GMP Assessment Standards for Third Parties

Cleaning Validation
Manufacture of APIs
AS 22.1
1.

Purpose and Scope

This module describes the strategy and basic requirements for validation of cleaning
procedures in the manufacture of APIs and intermediates in order to avoid chemical
and microbiological contamination.
The preparation of a cleaning validation master plan, a worst case concept and matrix
approach are included, together with acceptance criteria, minimum number of cleaning
runs, preparation of validation protocols and report are also described.

2.
Third Party

Responsibilities

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

4.1

Process Summary

Date of Issue: March, 2007 Edition 01 GQO Policy&Communication

GMP Assessment Standards for Third Parties

Chapter

Process Flowchart (1)

4.3

Identify Materials
Equipment and Cleaning
Procedures in Use

4.3

Perform RA and select

Criteria to establish worst
Case

4.4

Issue Cleaning Validation

Master Plan

4.4

Approve Cleaning
Validation Master Plan

Resp.

Ref.

B
C

Cleaning Validation
Master Plan

Plan Cleaning

Validation
required?

Yes

4.6

Issue Cleaning Validation

Protocol

4.6

Approve Cleaning
Validation Protocol

No

Perform Cleaning
according to SOP

Material and
Equipment cleaned

Cleaning Validation
Protocol

Perform Cleaning
according to SOP

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

2.15

GMP Assessment Standards for Third Parties

Process Flowchart (2)

Chapter

Resp.

Ref.

Equipment visually
clean?
Yes

Closed Equipment?

No

Yes

Perform
Rinses

No

No

Perform Swab

Analyse Samples

Produce Deviation
Report
Requirements for whole
Equip. Chain met?

Review Cleaning
Procedures

Yes
No

Validation Runs
complete?
Yes

4.7

Issue Cleaning Validation

Report

4.7

Approve Cleaning
Validation Report

Cleaning
Validation Report

Archive Validation
Documentation

Cleaning Procedures in
place and validated

Version:

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

3.15

GMP Assessment Standards for Third Parties

4.2

General Requirements

To enable validation, the following documents are to be established and approved in

the following order:
N10.5

Validation Master Plan

Validation Protocol
Validation Report

Changes can influence the validation status. To control these changes, change control
procedures must be in place. Revalidation may be necessary, if a new worst case is
introduced or the cleaning procedure is changed.
4.3
Risk
Assessment

Cleaning Validation Strategy (Risk Assessment)

Reference is to be given to the validation strategies in the respective local validation

policies. A risk assessment is necessary to determine the level of validation for each
cleaning procedure. The criteria to be considered in the risk assessment are:
Solubility of APIs and intermediates
Dosage levels / toxicity / potency
Equipment design and construction (including direct/indirect surface contact
area to product)
Dedicated/non-dedicated equipment
Critical equipment parts
Adsorption to surface material of the equipment
Non-sterile/sterile special consideration of microbiological, endotoxin and
particulate risks
Location of step within overall process
Manufacturing campaigns
Batch size and possible changeovers
Processing time scales
Cleaning intervals
Idle time and idle conditions
Safety risk for the patient
Number of products covered by the respective cleaning procedure
First versus re-validation
The cleaning validation risk assessment will also identify any APIs that are considered
to be a beta-lactam penicillin, steroid, and cephalosporin, oncological, Ames positive,
mutagenic or allergenic in nature. Cleaning procedures for equipment on which very
similar APIs / intermediates and processes are handled, may not need to be individually
validated. Following the risk assessment worst case situations are to be identified and a
matrix approach with groups of products may be selected for the validation. In the
matrix approach, either 3 elements of the same group are tested once or the worst case
of the group is tested 3 times.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

4.15

GMP Assessment Standards for Third Parties

Matrix
Approach

The same may be applied for equipment, i.e. groups of similar or equivalent
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
Cleaning Validation Manufacture of APIs
Date of Issue: March, 2007 Edition 01

5.15

GMP Assessment Standards for Third Parties

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.
4.4

Issue and Approval of the Cleaning Validation Master Plan

A Cleaning Validation Master Plan must be prepared, authorized and approved by

Quality Assurance and management of the areas involved, showing the extent of the
validation programme.
Training

The need for training, particularly for new processes or e.g. manual cleaning steps
must be assessed and executed.
4.4.1

