Professional Documents
Culture Documents
Cleaning Validation –
Manufacture of APIs
AS 22.1
2. Responsibilities
Third Party It is the responsibility of the management of the third party to be in substantial
compliance with this assessment standard and to ensure that manufacturing processes
are validated, and maintained in a validated state.
3. Definitions
None
4. Requirements
Identify Materials
4.3 Equipment and Cleaning
Procedures in Use
,
Perform RA and select
4.3 Criteria to establish worst
Case
Cleaning Validation
Approve Cleaning
4.4 Master Plan
Validation Master Plan
B
Plan Cleaning
C
Material and
Yes Equipment cleaned
Approve Cleaning
4.6
Validation Protocol
Perform Cleaning
according to SOP
Equipment visually
clean?
Yes
Perform
No Closed Equipment? Yes
Rinses
No
Perform Swab
Analyse Samples
Produce Deviation
Report
Requirements for whole
Equip. Chain met?
Review Cleaning
Procedures
Yes
No
Validation Runs
B complete?
No C
Yes
Archive Validation
Documentation
Cleaning Procedures in
place and validated
Version:
Matrix The same may be applied for equipment, i.e. groups of similar or equivalent
Approach equipments can be treated as a matrix and grouped according to risk assessment (same
material, size, complexity, configuration etc.)
The critical parameters that are used to select the products from each group that make
the worst case are (list non exhaustive):
• Lowest solubility in the specified solvent or in the specified detergent
• Complexity (relevance) of plant items used in the process
• Past experience and history of cleaning difficulties
• API
• Oral toxicity as applicable
• Dosage level
It is acceptable to select a range of similar APIs / intermediates or processes concerned
and to justify a validation study, which addresses the worst case regarding the selected
APIs / intermediates and corresponding cleaning procedures.
A single validation study may be carried out which takes account of the relevant
criteria. If a new API / intermediate is brought to a site / building, the risk assessment
for cleaning of the equipment used for this API / intermediate must be re-evaluated. If
the new API / intermediate are shown to be a new worst case, a revalidation must be
performed with it. If the new product is not a worst case, cleaning is only verified
following the normal cleaning SOPs, and no additional validation is required (e.g. 3
successful cleaning using the new product.
Number of Cleaning Runs:
Three predetermined runs of the cleaning procedure must be performed and shown to
be successful in order to prove that the cleaning procedure is validated. Refer to
Section 4.5 for details on what is involved in a cleaning procedure. In the matrix worst
case approach, only one cleaning run for each of three different APIs / intermediates of
the same category (or combination thereof) or three runs utilising the worst case
product of the same category is acceptable.
Dedicated Equipment:
For dedicated equipment cleaning validation may be reduced to the validation of the
removal of detergents / disinfectants and micro biological/endotoxin contamination (if
applicable). According to the result of the risk assessment, cleaning intervals must be
set up in order to prevent building up of residues or decomposed substances.
Detergents and Disinfectants:
It is desirable not to use complex detergents or disinfectants containing surfactants etc.
(i.e. preferably NaOH, H3PO4, H2O2, or other well defined components). If their use
cannot be avoided, only detergents or disinfectants should be used for which the
composition is known. If such information is not available, an alternative should be
selected. A procedure should be established to get information about critical changes in
the formulation of the detergent or disinfectant from the manufacturer. The removal of
detergents / disinfectants should be considered in the cleaning validation. In such case,
methods detecting single elements shown to be the worst case (e.g. phosphate) may be
applied.
Micro biological Contamination:
Micro biological contamination is possible if the last cleaning step is performed with
water or mixtures of organic solvents with water. For equipment which is cleaned by
refluxing organic solvents the risk of relevant contamination is minimal.
Dedicated • Dedicated equipment must be visually clean and must meet the microbiological
Equipme requirements (if applicable).
nt • The contamination by highly toxic (allergenic, cytostatic, hormone, mutagenic or
teratogenic properties) compounds in the following compound must be no more
than 10 ppm .
• The minimum therapeutic dose should be estimated for development substances
that are not yet fully characterized regarding their potency.
• Additional assumptions are to be considered for the calculation of the limits:
the entire residue (worst contamination found calculated for total surface area of
equipment module) of the previous product in the processing equipment will
contaminate one batch of the following product (worst case assumption). The
acceptable contamination at each product changeover should be calculated on the
basis of batch size of the following product, or on the basis of the minimum batch
size manufactured on the respective equipment. The complete calculation, with all
the assumptions made, must be documented.
• The minimum therapeutic dose (lowest single dose produced) and the unit dose
(highest single dose produced e.g. In case if there are three strengths, e.g., 10mg,
20mg & 30mg Tablets, “single dose” means 30mg) are required for the
calculation of cleaning limits.
