Technical Report No. 29 (Revised 2012) Points to Consider for Cleaning Validation

Paradigm Change in Manufacturing OperationsSM

PDA Task Force on Technical Report No. 29 (Revised 2012): Points to Consider for Cleaning Validation

Authors Destin A. LeBlanc, Cleaning Validation Technologies Jamie Osborne, Siegfried (USA), Inc. (Chair) Greg Randall, Baxter Bioscience Gretchen Allison, Pfizer Pierre-Michel Riss, Eli Lilly Jennifer L. Carlson, Genentech George Verghese, STERIS Corporation Koshy George, Consultant Igor Gorsky, ConcordiaValSource Jenn Walsh, Bristol-Myers Squibb Irwin S. Hirsh, Novo Nordisk AS Vivienne Yankah, Sanofi-Pasteur, Ltd.

The content and views expressed in this Technical Report are the result of a consensus achieved by the authorizing Task Force and are not necessarily views of the organizations they represent.

Points to Consider for Cleaning Validation Technical Report No. 29 (Revised 2012)

ISBN: 978-0-939459-48-3 © 2012 Parenteral Drug Association, Inc. All rights reserved.

Paradigm Change in Manufacturing Operations (PCMOSM)

PDA launched the project activities related to the PCMO program in December 2008 to help implement the scientific application of the ICH Q8, Q9 and Q10 series. The PDA Board of Directors approved this program in cooperation with the Regulatory Affairs and Quality Advisory Board, and the Biotechnology Advisory Board and Science Advisory Board of PDA.

Although there are a number of acceptable pathways to address this concept, the PCMO program follows and covers the drug product lifecycle, employing the strategic theme of process robustness within the framework of the manufacturing operations. This project focuses on Pharmaceutical Quality Systems as an enabler of Quality Risk Management and Knowledge Management.

Using the Parenteral Drug Association’s (PDA) membership expertise, the goal of the Paradigm Change in Manufacturing Operations Project is to drive the establishment of ‘best practice’ documents and /or training events in order to assist pharmaceutical manufacturers of Investigational Medicinal Products (IMPs) and commercial products in implementing the ICH guidelines on Pharmaceutical Development (ICH Q8, Q11), Quality Risk Management (ICH Q9) and Pharmaceutical Quality Systems (ICH Q10).

The PCMO program facilitates communication among the experts from industry, university and regulators as well as experts from the respective ICH Expert Working Groups and Implementation Working Group. PCMO task force members also contribute to PDA conferences and workshops on the subject.

PCMO follows the product lifecycle concept and has the following strategic intent:

• Enable an innovative environment for continual improvement of products and systems

• Integrate science and technology into manufacturing practice

• Enhance manufacturing process robustness, risk based decision making and knowledge management

• Foster communication among industry and regulatory authorities

The Product Life Cycle

Pharmaceutical Technology Commercial Product
Development Transfer Manufacturing Discontinuation

For more information, including the PCMO Dossier, and to get involved, go to www.pda.org/pcmo

Table of Contents

1.0 Introduction .........................................................1
1.1 Purpose/Scope ................................................ 1
2.0 Glossary of Terms ...............................................3
2.1 Definition of Acronyms .................................... 5

• 3.0 Cleaning Process Design and Development .......7 3.1 Cleaning Process Design ................................. 7 3.2 Cleaning Process Overview ............................. 8 3.2.1 Physical-chemical Aspects ................. 9

• 3.3 Design Considerations ................................... 10 3.3.1 Location of Cleaning .......................... 10 3.3.1.1 In-Place Cleaning .......................... 10 3.3.1.1.1 Clean-in-Place (CIP) Systems ....... 10 3.3.1.1.2 Solvent Reflux Cleaning ................ 11 3.3.1.1.3 Placebo Batches as a Cleaning Method .......................... 11

