16/17 November 2021
At random intervals the Parenteral Drug Association (PDA) publishes so-called "Technical Reports" (TR) concerning GMP topics. They are a potential source to get more information on the state of the art concerning the respective topic.
The PDA published the Technical Report No 29 on "Points to Consider for Cleaning Validation" as early as 1998. This report has now been published again in an updated version. With this revision its content increased from originally 23 pages to now 95 pages.
The Report is divided into 13 chapters:
2. Glossary of Terms
3. Cleaning Process Design and Development
5. Residue and Limits
7. Analytical Methods
8. Maintenance of Validated State
10. Special Considerations
11. Regulatory and Guidance Documents
13. Suggested Readings
Reasons for the revision were the integration of a life cycle concept in the cleaning validation and an update of the guidelines ICH Q8, Q9 and Q10. The document is directed both at manufacturers of medicinal products and at manufacturers of active pharmaceutical ingredients. The Report also addresses biotechnology manufacturers but points out explicitly the existence of the separate TR No 49 on that topic (see also GMP-News dated 12 October 2011). It is not the intent of the Report to provide a detailed plan or roadmap for performing a cleaning validation nor is it intended to be a check list. The introduction states that because of the complexity of the single steps there are multiple ways for a cleaning validation based on a risk analysis.
In parts the Report gives some good tips for the praxis. In the chapter "Cleaning Process Designs and Development" (chapter 3), for example, advice is given on the determination of process controls and on points a cleaning SOP should contain. In accordance with modern GMP vocabulary examples for Critical Process Parameters (CPP) and Critical Quality Attributes (CQA) are presented. As examples for CCPs hold times are mentioned and product and cleaning agent residues are indicated as examples for CQAs. CCPs and CQAs in the context of cleaning validation are already described in the TR 49 "Points to Consider for Biotechnology Cleaning Validation".
Chapter 4 (Qualification) is closely based on the newer concepts on process validation. The emphasis in this section is on process qualification, e.g. the runs performed to demonstrate that the cleaning works. This chapter also includes the aspect of equipment qualification if it influences the cleaning validation (for instance a CIP system). The Report reflects the life cycle model since validation within the meaning of the Report comprises development and design of the cleaning process, the process qualification itself as well as maintenance of the validated state. Parallels to the FDA Guidance on process validation of 2011 (although it does not address the cleaning validation) are intended! Insofar the Report consequently discusses the number "3" for validation runs and recommends determining the number by means of a rationale. A separate sub-point (4.4) addresses the topic cleaning verification, a concept used in the field of clinical sample manufacturing.
The chapter 5 (Residues and Limits) contains 12 pages and is thus very long. It presents several approaches to an acceptable residue level. Possible approaches mentioned are for example ARL based on the dose of active pharmaceutical ingredient, ARL based on toxicity but also ARL based on ISPE's Risk-MaPP-Baseline (see GMP-News dated 25 November 2010) etc. Equations for calculations are presented for each approach. Additionally, there is one example for a calculation. The discussion of microbiological limits, also as concerns endotoxins is relatively brief on about one page. The visually clean criterion is mentioned, too and the Report even gives a possible example with reference to chapter 6 (in this case 6.6.3. Training for Visual Inspection) and 7 (Analytical Methods) for a quantitative application.
Chapter 6 (Sampling) provides a very clearly structured comparison of advantages and disadvantages of sampling methods (rinse sampling and swab/wipe sampling) in a table. It also discusses the advantages and disadvantages of final rinse as opposed to post final rinse. Interestingly, the Report also lists placebo sampling as possibility. This sampling is seen very critical by the FDA. But it is discussed rather as support for swab or rinse sampling. According to the Report the use of recovery rates below 50 % should be justified in a written rationale. The Report gives reasons why no recovery studies are necessary for microbiological sampling (including endotoxins). This part and other parts of this chapter are already described in the TR 49 "Points to Consider for Biotechnology Cleaning Validation".
Chapter 7 (Analytical Methods) gives an overview over possible analytical methods (chromatography, spectrophotometry, microscopy, TOC...) in the context of the cleaning validation and provides information on the validation of the analytical methods. Reference is made to the Guideline ICH Q2(R1).
Within the meaning of the life cycle concept chapter 8 (Maintenance of Validated State) addresses process alarms, change control, routine monitoring and trending as parts of this concept. A periodic review should then also be part of the life cycle concept. Consequently, the Report points out that no regular cleaning revalidation is necessary any more if the life cycle concept is applied. The Report states that significant changes in the cleaning process directly lead to a new cleaning validation (taking into account the data of the previous cleaning process, if comparable).
Surprisingly short is the chapter Documentation (chapter 9). It contains only 5 pages and one page with flowcharts. Although it is no regulatory requirement, the authors of the revised Technical Report 29 recommend nevertheless compiling a cleaning validation master plan (or a comparable document). On one DIN A4 page a lot of bullet points are listed that present possible points of content of the cleaning validation masterplan. The Report also addresses the harmonisation of cleaning programmes for different sites. Both topics are also discussed in the TR 49 "Points to Consider for Biotechnology Cleaning Validation". A documents flowchart illustrates which documents must be created in which part of the life cycle and the chronology of the documents. The chapter also presents examples for contents of a validation protocol; in this chapter referred to as "process performance qualification (PPQ) protocol ". Interestingly, the Report mentions in this context not only commissioning documents but also IQ and OQ protocols and reports as part of the process validation. Substitution of IQ/OQ-activities by verification, as favoured by the ISPE (see GMP-News dated 25 November 2009 and 21 March 2012 ) is not explicitly mentioned although the ASTM Guide E 2500 on this topic is listed under the chapter "Suggested Readings" (chapter 13). It is mentioned explicitly that the number of runs should be based on cumulative knowledge from the development of cleaning processes and from qualification stages but not on a statistical evaluation.
Chapter 10 (Special Considerations) is rather long, containing 15 pages. It addresses points such as cleaning agents, PAT, holding times, measurement systems analysis, cleaning for active pharmaceutical ingredient manufacture, specifics on dosage forms, excipients, dedicated equipment etc.
Chapter 11 (Regulatory and Guidance Documents) lists the relevant (regulatory) guidance documents by FDA, EU, WHO PIC/S. The Report closes with the references (chapter 12) and suggested readings (chapter 13).
Conclusions: The Technical Report 29 in its revised edition actually is the most comprehensive and modern document on cleaning validation. There are some parallels to the TR No 49 "Points to Consider for Biotechnology Cleaning Validation". But the application of the life cycle concepts for the cleaning validation is much more distinctive in the TR 29 than in the TR 49 that was published 1.5 years earlier. This can be seen, for example, in the TR 29 requirement to define the number of validation runs based on knowledge from the development of cleaning processes, without mentioning a concrete number. In the TR 49 it is still stated that in the absence of a rationale the "magical" three runs can still be contained in Master Plans. The complete renunciation to a formal revalidation stated in the TR 29 is also heading in this modern direction. Unfortunately, the Report does not elaborate on EMA's "Concept Paper on the development of toxicological guidance for use in risk identification in the manufacture of different medicinal products in shared facilities" (see GMP-News dated 22 February2012) that also addresses cleaning limits. Furthermore and unfortunately, the Report is subject to payment.