Procedure for Cleaning Validation

Standard Operating Procedure Title: Procedure for Cleaning Validation

Department	Validation/Technical Services		Document no	VAL020
Prepared by:		Date:		Supersedes:
Checked by:		Date:		Date Issued:
Approved by:		Date:		Review Date:

Document Owner

Validation Manager

Affected Parties

All Validation, Technical Service, Operations, Quality Assurance, Engineering and Project staffs involved in cleaning validation projects.

Purpose

To describe procedures to be followed during the cleaning validation of processes and equipments.

Scope

This procedure is to be followed by personnel involved in cleaning validation activities, typically the following departments are involved, Validation, Quality Assurance, Laboratory, Project Engineering and Operations.

Definitions Standard Operating Procedure

Cleaning Validation	cleaning validation is a validation program to verify that the processes and procedures used to clean product residue from process equipment and components, will consistently and significantly reduce the amount of active and/or excipient(s) and cleaning agent(s) to a concentration within calculated acceptance limits
Actives	The main or primary ingredient in a product, that is intended to induce a change in the recipient
Acceptance Limit	The quantity of compound(s) permitted to carry-over in subsequent product without any adverse effects to the product or consumer.
Excipient(s	The ingredients in a product, other than the Active ingredient
Hot Spot	A difficult-to-clean location, which if improperly cleaned would lead to contamination, which would be uniformly distributed in subsequent batches (e.g. inside the bulk tank).
Limit of Detection	The Limit Of Detection (LOD) represents the lowest detectable mass or concentration that can be observed by an analytical method.
Limit of Quantitation	The Limit Of Quantitation (LOQ) represents the lowest quantifiable mass or concentration that can be reliably measured repeatedly and accurately
NOEL	No Observable Effect Limit. This is the limit at which no effects to the subsequent product or recipient can be detected.
Residual CarryOver	The concentration of primary or secondary ingredients from the previous lot or batch, of solid or liquid product, which is transferred to the current manufactured lot or batch.
Safety Factor	A value incorporated into the allowable carry-over that ensures the residual

Title: Procedure for Cleaning Validation

1.1.1. Validation

This area is responsible for training in the use of this SOP, document preparation and testing requirements for particular projects. Provide instruction on specific test procedures and written test protocols. Develop and implement relevant testing templates and calculation spreadsheets. For large validation projects provide a testing and documentation resource to complete the validation activities.

1.1.2. Quality Assurance (QA Manager or Validation Manager)

Review and authorisation of documentation associated with cleaning validation.

1.1.3. Engineering (Projects)

Review and checking documentation associated with cleaning validation. Engineering is responsible for design, installation, and commission and in some projects validation of new and modified cleaning equipment processes. Systems include but are not limited to: product transfer pipework, mixing vessels. Initiating changes to current cleaning processes and procedures by initiation of change requests.

1.1.4. Operations

Initiating changes to current cleaning processes and procedures by initiation of change requests. Review of validation plans and validation test protocols. Provide resource assistance to the specific cleaning validation tasks such as running collecting swab and rinse samples, removal of complex equipment components.

1.1.5. Laboratory

Provide validated Analytical test methods for accurate product residue detection, including swab and rinse surface recovery data. Perform Analytical testing of swab and rinse samples collected during validation using validated procedures. Review and approve Analytical test methods and results, provide documented test results to relevant departments. Review sampling procedures and acceptance criteria for bioburden sampling after cleaning. Perform analysis of bioburden samples and report results

.

2. Types of Cleaning Process and Cleaning Agents

2.1. Manual Cleaning

Effective manual cleaning practices must be established by focusing on the following two areas:

2.1.1. Standard Operating Procedures (SOP)

SOPs will be developed during the Operational Qualification phase of the project. This will be outlined as part of the Validation Plan. If consistently unacceptable or erratic results are obtained the SOP should be considered one of the possible problems and modifications to the procedure may be required. Procedures must be written in a manner, which prevents variation between operators.

2.1.2. Operator Training

Operators must be suitably trained in the use of the manual cleaning SOP.

2.2. Automatic Cleaning In Place (CIP)

Standard Operating Procedure

Title: Procedure for Cleaning Validation

1. Worst-case product is the same as previously validated and acceptance criteria is the same or higher than previously validated.
2. Cleaning validation data is available on the previously validated identical process.

An explanation for reduced testing should be described in the relevant Validation Plan, protocol or change request for the process. Reduced testing may include reducing the number of tests and reducing the sample locations to a few key critical areas known to be “critical sites” or “hot spots”.

