Hold Time Studies: a lost parameter for cleaning validation.

Publication: Journal of Validation Technology

Publication Date: 01-MAY-07

Article Excerpt
INTRODUCTION

With all of the work and focus on cleaning validation, (1-7) one facet of the process often overlooked or not understood is the aspect of
Hold Time Studies. So, what exactly are Hold Time Studies? There are two aspects of "hold times" generally evaluated for validated
cleaning processes in pharmaceutical manufacturing:

* Clean Hold Times:

The time elapsed from the end of the cleaning process until the beginning of the use of the cleaned equipment for manufacture of the
next product

* Dirty Hold Times:

The time elapsed from the end of manufacturing until the beginning of the cleaning process

Either of these two time periods can have a significant impact upon the cleaning process. Keep in mind that a cleaning validation study
is a reflection of the process(es) used for cleaning and maintaining items in a cleaned state.

An investigator may note two different types of situations during an audit. One is that equipment is stored with a status of "Clean--
Ready for Use" for perpetuity. That is, no time limit has been placed on when the item is to be recleaned. Questions that are asked
include:

* Is this equipment really clean now?

* Do Standard Operating Procedures (SOPs) indicate how long the cleaned equipment can be stored prior to re-cleaning?

* Does adequate data exist to support the storage of the cleaned equipment?

A second observation regards dirty equipment held over a period of days--sometimes longer--prior to cleaning. This can be problematic
for cleaning--especially if you deal with liquids, which dry and crystallize onto the surface, or if you handle powder, which is hygroscopic
and soon transforms into a paste. Questions for these situations include:

* What is the impact on the surface of the equipment being held for that period of time?

* How is the dirty equipment held so as to not contaminate other items?

* Is there data to support the cleaning of the dirty equipment after it has been held for long periods of time? (To illustrate: cleaning off a
powder or liquid is handled much differently from cleaning off a paste or a crystallized substance.)

This article is presented as a guide to understanding the approach to conducting validation studies which compile data in support of
typical operational practices.

CLEANED EQUIPMENT HOLD TIME VALIDATION

This section covers issues related to the "Cleaned Equipment Hold Time" (which will be abbreviated CEHT). CEHT is sometimes called
the expiration or expiry period for the cleaned equipment.

Why CEHT Is Important for the Control of a Cleaning Process

Essentially, the best reason to conduct such a study is that nothing stays clean forever, no matter how well protected it is in storage.
Re-contamination of the equipment may be an event-related phenomenon. Heating, Ventilation, and Air Conditioning (HVAC),
personnel, storage areas, etc., may all have an impact upon the clean status of equipment. In dealing with possible ways the equipment
could be re-contaminated, one should consider both endogenous sources (such as the growth of microorganisms already within the
equipment) and exogenous sources (such as the entry of external contaminants into the equipment).

Three Important Issues for the CEHT Include:

1) The characteristics of the cleaned equipment

2) The nature of possible re-contaminants

3) The storage conditions of the equipment

NOTE: These three factors are interrelated in terms of effects on re-contamination of cleaned equipment.

Equipment Storage Concerns

A major issue related to the characteristics of the cleaned equipment is whether the equipment is stored wet or in a manner such that
microbial proliferation is a possibility. This is covered in the Food and Drug Administration's (FDA's) Cleaning Validation Guidance (1). If
the equipment is stored wet for a sufficient length of time, there is reasonable probability that microbes will grow to an unacceptable
level.

Another issue related to the characteristics of the equipment involves possible routes of entry for external contaminants. For small
pieces of equipment (scoops, for example), this involves exposure of the item itself. For larger pieces of equipment (such as tanks), this
involves any opening in the equipment.

For possible re-contamination, the two major sources are as follows:

* Microbes that may already be in the cleaned equipment

* External "dust" which is in the storage atmosphere

Residues, such as product residue and cleaning agent residue, which are in the equipment at trace levels, are generally not expected
to change over time.

NOTE: The only exception to this may involve an active, which is present in the cleaned equipment at an acceptable level at the end of
the cleaning process, but which, over time, degrades to a point that would make the equipment unacceptable for use.

Storage conditions include any steps taken to protect the equipment, such as: wrapping equipment in a plastic film or covering
openings in the equipment with a bonnet of plastic film. Consideration of storage conditions includes the room in which equipment is
stored. Conditions of the room include temperature, humidity, air quality (i.e., viable and non-viable particles), and external access.

Establish the Holding Time for Clean Equipment

Helpful Hint:

It is recommended that the Validation Group contact the Manufacturing (or Scheduling) Group to determine, under normal conditions,
the longest holding time interval that might be used for the equipment after cleaning.

Objective of CEHT

The purpose of the CEHT is to adequately protect the equipment during the designated time period including a conservative safety
margin. Another purpose is to provide ample justification that equipment remains safe to use throughout that time period.

Analyze the Storage Situation

Study the storage situation closely and consider factors such as:

* Characteristics of the cleaned equipment

* The nature of possible re-contaminants

* The storage conditions

Be Proactive

While considering the situation and factors unique to your storage circumstances, verify what can be done to adequately protect the
equipment from re-contamination.

Justifythe Holding Time of CleanedEquipment

A professional judgment should be made based on an analysis of the storage situation. If equipmentis adequately cleaned and then...