Cleaning Validation In Active Pharmaceutical Ingredient

Table of contents
1.
Foreword....................................................................................................…..... 2
2.
Objective....................................................................................................…..... 3
3.
Scope..……................................................................................................…..... 4
4.
Potential residues ……………………………..................................................
5
5.
Current regulatory guidance………………....................................................
6
6.
Cleaning validation policy........................................................................…..... 7
7.
Levels of cleaning.………….....................................................................….....
8
8.
Elements of cleaning validation...............................................................….....
10
8.1
Establishment of acceptance criteria…....................................................
12
8.1.1
chemical determination ........................................................................
12
8.1.2
physical determination .........................................................................
13
8.1.3
microbiological determination..............................................................
13
8.2
Cleaning procedures ...............................................................................
13
8.3
Sampling ................................................................................................
15
8.4
Analytical methods…. ............................................................................
16
8.5
Validation protocols ...............................................................................
17
8.6
Validation reports...................................................................................
18
9.
Minimum requirements...........…..............................................................…..... 20
10.
Change control…………..........…..............................................................…..... 21
11.
Summary………………...........…..............................................................…..... 22
12.
References…………..…...........…..............................................................…..... 23

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Guide to Cleaning Validation in API plants
1. Foreword
This Guideline has been produced by the Active Pharmaceutical Ingredients Committee
(APIC) Working group.
Different organizations will be influenced by their companies and the markets that they
serve in the approaches that they take and the policies that they have with respect to
the subject.
It is also valuable to bear in mind that this is an area that is changing rapidly and what
was considered as being acceptable 2-5 years ago is now not adequate. Therefore,
companies should be aware of the need to continuously update themselves on current
regulatory requirements.
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Guide to Cleaning Validation in API plants
2. Objective
The intention of this document has been to define a comprehensive approach to the
Validation of Cleaning procedures in Active Pharmaceutical Ingredient manufacturing
facilities.
Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture
may be defined as:
The process of providing documented evidence that the cleaning methods
employed within a facility consistently controls potential carryover of product
(including intermediates and impurities), cleaning agents and extraneous
material into subsequent product to a level which is below predetermined levels.
It is necessary to Validate Cleaning procedures for the following reasons:
a.
It is a customer requirement - it ensures the safety and purity of the product.
b. It is a regulatory requirement in Active Pharmaceutical Ingredient product
manufacture.
c.
It also assures from an internal control and compliance point of view the quality
of the process.
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Guide to Cleaning Validation in API plants
3. Scope
This Document will serve to:
1.
Define the basic concepts and terms associated with Cleaning Validation in the
Active Pharmaceutical Ingredient industry.
2.
Serve as a guide from which Masterplans, Protocols and Reports may be
compiled.
Note: General validation principles and a glossary of terms also relevant to cleaning
validation are detailed in the CEFIC / EFPIA Guide entitled ‘Good Manufacturing
Practices for Active Pharmaceutical Ingredient Manufacturers’.
It applies to sterile API’s only up to the point where the API is rendered sterile.
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Guide to Cleaning Validation in API plants
4. 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
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Guide to Cleaning Validation in API plants
5. Current regulatory guidance
Refer to the reference section of this document for details of current Regulatory
Guidance.
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Guide to Cleaning Validation in API plants
6. Cleaning validation policy
The main focus of this document will be to describe equipment and ancillary equipment
/ process Cleaning Validation in an Active Pharmaceutical Ingredient manufacturing
plant. However, it is appropriate to start by giving a brief introduction as to how the
concept of Cleaning Validation should be approached in a facility.
It is advisable for Active Pharmaceutical Ingredient manufacturing facilities to hold an
official Cleaning Validation Policy. Specific department responsibilities should be
outlined in this and it should be approved by senior management. This policy should
serve to provide a general guideline and direction for company personnel, regulatory
authorities and customers as to how the company deals with areas associated with
Cleaning Validation.
The policy should incorporate the following types of statements:
• Definition of terms employed during validation i.e. rinse vs. flush vs. wash etc.
• A statement specifying what company policy is on validation of cleaning
procedures related to equipment (including ancillary) and processes.
• Company policy re dedication of equipment in certain cases (if products are
deemed too dangerous and / or highly active to manufacture on multi-product
equipment).
• Analytical validation policy.
• The policy should also state the rational for the methods by which acceptance
criteria is determined.
• Revalidation policy.
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Guide to Cleaning Validation in API plants
7. Levels of cleaning
The degree or level of cleaning and validation required for processes in Active
Pharmaceutical Ingredient manufacturing depends largely on:
• The equipment usage (i.e. dedicated equipment or not)
• The stage of manufacture (early, intermediate or final step)
• The nature of the potential contaminants (toxicity, solubility etc.)
