CLEANING VALIDATION

BY

ABHISHEK MORRIS

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 CLEANING VALIDATION
Background

Through its regulatory activities, FDA became aware in the

early 1960's of the potential health hazards of product residues

FDA inspections revealed manufacturing practices leading to

contamination of certain drug preparations with penicillin

Amendments to drug regulations for current good

manufacturing practices (GMPs) were published January 29,
1965 for the control of cross contamination by penicillin.

In October 1965 the Division of Antibiotics and Insulin

Certification, now the National Center for Antibiotics Analysis
(NCAA), published methods for penicillin analysis, titled
“Procedures for Detecting and Measuring Penicillin
Contaminants in Drugs”.

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CLEANING VALIDATION
Background

In 1963 The FDA published a Guide to Inspections

”Validation of Cleaning Processes”, intended to cover
equipment cleaning for chemical residues only. In this
document FDA outlines what is expected:

a) Expects firms to have written procedures (SOPs)

detailing the cleaning processes.

b) Expects firms to have written general procedures on

how cleaning processes will be validated.

c) Expects firms to conduct the validation studies in

accordance with the protocols and to document the
results of studies.

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Definition

EU and Australian Code of GMP

“Cleaning validation is documented evidence that an

approved cleaning procedure will provide equipment which is
suitable for processing medicinal products”.

21 CFR 211.176, Penicillin contamination, states:

“If a reasonable possibility exists that a non-penicillin
drug product has been exposed to cross-contamination
with penicillin, the non-penicillin drug product shall be
tested for the presence of penicillin. Such drug product
shall not be marketed if detectable levels are found
when tested according to procedures specified in
‘Procedures for Detecting and Measuring Penicillin
Contamination in Drugs”.

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Examples of cGMP requirements

21 CFR 211.67 (a)

“Equipment and utensils shall be cleaned,

maintained, and sanitized at appropriate
intervals to prevent malfunctions or
contamination that would alter the safety,
identity, strength, quality, or purity of the
drug product beyond the official or other
established requirements”.

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Examples of cGMP requirements

EU and Australian CMP, 5.18

“Contamination of a starting material or of a product by

another material or product must
be avoided….... The significance of this risk varies with
the type of contaminant and of product being
contaminated. Amongst the most hazardous contaminants
are highly sensitizing materials, biological preparations
containing living organisms, certain hormones, cytotoxics,
and other highly active materials”.

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Examples of cGMP requirements

WHO, Annex 4, 4.11

“It is of critical importance that particular attention is

paid to the validation of analytical test methods,
automated systems and cleaning procedures”.

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Principle

Pharmaceutical products and active pharmaceutical

ingredients (APIs) can be contaminated by other
pharmaceutical products or APIs, by cleaning agents, by
micro-organisms or by other material (e.g. air-borne
particles, dust, lubricants, raw materials, intermediates).

In many cases, the same equipment may be used for

processing different products. To avoid contamination
of the following pharmaceutical product, adequate
cleaning procedures are essential.

Cleaning procedures must strictly follow carefully

established and validated methods of execution. This
applies equally to the manufacture of pharmaceutical
products and active pharmaceutical ingredients (APIs).
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General requirements

Normally only cleaning procedures for product contact

surfaces of the equipment need to be validated.
Consideration should be given to noncontact parts into
which product may migrate. For example, seals,
flanges, mixing shaft, fans of ovens, heating elements
etc.

Cleaning procedures for product changeover in the case

of marketed products should be fully validated.

Cleaning procedures for products and processes which

are very similar, do not need to be individually
validated.”.

Generally in case of batch-to-batch production it is not

necessary to clean after each batch. However, cleaning
intervals and methods should be determined. 9
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General requirements

It is considered acceptable to select a representative

range of similar products and processes concerned and
to justify a validation program which addresses the
critical issues relating to the selected products and
processes. A single validation study under consideration
of the “worst case” can then be carried out which takes
account of the relevant criteria. This practice is termed
"Bracketing” or “grouping

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General requirements

At least three consecutive applications of the cleaning

procedure should be performed and shown to be successful
in order to prove that the method is validated.

Raw materials sourced from different suppliers may have

different physical properties and impurity profiles. Such
differences should be considered when designing cleaning
procedures, as the materials may behave differently.

