Cleaning Validation: WHO Supplementary Training Modules

WHO Supplementary Training Modules
Cleaning validation
John Startup
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
Validation
Part 1. General overview on qualification and validation Part 2. Qualification of HVAC and water systems Part 3. Cleaning validation
Part 4. Analytical method validation

Part 5. Computerized system validation Part 6. Qualification of systems and equipment Part 7. Non sterile product process validation
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Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
Supplementary Training Modules on Good Manufacturing Practice
Cleaning Validation
Part 3
WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 3

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Validation
Objectives
To discuss principles and approaches to cleaning validation including:
Protocols and reports Personnel and equipment Use of detergents Microbiology Sampling Analytical methods and Acceptable limits
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Validation
Principle
The objectives of GMP include prevention of possible contamination and cross-contamination
Contamination by a variety of substances contaminants (e.g. microbes, previous products (both API and excipient residues), residues of cleaning agents, airborne materials (e.g. dust and particulate matter), lubricants and ancillary material, such as disinfectants Also decomposition residues from product or detergents
1.1 1.2
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Validation
Principle (2)
Adequate cleaning procedures important Documented evidence needed - cleaning procedure will provide clean equipment, suitable for intended use. What is the objective of cleaning validation? product, detergent and microbial residues prevent possible contamination and cross-contamination
1.3 1.4
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Validation
Principle (3)
Where is cleaning validation required? Not necessarily for non-critical cleaning, e.g. between batches of the same product (or different lots of the same intermediate in a bulk process), or of floors, walls, the outside of vessels, and following some intermediate steps.
Considered important in multiproduct facilities - should be performed, e.g. for equipment, sanitization procedures and garment laundering.
1.5 1.6
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Validation
Scope
Guidelines: General aspects of cleaning validation
Excluding specialized cleaning or inactivation e.g. for removal of viral or mycoplasmal contaminants in the biological manufacturing industry. Normally cleaning validation needed for critical cleaning, e.g. between manufacturing of one product and another contact surfaces (products, drug products and API).
2.1 2.2
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Validation
General
Written SOPs for cleaning processes validated
Cleaning policy and cleaning validation procedure to cover: contact surfaces; cleaning after product changeover; between batches in campaigns; bracketing products for cleaning validation; and periodic evaluation and revalidation of the number of batches manufactured between cleaning validations.
3.1 3.2
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Validation
General (2)
The company has to prove consistency
What are the variables when a cleaning procedure is followed?
How many consecutive applications of the cleaning procedure should be performed?

