QM6.8-01_Cleaning Validation_fields
Quality Manual
Group Quality Assurance y For internal use only y All rights reserved
Cleaning Validation
Quality Module QM6.8*
Edition 01
Prepared by: Michel Crevoisier (original on file)
Date:
7-Dec-2011
Senior QA Expert, ChemOps Switzerland
Michel Crevoisier
Quality Standards Review by: Montse Montaner (original on file)
Date:
13-Jan-2012
Quality Systems and Standards
Montse Montaner
Approved by: Juan Andres (original on file)
Date:
15-Jan-2012
Novartis Quality Leadership Team
Juan Andres
*Replaces former Quality Module N10.15 and N10.16 and QM6.20 CIBA
Authorization for Operational Use at:
Approved by: Date:
QA Head
Approved by: Date:
Site Head
Version: Replaces: All Actions for Implementation Completed
Implementation Verified by:
Date: QA Head
Table of Contents
1. Purpose and Scope (4)
2. Responsibilities (4)
3. Requirements (4)
3.1 General Requirements (4)
3.2 Prerequisites (5)
3.3 Written Cleaning Procedures (5)
3.4. Risk Assessments (6)
3.4.1 General (6)
3.4.2. Microbiology (7)
3.5. Validation (7)
3.5.1. Approach to Cleaning Validation (7)
3.5.2. Implementation (8)
3.6. Limits for Chemical Cleanliness of Manufacturing Equipment (10)
3.6.1 Limits for Highly Active Substances (10)
3.6.2 Limits for Non Highly Active Substances. General Rules (10)
3.6.3. API manufacturing (10)
3.6.4. Pharmaceutical Manufacturing (11)
3.7. Limits for Microbiological Cleanliness of Manufacturing Equipment (12)
3.8. Analytical Methods and Visual Checks (12)
3.9. Documentation (12)
4. Definitions (13)
5. Revision History (13)
6. Annexes (13)
SOP References for Site Operational Use (15)
Scope
and
1. Purpose
This module describes the basic requirements for the validation of cleaning processes in the manufacture of Novartis products.
In this Quality Module, the term “cleaning” means the cleaning of manufacturing equipment between different products. The term “products” means finished products including drugs, biologics, vaccines, and medical devices.
Although the requirements are mostly targeted at the cleaning of multiproduct equipment, in essence they also apply to the cleaning of dedicated equipment. The module does not detail cases where it is obvious that a requirement does not apply to dedicated equipment; where it is not obvious, the module addresses the differences.
The regulations cited in this module are not all inclusive, and all local regulations must also be complied with. In case local regulations are stricter than these requirements, the local regulations apply.
This module represents Novartis requirements for compliance with regulatory requirements and expectations, in consideration of the current operating environment and existing industry trends.
This module applies to all Novartis Divisions and Business Units henceforth referred to as “Novartis”.
2. Responsibilities
Role Refer to QM Section
Production units 3.1.
Quality Assurance 3.1.
3.9.
Manufacturing units 3.4.1.
3.6.2.
3.6.3.
3.8.
Management 3.9.
3. Requirements
Requirements
3.1 General
In manufacturing of products, the cleaning processes must be validated, whether they are executed manually or automatically.
In manufacturing of API, cleaning procedures should be validated. Cleaning validation must be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality.
The approach followed for the validation of a cleaning process should be the same as the approach recommended for the validation of a manufacturing process.
If possible, every assessment of cleanliness must include a visual check.
The composition of detergents and disinfectants must be known.
The Production Units are responsible to establish cleaning procedures and to validate the cleaning processes.
QA is responsible for final approval of all validation documents. Array
3.2 Prerequisites
To enable the validation of a cleaning process, the following quality systems and prerequisites must be in place:
?Change control;
?Deviation handling;
?OOS procedure
?Validation Master Plan;
?The equipment to be cleaned must be qualified, including, if applicable, o computerized systems used for CIP
o utilities (air, water)
o rooms
?The operators must be trained in the cleaning procedures;
?The analytical methods to assess the efficacy of the cleaning must be available and validated.
The following documents must be prepared and approved for the validation of a specific cleaning process:
?Written Master Cleaning Procedure and corresponding Master Cleaning Record;
?Risk Assessment(s);
?Validation Protocol.
Procedures
Cleaning
3.3 Written
Master Cleaning Procedures and their corresponding Master Cleaning Records must be established in writing and followed for cleaning of equipment and utensils used in the manufacture, processing, packing, or holding of an intermediate, an API, or a product.
A cleaning procedure must describe the cleaning of each piece of equipment.
