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Table of Contents Page

|PURPOSE |………………………....................................................... |2 |

|SCOPE |………………………....................................................... |2 |

|DEFINITIONS |………………………....................................................... |2 |

|ASSOCIATED DOCUMENTS |………………………....................................................... |4 |

|RESPONSIBILITIES |………………………....................................................... |5 |

|HEALTH and SAFETY |………………………....................................................... |5 |

|PROCEDURE |………………………....................................................... |6 |

|APPENDIX LISTING |………………………....................................................... |10 |

PURPOSE

The purpose of this Quality Procedure is to instruct upon:

• The visual inspection of product contact equipment to be performed on clean, dry equipment to ensure equipment is visibly clean, free of surface anomalies and ready for use

SCOPE

This Quality Procedure applies to any Business Units of that manufacture commercial product under current Good Manufacturing Practices (cGMP).

For operations related to Cosmetic, Food Supplements and Medical Devices products, this procdure may be fully or partially applied according to specific customer requirements and relevant EU guidelines.

Non-product Contact Equipment is excluded from this procedure as ineffective cleaning does not result in cross contamination.

Disposable equipment is designed for one-time use and is outside the scope of this procedure.

DEFINITIONS

|Baseline Visual Inspection |A visual inspection with the objective of documenting permanent surface anomalies so as to avoid visual inspection |

| |failures due to inherent equipment characteristics. |

|Equipment Classification Level|Equipment assets within a system where operation or maintenance activities can affect the critical quality attributes, |

|1 |the critical aspects, or the critical process parameters of the product the system delivers. |

| |(as per Quality Policy, , Systems Qualification) |

|Enhanced Visual Inspection |An intrusive visual inspection performed as part of equipment verification or validation activities or in response to a|

| |visual observation. Product contact surfaces are inspected more closely with a direct line of sight, not through a |

| |sight glass. |

|Extraneous Matter |Discrete, particulate material not belonging to that in which it is contained. For example, particulate recovered that |

| |originated from process equipment but is not part of the process stream. |

|General Visual Inspection |Non-intrusive visual inspection of equipment performed post-cleaning or prior to use to verify equipment cleanliness. |

|Intrusive inspection |Inspection that requires non-routine equipment entry or non-routine disassembly of equipment. |

|Level 1 Systems |A system containing classification level 1 assets. Can contain classification level 2 or 3 equipment assets. |

| |(as per Quality Policy, , Systems Qualification) |

|Level 1 Product Contact |All process equipment that receives a visual inspection post-cleaning per specified acceptance criteria. |

|Equipment |(as per Quality Policy, , Systems Qualification) |

|Non-Intrusive Inspection |Inspection performed through a sight glass or without additional break down or opening of equipment. |

|Product Contact Equipment |Equipment which comes into direct contact with either an active ingredient or an excipient. |

|Surface Anomaly |Physical imperfection found on the equipment surface that requires assessment. |

|Visual Discontinuity |Physical imperfection found on the equipment surface that is inherent to the equipment that may not require assessment.|

|Visual Inspection |The visual examination of the product contact surfaces of equipment to determine if equipment is clean and free of |

| |visible residues, extraneous matter, and to identify surface anomalies. |

|Visible Residues |Residue that remains after cleaning but can be removed with additional physical force such as wiping or scraping. |

ASSOCIATED DOCUMENTS & REFERENCES

✓ PDA Technical Report No. 29, Points to Consider for Cleaning Validation

✓ PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation

✓ International Society for Pharmaceutical Engineering (ISPE), Guides:

o Science and Risk-Based Approach for the Delivery of Facilities, Systems, and Equipment (2011)

✓ US FDA Current Good Manufacturing Practice, Validation of Cleaning Processes

✓ EU current Good Manufacturing Practices - Volume 4 of Annex 15

✓ EU current Good Manufacturing Practices Chapters 3 (Premises and Equipment) and 5 (Production)

✓ US Code of Federal Regulations, Title 21, Food and Drugs (Where Applicable)

o 21 CFR Part 210 and 211

✓ WHO guidelines for Good Manufacturing Practices, Annex 4, Technical Report Series 937, 2006

✓ US FDA - Guidance for Industry-Process Validation: General Principles and Practices – January 2011 – Revision 1

