程分析技術應用和算法（如果使用PAT）
• Product Characterization Testing Plan (i.e., tests not included in the product Release Test panel)
產品表徵試驗計劃（即不包括產品放行檢驗中的試驗）
• Manufacturing Technology – assessment of production equipment capability and compatibility with process requirements (may be covered in Stage 2a)
生產技術-按工藝要求評價生產設備能力和適應性（也可以在第二階段2a 中進行）
Scale-up/Scale-down Approach (Evaluation/Qualification of Laboratory Models)
放大/縮小方法（實驗室模型評價/確認）
• Development Documentation 藥品開發文件
Process Design Report 工藝設計報告
• Process Validation Master Plan
工藝驗證主計劃
三、對工藝設計報告的要求
The process design report is also a Stage 1 output. As a living document that describes in detail the intended commercial process, it may have various titles in internal procedures. Stage 1 study data are used to support this document and to justify the ranges, and process control strategy. Additional data and process knowledge are gained gathered as the manufacturing process changes, and are incorporated during Stages 2 and 3. The process design report, this document should be updated to include this new information. This
comprehensive document includes:
工藝設計報告也是階段1的輸出，作為一份詳細描述預期的商業工藝的動態文件，它可能在內部程序裡有各種各樣的名稱。階段1研究數據被用於支持這個文件以及證明範圍和工藝控制策略。生產工藝變更時收集到的額外的數據和工藝知識收集起來並在階段2和3中整合。工藝設計報告應該被更新以包括這信息的更新，這全面的文件包括：
• Reference to CQAs and supporting risk assessments
CQAs的引用和支持性的風險評估
• Process flow diagrams
工藝流程圖
• Process description tables
工藝描述表
• Inputs (in-process controls)
輸入（中間過程控制）
• Outputs (in-process tests and limits, in-process specifications)
輸出（中間過程檢測和限度，中間控制質量標準）
• Process parameters and ranges
工藝參數和範圍；
• Classification of parameters for risk of impact to CQAs and process performance
對CQAs和工藝性能有影響風險的參數分類
• Design space, as appropriate
設計空間，視情況而定；
• Justification and data supporting all parameter ranges (e.g., characterization data, development studies, clinical manufacturing history)
支持所有參數範圍的合理說明和數據（例如，表徵數據、開發研究、臨床生產歷史）；
四、工藝控制策略的描述
Establishing an effective and appropriate process control strategy is one of the most important outcomes of pharmaceutical development in Stage 1. An appropriate control strategy is based on knowledge and experience gained in Stage 1 and its effectiveness will dictate the extent to which a manufacturing process remains in a state of control. As with the other aspects of stage, 1 discussed above, the development of an effective process control strategy is an iterative process. It starts, early in development and evolves as
process and product knowledge increase. A robust control strategy encompasses all elements of individual unit operations in the process. All product quality attributes and process parameters, regardless of whether
they are classified as critical, are included in a complete process control strategy which includes the following elements:
建立一個有效和適當的工藝控制策略是階段1中藥品研發中最重要產出之一。一個恰當的控制策略是基於在階段1中獲得的知識和經驗，它的有效性關係到生產工藝保持受控狀態的程度。正如上面討論的階段1的另一個方面，一個有效的工藝控制策略的開發是一個反覆的過程。它開始於研發早期並隨著工藝和產品知識的增加而增加。一個具耐受性的控制策略包含工藝中單個單元操作的所有要素。所有產品質量屬性和工藝參數，不管它們是否被歸類為關鍵，都將包括在一個完整的工藝控制策略中，完整的工藝控制策略包括下列元素：
Raw Material Controls
原料控制
The ability to manage the quality of the inputs (raw materials and components) to assure a consistent output is an essential aspect of a process control strategy. Inputs should be categorized based on their potential risk for introducing variability or contaminants into the product and/or process. Product variability may include changes to CQAs, whereas process variability may include inconsistencies in yield, reaction kinetics, filterability, or other non-product, quality-related effects. For many raw materials used in the manufacturing process, selection of appropriate grades (based on purity, chemical and physical characteristics, and/or microbial specifications, such as endotoxin) may be an adequate level of control. For higher risk raw materials, understanding the contribution to product and process variability may be
essential to establishing specifications for those materials. Once the relationships are understood, appropriate risk reduction steps can be made part of the control strategy (see Section 6.1.4).
