Title: Cleaning Validation

OBJECTIVE:
To define the minimum requirements for validation of cleaning procedures for equipment
associated with the manufacture of drug products to assure that fitness for use of each end product
is adequately protected. Also, this procedure established limits for acceptable cleaning levels on
swab tests or rinse samples used to validate the cleaning of equipment.
RESPONSIBILITY:
- Production engineering: Equipment structure, surface area
- Production department: leaning process
- !: "ampling, cleaning evaluation, analytical method validation, acceptance criteria determination
- !A: #eviewing and final approval.
PROCEDURE:
leaning $alidation:
$alidation team %Engineering, production, !&
a. omplete description of the equipment to be cleaned' rationale for its use as a model and
list of other equipment for which it serves as a model, if so used.
b. Type of manufacturing process involved.
c. (dentification of all products for which cleaning validation is being performed' rationale
for selection of a model formulation in the cleaning validation protocol, if used.
d. )escription of process to be used in cleaning %e.g., lean-(n-Place system %(P&,
equipment washer %*P&, manual&.
e. (dentification of cleaning agents, concentration, procedure used, temperature %ambient
or specific&, technical data sheets as appropriate, and rationale for their selection %e.g.
nature of the material to be cleaned, compatibility with surface to be cleaned&.
f. onditions under which the cleaning validation is to be performed. %+or cleaning other
than after a production scale run, a rationale indicating that conditions accurately reflect
manufacturing conditions must be included&.
,ote: -orst case conditions need to be considered for cleaning validations %e.g. reduced
cleaning cycle parameters, less cleaning agent concentration, lower pressure, etc.&, including
.ustification and rationale for use of these conditions.
g. leanliness acceptance criteria %e.g. acceptable chemical, drug product, e/cipient, and0or
cleaning agent& residue levels, microbiological alert levels and0or action levels, detection
of specific organisms of concern&' and rationale for their selection. %"ee section 1,
alculation of Acceptance riteria&.
h. "ampling methods %e.g., swab, rinse&, analytical test methods e.g., 2$, 3P4, 5, and
including limits of detection&, visual inspection techniques, and other test methods as
applicable.
i. opy of the cleaning procedure to be validated.
.. Approvals required for acceptance of the protocol by all the validation team and !A.
6. E/ecution of leaning 7ethod $alidation
a. Perform, or have performed, equipment cleaning validation in accordance with an
approved equipment cleaning validation protocol.
b. (nvestigate non-conforming results. )ocument the investigation and include a
description of the situation, all ancillary information and data related to the investigation,
conclusions as to the probable cause, and recommended actions with rationale.
c. E/ecute approved cleaning protocol %s& under conditions which reflect actual
manufacturing processes. All acceptance criteria must be met for the validation to be
considered complete. Any swab or rinse failures must be e/plained.
6& +or dry product operations, perform three successful consecutive cleaning validation
runs for each piece of equipment listed in the protocol.
8& +or parenteral operations, successfully complete an approved cleaning protocol a
minimum of three consecutive times to validation a cleaning process.
6. +inal Equipment leaning $alidation Pac9age
a. The final equipment cleaning validation pac9age includes:
6& The approved cleaning validation protocol.
8& All data developed to support the validation, including data supporting ad.ustments
to the original protocol, if any.
:& A final summary which should include a discussion on the possible need to conduct
routine monitoring studies to ensure the cleaning systems continue to perform as
validated.
;& Approvals.
a. The final equipment cleaning validation pac9age must be reviewed and approved by
department heads of each of the following areas: Technical services and0or validation,
and !. *ther areas may be added as appropriate.
6. #evalidation of Equipment leaning 7ethod%s&
a. #evalidation of equipment cleaning procedure%s& is performed when determined to be
appropriate.
b. (f a new product is introduced into the equipment. the appropriateness of the cleaning
procedure must be established and documented in the validation pac9age or addendum
to the validation pac9age for the product by technical "ervices0$alidation and !.
Approvals %)epartment 3ead level or above& are required.
6. alculation of Acceptance riteria
a. *btain the surface area for the equipment included in the cleaning validation
protocol.
b. )etermine the smallest manufactured strength or smallest dose administered
parentally of the product under study %A&.
c. *btain a list of all manufactured products which share equipment in common
with the compound under study' list batch si<es, number of dosage units per
batch, solution concentration, and ma/imum daily therapeutic dosage for these
products.
d. )etermine the surface area of equipment shared in common between the active
ingredient under study %A& and each of the other products %=&.
e. 2sing the formulas in Attachment A, calculate the ma/imum amount of active
ingredient%A& which would be permitted in a four %;& square inch swab to ensure
that the ma/imum carryover an active ingredient %A& to the ne/t manufactured
product %=& does not e/ceed the most restrictive of the following criteria:
6& 7ethod 6-A ma/imum of 606>>> of the smallest dose
manufactured0administered appearing in the normal ma/imum daily
therapeutic dose of the ne/t product.