For changes to current cleaning processes and procedures the extent of retesting will in most cases be reduced to a single test, this shall be stated and approved as part of the change request process as in SOP QMS-030.

3.3. Select WorstCase Product for Cleaning

For multi-product equipment it is not practical to validate cleaning of all products produced in a particular process/equipment that has one cleaning process and where products are alike in formulation and dosage form. In such cases, it is considered acceptable to select a worst-case product to represent all products in the process for the purposes of cleaning validation. The worst-case selection is based on a scientific justification i.e. the least soluble product produced on a particular equipment or process. This product is then used to validate cleaning for that process/equipment.

3.4. Select Product to use for acceptance criteria calculations

1. Calculation of acceptance criteria is to be based on the most toxic product within a group of products produced in a given process.
2. Find the product within the product group, which has the lowest active toxicity value in mg/kg, this is the most toxic product. This product will be used for the calculation of acceptance criteria.

3.4.1. Example of selecting worstcase product and product for acceptance criteria calculations

Note -a low toxicity value means high toxicity, a high value means low toxicity.

Active	Active solubility (mg/mL)	in	water	Active Toxicity (mg/kg)
1	60			90
2	400			2800
3	70			0.30

From the above table of product data, Active 1 is the least soluble product in water since it has a value of 60 mg/mL and is therefore the worst-case product in this group.

Active 3 is the most toxic product since it has the lowest toxicity value of 0.3 mg/kg. Therefore the acceptance criteria is calculated using active 3 product data.

3.4.2. New Products Introduced to the Production Facility

If a new product is introduced into the facility the solubility and toxicity of the new product should be compared against the current list of products in the same product type group and following assessment should be made:

• If the new product is less soluble than the current least soluble product within the product group then this product becomes the new worst-case

Standard Operating Procedure Title: Procedure for Cleaning Validation

SF = safety factor = 1000. This is based on biological activity levels of 1/1000 of the normal active concentration. Example Calculation MAC = 0.25mg x 200,000mL = 25.0 mg

1000 x 2.0mL

Therefore the total quantity of residual product allowable in a subsequent production

batch is 25.0 mg.

3.6.4. Calculating Acceptance Limits For Swabs

1. Take the calculated MAC for the product and divide this number by the total internal surface area of the total product processing system, i.e. preparation and holding vessels + pipework + filling machine. This figure is the amount of residue allowed throughout the entire process, the assumption being that there is even distribution of product residue throughout the process equipment.
2. Example calculation: The allowed residue in the entire process = MAC/total surface area

2

= 25.0mg/56715 cm

22

= 0.00044 mg/cm (MAC/cm )

The overall surface area is derived from the following (only as example):

.

EQUIPMENT/S	EQUIPMENT INTERNAL SURFACE
	AREA
	(cm 2)
Mixing tank	26745
Holding tank	26745
Transfer lines	965
Filling Machine	2260
Total	56715

This calculated value determines the amount of residual product allowed to remain on 1 square centimetre of the equipment after cleaning. This value is then multiplied by the area to be swabbed to give the allowed limit per swab sample.

2

If swabbing a 10 cm x10 cm (100 cm ) surface area and placing the swab in 25.0ml of swabbing solution then the following applies:

2

Limit for swab sample = MAC/cm x Swab area Volume of Swab Solution

22

= 0.00044 mg/cm x 100 cm = 0.0088 mg/mL (8.8g/ml or ppm per swab)

25.0 ml

2

In this case, swab sample results for 100 cm must be ≤8.8 g/mL of active to prove

2

that the cleaning process is satisfactory. The value 0.00044 mg/cm was derived from the MAC allowed per swab calculation above.

3.6.5. Calculating Acceptance Limits For Rinse Samples

1. Calculating required rinse volume:

Standard Operating Procedure Title: Procedure for Cleaning Validation

3.7. Flowchart – Cleaning Validation

3.1. Identify

3.3. Select the Worst

Process/Equipment ^{3.2. Check if}

Cleaning Validation Case product for

and the product type

is Required Cleaning

produced

Review 3.4. Select product to procedure and use for acceptance Retest criteria calculations

Fail

3.5. Check if Analytical

Section 4. Analytical 3.6. Calculate

Yes Method Validation

Method Validation Acceptance Limit for Rinse & swab samples ^Required

Recalculate Acceptance criteria Based on Recovery results

Write OQ Test 3.6. Calculate protocols. Test using Acceptance Limit for No worst case product Rinse and swab samples

Approve Protocols

Passes 3 times _{Investigate and Fail} Protocol Execution

Complete Test

Contaminate with worst

Retest 3 times

Protocol

case product

^{In Process} Change Control

Monitoring

Revalidation

Standard Operating Procedure

Title: Procedure for Cleaning Validation

relevant changes should be made prior to use and the final test protocol checked and authorised.

