In developing the sampling plan for a validation study, it makes scientific sense
to
incorporate an understanding of the acceptance criteria and the limitations of the
sampling method relative to the surface to be sampled.
The two methods of sampling generally employed are swab and / or rinse
sampling. (If neither or these methods is shown be a scientifically sound method
for testing in a specific instance then an alternative is to consider testing the next
product.)
The selection of either of these techniques must be consistent with sound
scientific judgment and must support the objective of the study, which is to
demonstrate that the amount of residual material in the equipment has been
reduced to acceptable levels.
Each method is described in brief below.
1. SWAB:
· Swab sampling does not cover the entire equipment surface area therefore
sites must be chosen with care. It is important that, as a minimum, the
swab sites represent worst case locations on the equipment and that the
result is then extrapolated to account for the total product contact surface
area. This calculation makes it possible to make a worst case determination
of potential carryover into subsequent product.
· Due to the nature of this method which employs physical forces as well as
chemical forces it may be necessary to perform sampling technique
evaluation.
· Swabbing efficiency (% recovery) for the swabbing method must be
determined.
· It is necessary to ensure that extractables of the swab do not interfere with
the sampling method.
· Using this technique it is possible to sample insoluble residues due to the
physical action associated it.
2. RINSE:
· The solvent rinse occurs after cleaning has been completed
· This method is not as direct as swabbing but will cover the entire surface
area (and parts inaccessible to swabs)
· It is important to ensure chosen solvent has appropriate recovery for
residues being quantified
· This method allows much greater ease of sampling than swabbing
· A reduced no of samples are required to generate a carryover figure.
(Other sampling methods which may be employed in addition to swab / rinse
sampling during a validation may include: placebo sampling, testing subsequent
batches for residues, use of coupons (test pieces), etc. )
Tuesday, December 8, 2009
Cleaning procedures
Written cleaning procedures for each piece of equipment and process1 must be
prepared. It is vital that the equipment design is evaluated in detail in
conjunction with the product residues to be removed, the available cleaning
agents and cleaning techniques when determining the optimum cleaning
procedure for the equipment.
Cleaning procedures should be sufficiently detailed to remove the possibility of
any inconsistencies during the cleaning process.
A. Equipment parameters to be evaluated
· Identification of the equipment to be cleaned
· Difficult to clean areas
· Property of materials
· Ease of disassembly
· Fixed or not
· Etc.
B. Residues to be cleaned
· Cleaning limits
· Solubility's of the residues
· Length of campaigns
· Etc.
C. Cleaning agent parameters to be evaluated
· Preferably materials that are normally used in the process
· Detergents available (as a general guide, minimize use of detergents unless
absolutely required)
· Solubility properties
· Environmental considerations.
· Health and safety considerations
· Etc.
D. Cleaning techniques to be evaluated
· Manual cleaning
· CIP (Clean-in place)
· COP (clean-out-of-place)
· Semi automatic
· Automatic
· Time considerations
· Number of cleaning cycles
· Etc.
E. Other requirements
Procedures must be determined to be operator independent i.e. rugged and
reproducible, during the validation studies.
The Cleaning documentation should include the following items in order to ensure that
it can be followed reproducibly and maintained subsequent to Validation.
· Detailed definition of levels of cleaning to be performed.
· Detailed description of cleaning methods.
· The necessity to inspect and verify equipment cleanliness prior to manufacture of
next batch should be stated in the SOP and recorded on the batch record.
· The SOP should detail where verification of cycle parameters (if automated) and
checklists (for complex manual procedures) is necessary.
· Where microbial contamination may be an issue, consideration should be given to
the integrity of the vessel prior to manufacture.
Written cleaning procedures may also include additional items not specified above,
these would include, as an example, the steps needed to protect the equipment from
contamination after cleaning.
prepared. It is vital that the equipment design is evaluated in detail in
conjunction with the product residues to be removed, the available cleaning
agents and cleaning techniques when determining the optimum cleaning
procedure for the equipment.
Cleaning procedures should be sufficiently detailed to remove the possibility of
any inconsistencies during the cleaning process.
