Technical Report - Assistance for Biotechnology Cleaning Validation

Since the nineties, cleaning validation has been a topic in the area of GMP. Assistance is given by the "FDA-Guide to Inspection of", PIC/S-document PI 006 and by a document of the Canadian regulatory authority. Interestingly, this document is also is available in French.

All documents mentioned cover the topic of cleaning validation in a general way. The focus of the PDA's Technical Report No. 49 is on biotechnologically-manufactured products. The document consists of 68 pages, divided into 16 chapters:

1. Introduction
2. Glossary of Terms
3. Cleaning Process Design and Development
4. Acceptance Limits
5. Sampling Methods
6. Analytical Methods
7. Cleaning Validation Protocols
8. Maintenance of Validated State
9. Master Planning for Cleaning Validation
10. Risk Assessment and Management
11. Special Considerations
12. Regulatory Issues
13. References
14. Suggested Reading
15. Appendix - Carryover Calculations
16. List of Acronyms

The introduction states explicitly that the report is not a detailed plan. Instead it presents "points to consider" when designing a cleaning validation program for biotechnology manufacturing. Much of the information is even applicable to plasma fractionation and egg-based vaccine manufacturing.

On nine pages, chapter three describes the development of a cleaning process in a very comprehensive manner. This chapter also contains considerations on equipment and plant design (such as on piping), on the performance of cleaning development experiments as well as recommendations on how to define a design space for the cleaning process.

Chapter four (Acceptance Limits) specifically addresses biotechnological aspects with the focus on TOC measurements. Fortunately, specific criteria commonly used by industry are also mentioned. Sample calculations based on the dose are given in chapter fifteen. There is also an example concerning cleaning agents.

Chapter five on sampling methods makes particular reference to "swab sampling" and "rinse sampling" but also uses the term "direct sampling" for techniques such as the use of visual inspection. Tables depict comparisons between swab sampling and rinse sampling as well as final rinsing and post final rinsing. Special attention is paid to recovery studies, including those concerning visual examination. The report mentions specific recovery rates even with the corresponding values for standard deviation. According to the report recovery studies are not required for microbiological sampling or for endotoxin sampling. The reasons for this are indicated. Two pages of this chapter covering a total of seven pages are on the training of samplers.

Chapter six on analytical methods discusses how to select the appropriate assay methods, problems arising in connection with the application of these methods, the use of nonspecific assays (also concerning endotoxins and bioburden) and assay method validation. In terms of method validation, reference is made to ICH Q2R1. Furthermore, the report provides interesting assistance by applying compendia methods concerning the measurement of TOC. Validation of the visually clean criterion is also addressed.

Chapter seven on cleaning validation protocols is rather short covering little more than one page. This chapter also addresses cleaning verification protocols and the use of worst case scenarios. The problem of the number of runs in a protocol is discussed very openly. With reference to the fact that the FDA no longer defines a certain number of runs, it is suggested that a rationale should be provided for determining the number of runs. But it is stressed, nevertheless, that the magical number of three runs can be specified in the master plans unless there is a rationale for a different number.

The chapter on "Maintenance of Validated State" comprises three pages and is again a little longer than the previous one. According to the report, a robust change control system taking cumulative changes into account is critical. The report recommends a periodic monitoring (risk-based!) and trending. Monitoring is considered as being more helpful than a periodical revalidation.

Master planning for cleaning validation is addressed relatively late, i.e. not until chapter nine. A list of the elements of a master plan in this chapter is very helpful. Harmonization of cleaning programs at more than one site as well as cleaning validation when manufacturing clinical samples is addressed.

The question of risk management (chapter ten) is also dealt with at a rather late stage. Its use is strongly recommended as early as during development of a cleaning process. This topic is also addressed in the previous chapters. A table presents the potential risk influences on a cleaning process in an exemplary way. These risk influences are critical process parameters (CPP) such as hold times and critical quality attributes (CQA) such as cleaning agent residues.
Chapter eleven (Special Considerations) has nine pages and is again a little longer. At the beginning, the grouping/family approach is addressed which also concerns the equipment. The report uses a new term in relation to equipment: "confirmatory validation runs". They (perhaps only one run) are an option for including non worst case equipment in the validation. Further topics include cleaning agents, special issues and equipment (chromatography columns, tangential flow filtration filter systems, centrifuges). Another sub-chapter deals with non-product contact surfaces. Buffers, media, lyophilizer and packing equipment are mentioned. In terms of the surfaces of lyophilizer, concrete proposals are made regarding limits. Another topic of this chapter concerns viruses, mycoplasma and prions as well as single-use equipment and PAT. In the last part, product changeover and clean hold times are considered.

Chapter twelve cites regulatory documents (such as the guidelines mentioned above) and chapter fourteen refers to suggested reading. Carryover calculations (chapter fifteen) and a list of acronyms (chapter sixteen) conclude the report.

Conclusion: The report is very comprehensive. Many topics can be used for the cleaning validation of conventional active ingredients. The report demonstrates its real strengths when dealing with specific biotechnological issues. In this area, it offers specific support, especially by indicating details. Thanks to the integration of "modern" GMP aspects (risk management, design space, PAT), the report is up to date.

You can also order the Technical Report.

Sven Pommeranz
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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