4.3.1. Purpose

Swab recovery studies must be conducted for the specific product to be tested on the production equipment. This must be completed before swab samples can be taken from equipment surfaces. This will ensure that the product is adequately recovered from the equipment surface based on the appropriate selection of swab material and solvent.

Method Validation studies shall determine the repeatability, reproducibility, and recovery of the swabbing analysis from the equipment surfaces. If recovery results do not meet the acceptance criteria, a different swab type, different solvent, or different swabbing method may need to be used.

4.3.2. Swabbing Procedure

Swab recovery studies are performed by spiking 316L stainless steel plates (or other production material if more relevant for a particular process). Product is evenly distributed onto the plate at concentrations above and below the acceptance criteria calculated in step 3.6, “Calculating limits for Rinse and swab samples”.

The stainless steel plates must be large enough to allow a 10cm x 10cm (100cm) surface area to be swabbed. Allow the product to dry on the sample surface before swabbing.

Following is a recommended procedure to follow which has been shown to work well for Method Validation tests:

Place 2 swabs into 1 clean 40mL Total Organic Carbon (TOC) vial containing the required volume of extraction solvent (usually 25mL). The 2 swabs are to be used for the same 10x10cm surface and placed back into a single vial.

The swab surface is pressed on the side of the glassware to express excess water prior to use. The swabbing is conducted covering the area in one direction then using the flip side of swab surface swab in a perpendicular direction. Firmly press down on the swab handles to ensure proper surface contact. The second swab is removed from the solvent and the first swab placed back into the solvent.

The procedure is repeated with the second swab ensuring that the exact same 10cm x 10cm area is swabbed; the swab is placed back into the solvent. The swab handles are cut with a clean pair of scissors making certain that no foreign particles are introduced into the solution. The solution is vortexed for 30 to 60 seconds.

TOC samples should be analysed as soon as possible after sample collection, i.e. within 12 hours.

Standard Operating Procedure

Title: Procedure for Cleaning Validation

5.5.1. Swab sampling

The swab method should be based on the procedure validated by the analytical laboratory. In many cases the surface of production equipment will not be a flat stainless steel surface. Therefore the swab must be done as close as practically possible to the validated swab procedure.

Non-standard swab areas

2

Where it is not possible to swab 100cm the actual area swabbed is recorded and an adjustment to the acceptance limit is made. For example, if the swab area is only

2

50cm the limit is halved.

5.5.2. Rinse sampling

The rinse method should be based on the procedure validated by the Analytical laboratory.

Non-standard rinse volumes

Where it is not possible to rinse to the required ratio of Rinse:Surface area, the actual volume used is recorded and an adjustment to the acceptance limit is made. For example, if the rinse volume calculated is 1L and 2L was required the limit is then halved.

5.6. Monitoring During Automated Cleaning Cycle

The main data required from any test is cleaning water flowrates, cleaning time and water temperatures.

5.7. Collecting Rinse Samples

In some cases for each rinse sample both a chemical and microbiological sample is

st

required, if this is the case collect the microbiological sample 1then aseptically transfer some of the solution into a sample container for chemical testing.

For manual rinse samples the following precautions should be followed. Containers for collecting samples i.e. sample jars, trays, buckets, etc. must be clean and thoroughly rinsed with distilled water, especially when taking conductivity measurements and for TOC analysis. For TOC testing use clean TOC vials or glass Schott bottles. Any devices such as manual valves used to collect samples must be of a cleanable design and always cleaned prior to use. Containers used to pressure transfer water samples through product lines must also be clean and rinsed thoroughly with Distilled water. For TOC testing it is important to collect a small sample of the rinse water used as a blank sample to measure the background TOC.

5.8. Collecting Swab samples

The principles explained under rinse samples also apply to swab sampling. The swabbing procedure must be based on the procedure validated as part of the analytical method validation. The relevant file for method validation should be used as a basis for describing the swabbing procedure in the test protocol.

5.9. Collecting Microbiological samples (bioburden)

The main requirements are that sample containers are pre-sterilised; the sample valves used

°

are clean and pre-sanitised by flushing with 80 C distilled water for 5 minutes.

5.10. Failed Results

Any failures of the rinse and swab samples must be dealt with by investigating the reasons for the failure; making changes to procedures and then repeating the test. Sampling, testing, re-sampling and re-testing the same equipment should not be conducted if test results