Pharmaceutical Cleaning Validation

Pharmaceutical Cleaning Validation is a critical part of a process validation checklist, as is equipment validation if you wish to ensure FDA or TGA compliance. For both Active Pharmaceutical Ingredient (API) and Final Dosage manufacturing plants, it is advisable that you have these included in your overall site Validation Master Plan (VMP) as well as a written Cleaning Policy.

Equipment cleaning should be part of the overall facility design and should be included as part of any Pharmaceutical Manufacturing site Validation Master Plan.

Policies provide a guideline and direction to company personnel, regulatory authorities and customers as to how the company deals with Cleaning Validation.

Should the manufacturing facility be complex and large, it is advisable to have a separate Cleaning Validation Plan, if not, the information below can be included in the VMP.

Pharmaceutical Cleaning Validation Policy

The cleaning validation policy should incorporate the following types of statements:

Definition of validation terms i.e. rinse vs. flush vs. wash.
A statement specifying what the company policy is on validation of cleaning procedures related to equipment (including ancillary) and processes.
Company policy, dedication of equipment in certain cases (if products are deemed too dangerous and / or highly active to manufacture on multi-product equipment).
Analytical validation policy.
The rational for the methods by which acceptance criteria is determined.
Revalidation policy.

Cleaning Validation Master Plan

In broad terms the VMP should include the following elements.

Risk Assessment
Establishment of acceptance criteria
Cleaning methods and procedures

- characterisation of the products

- calculations in pharmaceutical cleaning validations

- determination and characterization of the cleaning agents
Analytical method and its validation
Sampling Procedure and necessary validation of same
Training Records
Change Control procedure
Validation protocols
Validation Summary Report

Cleaning Validation and Process Analytical Technology (PAT)

Cleaning Validation is a critical aspect of pharmaceutical batch manufacturing systems. Production run campaigns are followed by downtime periods of ‘Change-Over’ and this can have considerable impact on production capacity and profitability. Preventing cross contamination that can potentially harm a patient is of critical importance in multipurpose plants. Based on the result of your risk assessment you should decide on the level of science needed to justify your cleaning validation strategy.

For example, in an API manufacturing plant, a reactor vessel with a Cleaning In Place (CIP) system has to be thoroughly cleaned by a validated process before the next production cycle can start.

If large volumes of solvents such as methanol and acetone are used, samples from the wash cycle are measured off-line by HPLC. This is time consuming and costly.

Using Process Analytical Technology (PAT) philosophies, an alternative could be to install an on-line analyser that has a fast response time and the sensitivity to monitor the status of the cleaning process in real time. This gives you quick feed back and ensures that your cycle times are optimal.

Alternatively, if the solvent is water, an in line Total Organic Carbon (TOC) analyser can be used. If you would like to know more about conducting an in-depth study of your plant, your change over costs and the efficiency, please contact us.

Cleaning Validation of CIP Systems

The cleaning validation of CIP systems can be even trickier, in terms of spray ball selection and recirculation rates. PharmOut has the engineering expertise to assist in CIP design review.

PharmOut can provide guidance for inspection cleaning validation, calculations in pharmaceutical cleaning validations.

Process Analytical Technology (PAT) Initiative

Want know more about PAT? You could spend hours reading on the FDA website at: Process Analytical Technology (PAT) Initiative. Alternatively, you could call a PharmOut validation consultant and we could use our experience to identify new opportunities to reduce cycle times and implement them.