A. Equipment parameters to be evaluated
· Identification of the equipment to be cleaned
· Difficult to clean areas
· Property of materials
· Ease of disassembly
· Fixed or not
· Etc.
B. Residues to be cleaned
· Cleaning limits
· Solubility's of the residues
· Length of campaigns
· Etc.
C. Cleaning agent parameters to be evaluated
· Preferably materials that are normally used in the process
· Detergents available (as a general guide, minimize use of detergents unless
absolutely required)
· Solubility properties
· Environmental considerations.
· Health and safety considerations
· Etc.
D. Cleaning techniques to be evaluated
· Manual cleaning
· CIP (Clean-in place)
· COP (clean-out-of-place)
· Semi automatic
· Automatic
· Time considerations
· Number of cleaning cycles
· Etc.
E. Other requirements
Procedures must be determined to be operator independent i.e. rugged and
reproducible, during the validation studies.
The Cleaning documentation should include the following items in order to ensure that
it can be followed reproducibly and maintained subsequent to Validation.
· Detailed definition of levels of cleaning to be performed.
· Detailed description of cleaning methods.
· The necessity to inspect and verify equipment cleanliness prior to manufacture of
next batch should be stated in the SOP and recorded on the batch record.
· The SOP should detail where verification of cycle parameters (if automated) and
checklists (for complex manual procedures) is necessary.
· Where microbial contamination may be an issue, consideration should be given to
the integrity of the vessel prior to manufacture.
Written cleaning procedures may also include additional items not specified above,
these would include, as an example, the steps needed to protect the equipment from
contamination after cleaning.
Establishment of acceptance criteria
The Cleaning Validation should demonstrate that the procedure consistently
removes residues of the substance previously manufactured down to levels that
are acceptable and that the cleaning procedure itself does not contribute
unacceptable levels of residual materials to the equipment. The limits set
should be practical, achievable and justifiable.
In Active Pharmaceutical Ingredient manufacture there may be partial reactants
and unwanted by-products which may not have been chemically identified.
Therefore, it may be necessary to focus on by-products as well as the principle
reactant. Companies should decide on which residue(s) to quantify based on
sound scientific rational.
Chemical determination
It is generally the residual Active Pharmaceutical Ingredient or intermediate,
which is of greatest concern rather than reaction side products or residual
impurities.
There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested )
Note FDA Statement on 0.1% impurities
Guide to Cleaning Validation in API plants
FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise,
June 98: „...we have found that some firms have incorrectly applied as
their acceptance limit the 0.1% impurity identification threshold as
discussed in both the ICH impurity guideline and the U.S.P. General
Notices. This application of the 0.1% impurity threshold is
inappropriate because the limit is intended for qualifying impurities that
are associated with the manufacturing process of related compound and
not extraneous impurities caused by cross contamination. ...“ ) may be
used depending on the stage of the process.
It is also necessary to evaluate the ability of the cleaning procedure to
remove any cleaning agents introduced. The acceptance criteria for the
residual-cleaning agents should reflect the absence of these materials,
within the range of the capabilities of the assay and sampling methods.
The individual company must decide on the Acceptance Criteria which
are justifiable for their particular situation.
Physical determination
There should be provision during routine cleaning for a visual examination of
the equipment, verifying that it is free of visible residues. The validation
protocol should include this requirement as an acceptance criteria. During
validation, special attention should be given to areas that are ‘hard to clean’
(e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would
be difficult to verify on a routine basis.
Microbiological determination
Appropriate studies should be performed (e.g. swabs and/or rinse sampling)
where the possibility of microbial contamination of subsequent product is
deemed possible and presents a product quality risk.
removes residues of the substance previously manufactured down to levels that
are acceptable and that the cleaning procedure itself does not contribute
unacceptable levels of residual materials to the equipment. The limits set
should be practical, achievable and justifiable.
In Active Pharmaceutical Ingredient manufacture there may be partial reactants
and unwanted by-products which may not have been chemically identified.
Therefore, it may be necessary to focus on by-products as well as the principle
reactant. Companies should decide on which residue(s) to quantify based on
sound scientific rational.
Chemical determination
It is generally the residual Active Pharmaceutical Ingredient or intermediate,
which is of greatest concern rather than reaction side products or residual
impurities.
