Cleaning of Dedicated Equipment: Why Validation is needed

Cleaning of pharmaceutical equipment is essential to reduce the risk of product contamination and, as stated in
relevant guidelines and as recognized by the pharmaceutical sector, this can be achieved only if the cleaning
procedure has been validated. International Conference on Harmonization (ICH) guidance ICH Q9 (1)
encourages that a quality risk management approach be considered and that, based on the level of risk, cleaning
processes may be subject to different levels of validation or verification.
This article covers cleaning validation of equipment dedicated to the production of a single API; equipment
used for manufacturing a class of products (e.g., penicillin) should be considered as shared equipment and is not
addressed here.
Generally speaking, when one thinks of cleaning validation, the first thing that comes to mind is prevention of
cross-contamination, which obviously applies only when equipment is used for manufacturing more than one
product. So why is cleaning validation talked about with regard to dedicated equipment? Section 12.70 of the
guideline ICH Q7, states that, Cleaning procedures should normally be validated. In general, cleaning
validation should be directed to situations or process steps where contamination or carryover of materials poses
the greatest risk to API quality (2). Table I highlights the differences between the approach to clean shared
and dedicated equipment.
Table I: Differences between cleaning of dedicated and shared equipment.
Points to consider

Dedicated

Shared

Cleaning validation

Equipment design

Identification of sampling points

Selection and validation of sampling methods

Cross-contamination

Identification of potential contaminants

Acceptance criteria (for chemical and

microbiological residues, as applicable)
Cleaning procedure

Y (if

Clean/dirty hold time

Y (if applicable)

applicable)

Validation of analytical method

Validation protocol/report

Campaign length validation

Cleaning verification

Y (if campaign production approach

is applied by the company)
Y

As indicated in Table I, most points apply to both cases, meaning that great care needs to be given also when
planning cleaning validation activities of dedicated equipment.
For dedicated plants/equipment, there is no risk of cross-contamination among different active substances;
nevertheless, a wide range of possible contaminants must be evaluated on a case-by-case basis (3), taking into
consideration the type of process (i.e., chemical synthesis, extraction from natural sources, fermentation,
physical steps, etc.), the final product, and the materials used during the manufacturing process (i.e., starting
and raw materials, solvents, and reagents). As for cleaning validation of shared manufacturing plants, even for
dedicated plants/equipment, it is necessary to identify all possible sources of contamination. Some key points to
be considered are summarized in Table II.
Table II: Potential contaminants and control strategies
Potential contaminants

Control strategies

Residues of processed materials

Contaminants could be reduced below acceptable levels if appropriate

(raw and starting materials,

in-process controls monitoring reaction completion is in place and the

intermediates)

process has been validated.

Residues of toxic by-products generated during a manufacturing process

Residues of by-products

must be monitored. In the Thalidomide case, one of the two enantiomers

was later discovered to be teratogenic; in other cases different enantiomers
can have different pharmacological or toxicological profiles.

Adequate studies (e.g., forced degradation studies) should be conducted

Residues of degradation products

in case the residues of the product are not stable throughout the whole
length of the production campaign.

Residues of solvents used during

manufacturing process
Residues of detergents or solvents
used for cleaning during
a production campaign or between
different campaigns

Acceptable limits level of contaminants should be established based

on toxicity calculation (9). The impact will depend on the stage of the
production process; the closest to the final product, the biggest the impact.
Potential reactions between the solvents used for cleaning and the
reagents/starting materials should be evaluated (e.g., contamination of
antiretroviral drug Viracept [Nelfinavir] with ethyl mesylate (10)).
Sanitizers could be used to sanitize the equipment at the end of a

Residues of sanitizers

production campaign. When the active substance has to meet

microbiological specification they could be used more often during a
production campaign.

Microbiological contamination,

These factors should be considered in case of active substances with

endotoxins

microbiological or endotoxin content requirements.

Materials used during

manufacturing (e.g., filtering aids,
charcoal, plastic particles from
gasket, glass particles from glasslined tanks, paper particles from
filters, lubricants from motors and
bearings, fibers from personnel

Many materials used during production could represent a source of

contamination if not removed or if maintenance and/or assembling of the
equipment are not performed correctly.

garments, diatomaceous earth,

small slivers of stainless steel,
etc.)

Only cleaning procedures that have been validated ensure that any undesirable residues have been effectively
removed below a level that has been demonstrated to be acceptable and that does not pose a risk to patients.
Cleaning validation is time and resources consuming; however, some companies might prefer not to use shared
facilities and, instead, dedicate an entire building, manufacturing line, or piece of equipment for the
manufacture of a single product. If they use disposable equipment, such as single-use bioreactors, compatibility
of the disposable equipment with the process should also be assessed.

Companies manufacturing only one product use dedicated equipment by default. In addition, companies must
use a dedicated facility, line, or equipment, if:

The calculated limits of undesirable residues are too low and therefore the potential residues would not be
detectable with the available analytical methods (2).

The acceptance criteria are too low and cannot be achieved (i.e., for some high potency active substances).

