A validation report is necessary to present the results and conclusions and
secure approval of the study. The report should include the following:
· Summary of or reference to the procedures used to clean, sample and test
· Physical and analytical test results or references for same, as well as any
pertinent observations
· Conclusions regarding the acceptability of the results, and the status of
the procedure(s) being validated
· Any recommendations based on the results or relevant information
obtained during the study including revalidation practices if applicable.
· Approval of conclusions
· Review any deviations for the protocol that occurred.
· In cases where it is unlikely that further batches of the product will be
manufactured for a period of time it is advisable to generate interim
reports on a batch by batch basis until such time as the cleaning validation
study has been completed. (Typically, in Active Pharmaceutical
Ingredient Pharmaceutical manufacture, verification is deemed
appropriate during development of the cleaning methods. Where
products are manufactured infrequently, verification may be applied over
a period of time until all measuring data has been collected for the
Validation Report.)
· The report should conclude an appropriate level of verification
subsequent to validation.
Tuesday, December 8, 2009
Validation protocols Cleaning
A Validation Protocol is necessary to define the specific items and activities
that will constitute a cleaning validation study. It is advisable for companies to
have drawn up a Master Validation plan indicating the overall Cleaning
Validation strategy for either the product range / equipment type / entire site.
The protocol must be prepared prior to the initiation of the study and must
either include or reference the documentation required to provide the following
information:
· The objective of the study:
What cleaning process is to be validated (indicating the product to be
removed and the equipment from which it is to be removed)?
If this study is to be employed to demonstrate the acceptability of the
cleaning procedure for a group of products the rational for doing so
should also be detailed here.
The cleaning procedure(s) to be validated should be identified i.e.
cleaning agents, soakage times, equipment parameters, number of
cleaning cycles etc.
· Scope of the study:
The company must evaluate the process and determine which residues are
to be tested for and which are not to be based on sound scientific
rational.
What residues (including cleaning agents) are to be tested for, why those
residues (if more residues may be present than are being tested for all
residues should be under control see comments at 8.4). How many times
should the study be run before a report is compiled and recommendations
made.
· Listing of the process parameters to be verified
This is particularly necessary when automated or semi-automated
cleaning techniques are to be employed.
· Sampling and inspection procedure to be used.
The types of sampling methods to be used, where the samples are to be
removed from and how many samples are to be taken. Any particular
requirements should also be stated i.e. for sterile sampling / sampling
light sensitive products.
An equipment sampling diagram should be referenced.
· Personnel responsibilities during the study
that will constitute a cleaning validation study. It is advisable for companies to
have drawn up a Master Validation plan indicating the overall Cleaning
Validation strategy for either the product range / equipment type / entire site.
The protocol must be prepared prior to the initiation of the study and must
either include or reference the documentation required to provide the following
information:
· The objective of the study:
What cleaning process is to be validated (indicating the product to be
removed and the equipment from which it is to be removed)?
If this study is to be employed to demonstrate the acceptability of the
cleaning procedure for a group of products the rational for doing so
should also be detailed here.
The cleaning procedure(s) to be validated should be identified i.e.
cleaning agents, soakage times, equipment parameters, number of
cleaning cycles etc.
· Scope of the study:
The company must evaluate the process and determine which residues are
to be tested for and which are not to be based on sound scientific
rational.
What residues (including cleaning agents) are to be tested for, why those
residues (if more residues may be present than are being tested for all
residues should be under control see comments at 8.4). How many times
should the study be run before a report is compiled and recommendations
made.
· Listing of the process parameters to be verified
This is particularly necessary when automated or semi-automated
cleaning techniques are to be employed.
· Sampling and inspection procedure to be used.
The types of sampling methods to be used, where the samples are to be
removed from and how many samples are to be taken. Any particular
requirements should also be stated i.e. for sterile sampling / sampling
light sensitive products.
An equipment sampling diagram should be referenced.
· Personnel responsibilities during the study
Analytical methods Cleaning Validation
In order for the analytical testing of the cleaning validation samples (swabs or
rinses) to yield meaningful results, the analytical methods used should be
validated. This should be documented.
The basic requirements are:
· The ability to detect the target substance(s) at levels consistent with the
acceptance criteria
· The ability to detect the target substance(s) in the presence of other
materials that may also be present in the sample (selectivity)
(Companies might want to consider the following:
Where more than one impurity is suspected (which is probably the normal
case in API manufacturing) a method could be proposed that is not
necessarily specific for each of the impurities but detects them all
together. Then additionally the assumption must be made, that the worst
case (e.g. most active) impurity represents the whole residue. This is
secure approach for the patients and could be accepted by the authorities.
It is also an practicable approach for the industry because such methods
are for example dry residue determination for non volatile impurities or
TOC determination for water rinses, which are very simple methods. )
· The analytical method should include a calculation to convert the amount
of residue detected in the sample to 100% if the recovery data generated
indicates a recovery outside of an allowed range.
· Stability of samples over time if the time interval between removal and
testing of samples potentially effects sample integrity.
rinses) to yield meaningful results, the analytical methods used should be
validated. This should be documented.
The basic requirements are:
· The ability to detect the target substance(s) at levels consistent with the
acceptance criteria
· The ability to detect the target substance(s) in the presence of other
materials that may also be present in the sample (selectivity)
(Companies might want to consider the following:
Where more than one impurity is suspected (which is probably the normal
case in API manufacturing) a method could be proposed that is not
necessarily specific for each of the impurities but detects them all
together. Then additionally the assumption must be made, that the worst
case (e.g. most active) impurity represents the whole residue. This is
secure approach for the patients and could be accepted by the authorities.
It is also an practicable approach for the industry because such methods
are for example dry residue determination for non volatile impurities or
TOC determination for water rinses, which are very simple methods. )
· The analytical method should include a calculation to convert the amount
of residue detected in the sample to 100% if the recovery data generated
indicates a recovery outside of an allowed range.
· Stability of samples over time if the time interval between removal and
testing of samples potentially effects sample integrity.
Sampling Cleaning Validation
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. )
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. )
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.
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