It is usually not considered acceptable to "test until clean".

This concept involves cleaning, sampling and testing, with
repetition of this sequence until an acceptable residue limit
is attained. For the system or equipment with a validated
cleaning process, this practice of "test until clean" should
not be required. The practice of "test until clean" is not
considered to replace the need to validate cleaning
procedures.
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General requirements

Products which simulate the physicochemical

properties of the substance to be removed may be used
instead of the substances themselves, where such
substances are either toxic or hazardous.

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Some general questions
Several questions should be addressed when evaluating the cleaning
process. For example:

a) At what point does a piece of equipment or system become clean?

b) What does visually clean mean?

c) Does the equipment need to be scrubbed by hand?

d) What is accomplished by hand scrubbing rather than just a solvent

wash?

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Some general questions
e) How variable are manual cleaning processes from batch
to
batch and product to product?

f) What is the most appropriate solvent or detergent?

g) Are different cleaning processes required for different

products in contact with a piece of equipment?

h) How many times need a cleaning process be applied to

ensure adequate cleaning of each piece of equipment?

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Equipment cleaning strategies

Dedicated
Campaign
Common

Cleaning of processing areas also requires validation.

The general principles outlined in this presentation are
applicable. Sampling methods and limits should be
appropriate to the material be processed.

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Some points to consider

Required written procedures that are standardized

Required written protocols

Justification for limits set

Equipment and product mix for common and dedicated

equipment

Use of manual verses automatic cleaning procedures,

such as CIP

Ongoing program of monitoring effectiveness

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Some equipment & product considerations
Use of “worst case” (e.g. smallest batch size, smallest number of
maximum daily doses, hardest to clean) product as a marker for
easier other products
Grouping of products
For example grouping based on; those products capable of causing
the largest possible problems if contaminated, or if they contaminate
other products; drug solubility and; equipment.
Identification of items of equipment that contribute most to cross
contamination of the next product
Identification of “worst case” locations in equipment , i.e. the design
of the equipment should be carefully examined.
Critical areas (those hardest to clean) should be identified,
particularly in large systems that employ semi-automatic or fully
automatic clean-in-place (CIP) systems.
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Some equipment & product considerations

Dedicated equipment should be used for products which

are difficult to remove (e.g. tarry or gummy residues in
the bulk manufacturing), for equipment which is
difficult to clean (e.g. bags for fluid bed dryers), or for
products with a high safety risk (e.g. biologicals or
products of high potency which may be difficult to
detect below an acceptable limit).

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Residue detection
Visual checking
- Suitable for dedicated equipment
- Include in all protocols and routine monitoring
Chemical tests
- Specific methods such as; high performance liquid
chromatography (HPLC), ion selective electrodes, flame
photometry, derivative UV spectroscopy, enzymatic detection
and titration

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Residue detection
Methods validation and recovery studies

Involves the use of the sampling and detection method on known

spiked surfaces at representative levels, typically spiked at 50%,
100% and 150% of the acceptable limit and at lower expected
actual levels to show linearity with documented % recovery as
analyzed and to determine the limit of detection and limit of
quantitation. Ideally the expected
values and limits should be multiples of the limits of
quantization.

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Residue detection
Chemical tests
a) Non-specific methods that detect the presence of a blend of
ingredients such as: total organic carbon, pH, and conductivity.
b) Specific methods. The FDA prefers specific methods, but
will accept non-specific methods with adequate rationales for
their use.
c) Chemical limits can be expressed as a maximum
concentration in the next product (ug/ml), amount per surface
area (ug/cm2), amount in a swab sample (ug or ug/ml),
maximum carryover in a train (mg or g), or concentration in
rinse water (ug/ml). There can be a calculated safety based
acceptance limit, a lower internal action level, and a lower
process control level based on actual manufacturing and
measuring experience.
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Residue detection

c) Chemical limits can be expressed as a maximum

concentration in the next product (ug/ml), amount per surface
area (ug/cm2), amount in a swab sample (ug or ug/ml),
maximum carryover in a train (mg or g), or concentration in
rinse water (ug/ml). There can be a calculated safety based
acceptance limit, a lower internal action level, and a lower
process control level based on actual manufacturing and
measuring experience.