• 3.3.1.2 Out-of-Place Cleaning ................... 11 3.3.1.2.1 Clean-Out-of-Place Systems ......... 12 3.3.2 Automated vs. Manual Systems ....... 12 3.3.2.1 Manual Processes ........................ 12 3.3.2.2 Semi-Automated Processes ......... 12 3.3.2.3 Automated Processes .................. 13 3.3.3 Soil Evaluation and Categorization ..... 13 3.3.3.1 Soil Categories ............................. 13 3.3.3.2 Soil Removal................................. 13 3.3.4 Equipment Considerations ................. 14 3.3.4.1 Dedicated – Nondedicated Manufacturing Equipment ............ 14

• 3.3.4.2 Nonproduct Contact – Product Contact Surfaces .......................... 15

• 3.3.4.3 Low-Risk Sites – High-Risk Sites . 15 3.3.4.4 Materials of Construction ............. 15 3.3.5 Operational Considerations ................ 15 3.3.6 Cleaning Agent Selection .................. 16 3.3.7 Product Considerations...................... 16 3.3.7.1 Product Risk Considerations ......... 17

• 3.4 Cleaning Development Laboratory Experiments ................................ 17 3.4.1 Soil Selection .................................... 17 3.4.2 Parameter Selection .......................... 18 3.4.2.1 Parameter Interactions ................ 19 3.4.3 Measurements to Determine Cleaning Effectiveness ...................... 19

• 3.5 Cleaning Process Scale-Up ............................ 19 3.5.1 Setting Process Controls ................... 19

• 3.6 Applying the “Design Space” Concept to

Cleaning Processes ...................................... 20
3.7 Standard Operating Procedures ..................... 21
3.8 Operator Training for the Cleaning Process .... 21 3.9 Introduction of New Products to a Validated Cleaning System ............................ 22
4.0 Qualification ......................................................23
4.1 Protocol Elements .......................................... 23
4.2 Key Protocol Issues ...................................... 23
4.2.1 Number of Runs in a Protocol ............ 24
4.2.2 Mock Soiling ..................................... 24
4.2.3 Worst-Case Process Conditions ........ 24
4.2.4 Disposition of Products and Equipment during Validation ................................ 25
4.3 Grouping/Family Approach ............................ 25
4.3.1 Product Grouping ............................... 26
4.3.2 Equipment Grouping .......................... 26
4.3.3 Introduction of a New Product or Equipment into a Group ..................... 27
4.4 “Cleaning Verification” Documentation .......... 27
5.0 Residue and Limits ............................................29
5.1 Considerations for Developing Limits ........... 29
5.2 The Basis for Quantitative Limits ............ 30
5.3 Acceptable Concentration of Residue in
Next Product ..................................... 30
5.3.1 ARL Based on Drug Active Dose ....... 30
5.3.2 ARL Based on Toxicity ....................... 31
5.3.2.1 ADE Determinations Based on ISPE’s Risk-MaPP .................................... 31
5.3.2.2 Toxicity Calculations Based
on LD50Data ................................. 32
5.3.3 Other ARL Determinations ................. 33
5.4 Acceptable Total Carryover ........................... 33
5.5 Surface Area Limit ......................................... 34
5.6 Limit in Protocol Samples .............................. 34
5.6.1 Limit per Swab .................................. 34
5.6.2 Concentration Limit in
Extracted Swab Solvent .................... 34
5.6.3 Concentration Limit in
Rinse Sampling Solution .................... 35
5.7 Consolidated Expressions .............................. 35
5.8 Example Calculations .................................... 36
5.9 Other Considerations ..................................... 36
5.9.1 Multiple Next Products ...................... 36 i
5.9.2 Next Product in Verification
Approach ........................................... 37
5.9.3 Default Limits .................................... 37