The cleaning procedures must include, but are not limited to the following:
?Assignment of responsibility for cleaning equipment;
?Cleaning schedules, including, where appropriate, sanitizing (disinfection)
schedules;
? A description in sufficient detail of the methods, equipment, and materials used in cleaning operations;
?When appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning;
?Instructions for the removal or obliteration of previous batch identification;
?Instructions for the protection of clean equipment from contamination prior to use;
?Inspection of equipment for cleanliness after cleaning or immediately before use, if practical; and
?The maximum time that may elapse between the completion of processing and equipment cleaning (the "dirty hold time").
3.4. Risk Assessments
3.4.1 General
The manufacturing units must assess the risks associated with their
changeover processes in general and with specific cleaning processes in
particular.
The risk assessments must consider the following points:
?Dedicated/non-dedicated equipment;
?Products covered by the respective cleaning procedure;
?Batch size and possible changeovers;
?Formulation attributes i.e. solid, semisolid, liquid, particularly
penetration of equipment seals and joints;
?Excipients;
?Location of step within overall process;
?Characteristics including solubility, of APIs, excipients, and
intermediates;
?Dosage levels / toxicity / potency;
?Manufacturing campaigns;
?Processing time scales;
?Cleaning intervals, particularly of dedicated equipment, to prevent the accumulation of residues or decomposed substances;
?Idle time and idle conditions, dirty hold time and clean hold time;
?Non-sterile/sterile: special consideration of microbiological, endotoxin and particulate risks;
?Equipment design and construction (including direct/indirect surface contact area to product);
?Critical, difficult to clean equipment parts;
?“Hot Spots” should be identified where a possible carry-over can contaminate one single dose, e.g. tablet press, encapsulation
machine, tablet filler;
?Adsorption to surface material of the equipment;
?Past experience and history of cleaning difficulties;
?Removal of detergents;
?Microbiological contamination, need to disinfect or sterilize;
?Removal of disinfectants or sanitizing agents;
?Safety risk for the patient.
If a new product or new equipment is introduced to a site, the risk assessment must be reevaluated.
3.4.2. Microbiology
For API for parenteral use, requirements for bioburden apply to the last
processing steps prior to pharmaceutical formulation like drying, blending,
milling etc. In earlier stages microbiological requirements may be appropriate if special growth promoting conditions exist and if no reduction of
microorganisms can be expected by any of the following processing steps.
For equipment which is disinfected, but not sterilized, the efficacy of cleaning
and disinfection needs to be validated in terms of chemical cleanliness (no
residues of products, foreign matter, detergents, disinfectants etc.) and
hygienic cleanliness (no contamination with bacteria or fungi).
Special attention must be given to the clean hold time of equipment for which microbiological requirements apply.
See Annex 1 for Microbial Contamination Risk Factors to be considered.
3.5. Validation
3.5.1. Approach to Cleaning Validation
Cleaning Process Validation is defined as the collection and evaluation of
data, from the cleaning process design stage through commercial production, which establishes scientific evidence that a cleaning process is capable of
consistently delivering a clean equipment, i.e. to provide equipment which is
suitable for processing of products and APIs.
Cleaning Process Validation involves a series of activities taking place over
the lifecycle of the equipment and its associated cleaning procedure(s).
The approach is structured in three stages:
?Stage 1 – Cleaning Process Design: The cleaning process is defined during this stage based on knowledge gained through development
and from comparable cleaning procedures.
?Stage 2 – Cleaning Process Qualification: During this stage, the
cleaning process design is evaluated to determine if the process is
capable of reproducible cleaning.
?Stage 3 – Continued Cleaning Process Verification: Ongoing
assurance is gained during routine cleaning that the process remains
in a state of control.
The equivalent of a “validated state” is reached with the closing of stage 2
and then the process proceeds to stage 3 with the with the continued process verifications. The continued process verification requirements for stage 3
must be defined in the Cleaning Validation Master Plan (3.5.2.1) and
periodically evaluated (3.5.2.4). The Cleaning Validation must be periodically reassessed, at minimum at least every 5 years.
3.5.2. Implementation
3.5.2.1. Cleaning Validation Master Plan
Each manufacturing unit must establish a cleaning Validation Master
Plan according to the Quality Module QM6.3.
The plan must describe the criteria to promote a cleaning process
from validation stage 2 to 3.
The plan must list all the cleaning procedures of the unit with
?an identifier of the cleaning procedure, a unique name or a unique ID number;
?whether the cleaning procedure must be validated or not;
?if it has to be validated, the stage of validation : 1, 2 or 3;
?The scheduled validation activities (cleaning process
developments, qualifications, and continued verifications,
depending on the validation stage).