8& 7ethod 8 is available, a ma/imum of the e/posure appearing in the normal
ma/imum daily dose of the ne/t product, the smallest dosage strength made
should be used to establish the acceptance limits for that product line.
:& 7ethod :- A ma/imum of 6> ppm of active ingredient %A& appearing in a
final mi/ture of another product %=&.
;& 7ethod ;- A ma/imum of 6>> micrograms active drug per unit swab area %;
inch squared&' i.e., visibly clean.
a. 7a9e this calculation for all manufactured products which share the equipment
under study with the active compound %A&.
,ote: (n the case of rinse samples, appropriate calculations of active ingredient
in the rinse solvent must be made, in order to compare analytical results to swab
limits.
b. ompare results of above calculations for each product sharing equipment with
the active ingredient under study %A&. The lowest calculated permissible residue
per swab obtained among all products sharing equipment with the compound
under study is to be used as the acceptance criteria %ma/imum permissible level
of active ingredient under study& for the cleaning validation protocol. (f the
lowest level is obtained by method ;, a study must be performed to demonstrate
the 6>> microgram per swab area is visibly clean.
c. 2pon initial construction of a matri/, evaluate all possible combinations of
product interactions %including lot si<e, surface areas and total dose per day& for
determination of lowest acceptance level %worst case& for each possible product
combination. %"ee Attachment = for sample matri/.&
d. "ubsequent additions of new products after establishment of the matri/ require
determination of ?worst case@ acceptance criteria which will be added to the
matri/ previously established acceptance criteria in the matri/ will not be altered
with the addition of a new product to the system.
e. (f an analytical methodology used in a swab assay is not sensitive enough to
validate an acceptance limit, considerations should be made to have dedicated
equipment or reevaluate the acceptance limit.
ATTACHMENT A
11!!! MTHOD
7g of active ingredient %A& permitted per four square inch swab area A
( / B C 7
D 4
-here:
( A %606>>> of smallest strength product A manufactured&0day e/pressed
as mg0day
D A 7a/imum dosage units product = ta9en0day
BA ,umber of dosage units per batch of final mi/ture of product = ta9en0day
4 A Equipment surface area in common to products A and e/pressed in square inches
7 A ; square inches0swab
E,ote: +or parenteral products,
( A 606>>> of smallest dose of product A0day e/pressed as mg0day
D A 7a/imum daily dose of product = %mg0day&0 concentration of product
= %mg0m4&
B A 4ot si<e of product = %m4&.
E"AMPLE
11!!! Met#od
(n this e/ample, product A is represented by :> mg and product = by 8>> mg.
The parameters are found in the attached model matri/ %Attachment =&.
The number of mg of the :> mg strength of allowed per four square inch swab area in relation
606>>> / 6F mg0day 1>>> units ; sq. inches
C C
; dosage units0say %;G>> H :F1>& sq. in. "wab
A >.6>> mg of product A activity0swab
METHOD$%
6. This method is identical to the 606>>> method with the e/ception that if there is a ma/imum
e/posure limit is established for any product A, substitute its implied basic limit for 606>>>
smallest strength manufactured.
7g of active ingredient %A& permitted per four square inch area A
* / P / ! 0 day B
C C
D 4 7
-here:
D A 7a/imum dosage units product = ta9en0day
B A ,umber of dosage units per batch of final mi/ture of product =
4 A Equipment surface area in common to products A and = e/pressed in square
inches
7 A ; square inches0swab
* A the ma/imum e/posure of product A e/pressed as g0m
:
of air
P A 6 mg06>>> g
! A 6F.11 m
:
which is the quantity of air inspired by an operator under moderate
e/ertion during a wor9 shift
E,ote: +or parenteral products,
D A 7a/imum daily dose of product = %mg0day&0concentration of product =
%mg0m4&
B A 4ot si<e of product = %m4&
E"AMPLE
(n this e/ample, product A is represented by :> mg and product = by 8>> mg. The parameters are
found in the attached model matri/ %Attachment =&. The amount of active drug A from formulation
allowed per four square inch swab area in relation to the product = is as follows:
%%68 g0m
:
& C %6 mg 0 6>>g& C %6F.11m
:
&&0day
C
; dosage units0day
1>>> units ; sq. in.
C A >.6: mg Product A activity0swab
%;G>> H :F1>& sq. in. swab
1! PPM METHOD
7g of active ingredient %A& permitted per four square inch swab area A
# C " C 2
T
-here:
# A 6> mg Product A
9g Product =
" A ,umber of 9g per batch of final mi/ture of product =
T A Equipment surface area in common to products A and = e/pressed in square
inches.
2 A ; square inches0swab
E"AMPLE
1! PPM Met#od
(n this e/ample, product A is represented by :> mg and product = by 8>> mg. The parameters are
found in the attached model matri/ %Attachment b&. The amount of active drug from the :> mg
formulation allowed per four square inch swab are in relation to the is as follows:
6> mg :.> 9g ; sq. inches
C C
9g %;G>> H :F1>& sq. in. swab
A >.>6; mg product A activity 0 swab