確保始終如一的輸出的管理輸入（原料和包材）質量的能力是工藝控制策略必不可少的，輸入應該基於它們引入變化或汙染到產品和/或工藝中的潛在風險而進行分類。產品變異性可能包括CQAs的改變，反之工藝變異性可能包括收率不一致、反應動力學、過濾性或其它非產品質量相關影響。對於生產工藝中所用的許多原料，選擇適當級別（基於純度、化學和物理特性、和/或微生物標準例如內毒素）可能是一個充足的控制水平；對於高風險原料，理解其對產品和工藝變異性的促成程度對建立那些物料的標準是必不可少的，一旦這關係被理解，適當的風險降低步驟能採用成為控制策略的部分（見6.1.4節）。
In-Process and Release Specifications
中間過程和放行標準
In-process and product specifications may be related to product safety and efficacy or may assure product consistency. Confirmed failure to meet a product specification (in-process or product) disqualifies material from clinical or commercial use. Guidance on setting specifications is provided in ICH guidance documents Q6a and Q6b.
中間過程和產品標準可能與產品安全性和有效性相關或可能保證產品一致性，確認不符合產品標準（中間體或產品）取消臨床或商業使用物料資格。關於設置標準的指南在ICH指南文件Q6a和Q6b中提供。
In-Process Controls
中間過程控制
In-Process Controls (IPCs) are inputs to the process and are checks performed during production to monitor and, if appropriate, to adjust the process, and/or to ensure that the intermediates or product conform to specifications or other defined quality criteria.
過程控制是工藝的輸入以及在在生產過程中執行檢查以監控和調整工藝（如果適當），和/或確保中間體或產品符合標準或其它規定質量標準。
Performance Parameters
性能參數
Performance parameters (e.g., tablet/capsule disintegration; harvest or peak growth cell densities/ viability) are process outputs that cannot be directly controlled but are indicators that the process has performed as expected.
性能參數（例如：片劑/膠囊崩解、收穫期或生長高峰期的細胞密度/活力）是工藝輸出，不能直接控制但它反映工藝是否按預期。
Process Parameter Set Points and Ranges
工藝參數設置點和設置範圍
Knowledge of the effects of process parameter variability on the output of each Unit Operation and on the final product evolves during Process Development and Process Characterization (Section 3.7). This information, along with process equipment capability (Section 4.1), is used to establish parameter set points and ranges (including ranges for alarms and deviations). It may also be used to assess the severity of process deviations caused by parameter excursions. Parameter ranges may be designated as normal
operating ranges (NORs), or where proven by supportive data, as proven acceptable ranges (PARs).
工藝參數可變性對每個單元操作的輸出和最終產品的影響的知識在工藝發展和工藝表徵過程中演變（3.7節），這信息連同工藝設備能力（4.1節）被用於建立參數設置點和範圍（包括警戒限和行動限範圍），也可用於評估由參數漂移所致的工藝偏差的嚴重性。參數範圍可能被指定為正常操作範圍（NORs），或當有支持數據證實時作為已證實的可接受範圍（PARs）。
Process Monitoring (Data Review, Sampling, Testing)
工藝監控（數據審核、取樣、測試）
Process monitoring includes measurement data (e.g., flow rates, temperatures, volumes, pH), inprocess sampling plans, and appropriate analytical assays. Data collection and analysis begins in Stage 1 and are
integral parts of Stage 2, Process Performance Qualification. The data collection effort eventually evolves into the continued process monitoring program described for Stage 3, Continued Process Verification (see
Section 5.0, 「Continued Process Verification, Stage 3」).
工藝監控包括測量數據（例如流速、溫度、體積、pH）、過程取樣計劃、以及適當分析檢測。數據收集和分析在階段1開始以及是階段2不可缺少的部分。數據收集工作最終發展成為階段3中描述的持續工藝監控程序（見5.0節）
Processing and Hold Times
加工和保留時間
Hold conditions and times are an essential part of the process control strategy for all process intermediates (or in-process materials), drug substance, bulk drug product, and prepared solutions. Studies should be performed to support these limits. Time limits for processing steps should also be part of the control
strategy.
