22.06.2018 | LOGFILE Feature 26/2018

An excerpt from the GMP Series PDF Download A Pharma Guide to Cleaning Validation

Principles of Cleaning Process Requirements

6 minutes reading time | by Michael Hiob


Cleaning processes should remove residues from surfaces that come in contact with the product to prevent the cross-contamination of subsequent products.

At the same time, measures must be put in place to maintain the cleaning status over a specific period of time.

The cleaning process and cleaning agent used must not put the medicinal product or manufacturing equipment at risk. This applies, for example, to cleaning agent residues, to residual humidity after cleaning or to the integrity of surfaces that have contact with the product.

Residues adhere to surfaces because of adhesive effects such as van der Waals forces, electrostatic attraction or mechanical bonding caused by the roughness of the surface material. The cleaning process is meant to overcome these adhesive forces, e.g. by mechanical effect, soaking/dissolving, emulsifying, by oxidation of the residues or the formation of salts, which makes it easier to dissolve the residues in water so that they can be rinsed off.

The success and efficiency of the cleaning process depends on the following parameters being controlled by the respective method:

  • amount and/or concentration of the cleaning agent
  • mechanical measures
  • cleaning time and temperature and
  • the number of rinsing cycles required

Figure 1 Determination of cleaning instructions

Written cleaning instructions must be created for all components that come in contact with the product.

When creating cleaning instructions, the aspects in Figure 1 must be taken into account.

When the key elements of the cleaning process have been established, the details must be outlined in a cleaning instruction. The regulatory content shown in Figure 2 must be kept in mind.

Figure 2 Regulatory content of cleaning instructions

Cleaning instructions must be related to specific equipment or groups of equipment and to specific products or product groups.

The responsible staff members must receive training on the cleaning instructions. The effectiveness of the training, especially in the case of manual cleaning processes, must be regularly checked on site.

The instructions and documentation must be available on site. They should be regularly checked for deviations and trends and to ensure they are up to date. It should be clear from the equipment documentation,

  • which product was previously manufactured on the equipment
  • when the equipment was cleaned
  • until when the cleaned equipment can be used before it needs to be cleaned again.

log book should be kept for important or critical pieces of equipment in which all validations, calibrations, maintenance work, cleaning work and repairs are entered with the date and name of the persons who carried out these activities.

An effective cleaning process must be able to remove product residues or their degradation products, residual cleaning agents and microbiological contamination until a specific limit is reached. Other potential sources of contamination such as lubricants, packaging material remnants, cleaning material remnants (e.g. brush hairs, textile fibres) and every type of airborne contaminant (dust particles) must also be considered. The rationale for setting limits for the transfer of product residues, cleaning agents and microbial contamination should be logical and based on the materials involved. The limits should be achievable and verifiable.

A cleaning process interacts with

  • the physicochemical properties of starting materials, including their impurities from the supply chain
  • the design of the manufacturing equipment
  • the climatic, particulate and microbiological environmental conditions
  • the technical equipment used for cleaning and
  • the personnel that carry out and monitor the cleaning process

These interactions influence the effectiveness of the cleaning process. Knowing and mastering them is essential if the cleaning process is to be validated.

This text is an excerpt from the GMP Series Download A Pharma Guide to Cleaning Validation

Michael Hiob


Michael Hiob, PhD
Supervisor of GMP inspections and Ministerial Pharmaceutical Director at the Ministry of Social Affairs
E-Mail: michael.hiob@sozmi.landsh.de

A Pharma Guide to Cleaning Validation

Does your cleaning validation meet the current requirements of Annex 15 to the EU GMP Guidelines? And are you already familiar with the new requirements for establishing limits in cleaning validation?

Michael Hiob, a German Ministerial Pharmaceutical Director and former GMP inspector, gives a comprehensive overview on agency expectations and tells you how to set up a risk-based cleaning validation in consideration of the lifecycle approach for products and processes.

Dr. Jens Hrach, toxicologist, explains what the new PDE approach is about and points out its implications for cleaning validation.

Cleaning validation is not new, but the official requirements were updated in the revised Annex 15 in order to reflect the current state of the art. Three aspects are in the foreground:

  • The lifecycle of the process should be taken in consideration.
  • A quality risk management approach should be applied.
  • Limits for the carryover of product residues should be based on a toxicological evaluation (PDE report).

The download is an excerpt from the unparalleled GMP Compliance Adviser.

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