✓ ICH Q8 - Pharmaceutical Development

✓ ICH Q9 - Quality Risk Management

✓ ICH Q10 – Pharmaceutical Quality System

✓ Quality Policy, , Quality Risk Management

✓ Quality Policy, , Systems Qualification

✓ Quality Guideline, , Management of Deviations

✓ Quality Guideline, , Cleaning Validation

✓ Quality Procedure, , Management of Validation Deviations

RESPONSIBILITIES

|WHO |WHAT |

|Heads of Business Units (BUs/DCs) |Implementation and verification of the Procedure at respective BUs/DCs |

|BUs/DCs Management | |

|Heads of the Quality Management of BUs | |

|Management Team of BUs |Implementation of the Procedure at respective BUs/DCs |

|Global Quality Members |Verification of the Procedure at respective BUs/DCs |

| |Ensures the necessary supporting Quality Policies and Guidelines and Procedures are |

| |aligned and implemented |

|Site Quality Operations |Participate in investigation process |

| |Approve strategy for mitigation and/or continued processing in response to visual |

| |observations |

|Site Qualification / Validation |Perform and document baseline and enhanced visual inspections |

| |Report any surface anomaly |

| |Participate in investigation of surface anomalies |

| |Determine if new Baseline Visual Inspection is required following equipment changes |

|Site Maintenance Engineering |Develop and execute strategy for mitigation in response to visual observation |

| |Report any surface anomaly |

| |Report any visual observations |

HEALTH and SAFETY

Each colleague performing a defined task must use the required personal protective equipment (PPE) related to the task to be performed as defined and specified in the applicable task safety assessment. The applicable task safety assessment will detail the safety precautions to follow and the required PPE necessary for the task to be performed.

PROCEDURE

GENERAL

Equipment visual inspections fall into the following categories:

• Baseline Visual Inspection

A visual inspection with the objective of documenting permanent surface anomalies so as to avoid visual inspection failures due to inherent equipment characteristics

• General Visual Inspection

Non-intrusive visual inspection of equipment performed postcleaning or prior to use to verify equipment cleanliness.

• Enhanced Visual Inspection

An intrusive visual inspection performed as part of equipment verification or validation activities or in response to a visual observation. Product contact surfaces are inspected more closely with a direct line of sight, and not through a sight glass.

All three types of visual inspections are necessary to ensure that product contact equipment is clean, free of residue and surface anomalies and is ready for production use.

General Requirements

• Visual inspections are to be performed on clean, dry equipment. The requirements to use supplemental lighting must be recorded in the test protocol.

• Supplemental lighting must be used if vessel or ambient lighting is not adequate.

o Supplemental lighting type and model must be specified in site procedures.

• Clear instructions regarding supplemental lighting use must be included in the test protocol to ensure visual inspection repeatability and minimize inspection variability.

Baseline Visual Inspection

• A baseline visual inspection must be established for all Level 1 system product contact equipment as per Quality Policy, , Systems Qualification.

20 Inspection Requirements

• The locations for inspection to be specified in the test protocol are with minimum requirements identified within Appendix 1.

• Initial baseline visual inspections are to be performed after equipment installation and cleaning.

• Baseline visual inspection must be performed prior to the start of a cleaning validation study.

• The need to re-baseline must be assessed after significant equipment modifications. If the product contact surface is modified, the baseline must be re-established and compared back to the previous baseline.

• Baseline visual inspection can be intrusive and may require non-routine equipment entry or disassembly of equipment which must be documented in the test protocol. Product contact surfaces are inspected with an unobstructed line of sight.

• Equipment surfaces must be clean and dry prior to inspection.

o Minimal condensate is acceptable if this is a normal observation for the equipment

• If supplemental optical devices, such as an enhanced mirror or a borescope are used, documented evidence of capability and calibration such attached to the test protocol.

• Identify and differentiate between any surface anomalies or visual discontinuities that are inherent to the equipment based on categorisation in Appendix 2.

• Refer to Section 6 for response to visual observations recorded.

21 Inspection Documentation Requirements

• All surface anomalies or visual discontinuities identified during the Baseline visual inspection must be recorded in the test protocol.

o Include a specific and detailed description that contains objective information describing the nature and location of the surface anomaly or visual discontinuity.

o Include photograph of the surface anomaly or visual discontinuity where appropriate.

• An example Inspection report is presented as Appendix 3.

General Visual Inspection

23 Inspection Requirements

• General visual inspection is a component of the cleaning continuous monitoring program.

• General visual inspection is a critical quality attribute for the process cleaning.

• General visual inspections are non-intrusive. All visible product contact surfaces that can be seen through a tank sight glass or without additional break down or opening of equipment must be inspected. Refer to Appendix 1 for a list of minimum locations to be inspected by equipment type.

• If a more intrusive visual inspection is required on a particular piece of equipment as part of routine visual inspection, the specific requirements, such as lighting requirements and additional inspection locations must be defined in the test protocol.

• Equipment surfaces must be clean and dry prior to inspection.

o Minimal condensate is acceptable if this is a normal observation for the equipment

• General visual inspections must note the presence of any visible residues or physical defects such as:

o Visible residue

o Cleaning solutions and standing liquids

o Extraneous matter and foreign objects or materials

• Refer to Section 6 for response to visual observations recorded.