Training of personnel
3.3, 5.1
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Validation
Cleaning validation protocols
Approved by QC or QA and to cover, e.g.
disassembly of system; pre-cleaning; cleaning agent, concentration, solution volume, water quality; time and temperature; flow rate, pressure and rinsing; complexity and design of the equipment; training of operators; and 4.1.1 4.1.2 size of the system.
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Validation
Cleaning validation protocols (2)
The cleaning validation protocol should include: objectives, responsible people; description of the equipment including the make, model, serial number or other unique code; time intervals; bioburden; cleaning procedures; equipment used for routine monitoring (e.g. conductivity meters, pH meters and total organic carbon analysers); number of cleaning cycles; sampling procedures (e.g. direct sampling, rinse sampling, in process monitoring and sampling locations) and the rationale for their use
4.1.3
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Validation
The cleaning validation protocol should include (2): data on recovery studies (efficiency of the recovery of the sampling technique should be established); analytical methods; acceptance criteria (with rationale for setting the specific limits) including a margin for error and for sampling efficiency; cleaning agent to be used; revalidation requirements.
4.1.3
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Validation
Cleaning agent used, scientifically justified and based on: the solubility of the materials to be removed; the design and construction of the equipment and surface materials to be cleaned; the safety of the cleaning agent; the ease of removal and detection; the product attributes; the minimum temperature and volume of cleaning agent and rinse solution; and the manufacturer's recommendations 4.1.3
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Validation
Bracketing:
Very similar cleaning procedures for products and processes no need for individual validation. Worst case may be acceptable and should be justified. Consider type of products and equipment; allowed only where products are similar in nature or property and processed on the same equipment; and identical cleaning procedures used.
4.1.4 4.1.6
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Validation
Bracketing:
Representative product - most difficult to clean.
Equipment - only when it is similar or the same equipment in different sizes (e.g. 300 l, 500 l and 1000 l tanks). Alternative approach may be to validate the smallest and the largest sizes separately.
4.1.7 4.1.8
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Validation
Cleaning validation reports
The relevant cleaning records (signed by the operator, checked by production and reviewed by quality assurance) and source data (original results) should be kept. The results of the cleaning validation should be presented in cleaning validation reports stating the outcome and conclusion.
4.2.1
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Validation
Equipment
Cleaning of contact surfaces to be validated, with consideration to non-contact parts. Critical areas should be identified. Dedicated equipment for: products which are difficult to clean, equipment which is difficult to clean, products with a high safety risk where it is not possible to achieve the required cleaning acceptance limits using a validated cleaning procedure.
6.1 6.2
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Validation
Equipment (2)
If one SOP for cleaning a piece of equipment, review: products being produced, cleaning in a large campaign, cleaning between batches of different products.
The design of equipment may influence the effectiveness of the cleaning process. Consider design, e.g. V-blenders, transfer pumps or filling lines.
6.3 6.4
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Basic Principles of GMP

Which are the critical areas for sampling? What would be considered an appropriate approach for cleaning validation for this piece of equipment?
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Which are the critical areas for sampling? What would be considered an appropriate approach for cleaning validation for this piece of equipment?
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Validation
Detergents
Released by quality control and meet food standards or regulations
Composition known Easily removed with rinsing - demonstrated - with acceptable limits defined If persistent residues (e.g. cationic detergents) - avoided Consider also detergent breakdown
7.1 7.4
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Validation
Microbiology
Prevent microbial growth and remove contamination Documented evidence routine cleaning storage of equipment The period and conditions storage of unclean equipment before cleaning between cleaning and equipment reuse Equipment stored in a dry condition after cleaning (no stagnant water) Control of bioburden important 8.1 8.5
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What is important about cleaning validation for components/ parts of equipment?
Consider also the different materials, e.g. stainless steel contact surfaces, silicon seals and others
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Validation
Sampling (General)
Clean as soon as possible after use especially topical products, suspensions and bulk drug or where the drying of residues will directly affect the efficiency of a cleaning procedure
Two methods of sampling: direct surface sampling and rinse samples Combination of the two - most desirable
9.1.1 9.1.2
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Validation
Sampling (General) (2)
Re-sampling: not to be done before or during cleaning
Constant re-testing and re-sampling: can show that the cleaning process is not validated may indicate presence of unacceptable residue and contaminants resulting from an ineffective cleaning process
9.1.3
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Validation
Direct surface sampling (direct method)
Most commonly used method
Use swabs (inert material) - type of sampling material should not interfere with the test
Factors to be considered include: supplier of the swab, area swabbed, number of swabs used, whether they are wet or dry swabs, swab handling and swabbing technique
9.2.1
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Validation
Direct surface sampling (direct method) (2)
Other factors include: location from which the sample is taken (including worst case locations, identified in the protocol) composition of the equipment (e.g. glass or steel)
Critical areas (hardest to clean) e.g. in semi-automatic/fully automatic clean-in-place systems Use appropriate sampling medium and solvent
9.2.2 9.2.4
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Validation
Rinse samples (indirect method)
Allows sampling of: a large surface areas that are inaccessible or that cannot be routinely disassembled
Provides an "overall picture" Useful for checking for residues of cleaning agents In combination with other sampling methods such as surface sampling
9.3.1
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Validation
Rinse samples (indirect method) (2)
The manufacturer has to provide evidence that samples are accurately recovered
What is considered acceptable in terms of recovery?
9.3.2
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Validation
> 80% is considered good
Recovery
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Validation
> 50% is considered reasonable
Recovery
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Validation
> 50% is considered reasonable
Recovery
< 50% is considered questionable
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Validation
Batch placebo method
A placebo batch is manufactured and checks are done for carryover of the previous product Expensive and laborious process Little assurance that the contaminants are dislodged Particles not necessarily uniformly dispersed Method used in conjunction with rinse and/or surface sampling method(s) Samples taken throughout the process of manufacture Sensitivity of the assay may be greatly reduced by dilution of the contaminant 9.4
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Validation
Analytical methods
Validated analytical methods able to detect residuals or contaminants: specific for the substance(s) being assayed at an appropriate level of cleanliness (sensitivity)
Sensitive and specific - may include: chromatographic methods (e.g. high pressure liquid chromotography (HPLC), gas chromotography (GC), and high pressure thin-layer chromatography (HPTLC)). Others include (alone or in combination), e.g. total organic carbon (TOC), pH, conductivity, ultraviolet (UV) spectroscopy, and ELISA
10.1, 10.2, 10.5
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Validation
Analytical methods (2)
Validation of the analytical method should include, e.g. precision, linearity and selectivity (the latter if specific analytes are targeted); limit of detection (LOD); limit of quantitation (LOQ); recovery, by spiking with the analyte; and reproducibility
Detection limit (sufficiently sensitive) to detect the established acceptable level of residue / contaminants
10.3 10.4
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Validation
Establishing acceptable limits
Limits: Practical, achievable and verifiable Rationale: Logical, based on knowledge of materials
Each situation assessed individually