5.9.4	Use of Different Safety Factors .......... 38
5.9.5	Different Routes of Administration..... 38
5.9.6	Different Doses for
	Adults and Children ........................... 38
5.9.7	Human and Veterinary Products Manufactured on the Same Equipment ............................... 38
5.9.8	Residues of Genotoxic and Other Highly Hazardous Active Ingredients ............ 38
5.9.9	Limits Based on Analytical
	Detection Limits ................................ 39
5.9.10	Degradation of the Active Ingredient . 39
5.9.11	Limits Not Measureable .................... 39
5.9.12	Limits for Organic Solvents ................ 39
5.9.13	Dedicated Equipment ....................... 40
5.9.14	Dividing a Limit among Various Pieces of Equipment .......................... 40
5.9.15	Limits for Preferential Transfer to a First
	Portion of the Next Product ............... 40
5.9.16	Limits for Biotechnology Manufacture ...................................... 40
5.9.17	Products with More Than One Active Ingredient .......................................... 41
5.10 Bio	burden Limits ..................................... 41
5.11 En	dotoxin Limits ..................................... 42
5.12 Vis	ually Clean Criterion .......................... 42

6.0 Sampling ............................................................43
6.1 Sampling Method Selection .......................... 43
6.1.1 Direct Sampling Methods .................. 43
6.1.1.1 Visual Inspection .......................... 43
6.1.1.2 Instrumental Methods .................. 44
6.1.2 Rinse Sampling .................................. 44
6.1.2.1 Extraction Rinse Sampling for Small
Parts ............................................. 46 l
6.1.2.2 Solvent Reflux Sampling ............... 46
6.1.3 Swab and Wipe Sampling ................. 46
6.2 Placebo Sampling .......................................... 47
6.3 Sampling for Microbial and Endotoxin Analysis ........................................ 47
6.4 Additional Considerations............................... 48
6.5 Sampling Recovery Studies ........................... 48
6.5.1 General Considerations ...................... 48
6.5.2 Swab/Wipe Recovery ........................ 49
6.5.3 Rinse Recovery .................................. 50
6.5.4 “Recovery” in Visual Inspection ........ 51
6.5.5 Recovery for Bioburden and
Endotoxin Sampling ........................... 51
6.6 Training and Qualification of Samplers ........... 51

6.6.1	Key Issues for Training
	for Swab Sampling ............................ 52
6.6.2	Key Issues for Training for Rinse Sampling ........................................... 52
6.6.3	Training for Visual Inspection ............. 52
7.0 Analytical	Methods ...........................................54
7.1 Purpo	ses of the Analytical Methods .............. 54
7.2 Practi Metho i i	cal Considerations in Selecting Analytical ds ........................................................ 54 i i
7.3 Specii i Valida	fic vs. Nonspecific Analytical Methods for tion Protocols ....................................... 55 i
7.3.1	Regulatory Status of Specific and Nonspecific Methods ................... 55
7.4 Most	Commonly Used Analytical Techniques 56
7.4.1	Liquid Chromatography (LC) .............. 56
7.4.2	UltraViolet/Visible Spectrophotometry
	(UV/Vis) ............................................. 57
7.4.3	Total Organic Carbon (TOC) ............... 57
7.4.4	Conductivity ...................................... 57
7.4.5	Organoleptic Evaluation ..................... 58
7.5 Other	Useful Analytical Techniques ............... 59
7.5.1	pH ...................................................... 59
7.5.2	InfraRed (IR) ...................................... 59
7.5.3	Light Microscopy ............................... 59
7.5.4	Titrations ........................................... 59
7.5.5	Gravimetric Analysis ......................... 59
7.5.6	Enzyme Linked Immunosorbant Assay (ELISA) ................................... 60
7.5.7	Capillary Zone Electrophoresis (CZE) ...60
7.5.8	Atomic Absorption (AA) and Inductively Coupled Plasma (ICP) ...... 60
7.5.9	Ion Mobility Spectrometry (IMS) ....... 60
7.6 Micro	bial Test Methods ................................. 60
7.6.1	Endotoxin .......................................... 60
7.6.2	Bioburden .......................................... 60
7.7 Analyt	ical Method Validation ......................... 61
7.7.1	General Principles .............................. 61
7.7.2	Compendial Methods......................... 62
7.7.3	Visual Inspection ............................... 63
7.7.4	Bioburden Methods ........................... 63
7.7.5	Transfer to another Laboratory and Use of Contract Laboratories ............. 63
8.0 Maintena	nce of Validated State ........................64
8.1 Critica	l Parameter Measurement ................... 64
8.2 Proce	ss Alarms ............................................. 64
8.3 Chang	e Control .............................................. 65

