cleaning validation Summary

A validation policy should be written for a plant including cleaning validation.
An cleaning validation program should contain the following elements:
1. Assess equipment and products (previous, following)
2. Assess impact of this process on routine processes. If covered under bracketing
then no further validation is required.
3. Determine an appropriate cleaning agent and method
4. Determine acceptance criteria for the residue(s) (including cleaning agents).
5. Determine degree of evaluation required to validate the procedure.
6. Decide what residue(s) (including cleaning agents), are to be tested for based on
solubilities, toxicities etc. and document rational behind decision.
7. Develop sampling and analytical methods for recovery and detection of residues
(swab/rinse, HPLC/dry residue etc.)
8. Acceptance Criteria for the Validation
9. Compile and approve Validation protocol
10. Perform Validation Studies in accordance with protocol
11. Compile and approve a Validation report documenting studies, conclusions and
recommendations.
12. Revalidation policy

Cleaning Validation Minimum requirements

If company policy is not to validate all equipment cleaning procedures for all products
then as a minimum requirement the validation policy should encompass conditions
which represent the most appropriate challenges (worst case) to the procedure.
These would include, as an example, such things as:
· Removal of products which contain the products with the greatest biological
activity.
· Removal of products containing the products/intermediates/byproducts with the
least solubility.
These represent studies that are minimally required as part of a validation, the results
from which could be used to support lesser challenges to the procedure. It is often
termed product grouping.
· The maximum idle time before cleaning.
A validation program generally encompasses three consecutive successful replicates to
establish that the procedure is reproducibly effective although companies should
evaluate each situation individually.
Where equipment of similar size, design and construction is cleaned by the same
procedure, studies need not be conducted on each unit, as long as a total of three
successful replicates are done on similar pieces of equipment (equipment grouping).
Concurrent Validation may be appropriate when product is manufactured infrequently.

Cleaning Validation reports

A validation report is necessary to present the results and conclusions and
secure approval of the study. The report should include the following:
· Summary of or reference to the procedures used to clean, sample and test
· Physical and analytical test results or references for same, as well as any
pertinent observations
· Conclusions regarding the acceptability of the results, and the status of
the procedure(s) being validated
· Any recommendations based on the results or relevant information
obtained during the study including revalidation practices if applicable.
· Approval of conclusions
· Review any deviations for the protocol that occurred.
· In cases where it is unlikely that further batches of the product will be
manufactured for a period of time it is advisable to generate interim
reports on a batch by batch basis until such time as the cleaning validation
study has been completed. (Typically, in Active Pharmaceutical
Ingredient Pharmaceutical manufacture, verification is deemed
appropriate during development of the cleaning methods. Where
products are manufactured infrequently, verification may be applied over
a period of time until all measuring data has been collected for the
Validation Report.)
· The report should conclude an appropriate level of verification
subsequent to validation.

Validation protocols Cleaning

A Validation Protocol is necessary to define the specific items and activities
that will constitute a cleaning validation study. It is advisable for companies to
have drawn up a Master Validation plan indicating the overall Cleaning
Validation strategy for either the product range / equipment type / entire site.
The protocol must be prepared prior to the initiation of the study and must
either include or reference the documentation required to provide the following
information:
· The objective of the study:
What cleaning process is to be validated (indicating the product to be
removed and the equipment from which it is to be removed)?
If this study is to be employed to demonstrate the acceptability of the
cleaning procedure for a group of products the rational for doing so
should also be detailed here.
The cleaning procedure(s) to be validated should be identified i.e.
cleaning agents, soakage times, equipment parameters, number of
cleaning cycles etc.
· Scope of the study:
The company must evaluate the process and determine which residues are
to be tested for and which are not to be based on sound scientific
rational.
What residues (including cleaning agents) are to be tested for, why those
residues (if more residues may be present than are being tested for all
residues should be under control see comments at 8.4). How many times
should the study be run before a report is compiled and recommendations
made.
· Listing of the process parameters to be verified
This is particularly necessary when automated or semi-automated
cleaning techniques are to be employed.
· Sampling and inspection procedure to be used.
The types of sampling methods to be used, where the samples are to be
removed from and how many samples are to be taken. Any particular
requirements should also be stated i.e. for sterile sampling / sampling
light sensitive products.
An equipment sampling diagram should be referenced.
· Personnel responsibilities during the study

Analytical methods Cleaning Validation

In order for the analytical testing of the cleaning validation samples (swabs or
rinses) to yield meaningful results, the analytical methods used should be
validated. This should be documented.
The basic requirements are:
· The ability to detect the target substance(s) at levels consistent with the
acceptance criteria
· The ability to detect the target substance(s) in the presence of other
materials that may also be present in the sample (selectivity)
(Companies might want to consider the following:
Where more than one impurity is suspected (which is probably the normal
case in API manufacturing) a method could be proposed that is not
necessarily specific for each of the impurities but detects them all
together. Then additionally the assumption must be made, that the worst
case (e.g. most active) impurity represents the whole residue. This is
secure approach for the patients and could be accepted by the authorities.
It is also an practicable approach for the industry because such methods
are for example dry residue determination for non volatile impurities or
TOC determination for water rinses, which are very simple methods. )
· The analytical method should include a calculation to convert the amount
of residue detected in the sample to 100% if the recovery data generated
indicates a recovery outside of an allowed range.
· Stability of samples over time if the time interval between removal and
testing of samples potentially effects sample integrity.