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.,
penicillins) 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 Ihighlights 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

Clean/dirty hold time

Y (if

Y (if applicable)

applicable)
Validation of analytical method

Validation protocol/report

Campaign length validation

Y (if campaign
production
approach is applied
by the company)

Cleaning verification

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.
Potential contaminants

Control strategies

Contaminants could be reduced below

Residues of processed
acceptable levels if appropriate
materials
in-process controls monitoring reaction
(raw and starting materials,
completion is in place and the
intermediates)
process has been validated.

Residues of by-products

Residues of toxic by-products generated

during a manufacturing process
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.

Residues of degradation
products

Adequate studies (e.g., forced degradation

studies) should be conducted
in case the residues of the product are not
stable throughout the whole
length of the production campaign.

Residues of solvents used

Acceptable limits level of contaminants should

during manufacturing
process

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.

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

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).

Residues of sanitizers

Sanitizers could be used to sanitize the

equipment at the end of a production
campaign. When the active substance has to
meet microbiological specification they could
be used more often during a production
campaign.

Microbiological
contamination, endotoxins

These factors should be considered in case of

active substances with microbiological or
endotoxin content requirements.

Materials used during

manufacturing (e.g., filtering
aids, charcoal, plastic
particles from gasket, glass
Many materials used during production could
particles from glass-lined
represent a source of contamination if not
tanks, paper particles from
removed or if maintenance and/or assembling
filters, lubricants from
of the
motors and bearings, fibers
equipment are not performed correctly.
from personnel 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.