• Carry-over of detergents/disinfectants must be no more than 10 ppm within the
next batch of API manufactured in the equipment. A limit of 100 ppm is accepted
if supported by respective safety data of the detergent/disinfectant (e.g. Acute
Toxicity).
Cleaning The cleaning procedure must be prepared and approved by Production and QA ,
Procedure before starting the validation study. These may be updated as a result of the cleaning
validation.
Personnel Personnel involved in the validation of a cleaning procedure must be trained for
N4.1 cleaning requirements and cleaning validation requirements. Training records must be
available on any training received.
Analytical Any analytical procedures used in the validation study must be validated. The
Procedure analytical procedures must be challenged in combination with the sampling methods
N15.3
used in order to show that the contaminants can be recovered from the equipment
surface and to show the level of recovery as well as the consistency of recovery. This is
necessary before any conclusions can be drawn based on the analysis of the samples.
Method Recovery rates should be established for samples of the concerned API / intermediate.
Challenge The recovery rate from the concerned equipment materials (e.g. stainless steel, glass,
Teflon, plastics) which have contact with the API / intermediate or detergent /
disinfectant should be determined. The recovery tests may be conducted with material
plates, not on the equipment itself. Grouping may be applied based on risk assessment.
The recovery rate from the material plate should exceed 50 %. Otherwise the sampling
procedure and/or the swab material / rinse solution should be optimised. If it is not
possible to reach higher recovery values than 50 % the use of the sampling procedure
has to be explained in the validation protocol or report, or the method must be
replaced
All recovery tests should be conducted in triplicate at least. The lowest recovery is used
as correction factor when calculating the contamination (i.e., if the swab sampling is
found to recover 50%, the correction factor for the actual equipment swab samples
would be 2).
Intervals The intervals between production and cleaning and between cleaning and use should
be considered to ensure that the validation study covers the worst case occurring for
the respective equipment / facilities.
Documents for cleaning validation e.g. cleaning validation master plan, site cleaning
policy, equipment cleaning procedures must be available and approved prior to
conducting cleaning validation activities.
All cleaning procedures which are applied to a specific process, product, system or an
item of equipment must be described and evaluated. Any decision to validate must be
based on a thorough risk analysis, and the decision must be taken by Quality
Assurance and Production.
ingredients, in non dedicated plants, a selective method should be used (i.e., HPLC,
GC, CE) while measurement of the cleaning agent may utilise either a selective method
or a non selective method (for example TOC). The sensitivity of the analytical
procedures must assure that the limit of quantification is suitable to meet the
acceptance criteria for the train of equipment.
Key Acceptance / Rejection Criteria
Acceptance
criteria The acceptance criteria together with their limits for the concerned equipment and API
/ intermediate, the detergent / disinfectant, and the microbiological/endotoxin
contamination (if applicable) should be determined based on the requirements stated in
this module. All processes must be validated to visibly clean status.
should be stated on the basis of experience of the cleaning runs performed during the
validation. Criteria for re-validation should be specified. This report must be approved
by Quality assurance and the VMP amended accordingly.
4.8 Re-Validation
Purpose
To maintain the validation status of a cleaning procedure despite planned changes to
the cleaning procedure, the equipment / facilities or the APIs / intermediates may need
revalidation.
Description
There are two types of re-validation, periodic routine evaluation of validation status
and re-validation if necessary and re-validation due to a change or due to observations
in the annual product review. The kind of re-validation considered should be stated
and the reason for it. Periodic routine evaluation of validation status is performed by
on-going monitoring or analysis of samples following each cleaning after either a
defined time or a defined number of production campaigns. The degree of re-
validation due to a change or an observation in the annual product review should be
based on the risk assessment of the change / observation regarding the quality
characteristics.
Variables to be monitored
Re-validation may not need to cover all variables monitored in the initial validation
study, depending on the results of the risk-assessment. Evaluation of the influence of
the change observed on the cleaning efficiency determines what variables require
monitoring. The validation documentation for re-validation is to be established in the
same way as for the initial validation. The variables/systems not considered in the re-
validation should be stated together with the reason for not monitoring them.
5. Change Control
Changes to any aspect of the above described process must be authorised through a
formal change control procedure. This should include also quality and regulatory
issues.
Changes that may have an influence on the API / intermediate quality could be for
example:
• Changes of the cleaning procedure
• Changes of the equipment contact surface (material, geometry, size)
• Addition/removal of equipment
• Change of batch size
• Changes of the APIs / intermediates processed on the equipment
As a result of a request for such a change re-validation may be necessary before
the change is implemented.
7. Annexes
None