對所有工藝中間體（或過程物料）、藥物成分、原液藥物產品以及準備的溶液的保留條件和時間是工藝控制策略一個不可或缺的部分，應執行研究以支持這些限度，對工藝步驟的時間限度也應該是控制策略的一部分。
Process Analytical Technology (PAT)
過程分析技術（PAT）
Process Analytical Technology (PAT) is one approach to implement the Control Strategy (28). Using PAT, CQAs are monitored in real-time (using on-line or at-line analytics), and results are used to adjust CPPs during production to decrease product variability (CQAs) or achieve consistent CQAs at desired ranges with low variability.
過程分析技術（PAT）是執行控制策略的一個方法，使用PAT，CQAs被實時監控（用在線分析），在生產過程中其結果用於調節CPPs以減少產品變化（CQAs）或得到在期望範圍內的變化性小的已知的CQAs。。
PAT uses product and process knowledge as well as equipment automation and analytical instrumentation technologies. Successful application of PAT requires a thoroughly characterized process (Section 3.7) in which the relationship between CPPs and CQAs is explored using mathematical models, such as multivariate analysis. Application of this understanding to the Control Strategy (Section 3.9) also affects the design and qualification of the instrumentation and control systems in the manufacturing process.
PAT使用產品和工藝知識以及設備自動化和分析儀表技術，成功的PAT應用要求一個徹底的特徵化工藝（3.7節），在該特徵化工藝中，CPPs和CQAs間關係用數學模型探索，諸如多變量分析。對控制策略的理解的應用也影響生產工藝中測控系統的確認。
To support implementation of PAT, Stage 1 deliverables must describe the CQA monitoring scheme and the algorithm for adjusting CPPs based on the process response. Qualification of the equipment, measurement system, and process (Stage 2) must demonstrate the capability to adjust CPPs according to the established algorithm and confirm that these adjustments result in acceptable and predictable outputs. Therefore, PAT-based control methods need to be qualified (29).
為支持PAT的執行，階段1交付必須描述CQA監控計劃和基於工藝響應調節CPPs的算法。設備、測量系統以及工藝的確認（階段2）必須證明安裝建立的運算法則調整CPPs的能力以及確認這些調整導致的可接受的和預測的輸出。因而，基於控制方法的PAT需要被確認。
3.10 Clinical Manufacturing Experience – Batch Records and Production Data
臨床生產經驗-批記錄和生產數據
During Stage 1, clinical batches are used in clinical trials to support product approval. The data may be used along with formal process characterization data to support the establishment of manufacturing process parameters and the process control strategy. These data also comprise the beginning of the process monitoring that will continue after PPQ. Early-batch data may not include all controls implemented in the final commercial process, but the information is still valuable for evaluating the process performance. If used to support ranges and limits, clinical batch data should be included in the final process design report that will justify the process and the control strategy. The final batch records should be generated at the end of Stage 1. They will support the finalized commercial process and serve as a prelude to Stage 2.
在階段1過程中，臨床批被用於臨床試驗中以支持產品批准，這數據可能連同正式的工藝表徵數據一起被用於支持生產工藝參數和工藝控制策略的建立，這些數據也包含PPQ之後將繼續的工藝監控的起始數據。早期的批數據可能不包括所有在最終商業工藝中執行的控制，但這信息對評估工藝性能仍然有價值。如果用於支持範圍和限度，臨床批數據應該包括在最終工藝設計報告中用於證明工藝和控制策略。最終批記錄應該在階段1結束時產生，它們將支持最終的商業工藝和充當階段2的前奏。
In some cases, it may be appropriate to use data from clinical batches to support the PPQ Stage 2. The rationale for this approach should be documented and included in the Process Validation Master Plan.
在一些情況下，用來自於臨床批的數據支持PPQ階段2可能是適當的，這個方法的原理應該被記錄且包括在工藝驗證主計劃中。
六、工藝特徵描述
Process characterization is a set of documented studies in which operational parameters are purposely varied to determine their effect on product quality attributes and process performance. The approach uses the knowledge and information from the risk assessments to determine a set of process characterization studies to examine proposed ranges and interactions for process parameters. The resulting information is used to define the PPQ ranges and acceptance criteria. It can also be used to set the final parameter ranges and can be used to develop a Design Space if using an enhanced approach, i.e., incorporating advanced analytical and/or manufacturing control technologies, to process development. Experiments can be designed to examine proposed ranges and explore ones wider than those that will normally be used in operation. An element of process characterization may include multivariate designed experiments to define process design space. While univariate approaches are appropriate for some variables to establish a proven acceptable range (PAR), multivariate studies account for interactions between process parameters/material attributes (1).
