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8.C Cleaning validation master plan

Here you will find answers to the following questions:

  • When does it make sense to compile a separate master plan for the cleaning validation?
  • Which function is fulfilled by the cleaning validation master plan and what are the advantages?
  • Which aspects must be dealt with in the master plan?

The cleaning validation is a very complex task, whose inplementation requires a carefully thought out plan. In the planning phase, all relevant function areas should therefore be included (team). For extensive projects, it is also recommended to compile a validation master plan.

This master plan must be considered as a basic document fot the entire cleaning validation, that is, it gives an overview of the scope of the project, establishes essential requirements such as acceptance criteria, sampling procedures for document formats, and is also used as a planning and monitoring instrument.

The way in which such a master plan can be structured is presented in the Cleaning validation master plan checklist (see figure 8.C-1).

Figure 8.C-1 Cleaning validation master plan checklist  

Suggested structure for the cleaning validation master plan

I Definition of target (objective)

II Responsibilities

III Areas of application

IV Risk assessment

  • Products
  • Production equipment

V Validation matrix

VI Cleansing agents

VII Cleaning instructions

VIII Acceptance criteria

  • Visual checks
  • Active pharmaceutical ingredient residues
  • Cleansing agent residues
  • Microbiological status

IX Sampling procedures

  • Active pharmaceutical ingredient residues
  • Cleansing agent residues
  • Microbiological contamination

X Methods of analysis

  • Active pharmaceutical ingredient residues
  • Cleansing agents

XI Implementation of cleaning validation

  • Prerequisites
  • Type and number of the examinations
  • Measures taken when the acceptance criteria are exceeded
  • Maintaining the validated status

XII Validation planning

XIII Training

XIV Bibliography

XV Appendix

The need to clearly define the objective of cleaning validation is pointed out in the FDA Guide to Inspections of Validation of Cleaning Processes.

The responsibilities within this interdisciplinary project should be clearly defined and limited in order to guarantee a flawless process. This applies to the compilation, review and approval of documents and also to all tasks which are linked to practical implementation, such as training, sampling, analysis and materials acquisition.

If the master plan is only related to a certain section of the plant, the area of application should be precisely defined (e.g. manufacture of liquids/solids, packaging, etc.).

One very important section is the risk assessment, which is related to both products and production equipment. The objective of this risk assessment is, on one hand, to identify critical products which need to be included into the validation program, and, on the other hand, the differentiated consideration of the production equipment to be validated with view to the potential risk of cross-contamination. (See chapter 8.A Official requirements.)

Implementing a risk assessment leads to the establishment of the scope of validation (validation matrix) whilst taking the critical products and processes into consideration.

In the Cleansing agent section, all cleansing agents to be used should be listed. A short description of the most important product characteristics or compositions is advisable, provided that this cannot be found in special cleansing agent documentation.

The Cleaning instructions for production equipment as essential item of the cleaning validation should also be listed in the master plan.

A further core component of the master plan is the chapter on acceptance criteria. The rationale, that is, the scientific justification for setting limits for active ingredient residues, cleansing agent residues and microbiological contamination must be specified here.

In the section dealing with sampling procedures it must be defined which processes should be used to investigate active ingredient residues, cleaning agent residues and microbiological contamination. The accurate implementation of individual sampling procedures should be described in separate instructions which are referred to in the master plan.

Which methods of analysis to determine the residues should be used - e.g. HPLC, HPTLC, conductivity measurement, etc. - should also be referenced in the master plan in addition to the requirement that these methods are validated. It is recommended that all critical substances for which a validation should be implemented, be listed in this section, with details of the testing method to be applied. For the validation of analytical methods, the associated operating procedure can be referenced.

The chapter Implementation of cleaning validation summarises several important issues. First, the requirements to be met prior to the beginning of the cleaning validation should be defined (compare figure 8.C-2).

Figure 8.C-2 Prerequisites for cleaning validation

Prerequisites for cleaning validation

Qualification:

  • Installation qualification and operational qualification of the relevant production equipment are completed.

Training:

  • Training on cleaning instructions, sampling instructions and methods for analysis in addition to other operating procedures related to cleaning validation has been carried out and documented.

Documentation:

  • The master plan and validation protocols for the respective production equipment have been compiled and approved.

In addition, the number of test runs for each type of residue testing or for each critical substance must also be specified. According to PIC/S guideline PIC/S PI 006, section 7.3.6, three consecutive runs of positive cleaning are normally required to prove that the process has been validated.

It is also important to define measures to be taken if the acceptance criteria are exceeded, before the validation is carried out. This can be indicated in the master plan or in a separate operating procedure referred to in the master plan.

The topics of change control and revalidation must be addressed in the section entitled Maintenance of status. According to PIC/S guideline PIC/S PI 006, section 7.3.8 validated cleaning processes should be subjected to change control. With regard to the revalidation, a distinction should be made between a revalidation as a consequence of changes to equipment, products and processes and a revalidation which will be carried out periodically, at specified time intervals. The pharmaceutical company shall decide how these individual requirements are implemented.

The chapter on validation planning contains schedules and capacity estimates which are derived from the validation matrix.

According to PIC/S guideline PIC/S PI 006, section 7.5.1, staff who routinely carry out cleaning must be trained in the use of validated cleaning procedures. The training documentation for all training which is carried out must be available. It would, however, make sense to train the staff in cleaning instructions before the validation is carried out, to ensure the success of the cleaning validation. Instructions for sampling, instructions for analysis and other operating instructions which are directly related to the cleaning validation should as well be trained beforehand. In the Training chapter, both content-related and organisational aspects of training can be dealt with. (See chapter 2.C Training.)

If the master plan refers to literary resources, these must be summarised in a bibliography.

Finally, the scope and importance of the appendix to the master plan should not be underestimated. This is where all important information required for planning and implementing the project should be compiled, for example, data on products and active pharmaceutical ingredients (solubility, dosage, content of active drug substance in the formulation), data on production equipment (product contact surfaces), calculation of limits and tabulated lists of data from the previous chapters (overview of cleaning instructions for analysis, etc.). It is also advisable to integrate specifications regarding the formal aspects and content-related structure of validation protocols and reports within the master plan.

Summary

It is particularly useful to produce a separate master plan for the cleaning validation when dealing with extensive projects.

The master plan functions as a basic document for the validation. It presents an overview of the scope of the project, sets out essential requirements and is used as a planning and monitoring instrument. The compilation of all project-related data and definitions in a central document improves clarity and saves unnecessary repetition in individual validation protocols.

The master plan contains all project-related organisational and technical aspects with the degree of detail required for implementation.


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