The data to calculate safe threshold levels for toxic or sensitizing substances are not yet available or not
sufficient (4).

Planning for cleaning validation

Visual examination is not acceptable as the only test to check residue during initial validation studies. Even if
some literature data report proposed visual limits, this test does not meet ICH Q7 expectations, as it may depend
on too many variables that are difficult to standardize (5) and validate. After the cleaning validation has been
performed, visual examination could be used to detect gross contamination of the equipment immediately
before use (2).
As for non-dedicated facilities, equipment should be of appropriate design and adequate size and suitably
located for its intended use, cleaning, and sanitation (2). Design and technical aspects of equipment are covered
by good engineering practices (6) and some technical references; practical guidelines for equipment design are
also provided by food industry regulation (7). Equipment can be considered as cleanable if it is constructed
using adequate materials such as stainless steel or polymeric materials that are compatible with the process to be
carried out. Finished surfaces should be smooth and properly polished, and equipment should be appropriately
designed and assembled in a way that facilitates cleaning and prevents microbial growth (i.e., no dead legs, not
too many horizontal pipelines or excessive instrumentation, and ancillary components such as shafts, bearings,
and agitators should be easy to disassemble). Finally, the equipment should be easy to inspect.
Sampling method selection (swabbing and/or rinsing or other means [8]) is essentially related to type and design
of the equipment, nature of the residues, residues acceptance limits, and the analytical methods used for
residues quantification; the approach to sampling is the same for dedicated and shared facilities.
Cleaning validation of dedicated production equipment
There are three main aspects to consider when performing cleaning validation of dedicated production
equipment: campaign length, clean hold time (CHT), and dirty hold time (DHT).
If cleaning of equipment dedicated to one API production is not carried out after each batch but on a campaign
basis, it is necessary to validate the maximum campaign length (in terms of duration, number of batches, and
batch size) by demonstrating that manufacturing consecutive batches with no cleaning between them does not
lead to a build-up of undesirable residues that cannot be properly removed at the end of the campaign with the
selected cleaning procedure.
Recent inspection results show that lack of cleaning validation related to the maximum campaign length is still
an issue that is worth clarifying. During an inspection of a dedicated manufacturing facility, conducted by the

Italian Medicines Agency, Agenzia Italiana del Farmaco AIFA in 2015, it was observed that no validation
studies were performed to determine an appropriate campaign length (i.e., duration and/or number of batches
that can be manufactured before having to clean the equipment). Moreover, the company failed to put in place
intra-campaign controls aimed at verifying that during a production campaign the level of potential degradation
residues in the equipment was maintained to a minimum and below pre-established specifications.
CHT is defined as the time between the completion of cleaning and the beginning of the next manufacturing
operation. Clean equipment will not remain clean indefinitely depending on the length of the storage period and
the condition of the storage environment. Cleaning validation studies, therefore, should demonstrate that storage
conditions do not contribute to growth of microorganisms. Evaluations need to be performed on a case-by-case
basis; a CHT might not need to be defined if, for example, the equipment is always cleaned just prior to use.
The CHT also must be determined for dedicated equipment/facility. During an inspection conducted by FDA, it
was observed that tanks used for the manufacture of a single API, carried out a few months before, were not
cleaned since the last campaign. The interior of the equipment had accumulated approximately half an inch of a
white substance and contained a shallow pool of liquid at the bottom.
DHT is defined as the time between the end of manufacturing and the beginning of cleaning procedure. A
residue easy to remove, if cleaned immediately after use of equipment, could maybe be difficult to remove
when applying the same cleaning procedure if the cleaning was not performed immediately after use. This could
occur, for example, for the residues in a crystallization tank; the wet residues might be easy to remove while
the dried residues could require a different cleaning procedure. As for CHT, evaluations need to be performed
on a case-by-case basis. A DHT might not need to be defined if, for example, the equipment is always cleaned
right after use.
For the reasons mentioned previously, it can be concluded that it is crucial to conduct cleaning validation for
dedicated equipment. The quality of an API is intrinsically related to the cleaning procedure employed;
therefore, this aspect needs to be adequately addressed by the manufacturers and deeply reviewed by regulatory
authorities during GMP inspections.
References
1. ICH, Q9 Quality Risk Management (ICH, Nov. 9, 2005).
2. ICH, Q7 Good Manufacturing Practice Guide For Active Pharmaceutical Ingredients (ICH, Nov. 10, 2000).
3. A. Walsh, Pharmaceutical Engineering (November/December 2011).
4. EMA/CHMP/ CVMP/ SWP/169430/2012, Guideline on setting health based exposure limits for use in risk
identification in the manufacture of different medicinal products in shared facilities
5. PDA, Technical Report No. 29 (Revised 2012), Points to Consider for Cleaning Validation (PDA, 2012).
6. ISPE, Good Practice Guide: Good Engineering Practice (ISPE, 2008)
7. BS EN 1672-2:2005 Food Processing machinery-Basic concepts.
8. EDQM, EudraLex, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for
Human and Veterinary Use, Annex 15: Qualification and Validation (in force from October 1, 2015).