工藝表徵是一套文檔證明的研究，在該研究中操作參數被故意改變以確定它們對產品質量屬性和工藝性能的影響。該方法使用來自於風險評估的知識和信息以確定一套工藝表徵研究來檢驗工藝參數推薦的範圍及其交互作用。得到的信息被用於確定PPQ（工藝性能確認）範圍和接受標準。如果是用一個加強的方法來開發工藝，它也能用於設置最終參數範圍以及被用於開發一個設計空間，例如整合先進的分析和/或生產控制技術。實驗可以被設計用來推薦的範圍以及探索一些將用於正常運行更寬的範圍。工藝表徵的一個要素可能包括多變量設計實驗以確定工藝設計空間。當單變量的方法適用於為一些變量去建立證明可接受的範圍時（PAR），多變量研究可以對工藝參數/物料屬性間的交互作用給出解釋。
Since Studies designed to characterize the process and setting acceptable ranges for process parameters are usually performed at laboratory scale. The ability of laboratory-scale studies to predict process performance is desirable. When a laboratory scale model is used in development, the adequacy of the
model should be verified and justified. When there are differences between actual and expected performance, laboratory models and model predictions should be appropriately modified. In that the conclusions drawn from the studies are applied directly to the commercial-scale process, qualification of
laboratory-scale models is essential. Qualification of the scaled- down models should confirm that they perform in a manner that is representative of the full-scale process. This is shown by comparing operational parameters and inputs and outputs, including product quality attributes.
由於設計用來表徵工藝和為工藝參數設置可接受範圍的研究通常在實驗室規模進行，因此實驗室規模研究預測工藝性能的能力是值得期待的。當一個實驗室規模的模型被用在研發中時，該模型的充分性應該被證實和合理說明。當在實際和期望的性能間有差異時，實驗室模型和模型預測法應該適當糾正，因為從研究中得到的結論被直接應用到商業規模工藝。實驗室模型的確認是必不可少的，縮小比例的模型的確認應該證實它們的性能代表實際的生產規模工藝，這通過比較運行參數和輸入輸出，包括產品質量屬性。
Scaled-down models for chromatography steps for protein products can be qualified by performing multiple runs with input parameters at set points and comparing the results to the full-scale unit operation. Parameters evaluated should include those that affect process consistency, such as step yields, elution profile, elution volume, and/or retention time. These should then be combined with those that represent product quality, such as pool purity and levels of process-related and host cell-related impurities.
對用於蛋白產品的色譜層析步驟的縮小比例的模型能通過在設置點輸入參數執行多次運行以及比較與實際規模的單元操作間的結果來確認。評價的參數應該包括那些影響工藝一致性，諸如工序收率、洗脫圖、洗脫體積和/或保留時間，然後這些應該與那些代表產品質量諸如可憐的純度和工藝有關的水平以及與宿主細胞有關的雜質結合起來。
Pilot-scale models of small molecules that are representative of the commercial manufacturing process may be used for supportive PPQ data. In solid and liquid oral dosage forms, 10% of the commercial batch size and/or 100,000 units have been considered a representative scale (1). Scale-up effects for certain processes, such as mixing freely soluble substances, tablet compression, or liquid filling may be well-known. Batch sizes at 10% of bulk size or run times of 100,000 dosage units provide a sufficient duration to determine a degree of control and process characterization, while uncovering any preliminary major problems. Full-scale confirmation/evaluation may be carried out when small-scale studies are used to support PPQ.
代表商業生產工藝的小分子中試規模模型可能被用於支持PPQ數據，在固體和液體口服劑型，商業批量的10%和/或100000單位曾被考慮為一個代表性規模。某個工藝的放大的效果，諸如混合易溶解物質、藥片壓縮、或液體灌裝可能眾所周知。在原液10%的批量或運行100000劑量單位的倍數提供一個充分持續時間以確定控制程度和工藝特徵，而未覆蓋任何初步的主要問題。當小規模研究被用於支持PPQ時，實際規模確認/評估可能被執行。
For scale-down studies, the raw materials, component attributes, equipment, and process parameters should be comparable and indicative of the process intended for the commercial product.