There are a number of options available when determining acceptance criteria.
Where either toxicological or therapeutic data if available then calculation A or
B is preferable. If data is not available for either of these calculations or if the
result is more stringent calculation C should be used.
A. Limiting the level based on toxicity data.
An Acceptable Daily Intake (ADI) is calculated with suitable safety
factors applied and this is converted to the maximum allowable
carryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in each piece
of equipment, such that no greater than 1/1000 of the normal
therapeutic dose will be present per typical dose of the next product to
be run in the equipment. The validation protocol should include a
calculation, which ties this philosophy to the acceptance criteria for the
samples to be tested.
C. Limiting the level of product which could appear in the following
products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5% total
unknowns material may be present in the product being tested )
Note FDA Statement on 0.1% impurities
Guide to Cleaning Validation in API plants
FDA statement: P. Alcock, in Human Drug cGMP Notes, P. Motise,
June 98: „...we have found that some firms have incorrectly applied as
their acceptance limit the 0.1% impurity identification threshold as
discussed in both the ICH impurity guideline and the U.S.P. General
Notices. This application of the 0.1% impurity threshold is
inappropriate because the limit is intended for qualifying impurities that
are associated with the manufacturing process of related compound and
not extraneous impurities caused by cross contamination. ...“ ) may be
used depending on the stage of the process.
It is also necessary to evaluate the ability of the cleaning procedure to
remove any cleaning agents introduced. The acceptance criteria for the
residual-cleaning agents should reflect the absence of these materials,
within the range of the capabilities of the assay and sampling methods.
The individual company must decide on the Acceptance Criteria which
are justifiable for their particular situation.
Physical determination
There should be provision during routine cleaning for a visual examination of
the equipment, verifying that it is free of visible residues. The validation
protocol should include this requirement as an acceptance criteria. During
validation, special attention should be given to areas that are ‘hard to clean’
(e.g. agitator shafts, thermowells, discharge valves etc.) and areas that would
be difficult to verify on a routine basis.
Microbiological determination
Appropriate studies should be performed (e.g. swabs and/or rinse sampling)
where the possibility of microbial contamination of subsequent product is
deemed possible and presents a product quality risk.
Elements of cleaning validation
A brief outline of the various elements of a basic cleaning validation study is given
below .
This is followed by a more detailed view of the individual elements in this section.
I. Establishment of acceptance criteria
II. Cleaning procedure
· Identification of the equipment
· characterization of the products (Previous: activity/toxicity,
solubility, subsequent: dosage, lot size)
· determination and characterization of the cleaning agents
III. Analytical method and its validation
IV. Sampling Procedure and necessary validation of same
V. Validation protocol
VI. Validation report
below .
This is followed by a more detailed view of the individual elements in this section.
I. Establishment of acceptance criteria
II. Cleaning procedure
· Identification of the equipment
· characterization of the products (Previous: activity/toxicity,
solubility, subsequent: dosage, lot size)
· determination and characterization of the cleaning agents
III. Analytical method and its validation
IV. Sampling Procedure and necessary validation of same
V. Validation protocol
VI. Validation report
Cleaning validation Potential residues
The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of
Active Pharmaceutical Ingredients by both chemical and physical means through a
series of multiple step processes. Plants or individual pieces of equipment, including
ancillary equipment, may be used in multi-product manufacture or dedicated to
individual products.
The result of inadequate cleaning procedures is that any of a number of contaminants
may be present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient
2. By-products and/or degradation products of the Active Pharmaceutical
Ingredient
3. The previous product
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms
This is particularly the case where microbial growth may be sustained by the
product.
6. Cleaning agents themselves and lubricants
Active Pharmaceutical Ingredients by both chemical and physical means through a
series of multiple step processes. Plants or individual pieces of equipment, including
ancillary equipment, may be used in multi-product manufacture or dedicated to
individual products.
The result of inadequate cleaning procedures is that any of a number of contaminants
may be present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient
2. By-products and/or degradation products of the Active Pharmaceutical
Ingredient
3. The previous product
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms
This is particularly the case where microbial growth may be sustained by the
product.
6. Cleaning agents themselves and lubricants
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