8.4 Routine Monitoring ........................................ 66
8.5 Data Trending and Review ............................. 66
8.6 Evaluation of Cumulative Changes ................. 67
8.7 Training .......................................................... 67
8.8 Periodic Review ............................................. 67
9.0 Documentation ...................................................69
9.1 Cleaning Validation Master Plans .................. 69
9.1.1 Elements of a Comprehensive Plan .... 70
9.1.2 Harmonization of Site Cleaning
Validation Programs .......................... 71
9.2 Documentation for Design/Development ....... 71 i
9.3 Documentation for Qualification .................... 72
9.4 Documentation for Validation Maintenance ... 72
9.5 Other Documentation Considerations ............ 73

10.0 Special Considerations ....................................75
10.1 Cleaning Agents ..................................... 75
10.1.1 Types ................................................. 75
10.1.1.1 Water ............................................. 75
10.1.1.2 Organic Solvents ............................ 75
10.1.1.3 Commodity Alkali ........................... 75
10.1.1.4 Commodity Acids........................... 75
10.1.1.5 Formulated Detergents ................... 75
10.1.2 Factors in Selection ........................... 76
10.1.2.1 Broad Spectrum Effectiveness ....... 76
10.1.2.2 Substrate Compatibility ................. 76
10.1.2.3 Stability and Shelf Life ................... 76
10.1.2.4 Analyzability ................................... 76
10.1.2.5 Disposal ......................................... 76
10.1.2.6 Safety ............................................ 76
10.1.2.7 Toxicity .......................................... 76
10.1.2.8 Rinsability ...................................... 76
10.1.2.9 Quality ............................................ 76
10.2 Nonproduct Contact Surfaces ................. 76
10.3 Process Analytical Technology ............... 77
10.3.1 Timely Measurements ....................... 77
10.3.2 PAT for Cleaning Process Control ....... 77
10.3.3 Additional Considerations for Online
Measurements .................................. 78
10.4 Clean Hold Considerations ...................... 78
10.5 New and Used Equipment ...................... 80
10.5.1 New Equipment .................................. 80
10.5.1.1 Cleaning Procedure Development... 80
10.5.1.2 Post-Installation Cleaning ............... 81

10.5.1.3 Grouping Impact .............................. 81
10.5.1.4 Limit Calculation Impact .................. 81
10.5.2 Used Equipment ................................ 81
10.6 Measurement Systems Analysis (MSA) 81
10.6.1 MSA Components ............................. 82
10.6.2 Attribute R&R .................................... 82
10.6.3 Minimizing Variations ........................ 82
10.6.4 MSA and Cleaning Validation Strategy ............................ 82
10.7 Cleaning for API Manufacture ................. 83
10.8 Topical Drug Products ............................. 84
10.8.1 Topical Drug Products with Systemic Availability ......................... 84
10.8.2 Topical Drug Products with No or Limited Systemic Availability ............ 85
10.8.2.1 Adjusted Calculation ...................... 85 i
10.8.2.2 Modification Based on
Frequency of Application................ 85 i
10.8.2.3 Modification Based on Amount Applied per Surface Area ............... 85
10.8.2.4 Additional Considerations .............. 86
10.8.3 Additional Safety Considerations ....... 86
10.8.4 Additional Cleaning Considerations ... 86
10.9 Animal Drug Products ............................. 86
10.10 Packaging Components and Packaging Equipment ............................... 86
10.10.1 Primary Packaging Components ....... 86
10.10.1.1 Oral Dosage Forms Primary Packaging Components ................ 87
10.10.1.2 Parenteral Dosage Forms Primary Packaging Components ................ 87
10.10.2 Packaging Equipment ....................... 87
10.10.2.1 Primary Packaging Equipment ...... 87
10.10.2.2 Secondary Packaging Equipment . 88
10.11 Tubing and Hoses ................................... 88
10.12 Excipients ............................................... 89
10.13 Dedicated Equipment .............................. 89
10.13.1 Reasons for Dedication ..................... 89
10.13.2 Cleaning Validation Issues ................ 90