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Microbial considerations
a) Endotoxins
b) TAMC
c) The existence of conditions favourable to reproduction of
microorganisms (e.g. moisture, temperature, crevices and rough
surfaces) and
the time of storage should be considered. The aim should be to
prevent excessive microbial contamination.

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Microbial considerations
d) The period and when appropriate, conditions of
storage of equipment before cleaning and the time
between cleaning and equipment reuse, should form
part of the validation of cleaning procedures. This is
to provide confidence that routine cleaning and
storage of equipment does not allow microbial
proliferation.

e) In general, equipment should be stored dry, and

under no circumstances should stagnant water be
allowed to remain in
equipment subsequent to cleaning operations.

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Detergent considerations
The efficiency of cleaning procedures for the removal of
detergent residues should be evaluated. Acceptable limits
should be defined for levels of detergent after cleaning. Ideally,
there should be no residues detected. The possibility of
detergent breakdown should be considered when validating
cleaning procedures.

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Detergent considerations
The composition of detergents should be known.

If such information is not available, alternative detergents

should be selected whose composition can be defined. As a
guide, food regulations may be consulted. The manufacturer
should ensure that he is notified by the detergent supplier of
any critical changes in the formulation of the
detergent.

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Sampling methods principle

There are two methods of sampling that are considered to be

acceptable, direct surface sampling (swab method) and indirect
sampling (use of rinse solutions). A combination of the two
methods is generally the most desirable, particularly in
circumstances where accessibility of equipment parts can
mitigate against direct surface sampling.

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Sampling methods principle

Direct Surface Sampling (swabbing)

The suitability of the material to be used for sampling and of the
sampling medium should be determined. The ability to recover
samples accurately may be affected by the choice of sampling
material. It is important to ensure that the sampling medium and
solvent are satisfactory and can be readily used.

Rinse Samples
Rinse samples allow sampling of a large surface area. In
addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However,
consideration should be given to the
solubility of the contaminant.
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Sampling methods considerations
Swab samples
a) Reliable determination of residue
b) Locations must be carefully defined (use difficult to clean
locations).
c) Extrapolate sample area to whole area
d) Method recovery must be validated (e.g. spiking studies, recovery
target, LOD and LOQ, precision, linearity and selectivity)

Rinse samples
a) May be helpful where sites are inaccessible to swabs
b) Useful for cleaning agent residues
c) Must define volumes of rinse agent used
d) Method recovery must be validated

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Sampling method considerations

e) The choice of containers used in the analysis of samples is

very important. It has been shown that, in very dilute solutions,
surfactants can adsorb onto the surfaces of sample vials. This
will produce artificially low results in the analysis. Appropriate
spiking studies should be performed to ensure that this
phenomenon is not occurring and will not interfere with the
analytical method.

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Selection of limits - principle
Establishment of Limits

a) The pharmaceutical company's rationale for selecting limits

for product residues should be logically based on a consideration
of the materials involved and their therapeutic dose. The limits
should be practical, achievable and verifiable.

b) The approach for setting limits can be:

i) Product specific Cleaning Validation for all products, or
ii) Grouping into product families and choosing a "worst case"
product
iii) Grouping into groups of risk (e.g. very soluble products,
similar potency, highly toxic products, difficult to detect etc.).

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Selection of limits - principle

Carry-over of product residues should meet defined

criteria, for example the most stringent of the
following three criteria:

(a) No more than 0.001 (0.01%)of the normal

therapeutic dose of any product (or minimum dose if
there are number formulations with different
strengths) will appear in the maximum daily dose of
the following product

(b) No more than 10 ppm of any product will appear

in another
product,
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Selection of limits - principle

(c) No quantity of residue should be visible on the equipment

after cleaning procedures are performed. Spiking studies should
determine the concentration at which most active ingredients
are visible

(d) For certain allergenic ingredients, penicillins,

cephalosporins or potent steroids and cytotoxics, the limit
should be below the limit of detection by best available
analytical methods. In practice this may mean that dedicated
plants are used for these
products.