Organizational Structure of all Cleaning Validation Activities

The documentation of all cleaning validation activities comprises of or is contained in

the validation master plan, the validation protocol, the validation report, outlining the
validation strategy, the validation process, the cleaning procedures, key acceptance
criteria, sampling methods, the change control procedures applied and the approval
procedures.
4.4.2

Cleaning Procedures

There are three types of cleaning procedures as follows:

Manual Cleaning
This is performed manually by an operator using specified cleaning material which
might include high pressure jetting. It is equipment specific and therefore equipment
such as dryers, solids discharge equipment, solids charging equipment and bulk binds
will have different cleaning procedures. Manual cleaning practices are subject to
operator variability and therefore should only be performed by properly trained
operators.
Clean Out of Place (COP)
This involves disassembling process equipment and cleaning using manual methods or
recirculation washers.
Clean In Place (CIP)
This is typically a procedure in which the process equipment is cleaned without
disassembly by circulation or refluxing of cleaning solutions along the process flow
path. The procedure is not generally equipment specific (an exception would be a short
path still or bulk storage tank) but depends on the manufacturing process.
The CIP procedure employed may involve manual cleaning (if applicable), preliminary
cleaning, main cleaning and final rinse, also called analytical cleaning if samples are
taken for routine analysis. A pre-use rinse may be used after the CIP procedure is
completed in case it is not included in the normal CIP sequence after the plant is reconfigured for a new product. The definitions for these types of cleaning methods are
given below.
Cleaning Validation Manufacture of APIs
Date of Issue: March, 2007 Edition 01

6.15

GMP Assessment Standards for Third Parties

Post Campaign Flush:

Initial installation cleaning after the end of a campaign in case longer holding times
occur before the next one using a defined solvent mixture and/or acid or alkaline
solutions. Alternatively a standard CIP cycle may be applied between campaigns.
Pre-Use Rinse:
A solvent wash used to rinse out the plant immediately before the start of a new
product campaign using the solvent of the new process
Cleaning Sequence
Preliminary Cleaning:
The preliminary cleaning is performed using designated solvents, solvent mixtures, acid
or alkaline solutions.
This can be achieved using a defined series of cleaning runs or manual cleaning with
brushes or high pressure jetting and steam or to clean until visually clean or to clean to
a specific limit.
Main Cleaning:
The final rinse is done with an adequate solvent and there must be a system in place to
demonstrate that the plant is acceptably clean. A sample of the last rinse (sometimes
called Analytical Cleaning) is analysed and based on a satisfactory analysis the
equipment is released for further use.
4.4.3

Sampling Methods

Rinse Samples

Rinse samples are used for closed equipment or difficult to access equipment.
Wherever possible the entire equipment train or equipment module is boiled out with
an appropriate solvent. Equipment that cannot be heated is rinsed through with the
same solvent, preferably hot.

Swab Samples

Where solvent rinsing is not possible direct surface sampling with swabs is used based
on a risk assessment. If various areas of specific equipment are swabbed then the
highest residue is used to calculate the contamination. These individual equipment
results are combined with the rinse samples to give the residual contamination left in
the entire plant.
For cleaning validation studies swabbing of solvent rinsed equipment is carried out
where possible, to confirm the validity of rinse samples.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

7.15

GMP Assessment Standards for Third Parties

4.4.4

Key Acceptance Criteria

The acceptance criteria for the cleaning procedures are to be defined before performing
the cleaning validation. Criteria will include the acceptable amounts of chemical (APIs,
intermediates, detergents, disinfectants) and micro biological (microbial and biological)
contaminants.
Cleaning Limits
The limits of these contaminants are:
Primarily the equipment must be visually clean. If not a deviation report must be
issued and follow up action decided.
Final API Purification
The last step in the API purification process is defined as being immediately after the
isolation equipment used to separate the crystalline product from its crystallisation
mother liquors or appropriate purification procedures. This is immediately after the
final centrifuge, nutsche or nutsche dryer.
Dedicated
Equipme
nt

Dedicated equipment must be visually clean and must meet the microbiological
requirements (if applicable).
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 Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

8.15

GMP Assessment Standards for Third Parties

In addition to visually clean, the following criteria must be applied:

After Final Purification
API to API Dryer/Mill/Blender
For carry-over of API residues in drying, blending, milling equipment and further
equipment used after the last purification step (e.g. freeze dryers) in an API to API
sequence processed in multipurpose equipment, one of the two following criteria
applies based on the risk assessment:
- Not more than 1/1000 (0.1%) of it's minimal therapeutic dose in the single dose of
the following API
- Not more than 20 ppm contamination by an API in the following API. This limit is
derived from the 10 ppm limit being valid for drug products and considers the mixing
of APIs with considerable amounts of other ingredients during pharmaceutical
processing.
Intermediate to API Dryer/Mill/Blender
The following criteria applies for carry-over of intermediate residues in drying,
blending, milling equipment and further equipment used after the last purification step
(e.g. freeze dryers) in an intermediate to API sequence processed in multipurpose
equipment:
The contamination by an intermediate in the following API must not be more than 20
ppm. This limit is derived from the 10 ppm limit being valid for drug products and
considers the mixing of APIs with considerable amounts of other ingredients during
pharmaceutical processing.
Prior to Final Purification
For carry-over of API residues in an API to API sequence processed in multipurpose
equipment, one of the two following criteria applies based on the risk assessment:
- Not more than 1/1000 (0.1%) of it's minimal therapeutic dose in the single dose of
the following API
-Not more than 1000 ppm contamination by an API in the following.
Intermediate to Intermediate
The following criteria applies for carry-over of Intermediate residues processed in
multipurpose equipment in an Intermediate to Intermediate sequence prior to the
last purification step:
The contamination by an intermediate in the following intermediate must be no more
than 1000 ppm.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

9.15

GMP Assessment Standards for Third Parties

Intermediate to API NOT Dryer/Mill/Blender

The following criteria applies for carry-over of Intermediate residues processed in
multipurpose equipment in an Intermediate to API sequence prior to the last
purification step:
The contamination by an Intermediate in the following API must be no more than
1000 ppm.
API to Intermediate
The following criteria applies for carry-over of API residues processed in multipurpose
equipment in an API to Intermediate sequence prior to the last purification step:
The contamination by an API in the following Intermediate must be no more than
1000 ppm.
Intermediate to Intermediate - Same API
The following criteria applies for carry-over of intermediate residues processed in
multipurpose equipment in an Intermediate to Intermediate sequence of the same API:
The contamination by an intermediate in the following intermediate of the same API
must be no more than the carry over by the process itself. The equipment must be
visually clean.
Microbiological
Contamination

Microbiological and endotoxin (as applicable) contamination of the API by the

equipment must be prevented. Also, the time between cleaning and equipment re-use
must be considered in the cleaning validation procedure. The limits for the
microbiological and endotoxin contamination of equipment surfaces in contact with
APIs must be in accordance with the existing module Cleanliness Zoning in the
Manufacture of APIs (Non-sterile/sterile).
Where open handling of product occurs, the surrounding areas (floors and walls) must
be "visibly clean" of the API /intermediate and detergent / disinfectant. It may be
necessary to do an initial evaluation of the floors and walls to show that they are in
fact clean following the cleaning procedure.
4.5

The Cleaning Validation Process

Several requirements must be met before the validation of a cleaning procedure is

started.
Equipment

Equipment must be qualified, computerized systems used for CIP / COP must be
validated and qualification / validation documentation approved. The design of the
concerned equipment must be fully established, especially the contact surface area and
its material must be known. The equipment / facilities concerned must be examined
carefully with respect to the contact surface area. The areas hardest to clean must be
identified. The total contact surface area must be known before performing the
validation.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

10.15

GMP Assessment Standards for Third Parties

Cleaning
Procedure

The cleaning procedure must be prepared and approved by Production and QA ,

before starting the validation study. These may be updated as a result of the cleaning
validation.

Personnel
N4.1

Personnel involved in the validation of a cleaning procedure must be trained for

cleaning requirements and cleaning validation requirements. Training records must be
available on any training received.

