AS22[1].1-01%20Cleaning%20Validation_APIs

2024年1月26日发(作者：)

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.

4.1

Requirements

Process Summary

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

GMP Assessment Standards for Third Parties

ChapterProcess Flowchart (1) .4.3Identify MaterialsEquipment and CleaningProcedures in Use4.3Perform RA and select

Criteria to establish worst

Case,

4.4Issue Cleaning Validation

Master Plan4.4Approve Cleaning

Validation Master PlanCleaning Validation

Master PlanBCPlan CleaningValidation

required?NoPerform Cleaning

according to SOPYesMaterial and

Equipment cleaned4.6Issue Cleaning Validation

ProtocolCleaning Validation

Protocol4.6Approve Cleaning

Validation ProtocolPerform Cleaning

according to SOPA

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ChapterProcess Flowchart (2)ment visually

clean?YesNoClosed Equipment?YesPerform

RinsesNoPerform SwabAnalyse SamplesProduce Deviation

ReportRequirements for whole

Equip. Chain met?Review Cleaning

ProceduresNoYesBValidation Runs

complete?YesNoC4.7Issue Cleaning Validation

Report4.7Approve Cleaning

Validation ReportCleaning

Validation ReportArchive Validation

DocumentationCleaning Procedures in

place and validatedVersion:

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N10.5

4.2 General Requirements

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

the following order:

•

•

•

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 Cleaning Validation Strategy (Risk Assessment)

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.

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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 inthe formulation of the detergent or disinfectant from the manufacturer. The removal ofdetergents / 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

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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.

The need for training, particularly for new processes manual cleaning steps

must be assessed and executed.

4.4.1 Organizational Structure of all Cleaning Validation Activities

Training

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 re-configured for a new product. The definitions for these types of cleaning methods are

given below.

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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, acidor 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

Rinse Samples

Sampling Methods

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.

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.

Swab Samples

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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.

Dedicated

Equipment

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 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 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).

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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 inmultipurpose 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.

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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

Equipment

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

started.

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.

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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 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.

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.

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).

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 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.

Personnel

N4.1

Analytical

Procedure

N15.3

Method

Challenge

Intervals

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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:

•

•

•

•

•

•

•

•

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.

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.

Scope

Scope of the Validation

•

•

•

•

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

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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 theresults 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

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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.

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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

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