24 Inspection Documentation Requirements

• General visual inspections must be documented as part of a batch record for the product under manufacture.

Enhanced Visual Inspection

26 Inspection Requirements

• Enhanced visual inspections are performed as part of equipment verification or validation activities or in response to a visual observation.

• Enhanced visual inspections can be intrusive and may require non-routine equipment entry or disassembly of equipment. Product contact surfaces are inspected with an unobstructed line of sight.

• Supplemental optical devices, such as mirrors, cameras, or a borescope may be required.

• Inspection locations may vary, depending on the reason for the enhanced visual inspection or to perform enhanced degree of inspection.

• For an enhanced visual inspection in response to a visual inspection observation, the inspection may focus on the specific location where there was an observation.

27 Inspection Documentation Requirements

• Enhanced visual Inspections must be documented using retrievable GMP document, such as a maintenance work order, equipment/process specific documentation, or a study/validation protocol.

Response to Visual Observations

• Identify the type of visual inspection observation as per Appendix 2.

• Notify the manufacturing supervisor immediately of any visual inspection observation.

• Immediately proceed on required actions based on following decision table:

|IF |THEN |

|Surface Anomaly |Generate a maintenance work order to correct surface anomalies that do not conform to qualified surface |

|Rouging |finishes or that have the potential to impact the cleanability of the equipment. |

|Pitting |- - - |

|Scratches |Assess impact as per Quality Policy, , Quality Risk Management as required. |

|Abrasions |- - - |

| |If no correction is needed, update the Baseline Visual Inspection as required. |

|Visual Discontinuity |Refer to the equipment Baseline Visual Inspection Report for comparison. |

|Weld Defects |- - - |

|Repair/Polish Marks |If report differs from current condition, proceed to assess the requirement to correct visual discontinuities |

|Discolouration |that do not conform to qualified surface finishes or that have the potential to impact the cleanability of the |

| |equipment as per Quality Policy, , Quality Risk Management |

| |- - - |

| |If no correction is needed, update the Baseline Visual Inspection as required |

|Visual Residue |If observed during maintenance / operations - Generate a Quality Investigation as per Quality Guideline, |

|(Extraneous Matter) |, Management of Deviations |

|Oil / Grease |or |

|Foreign Debris |If observed during qualification/validation phase - must be addressed as per Quality Procedure, , Management of Validation Deviations |

|Visual Residue |If observed upon completion of validated cleaning process - Generate a Quality Investigation as per Quality |

|(Not Extraneous Matter) |Guideline, , Management of Deviations. If the visible residue cannot be manually removed from |

|Process Soils |the equipment, alternative methods of removal and potential impact must be determined per the investigation. |

|Cleaning Agents |or |

| |If observed during qualification/validation phase - must be addressed as per Quality Procedure, , Management of Validation Deviations |

|In All Instances |Document the observation on the applicable documentation, providing detail as to the location and nature of the|

| |observation |

APPENDIX LISTING

|APPENDIX NUMBER |APPENDIX TITLE |

|1 |Equipment Inspection Locations |

|2 |Visual Observation Classification |

|3 |Baseline Visual Inspection Report Example |

END OF PROCEDURE DOCUMENT

APPENDIX 1: Equipment Inspection Locations

|EQUIPMENT TYPE |Locations (as applicable) |

|Level 1 Product Contact Equipment |Requires a Baseline Visual Inspection per Section 3 and General Visual Inspection per Section 4 |

|Process Vessels and Tanks |Interior Surface |

| |Operational Level, Air/Liquid Interface |

| |Head Space / Top Dome |

| |Agitator Assembly |

| |Inlet and Outlet Ports |

| |Sprayball Shaft/Orifices |

| |Sidewalls and Vessel Bottom |

| |Baffles |

| |Sparger |

| |Vortex Breaker |

| |Outlet Valve |

|In-line filter housing and/or skid |Inside Wall of Housing |

| |Inlet/Outlet Ports |

| |Bottom of Filter Housing Assembly |

| |Spray Balls/Devices |

|Transfer Lines |Inlet and Outlet Ports |

|Additional Equipment |Requires a General Visual Inspection per Section 4 |

|Flex Hoses |Inlets and Outlets |

|Raw Material Totes |Interior Surfaces |

| |Inlet and Outlet Ports |

| |Spray Balls/Devices |

|Small Parts |All visible surfaces to ensure continuous monitoring of the integrity and cleanability of these |

|e.g. process connections, reducers, elbows, funnels, |parts as they are mobile, frequently handled, and may be critical product contact components |

|containers | |

END OF APPENDIX 1

APPENDIX 2: Visual Observation Classification

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|ROUGE |A general term used to describe a variety of discolorations on metal or polymer surfaces in |