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Selection of limits - principle

e) It should not be assumed that the contaminant will be uniformly

distributed throughout a system. The assumption that a residual
contaminant would be worn off the equipment surface uniformly,
or that the contamination might only occur at the beginning of the
batch, should not be made.

f) In establishing residual limits, it may not be adequate to focus

only on the principal reactant since chemical variations (active
decomposition materials) may be more difficult to remove.

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Selection of limits

Some points to consider:

General
a) Regulatory agencies do not set limits

b) Use of dedicated equipment wherever possible, e.g.

scoops, FBP, blenders, compression machines etc.

c) Total surface areas of all common equipment used

d) Validation data should support a conclusion that

residues have been reduced to an acceptable level

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Selection of limits

Some points to consider:.

Visually clean
a) Accepted by FDA for cleaning between batches of
the same product or different lots of the same
intermediate in a bulk process

b) Useful for both equipment and walls, floors etc. of

processing areas

c) Note that for many residues the visual detection limit

is in the order of 1-4 ug/cm2. It is possible that the
visually clean criteria will be the most stringent criteria.

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Selection of limits

Some points to consider:.

Medical dosage level is probably the most common basis for
limits calculations in the pharmaceutical industry. It is based
on allowing a certain fraction of a daily dose to carry over to a
daily dose of a following product. The fraction that reduces the
dosage is referred to as a safety factor or a risk assessment
factor and takes the form of a fraction such as 1/100th,
1/1000th, or 10,000th of the original daily dose.

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Selection of limits

Some points to consider:.

A commonly used limit is no more than one thousandth

(0.001) of the minimum daily dose of a current product will
appear in the maximum daily dose of a subsequent
Product

Where a there is a large product range, to reduce swabbing

work load, one approach is to identify which product is a
worst case (e.g. based on the smallest number of maximum
daily doses, i.e. batch size divided by maximum daily dose).

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Selection of limits

Some points to consider:.

a) No more than 10ppm of any product will appear in another
product

i) This has its origins in the regulations that apply to food products
in
the US.

ii) Also used in the USP for hazardous substances, such as heavy
metals and impurities.

iii) Assumes that residue is as harmful as a hazardous substance

iv) Useful for materials for which no toxicological data is available,

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Selection of limits

b) In the case of small final filling equipment such as filling needles

for vials or tablet punches and dies, it may be necessary to do
separate residue studies on the filling needles or punches and dies to
be sure that there was not enough residue just on that equipment to
contaminate the first few bottles or tablets of the next batch with the
maximum allowable carryover limit (MACO) of the previous
product.

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Protocol

The Cleaning Validation Protocol should include, for

example, the following:

a) The objective of the validation process.

b) Responsibilities for performing and approving the
validation study
c) Description of the equipment to be used.
d) The interval between the end of production and the
beginning of the cleaning procedures.

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Protocol

e) Cleaning procedures to be used for each product, each

manufacturing system or each piece of equipment.

f) The number of cleaning cycles to be performed

consecutively.
g) Any routine monitoring requirement.

h) Sampling procedures, including the rationale for why a certain

sampling method is used.

i) Clearly defined sampling locations.

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Protocol
j) Data on recovery studies where appropriate,

k) Analytical methods including the limit of detection and the

limit of quantitation of those methods or reference to them

l) Acceptance criteria and limits

m) Details of of product “grouping”

n) When Re-validation will be required.

o) A Final Validation Report. The conclusions of this report

should state if the cleaning process has been validated
successfully.

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Equipment considerations

In the case of a product changeover, the total surface area of

equipment common to each product has to be determined.

Assuming a swab area of 10 cm2 , the total amount of residue

present is determined by dividing the equipment surface area
(cm2 ) by 10 and multiplying this result by the residue quantity.
This is repeated for all common equipment in the “train” and the
total residue calculated by
adding all results together.

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Selection of limits

We first manufacture product A and then product B, "What is

an acceptable level of product A to carry over and be present in
product B and yet not cause a medical effect in the patient
consuming product B?" The math is.