The system used to manage the cleaning validation master plan shall
be such that the up-to-date master plan can be shown in print in a
timely manner.
3.5.2.2. Bracketing: Worst Case Concept
Cleaning procedures for products and processes which are very
similar do not need to be individually validated. It is considered
acceptable to select a representative range of similar products and
processes concerned and to justify a validation program which
addresses the critical issues relating to the selected products and
processes. A single validation study under consideration of the “worst
case” can then be carried out which takes account of the relevant
criteria. This practice is termed "Bracketing"
The products to be cleaned off can be grouped based on similar
characteristics (e.g. difficulty to clean, solubility, toxicity, allowed
residual limit, etc.)
The grouping of very similar cleaning procedures must be justified by
the risk assessments.
If a new product or new equipment is introduced, the bracketing and
the risk assessments must be reevaluated.
3.5.2.3 Stage 2: Cleaning Process Qualification
This stage corresponds to what was formerly referred to as “Cleaning
Validation”.
The objective of stage 2 is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be reduced to a minimum in the routine phase or omitted (see 3.5.2.4)
Stage 2 will have a higher level of sampling, additional testing, and greater scrutiny of cleaning performance than would be typical of routine cleaning.
The activities must be planned in a Cleaning Qualification Protocol (Validation Protocol) laying down how the performance of the cleaning process will be qualified. It must include the following, as appropriate:
?The objective of the qualification;
?Responsibilities for performing and approving the qualification study;
?Description of the equipment to be used;
?Description of the equipment to be cleaned;
?The interval between the end of production and the beginning of the cleaning procedures (dirty hold time)Cleaning
procedures to be used for each product, each manufacturing
system or each piece of equipment;
?Any routine monitoring requirement;
?Sampling procedures, including the rationale for why a certain sampling method is used;
?Clearly defined sampling locations;
?Data on recovery studies where appropriate;
?Analytical methods including the limit of detection and the limit of quantitation of those methods;
?The acceptance criteria, including the rationale for setting the specific limits;
?Other products, processes, and equipment for which the planned cleaning qualification is valid according to a
“bracketing” concept.
The number of cleaning runs for cleaning should depend on the complexity of the cleaning process. Typically three consecutive applications of the cleaning procedure should be
performed and shown to be successful in order to prove that the procedure is valid, but there may be situations where additional runs are warranted to prove consistency of the process.
A final Cleaning Qualification Report must be prepared. The conclusions of this report must state if the cleaning process has been qualified successfully.
The report must be approved by the Plant Management and QA.
3.5.2.
4. Stage 3: Continued Cleaning Process Verification
The manufacturing units must conduct a periodic evaluation of the
effectiveness of the cleaning processes to verify that the cleaning
procedures provide the expected results and remain in a state of
control.
The frequency of such verifications and the depth of analytical checks
shall depend on the criticality of the cleaning processes, their
complexity, and how often they are run.
QA must ensure that the periodic evaluation of the effectiveness of the
cleaning processes is done.
The results of the verifications must be documented in written and
approved by QA.
3.6. Limits for Chemical Cleanliness of Manufacturing Equipment
3.6.1 Limits for Highly Active Substances
The potential carryover of highly active substances is addressed in a separate Quality Module.
New substances for which no toxicological data are available yet must be
treated like highly active compounds until data allow a different approach.
Also refer to the respective Quality Module for guidance on the handling of
beta-lactam antibiotics, e.g. penicillins, cephalosporins, and carbapenems.
3.6.2 Limits for Non Highly Active Substances. General Rules
Manufacturing units must set the limits based on their knowledge of the
materials involved and the limits must be practical, achievable, and verifiable.
The arbitrary rules outlined in the following chapters 3.6.3 and 3.6.4 are
recommendations. Depending on the manufacturing units’ product mix, more
or less stringent values may be warranted. In either case the limits must be
justified by risk assessments that take account of the available
pharmacological/ toxicological data and possible duration of exposure.
The sensitivity of the analytical methods must be established in order to set
reasonable limits.
In the following, the term “residue” means all material which may remain in
equipment; it includes excipients, buffers, detergents, lubricants, dust,
decomposition products, etc.
3.6.3. API manufacturing
Manufacturing units may use different sets of limits for cleanliness depending on the use of the equipment:
?Limits for equipment used before a final purification step;
?Limits for equipment used during or after a final purification step.
3.6.3.1. Cleanliness Limits for equipment used before final purification
The equipment must be visually clean, AND
The amount of residue in the equipment must be less than 1000 ppm
of the following batch.