| |high-purity stainless steel systems. It is composed of metallic (primarily iron) oxides |

| |and/or hydroxides. |

|Class 1 Rouge |[pic] |

|Usually orange to red-orange to magenta and tends to migrate|[pic] |

|downstream from its origination point; not always visible | |

|without enhanced illumination. | |

|Weakly attached to the surface and is easily removed, may be| |

|migratory. | |

|Particulate in nature; these particles can be wiped off of a| |

|surface and are evident on a wipe. | |

| | |

|Class 2 Rouge | |

|Usually dark orange/red; is a form of active corrosion | |

|similar in appearance to common rust. | |

|Usually visible with basic illumination. | |

|This type of rouge is integral to the surface of the metal, | |

|and will not become migratory. | |

|Could potentially lead to damage and must be assessed for | |

|impact and remediation. | |

| | |

|Class 3 Rouge | |

|Blue or black; frequently found in areas under exposure to | |

|the high temperatures of clean steam systems. It is often | |

|blue upon first formation, and turns black as the layer | |

|thickens. | |

|Not a particulate like Class I rouge | |

|Extremely stable | |

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|PITTING |Pitting or Pitting Corrosion is a form of extremely localized corrosion that leads to the |

| |creation of small holes in the metal. |

|The driving power for pitting corrosion is the depassivation| |

|of a small area, which becomes anodic while an unknown but |[pic] |

|potentially vast area becomes cathodic, leading to very | |

|localized galvanic corrosion. | |

| | |

|Pits act as potential retention points for residual and | |

|microbiological contamination must be assessed for impact | |

|and remediation. | |

| | |

|Pitting can lead to structural weakening of the metal if | |

|located at a critical loading point. | |

| | |

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|Scratches |Manually induced superficial and line-like loss of material due to the action of a pointed |

| |object. Usually it appears as a long groove. |

|Scratches are the result of mechanical damage caused from | |

|mechanical wear and tear or actions. |[pic] |

| | |

|Scratches act as potential retention points for residual and| |

|microbiological contamination must be assessed for impact | |

|and remediation. | |

| | |

|Mechanical damage leads to: | |

|Change of material shape | |

|Change in axial alignment | |

|Change of material properties | |

|Change to the local distribution of stresses strains, and/or| |

|local loading | |

|Introduction of other anomalies or defects to materials | |

| | |

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|Abrasion |Erosion due to wearing down or rubbing away by means of friction, or to the impact of |

| |particles. |

|Abrasions are the result of mechanical damage caused from | |

|mechanical wear or rubbing (abrasive) actions. |[pic] |

| | |

|Abrasions act as potential retention points for residual and| |

|microbiological contamination must be assessed for impact | |

|and remediation. | |

| | |

|Mechanical damage leads to: | |

|Change of material shape | |

|Change in axial alignment | |

|Change of material properties | |

|Change to the local distribution of stresses strains, and/or| |

|local loading | |

|Introduction of other anomalies or defects to materials | |

| | |

| | |

| | |

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|Weld Defects |A welding defect is any flaw that compromises the usefulness of a weldment. |

| | |

|Common weld defects include: |[pic] |

|Lack of fusion | |

|Lack of penetration or excess penetration | |

|Porosity | |

|Inclusions | |

|Cracking | |

|Undercut | |

|Lamellar tearing | |

| | |

|Any of these defects are impact mechanical damage to the | |

|structure as they can all give rise to high stress | |

|intensities which may result in sudden unexpected failure | |

|below the design load. | |

| | |

| | |

|Welding imperfections are classified according to ISO 6520 | |

|while their acceptable limits are specified in ISO 5817 and | |

|ISO 10042. | |

| | |

| | |

| | |

| | |

|VISUAL OBSERVATION |DEFINITION / EXAMPLE |

|Discolouration |Exhibition of multi-faceted discoloration of metal surface |

|The area would normally exhibit multi-faceted discoloration | |

|with the colour and intensity varying dependent on |[pic] |

|progression. | |

| | |

|Upon contact inspection, if the surface is generally smooth | |

|to the touch with no evidence of pitting corrosion or damage| |

|to the underlying metal surface then this indicates that the| |

|Chromium Oxide layer which protects the underlying structure| |

|has not been damaged to the extent that the integrity of the| |

|base metal has been comprised. | |

| | |

|Generally the result of in-process generation of strong | |

|chemicals in the presence of heat which subject the surface | |

|to oxidative species. | |

| | |

|Should be assessed for process improvement to reduce | |

|occurrence. | |

| | |

| | |

| | |

| | |

END OF APPENDIX 2

APPENDIX 3: Baseline Visual Inspection Report Example

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END OF APPENDIX 3

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