Principles of the Cleaning Validation Protocol

This is an overview of the cleaning validation protocol and the validation of cleaning procedures for product contact manufacturing equipment used in the pharmaceutical and bio- pharmaceutical industry.

For product manufacturing in the pharmaceutical industry this protocol provides documented evidence that cleaning techniques employed in the manufacturing facility are able to prevent cross contamination and carryover.

Cleaning Validation (CV) must be applied to all products, impurities, intermediates, cleansing agents and other materials in the process stream according to predetermined standards. Part of this protocol will involve validating the maximum time, equipment can remain "dirty" (dirty hold) prior to cleaning and maximum time equipment remains "clean" (clean hold). Maximum time is considered the worst case scenario so that all lesser times are also validated.

Essential Purposes of this Protocol:

1. It is a regulated requirement included in FDA, WHO, PIC/S and EU regulations

2. It prevents batch contamination, minimizing the number of out of specification batches

3. It determines the safe hold times, both "clean" and "dirty", which aids in production scheduling

Presence of Contaminants

The objective of this protocol is to ensure effective cleaning systems are in place to reliably prevent contamination, including product cross contamination and reagent carryover. It is important to remember that the cleaning process can be simplified by using fewer products on a multi-product process train.

Analysis

To detect contaminants, rinse and swab analysis can be employed. Solubility and toxicity should be taken into consideration when designing methods of analysis. Visual analysis can also be useful. The methods of analysis that are ultimately chosen must be validated. This validation procedure should include spiking samples and swab areas with potential contaminants to perform recovery analysis. The limits of detection and quantification should be well inside specification limits.

Analytical methods should be able to detect the following contaminants:

1. Precursors to the end product

2. Degradation products produced by the pharmaceutical product

5. Microorganisms: this is especially important if a product can sustain microbial growth

6. Lubricants and cleansing agents

Components of the Cleaning Validation Protocol

CV protocols are written in accordance with a site Validation Master Plan and all relevant regulatory requirements. It should include, but is not limited to, the following points:

1. Definitions of the terms utilized during validation, for example flush vs. rinse

2. A statement which details the pharmaceutical facility's policy on cleaning validation associated with equipment, ancillary equipment, and processes involved in manufacturing the product

3. The company's policy on dedicated equipment in cases where the products are dangerous or too highly active to be manufactured using multi-product machinery

4. Details regarding maximum clean and dirty holds

5. Details of any products under consideration for cleaning

6. The company should also have a revalidation policy which will form part of the validation lifecycle

Overall, the cleaning validation protocol ensures that pharmaceutical products manufactured in a facility are aligned with all internal and regulatory specifications such as those set by the FDA. More importantly, the protocol documents the cleaning process and ensures that the product manufactured is free from contaminants and extraneous materials. Maximum clean and dirty holds are qualified during the cleaning validation protocol execution. Cleaning validation adds value through regulatory compliance and reduced batch contamination.

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