11.0 Regulatory and Guidance Documents .............91
12.0 References .......................................................92
13.0 Suggested Readings.........................................94

FIGURES AND TABLES INDEX

Table 3.1-1	CPP and CQA Considerations that have Potential Risk Impact to a Cleaning Process ................................. 7	Table 6.1.2-2 Table 6.1.3-1	Advantages and Limitations of Rinse Sampling .............................. 45 Advantages and Limitations
Table 3.1-2	The Cleaning Spectrum ....................... 8		of Swab/Wipe Sampling .................... 47
Table 3.2-1	Cleaning Process Steps (Examples) .... 9	Figure 9.5-1	Documentation for Process Flow ....... 74
Table 6.1.2-1	Comparison of Grab Sampling versus Separate Sampling Rinse ................... 45

1.0 Introduction

引言

Cleaning validation plays an important role in reducing the possibility of product contamination from pharmaceutical manufacturing equipment. It demonstrates that the cleaning process adequately and consistently removes product residues, process residues and environmental contaminants from the manufacturing equipment/system, so that this equipment/system can be safely used for the manufacture of specified subsequent products (which may be the same or a different product). As used in this Technical Report, “product” may be a drug product, active pharmaceutical ingredient, intermediate, or another type of formulation. If “drug product” is intended, that terminology will be utilized. Principles and practices given in this report may apply to a variety of manufacturing situations. It is incumbent on the reader to decide the appropriateness of those principles and practices to his/her specific situation.

清洁验证对于降低来自生产设备的药品污染的可能性有着重要作用。它证明了合适的清洁工艺可以 持续充分除去生产设备上/系统中产品残留、工艺残留和环境污染，所以该设备/系统可以安全地生 产后续产品（相同或不同产品）。在本技术报告中， “ 产品 ” 可以是制剂、药物活性成分、中间体或 其他处方类型。如果仅针对 “ 制剂 ” ，我们将用“制剂”这个术语。本报告给出的原则和规范可以 用于各种生产情况。读者应自行决定这些原则和规范是否适用他/她的具体情况。

This report builds on the 1998 PDA Technical Report No. 29, Points to Consider for Cleaning Validation (1) . This report also has utilized principles and specific wording from the 2010 PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation (2) . The authors of this revised Technical Report#29 would like to thank the members of the Task Forces who were responsible for those two earlier documents for making our job easier.

本报告建立在 1998 年 PDA 技术报告第 29 号 “ 清洁验证要点 ” (1) 的基础上。该报告还利用了 2010 年 PDA 技术报告第 49 号 “ 生物技术清洁验证要点 ” 的原则和具体内容 (2) 。本修订版技术报告第 29 号作者非常感谢这两个较早版本的工作组成员，使我们的工作变得更容易。

This revised Technical Report presents updated information that is aligned with lifecycle approaches to validation and the International Conference on Harmonisation (ICH) guidelines Q8 (R2) - Pharmaceutical Development, Q9 - Quality Risk Management and Q10 - Pharmaceutical Quality System (3,4,5) . Also, this report aims to assist readers who want to create or benchmark a cleaning validation program for their equipment and facilities.