Principal reactant and other chemical variations
Screening (thin-layer chromatography) in addition to chemical analyses where necessary

11.1 11.3
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Validation
Establishing acceptable limits (2)
There should be no residue from: Previous product
Reaction by-products and degradants

Cleaning process itself (e.g. detergents or solvents)
Remember: Uniform distribution of contaminants is not guaranteed

11.4
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Validation
The limit-setting approach can: be product-specific group products into families and choose a worst case product group products into groups according to risk, e.g. very soluble products, products with similar potency, highly toxic, or difficult to detect products use different safety factors for different dosage forms based on physiological response (this method is essential for potent materials)
11.5
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Validation
Limits may be expressed as: a concentration in a subsequent product (ppm), limit per surface area (mcg/cm2), or in rinse water as ppm.
Limits for carry-over of product residues should meet defined criteria. What are the three most commonly used criteria?
11.6 11.8
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Validation
The three most commonly used criteria are:
Visually clean No residue visible on equipment after cleaning. Spiking studies to determine the concentration at which most active ingredients are visible. (May not be suitable for high potency, low-dosage drugs.) No more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials). No more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
11.9
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Validation
The most stringent of three options should be used Certain allergenic ingredients and highly potent material should be undetectable by the best available analytical methods e.g. penicillins and cephalosporins e.g. anovulent steroids, potent steroids and cytotoxics
Dedicated manufacturing facilities needed

11.10 11.11
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Validation
Group session
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Cleaning Validation: WHO Supplementary Training Modules

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What are the main topics covered in the training workshop?

What are the main topics covered in the training workshop?

What are the three most commonly used criteria for establishing acceptable limits?

What are the three most commonly used criteria for establishing acceptable limits?

WHO Supplementary Training Modules

Part 4. Analytical method validation

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Supplementary Training Modules on Good Manufacturing Practice

WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 3

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

How many consecutive applications of the cleaning procedure should be performed?

Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

> 50% is considered reasonable

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

> 50% is considered reasonable

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Each situation assessed individually

Screening (thin-layer chromatography) in addition to chemical analyses where necessary

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Reaction by-products and degradants

Remember: Uniform distribution of contaminants is not guaranteed

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Dedicated manufacturing facilities needed

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

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