Cleaning Validation Technical Guide - What Does China Expect in Terms of Cleaning Validation?

There are various guidelines on the topic of cleaning validation. A recent addition is a technical guide from China's "National Food and Drug Administration Food and Drug Inspection Center." What does it contain?

This article is based on a machine translation of the guide into English. The guide is 73 pages long, divided into six chapters, an appendix, and references:

• Overview
• Fundamental Principles
• Cleaning Validation Risk Management
• Development of the Cleaning Process
• Cleaning Validation
• Continuous Cleaning Process Verification
• Appendix: Typical Case Studies
• References

The purpose of the document is to provide guidance and standardisation for the scientific management of cleaning validation activities for pharmaceuticals and active pharmaceutical ingredients. The guide refers to "cleaning life cycle management." The life cycle includes:

• Design of the cleaning process
• Cleaning process development
• Cleaning validation
• Continuous cleaning process verification

Health-based limits are specified in the guide as part of the cleaning process development. Table 3.1 provides a good overview of the quality risk management approach with possible outcomes in relation to each stage of the life cycle.

Cleaning Validation Master Plan

Furthermore, the term "cleaning validation master plan" is used. This master plan can be created separately as a standalone document or as part of a validation master plan and should be approved by Quality Assurance. It should describe concepts and strategies for cleaning validation. Additionally, the fundamental requirements and methods of cleaning validation should be outlined.

Worst-Case Scenarios

The topic of "worst-case scenarios" is addressed in considerable detail, both in relation to the product and to the equipment. With regard to the "grouping" of equipment, surface roughness is discussed at length. Measures for introducing a new product or device into the "grouping" are described using a decision tree.

The hold times (Dirty Hold Time (DHT) and Clean Hold Time (CHT)) are discussed in separate brief sections.

Table 4.1-1 describes cleaning steps and their functions. Another table (4.1-2) lists cleaning parameters and their impact on the cleaning process. The parameters are based on Sinner's Circle (time, agitation, concentration, temperature).

In describing the development of a cleaning process, the guide uses the terms Critical Quality Attribute (CQA) and Critical Process Parameter (CPP), as known from process validation. Table 4.4.1 provides an overview of these.

The planning of a cleaning process is divided into 3 subgroups:

• automated
• semi-automated
• manual

Cleaning Agents and Limit Calculations

Guidelines for selecting cleaning agents fill an entire A4 page. Limit calculations are described in detail, including formulas for HBEL calculations as well as for ppm calculations. This subsection also includes guidance on biological pharmaceuticals with TOC limits for upstream and downstream processes. The advantages and disadvantages of swab and rinse samples are again explained in tabular form.

Surprisingly, the recommendation on the subject of recovery rates is not to apply a correction factor when calculating limit values if the recovery is >70%. Recovery rates < 50% are considered unacceptable. The standard analytical methods are again listed in tables (Tables 5.4.2-1, 5.4.3-1).
Daily monitoring is recommended, as is a regular "audit review." The guide concludes with a glossary, an appendix, and references.

The appendix describes case studies on:

• Active pharmaceutical ingredients
• Sterile manufacturing
• Solid dosage forms

The references list well-known documents, such as Annex 15, technical reports from the PDA, and documents from the ISPE, PIC/S, and APIC.
Conclusion: The Chinese authority's "Cleaning Validation Technical Guide" is an interesting document with some surprising details.

This translation is not an official translation (translation for informational purposes only-no claim to accuracy). You can find the translation in the Members' Area of the ECA Academy website.