本修订版技术报告提出了更新的信息，即结合了生命周期的验证方法和国际协调会议（ICH）的指 导原则 Q8 (R2) -药物开发、Q9-质量风险管理和 Q10-制药质量体系 (3,4,5) 。此外，这份报告也有助 于读者建立或评估自己的设备、设施的清洁验证计划。

This Task Force was composed of European and North American professionals from pharmaceutical manufacturers, cleaning chemical suppliers, and consulting companies. The report has undergone a global, technical peer review to ensure concepts, terminology, and practices presented are reflective of sound science and can be used globally.

该工作组是由欧盟和北美的制药专家、清洁化学品供应商和咨询公司组成。该报告经过了一个全球 性的技术同行评审，确保概念、术语、规范科学、合理，可在全球范围使用。

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1.1 Purpose/Scope

目的 / 范围

This Technical Report covers all facets of cleaning validation for pharmaceutical manufacturers, including both manufacturers of APIs and drug products. It also applies to biotechnology manufacturing; however, the reader should consult PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation for more detail and specifics for biotechnology manufacturing (2) . We have included a lifecycle cleaning validation approach, including design/development of the cleaning process, process qualification (including the protocol runs), and ongoing validation maintenance. While the document discusses risk-based approaches, it does not provide details about risk-based manufacturing. PDA has formed a Task Force to write a Technical Report on that topic.

本技术报告涵盖了药品生产商清洁验证的各个方面，包括药物活性成分和药物制剂生产商。也可以 用于生物制药，但读者应该查阅 PDA 技术报告第 49 号“生物技术清洁验证要点” (2) ，获得生物 技术制造方面更多的细节和特性。我们采用了生命周期的清洁验证方法，包括清洗工艺的设计/开发、 工艺确认（包括方案实施）和持续验证维护。尽管采用了基于风险的方法，本报告没有详细论述基 于风险的生产。PDA 已经成立了撰写该主题技术报告的工作组。

We cannot emphasize enough how important risk analyses are in the selection of and validation of cleaning processes and their validation. This includes the traditional risk analysis based on effects on product quality and on patients. It also includes business risk considerations, such as steps taken to minimize lost product from contamination (even if detection systems are in place to prevent release of that contaminated product for consumer use).

我们怎么强调风险分析在清洁工艺的选择和验证过程中的重要性也不为过。这包括传统的基于对产 品质量和对患者的影响的风险分析。也包括商业风险的考虑，例如采取措施将产品污染损失降至最 低（即使有检测系统防止受污染的产品被放行）。

These practices and the associated guidance in this Technical Report are based on technical considerations and should be applicable in all regulatory environments. However, the intent of this Technical Report is not to provide a detailed plan or roadmap for a pharmaceutical manufacturer to perform cleaning validation. Rather, as the title suggests, it presents “points to consider” as one designs a cleaning validation program for process equipment based on an understanding of one’s manufacturing and cleaning processes. In cleaning validation, there are generally multiple ways to accomplish the same goal of a compliant, scientifically sound and practical cleaning validation program. Where options are given, the rationales for such options are also generally given. Examples are not meant to be prescriptive or limiting; they merely illustrate a certain practice. Actual acceptable practices should not be considered limited by the discussion in this Technical Report. Based on an understanding of the unique nature of any individual situation, different approaches or additional issues should also be considered. Sound science based on an understanding of the cleaning and manufacturing processes may lead to other equally acceptable practices. The Task Force that developed this document hopes that the report will be used in this spirit and will not be solely used as a checklist.

本技术报告中的这些规范和相关指南是基于技术考虑并可以用于所有监管环境。但是，本技术报告 的目的不是为药品生产商进行清洁验证提供详细的计划或路线图。相反，正如标题所示，本报告提 出了“清洁验证需考虑的要点”，基于对生产和清洁工艺的理解进行工艺设备清洁验证计划的设计。 在清洁验证中，通常有多种方式来建立合规的、科学合理的和切实可行的清洁验证计划。大凡选择 就有选择的理由。所举的例子并不意味着规范或限制，他们只是列举了某种做法。实际可接受的做

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