對於縮小比例研究，其原料、組件屬性、設備以及工藝參數應該是具可比性和能表明預期用於商業產品。
3.8 Product Characterization Testing Plan
產品表徵測試計劃
Some product characteristics may not be tested as part of the routine release test panel. Examples of such product characteristics include residual DNA levels for biotechnology products (when DNA clearance has been established at a level that clearly exceeds safety requirements) or final product porosity for solid oral dosage products (when dissolution testing is performed). In addition to release specifications, Stage 1 deliverables should include other tests on the DS, DP, or critical intermediates that are needed in order to claim a comprehensive understanding of the product and process.
一些產品表徵可能作為日常放行測試標準的一部分而不必測試，此類產品表徵例子包括生物技術產品的殘留DNA水平（當DNA清除率已經建立在一個能清晰超出安全要求的水平時）或固體口服製劑的最終產品的多孔性（當執行溶解度測試時），除了放行標準，階段1可交付的成果應該包括其它對DS、DP或關鍵的中間體的測試為了說明對產品和工藝的全面理解。
七、確定生產工藝的描述
生產工藝應設計成可以持續提供滿足所需質量屬性的產品。因為生產工藝是在開發過程中定義的，所以，工藝描述就是用於幫助風險評估的實施和控制策略開發的工具。生產工藝由一系列單元操作組成，工藝描述、方塊圖、工藝流程圖描述每個單元操作。生產工藝中的每個單元操作應用相似的詳細程度進行描述。每個工藝描述應包含如下信息：
• Process requirements, including raw materials, scale, and order of operations
工藝需求，包括原料、數量和操作順序；
• Set points and ranges for the process parameters
工藝參數設定點和範圍；
• Identification and quantity of all material flows (additions, wastes, product streams)
所有物料的鑑別和數量（附加物、廢棄物、產品流）；
• Testing, sampling, and in-process controls
檢驗、取樣和中間過程控制
• Hold times and hold conditions for product and additional solutions
產品和附加溶液的保持時間和保持條件；
• Estimated step yields and durations
估計步驟收率和持續時間；
• Sizing for equipment, including such items as chromatography columns and filtration units.
設備尺寸，包括色譜柱和過濾單元；
• Specific identification (manufacturer, part number) for manufacturing (e.g., filters) and product components(e.g., vials, stoppers)
生產（如過濾器）和產品包材（如玻璃瓶、瓶塞）的詳細標識（如生產商、零件號碼）；
• Other information necessary to successfully reproduce the process
•成功再現工藝所必須的其他信息。
圖3.3-1 描述了一個單元操作的工藝圖實例，並在表3.4-1 提供了一個工藝描述簡表。工藝知識及理解的發展反映在臨床批記錄中。這些都是在工藝描述中定義生產工藝的重要信息源。從臨床試驗物料生產中收集的數據可能有助於確定過程能力、設定標準、設計PPQ 方案和可接受標準、評價實驗室模型和轉移工藝。知識管理的策略和原則將在第6.5 節「知識管理」中進一步討論。
工藝描述是以報告的形式歸檔並可能編入產品技術轉移（TT）技術包。由於物料要求的增加（如工藝和分析開發、臨床需要），提高了對產品的理解導致CQAs 的變化，提高了對工藝的理解導致單元操作的增加、刪除或調整，第一階段工藝可能會改變。這些變化和支持性的說明應文件記錄下來。這些信息應保存在知識管理系統中。
Development and documentation of the commercial manufacturing process in Development Reports should precede formal process characterization studies. Increased knowledge gained during process characterization may require additional changes to the process description. All changes to the process
should be approved through change control procedures as defined by the Quality System.