Exception: If the previous product is a starting material in the
immediately following process, it is sufficient to visually inspect the
equipment for cleanliness if the changeover has been addressed in
the risk assessment.
3.6.3.2. Cleanliness Limits for equipment used during or after final
purifications
The equipment must be visually clean
AND
?if the therapeutic doses are known, no more than 0.1% of the minimum daily dose of any API will appear in a maximum daily
dose of the following API,
OR,
?if the therapeutic doses are unknown, the amount of residue in the equipment must be less than 20 ppm of the following
batch.
For detergents and disinfectants higher limits are accepted if
supported by special toxicological assessments.
3.6.
4. Pharmaceutical Manufacturing
The equipment must be visually clean, AND
No more than 0.1% of the minimum daily dose of any API will appear in a maximum daily dose of the following product.
For detergents and disinfectants the limits are set according to special toxicological assessments.
Particulate contamination is relevant for injectables and ophthalmics. The acceptance levels must be provided.
3.7. Limits for Microbiological Cleanliness of Manufacturing
Equipment
The microbiological requirements for product-contacting surfaces are defined in QM 7.5 "Microbiological Quality Assurance-Manufacturing".
The final rinse water must be tested against the same microbiological specification for total aerobic microbial count and endotoxin units as the one used for the water of the next product.
For endotoxin removal-washing steps, acceptable endotoxin removal must be demonstrated.
3.8. Analytical Methods and Visual Checks
After cleaning, the visible product contact surfaces of the equipment must always be visually checked for cleanliness and the check must be confirmed by a second person.
The manufacturing units must define what “visually clean” means in their operational environment. They must be able to translate “visually clean” in numbers, albeit in a good approximation. This knowledge is preferably built on own experimental data, e.g. obtained by analyzing swab samples of surfaces claimed to be visually clean, or on published values, if deemed reliable and appropriate.
Testing methods used for cleaning validation must be validated. As a minimum, the specificity, the limits of detection and of quantification (LOD/LOQ), and the recovery rates of swab sampling must be validated. The recovery rate of swab samples must be higher or equal to 50%, or, if using a swab technique which does not yield 50% recovery, it must be demonstrated that a better swabbing protocol could not be found with reasonable effort.
In stage 2 of the cleaning validation, specific and/or non specific tests must be used to show the effectiveness of the cleaning process. Specific tests show the amount of expected residue, usually the previous product; non specific tests (e.g. TOC, residue on evaporation, conductivity, etc.) are valuable indicators of unsuspected sources of contaminations like leaching of lubricants or of heating/cooling fluids.
In stage 2, the assessment of the final result should be supported by swab samples.
For the continual verification of the cleaning processes in stage 3, one can revert to fewer tests and testing in appropriate intervals.
3.9. Documentation
Cleaning Procedures, Validation Protocols and Reports must be approved by local management and QA and archived in accordance with local procedures.
4. Definitions
For definition of terms, see “Definition Glossary” at
http://www.gqa-to.novartis.intra/Pages/QualityManualIndex.aspx.
History
5. Revision
Edition 01
?Revised to new Quality Module format and numbering system. ?Incorporation of prior modules N10.15, N10.16, and QM6.20 (CIBA only)
6. Annexes
Annex 1 – Risk Factors for Microbial Contamination
Annex 1 – Risk Factors for Microbial Contamination
Risk Level Low Medium High Bioburden of preceding
product Low counts Medium counts High counts
Nature of preceding drug substance/ drug
product Synthetic substance
with antimicrobial
properties
Preserved or without
growth promoting
properties
Natural product,
protein, peptide,
compounds with growth
promoting properties
Process
Dry (water content
<0,7) e.g. milling,
distillation, dissolving in
organic solvents, high
temperature
With residual humidity
Aqueous solutions,
temperatures between
15 and 50°C
Cleaning agent
Organic solvents,
strong acids, strong
bases, bleach
water with
commercially available
cleaning agents
Pure water
Cleaning process Automated CIP with
high temperature Manual removal Manual, slow drying
Disinfection process Strong disinfectant long
application time e.g.
disinfection bath
Disinfectant with
moderate effectiveness No disinfectant
Equipment material Steel Silicon Natural material such
as cotton, latex Equipment surface Electropolished Visually smooth Rough imperfections
Design
All equipment parts
easy to reach and easy
to dry
Dismounted pipes with
large diameter
Fittings, valves, dead
legs, tubing
Ingress Closed system Partially closed system Open system with
manual interventions Campaign length Short Medium Long Storage time in dirty
condition with residual
moisture
None <24 h > 1d
Historical data of
bioburden and
endotoxins
No deviations Rare deviations Frequent deviations
SOP References for Site Operational Use