Analytical
Procedure
N15.3

Any analytical procedures used in the validation study must be validated. The
analytical procedures must be challenged in combination with the sampling methods
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
Challenge

Recovery rates should be established for samples of the concerned API / intermediate.
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.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

11.15

GMP Assessment Standards for Third Parties

4.6

Cleaning Validation Protocol

A validation protocol must be available prior to conducting the validation study and
must be authorized by Production and QA. The cleaning validation protocol must
cover the following topics:

Scope

A detailed description of how the validation of a specific cleaning procedure will

be performed.
A list of cleaning procedures, sampling plans, reference to the analytical methods
to be used
The risk assessment of the critical cleaning parameters for each cleaning method
or the reference to the separate document (as necessary)
Acceptance criteria and calculation formula of the equipment cleaning being
validated
The timelines and date when the study will be performed and completed and
when the report will be available
The calculations to be used to determine the contamination
The equipment and APIs / intermediates concerned are identified.
Responsible for execution, review, approval and documentation are stated.

Scope of the Validation

Three runs of the cleaning procedure must be performed and shown to be

successful.
The critical steps of the respective cleaning procedure (the critical parts of the
equipment regarding cleaning, and the worst case are determined, APIs /
intermediates based on their solubility, toxicity, dose, and production volume)
are identified by a risk assessment.
The interval between the last production run and cleaning of the equipment, the
campaign length and the idle time of the equipment between cleaning and use in
production needs to be considered in the risk assessment
The validation study described must be rationalised with the findings of the risk
assessment. The validity of the results of this validation study for other
equipment and APIs / intermediates is to be stated.

Sampling Procedures
The sampling must follow a rationalised plan to fully characterise the cleaning process
for validation purposes. The sampling procedures used (i.e. rinsing and / or direct
surface sampling by swabbing) should be determined based on their suitability,
considering the accessibility of the equipment contact surface area and the solubility of
the contaminant in the rinse solution. For cleaning validation studies, swabbing should
be carried out on all major items of equipment after they have been boiled or rinsed
out with solvent, e.g. reactors, filters, and dryers. These swab results are to
demonstrate that the equipment is acceptably clean and confirm the validity of the
rinse sample results.
Analytical / Microbiological Procedures
Reference to the analytical / microbiological/endotoxin procedures used for analyzing
API / intermediate, detergent / disinfectant, and microbiological contamination are to
be given together with their validation status. For the measurement of active
Cleaning Validation Manufacture of APIs
Date of Issue: March, 2007 Edition 01

12.15

GMP Assessment Standards for Third Parties

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
criteria

Acceptance / Rejection 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.
4.7

Cleaning Validation Report

Validation activities can be considered functionally complete when all raw data has
been generated, reviewed and found acceptable. This determination is to be
documented in the cleaning validation report. The cleaning validation report is to
cover the following topics:
Documentation of validation activities performed. It presents all pertinent findings and
conclusions, especially the validation status. Any deviation from the protocol or from
the acceptance criteria is to be described and rationalised, and consequence on
validation stated.
Description of Tests carried out / Expected Results
Reference to the respective validation protocol should be given, and the acceptance
criteria together with their limits are to be stated.
Detailed Summary of Results
The result of all tests is to be summarized for all contaminants considered including the
results of failed tests. The reference to all raw data must be provided.
Additional Tests / Deviations
All deviations and changes that occurred during the validation must be reviewed and
approved. Deviations in the analytical laboratory (out-of-specification (OOS) test)
must be subject to investigations according to applicable SOPs.
Review / Comparison of Results
The obtained results must be reviewed in regard to validation ranges of critical
cleaning parameters and acceptance criteria. The results should be compared with the
expected values. The outcome of the investigation performed for any deviation or
analytical OOS results must be reviewed, the effects on the product quality must be
discussed and the appropriate conclusions drawn.
Acceptance / Rejection Decision
The acceptance / rejection decision is to be stated after all activities are completed,
including any corrective actions and repetitions.
Conclusion / Recommendations
Recommendations for the extent of routine testing after cleaning, interval between
production and cleaning, interval between cleaning and use, and campaign length
Cleaning Validation Manufacture of APIs
Date of Issue: March, 2007 Edition 01

13.15

GMP Assessment Standards for Third Parties

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 revalidation 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 revalidation 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.

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

14.15

GMP Assessment Standards for Third Parties

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.

6.

Changes from Last Edition

This is a new Assessment Standard.

7.

Annexes

None

Cleaning Validation Manufacture of APIs

Date of Issue: March, 2007 Edition 01

15.15