Each of the above three bullets must be evaluated based on the next product, not
only toxicology etc. The rational for this statement is given below:
In general, the higher the potential for finished Active Pharmaceutical Ingredient
contamination the greater the requirement to validate cleaning methods to ensure
product safety.
Active Pharmaceutical Ingredient manufacturers may have different levels of cleaning
requirements in facilities based on the stage of the process being cleaned and the
subsequent product to be manufactured.
Table 1 on page 7 illustrates an example of how a company may decide on the level of
cleaning between lots.
It is the responsibility of the manufacturer to demonstrate that the level of cleaning and
validation performed is adequate based on each individual situation and on a justifiable
scientific rational.
Cleaning should be carried out as soon as practical after the end of processing and
should leave the plant in a suitable condition for next use.
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Guide to Cleaning Validation in API plants
Table 1: levels of cleaning
LEVEL
USED WHEN
CLEANING
VALIDATION REQUIRED
LEVEL 2
i.e.
• Product changeover of
yes – essential
equipment used in final
step
• Intermediates of one
batch to final step of
another
LEVEL 1
i.e.
• Intermediates or final
progression between level
Step of one product to
0 and 2 depending on
intermediate of another
process and nature of
contaminant based on
• Early Step to
scientific rational
intermediates in a
product sequence
LEVEL 0
i.e. in-campaign, batch to
no validation required
batch changeover
NB: ALL PROCESSES MUST BE EVALUATED INDIVIDUALLY
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Guide to Cleaning Validation in API plants
8. Elements of cleaning validation
A brief outline of the various elements of a basic cleaning validation study is given
below (see also Figure 1 on page 11).
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
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Guide to Cleaning Validation in API plants
Figure 1: Cleaning Validation Process
STAGE 1:
DETERMINE THE MOST APPROPRIATE CLEANING
DEVELOP AND VALIDATE THE
EVALUATE EQUIPMENT SURFACES
PROCEDURE FOR THE EQUIPMENT -
SAMPLING AND CHOSEN
AND DETERMINE
ANALYTICAL METHODS
1. Generate acceptance criteria data for the contaminant.
FOR THE COMPOUND(S) BEING
1. Worst case locations to sample (swab
2. The cleaning method will be determined by the process,
CLEANED
sampling)
the equipment the cleaning agents and the cleaning
techniques available.
1. Swab
1. Volume and type of rinse solvent to be
3. All aspects of the cleaning procedure should be clearly
2. Rinse
employed (rinse sampling)
defined in SOPs be they manual / CIP or COP
(determine % recovery, limit of detection,
1. Equipment surface area (necessary to
limit of quantitation, accuracy of method,
calculate carryover into subsequent
reproducibility, stability over time ...etc.)
batches)

STAGE 2:
STAGE 3
STAGE 4:
DEVELOP A CLEANING VALIDATION PROTOCOL
INTERIM REPORT:
GENERATE A CLEANING VALIDATION
FOR THE PRODUCT AND THE EQUIPMENT BEING
GENERATE INTERIM CLEANING
REPORT DETAILING THE ACCEPTABILITY
VALIDATION REPORTS ON A CLEAN BY
CLEANED
OF THE CLEANING PROCEDURE FOR THE
CLEAN BASIS DETAILING THE
EQUIPMENT AND THE PRODUCT
ACCEPTABILITY OF THE CLEANING
That should encompass for example:
PROCEDURE FOR THE EQUIPMENT AND
1. Introduction
The report should give a full detailed background and
THE PRODUCT.
2. Scope
introduction to the cleaning Validation study and
3. Equipment
should evaluate all data generated with respect to the
This is only required where there is a long
4. Cleaning procedure
acceptance criteria employed for the study. The report
period of time between manufacture of the
5. Sampling procedures
should also indicate the requirement if any for
validation runs (see stage 4 for reporting
6. Analytical testing procedure
revalidation (period of time /change control etc.)
requirements).
7. Acceptance/Cleaning limits.
8. Acceptance criteria for the validation.
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Guide to Cleaning Validation in API plants
8.1
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.
8.1.1
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
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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.
8.1.2 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.
8.1.3 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.
8.2
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.

1 If one cleaning procedure has been shown to be adequate for a number of products, then it is only
necessary to have one cleaning SOP for those products for each piece of equipment.
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Guide to Cleaning Validation in API plants
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
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Guide to Cleaning Validation in API plants
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.
8.3 Sampling
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
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Guide to Cleaning Validation in API plants
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. )
8.4 Analytical methods
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:
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Guide to Cleaning Validation in API plants
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.
8.5
Validation protocols
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.
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Guide to Cleaning Validation in API plants
• 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
• Test methods to be used (should be referenced): See Section 8.4.