The maximum allowable carryover, MACO

= (allowable carryover into a single daily dose of next
product) x (# of daily doses in complete batch of next product)

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Selection of limits

or,

MACO = ( allowable carryover into a single daily dose of next

product) x (batch size of next product divided by daily dose of
next product)

The allowable carryover of product A into a single dose of

product would be:
(Daily dose of A) divided by (Safety Factor)

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Selection of limits

Thus, the total maximum allowable carryover depends on four

variables:

The daily dose of product A

The safety factor selected
The batch size of product B
The daily dose of product B

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Selection of limits

Example 1

Let's suppose, for the present example, that we have two orally
administered products (A and B) manufactured using the same
equipment. Product A is formulated in two strength, a 500mg
dose and a 850mg dose, each dose is given once a day. The
maximum daily dose of Product B is 8 tablets and the batch
size is 320,000 tablets.

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Selection of limits

Example 1
The minimum daily dose of Product A, which is 500mg, is
used in the following calculation.

MACO= (Minimum daily dose of Product A/safety factor of

1000) x (# of daily doses in complete batch of next product)

MACO = 500/1000 x 320,000/8 = 20g

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Selection of limits

Example 2

Let's suppose, for the present example, that we have five

products (A, B, C, D, and E) in the current product grouping,
and they are all products given by the oral route of
administration. Let's further assume that the group of five all
has different dosages and batch sizes as represented in the next
slide.

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Selection of limits

Example 2
PRODUCT MAX
BATCH
DAILY DOSE mg
SIZE Kg
A 100 50
B 150 100
C 200 100
D 250 10
E 300 150

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Selection of limits

Example 2
The limits calculated will depend upon the specific
sequence of products manufactured, thus there are
20 different combinations and permutations of
possible manufacturing sequences for only a five-
product group. Even if the initial product is
specified, then there could be four other products
manufactured subsequently, thus four different
limits. For this reason, many companies use an
equation which takes into account the "worst case"
situations for all products in the same
group.

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Selection of limits

Example 2
If Product A is selected as the initial product. In
order to calculate a limit for carryover of product A
into any other product, we could use the following
equation:
MACO= (DTDA) x (WC#D)/SF
MACO = Maximum allowable carryover
DTDA = Daily therapeutic dose of product A
WC#D = Worst case # doses
SF = Safety factor (usually 1,000)

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Selection of limits

Example 2
The worst case number of doses in the following
product would be determined by a combination of
the largest daily dose (active plus excipients) of any
of the other product in the group and the smallest
batch size of any other product in the
group by the relationship:

Worst case = Smallest batch size*

Largest daily dose*
* of any other product in group

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Selection of limits

Example 2
The data show in Slide 60 for the current group of five
products shows that Product E has the largest Daily Dose
Weight (300 mg) and Product D has the Smallest Batch Size
(10 Kg) of the product group. Thus the Worst Case Number of
Doses would be:
Worst case # doses = 10,000,000 mg = 33,333 doses
300 mg/dose

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Selection of limits

Example 2
The 10 Kg was converted to mg so that the units would agree.
This value would now be substituted back into the MACO
calculation with the following results:

MACO = DTDA x WC#D in following product

SF
MACO = 10 mg x 33,333 = 333 mg
1000
We can now perform a 'worst case' calculation for each of the
five products in the group and this would reduce the number of
calculations from twenty down to five. The resulting
calculations for the group of five products are shown in the
next slide.

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Selection of limits

Example 2
PRODUCT MACO for all products in group mg
A 333
B 990
C 3330
D 6660
E 16650

The MACO for Product A, shown in slide 55, is the maximum

residue that can be present on the surfaces of all common
equipment in the train. This is regardless of which product is
being produced and which product is produced next.

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Selection of limits

Example 3
The limit of Product A (which contains the most potent active)
in Product B (which contains the least number of maximum
daily doses per batch)
MACO = D x E mg
where:
D = The minimum daily dose of the smallest strength of
Product A
E = The maximum number of daily doses per batch of Product
B

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Selection of limits

Example 3
In a tablet product grouping product A is the most potent. One
thousandth of the minimum daily dose is 0.0006 mg.

Product D has the least number of maximum daily doses per

batch, 50,000.

The MACO limit is 0.0006 x 50,000 = 30mg

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Selection of limits

Example 3
From swabbing, the total residue found on all common
equipment is 0.600 mg.

Based on the data, the cleaning procedure is acceptable

regardless of which product is being produced and which
product is produced next.

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 THANKYOU

ABHISHEK MORRIS