在開發報告中應先於正式的工藝表徵研究開發和歸檔的商業化生產工藝。在工藝表徵過程中獲得的知識的增加可能會要求增加工藝描述的變更。工藝的所有變更應按在質量體系中規定的變更控制程序獲得批准。
八、工藝驗證第一階段生產和技術的注意事項的描述
3.13 Stage 1 Manufacturing and Technology Considerations
階段1 生產和技術上的注意事項
生產設備的能力和程序對於將工藝參數保持在預先設定的限度範圍內的能力有關鍵影響。工藝設備的測量和控制能力是第二階段，工藝確認的主題。4.1部分有介紹設備確認活動應該確認設備對預期用途的適用性。
工藝流與設備和它們接觸的材質（例如聚合膜、橡膠、免洗袋和其它塑料部分）的相容性要能保證產品的安全和有效。產品接觸材質和溶出物、萃取物需要評價他們的相容性。這個工作在第一階段開始，可能包括一些需要長的前置時間的研究，並且應該結合階段二來完成。
工藝流與設備表面的相容性是對在生產接觸時他們的反應、吸收和穩定性的衡量。相容性測試是為了證明設備表面的材料性質不會因接觸溶液或其它產品相關物料而改變。另外，接觸材料也不應該改變工藝溶液或物料（通過吸附產品組分或者過量吸出而摻混產品）
Extractables are components of a material (e.g., a product contact surface that is used in drug manufacture or storage) that are recovered by use of an exaggerated force (solvent, time, temperature). Leachables are contact material components from process equipment or storage containers that migrate into the product under normal conditions of use.
萃取物是一種材料的成分（例如用於藥品生產或儲存的產品接觸表面），通過使用一種誇大的外力（溶劑、時間、溫度）而得到。浸出物是來自工藝設備或存儲容器的接觸材料的成分，它們在正常使用狀態下轉移到產品中。
來自於用於藥品生產、儲存、包裝得聚合膜盒的組件（塑料存儲器、濾器、內包裝材料、墊片、O形圈）的浸出物的種類和數量必須通過文件列明以此保證產品不會被摻入雜質。要結合文獻查閱、風險評估和實驗室研究來說明浸出物。各種確定測試的程度和浸出物種類的鑑別。還有可接受水平的設定的方法都已經出版。
• 「Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products」 (30)
• 「Evaluation of Extractables from Product-Contact Surfaces」 (31)
• 「Application of Quality by Design (QbD) Principles to Extractables/Leachables Assessment:
Establishing a Design Space for Terminally Sterilized Aqueous Drug Products Stored in a Plastic Packaging System」 (32)
• 「Leachables Evaluation for Bulk Drug Substances」 (33)
「口服吸入和鼻噴藥物的萃取物和浸出物的安全閾值和良好實踐」（30）
「產品接觸表面的萃取物的評價」（31）
「使用QbD對萃取物/浸出物評估的原則：為儲存在塑料包裝系統的最終滅菌的液體藥物確立設計空間」（32）
「原料藥的浸出物的評價」（33）
九、工藝驗證主計劃
A process validation master plan may be initiated during Stage 1 to prepare for Stage 2 activities. It should outline the validation strategy and supporting rationale, and typically includes:
一個工藝驗證主計劃可能在階段1到準備階段2活動期間被發起，它應該描繪概述驗證策略和支持原理，通常包括：
• Process characterization plan
工藝表徵計劃；
• Description of the manufacturing process and control strategy
生產工藝和控制策略的描述；
• Functions and responsibilities
部門與責任；
• PQ or PPQ plan:
PQ或PPQ計劃；
PPQ strategy (e.g., single unit operations or a combination of unit operations, bracketing, family, or matrix approaches) and a list of individual protocols; applicable ancillary studies, (e.g., mixing, media preparation, inprocess pool hold time, resin lifetime)
PPQ策略（例如單個單元操作或單元操作的合併、括號法、分組法或矩陣法）和單個草案、適用的輔助研究清單（例如混合、培養基準備、中間過程池持續時間、樹脂生命周期）；
• List of equipment and facilities to be used
所用的設備和設施清單；
• List of analytical methods and their status
分析方法和它們狀態清單；
• Sampling plan
取樣方法；
• List of protocols to be executed under the plan
在計劃下將被執行的草案列表；
• Proposed timeline and schedule of deliverables
建議的時間表和交付排期；
• Procedures for handling deviations and revisions
處理偏差和升版的程序；
• Continued Process Verification plan
持續工藝確證計劃
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