• Acceptance criteria
Physical: see section 8.1.2
Chemical: see section 8.1.1
(The rational for this criterion should be given along with a calculation
step.)
• Change control: See section 10.
• Approval of protocol before the study.
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Guide to Cleaning Validation in API plants
8.6
Validation reports
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.
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Guide to Cleaning Validation in API plants
9. Minimum requirements
If company policy is not to validate all equipment cleaning procedures for all products
then as a minimum requirement the validation policy should encompass conditions
which represent the most appropriate challenges (worst case) to the procedure.
These would include, as an example, such things as:
• Removal of products which contain the products with the greatest biological
activity.
• Removal of products containing the products/intermediates/byproducts with the
least solubility.
These represent studies that are minimally required as part of a validation, the results
from which could be used to support lesser challenges to the procedure. It is often
termed product grouping.
• The maximum idle time before cleaning.
A validation program generally encompasses three consecutive successful replicates to
establish that the procedure is reproducibly effective although companies should
evaluate each situation individually.
Where equipment of similar size, design and construction is cleaned by the same
procedure, studies need not be conducted on each unit, as long as a total of three
successful replicates are done on similar pieces of equipment (equipment grouping).
Concurrent Validation may be appropriate when product is manufactured infrequently.
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Guide to Cleaning Validation in API plants
10. Change control
Validated cleaning procedures should be included in the change control program. This
will ensure that any proposed changes are evaluated fully for their impact on the
validated state of the procedure. Where deemed necessary, the proposed revised
procedure may need to be validated prior to routine implementation.
Cf. Change control chapter in the CEFIC / EFPIA Guide entitled ‘Good
Manufacturing Practices for Active Ingredient Manufacturers’
In the absence of an intentional change to a procedure, it is reasonable to assume that
properly trained operators or a properly qualified automated system will be able to
execute the procedure reproducibly and obtain the desired outcome - reduction of
residue to acceptable levels. There may exist special circumstances that would suggest
that this assumption be verified via testing. This may be addressed by periodic reviews
or re-evaluations.
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Guide to Cleaning Validation in API plants
11. Summary
A validation policy should be written for a plant including cleaning validation.
An cleaning validation program should contain the following elements:
1. Assess equipment and products (previous, following)
2. Assess impact of this process on routine processes. If covered under bracketing
then no further validation is required.
3. Determine an appropriate cleaning agent and method
4. Determine acceptance criteria for the residue(s) (including cleaning agents).
5. Determine degree of evaluation required to validate the procedure.
6. Decide what residue(s) (including cleaning agents), are to be tested for based on
solubilities, toxicities etc. and document rational behind decision.
7. Develop sampling and analytical methods for recovery and detection of residues
(swab/rinse, HPLC/dry residue etc.)
8. Acceptance Criteria for the Validation
9. Compile and approve Validation protocol
10. Perform Validation Studies in accordance with protocol
11. Compile and approve a Validation report documenting studies, conclusions and
recommendations.
12. Revalidation policy
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Guide to Cleaning Validation in API plants
12. References
ICH:
• ICH Good Manufacturing Practice Guideline for Active Pharmaceutical
Ingredients. (July 23 1999)
PIC :
• Principles of Qualification and Validation in Pharmaceutical Manufacture -
Recommendations on Cleaning Validation. (ref. Document PR 1/ 99 March
1999)
FDA:
• Guide to inspections of validation of cleaning processes (July 1993)
• Biotechnology inspection guide (1991)
• Foreign inspection guide (1992)
• Guide to inspection of bulk pharmaceutical chemicals
• Guide to inspections of topical drug products
• Manufacture, processing or holding of active pharmaceutical ingredients, draft
document, FDA, March 1998.
CEFIC / EFPIA:
• Good Manufacturing Practices for Active Ingredient Manufacturers - August
1996.
PHRMA :
• Draft PhRMA BPC Cleaning Validation Guideline. (November 1996 Edition)
OTHER PUBLICATIONS
• S.W. Harder, ‘The validation of cleaning processes’, pharmaceutical technology.
(1984)
• James Agalloco, ‘Points to consider in the validation of equipment cleaning
procedures’, Journal of parenteral science and technology. (October 1992)
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Guide to Cleaning Validation in API plants
• Fourman Mullen, ‘Determining cleaning validation acceptance limits for
pharmaceutical manufacturing operations’, pharmaceutical technology. (April
1993)
• Mc Cormick, Cullen, ‘Cleaning validation’, pharmaceutical process validation,
second edition. (1992)
• Mc Arthur, Vasilevsky, ‘Cleaning validation for biological products: case study’,
pharmaceutical engineering. (November / December 1995)
• Zeller, ’Cleaning Validation and residue limits: a contribution to current
discussions’, pharmaceutical technology Europe. (November 1993)
24