Identifying Difficult-To-Clean Or -Inspect Surfaces In Manufacturing And Packaging Equipment

This article describes a practical risk-based approach for assessing and identifying the surfaces, areas, or sites of manufacturing and packaging equipment that are cleaned upon completion of oral solid dosage manufacturing production. As stated in the FDA’s Guide to Inspections Validation of Cleaning Processes (7/93), “the firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results.” Therefore, for a cleaning validation program that will successfully qualify and continually verify well-designed cleaning processes, meaningful and methodical recovery studies need to be conducted.

The approach is based on thorough assessment and evaluation of all critical equipment that plays a major role in product manufacturing and identification of difficult to clean or inspect surfaces, areas, or sites, including: (i) visual inspection of the equipment and parts; (ii) expertise and empirical knowledge from the subject matter expert (SME) involved in the processing and cleaning of the equipment and parts; and (iii) recommendations from the equipment manufacturer. The assessment should be performed and documented using appropriate templates or forms for consistency and document control. These types of assessments are the basis for a successful cleaning validation program.

Recovery Studies Approach

First of all, an SME(s) should perform an assessment to identify the surfaces/areas/sites of equipment/parts and use a risk-based approach to classify difficulty in cleaning. An assessment should be performed separately for each piece of equipment; however, similar equipment (same name, model, design, working principle, scale, and manufacturer) may be grouped for a risk assessment. There are two ways to perform a risk assessment:

• Determine difficult to clean areas by a visual residue inspection.
• Determine difficult to clean areas on clean equipment, by assessing the residue level that can be accumulated during the processing of the product.

Identification of Areas/Sites/Surfaces using Visual Residue Inspection

It is prudent to use a well-designed template to document the equipment name and number, the product name and strength processed, the date the was product processed, and the date the visual inspection is performed or the pictures are taken. The SMEs, along with quality team, should perform assessments for visible residue level (VRL) and surface cleanability level (SCL).

It is more beneficial when VRL and SCL assessments are performed at the same time. The team visually inspects all surfaces, areas, or sites of the equipment with residue in a dirty state (after use and prior to cleaning, or right after discharging the product).  The first step is to identify all of the direct product contact (DPC), indirect product contact (IPC), and on-product contact (NPC) surfaces, sites, or areas of the equipment and part(s). It is a good practice to take pictures of these surfaces, areas, and sites. Pictures can be taken with all the parts disassembled, as necessary for a specific situation. The firm may decide to create a photo library of all the equipment pictures taken. Pictures can be arranged with the DPC parts first, followed by IPC and NPC parts. Arrows can be used to point to the locations/areas/sites of interest. It is important to carefully label the identified surfaces, areas, and sites in the pictures in the photo log using the format “DPC-X,” “IPC-X,” and “NPC-X,” similar to the example illustration in Table 1.

Table 1: Illustration of Contact Area Notations

For example, the third direct product contact surface area/site of equipment number or asset number 1045 could be identified as 1045-DPC-3.

Table 1 represents an example of residue type commonly seen in oral solid dosage manufacturing facilities. Based on the physical characteristics and extent of residue contact, accumulation, or presence on each of the DPC, IPC, and NPC parts identified upon visual inspection, rate the VRL of each residue type in an increasing order of difficulty to clean, as shown in Table 2.

Table 2: Rating of the Residue Type Contact on the Sites/Areas/Surface of Equipment

If additional types of residue are present in a specific manufacturing environment (listed or not listed in the table above), identify and rate them accordingly. This exercise should be performed by or guided by SMEs.

The next step is to assess all the surfaces, areas, and sites of DPC, IPC, and NPC parts of the equipment based on the material of construction, design, geometry, and accessibility. The SMEs should rate the SCL of each of the areas or sites in an increasing order of difficulty to clean, as shown in Table 3.

Table 3: Rating of Surface Cleanability Based on the Nature, Type, and Geometry of Surfaces, Areas, and Sites of Equipment

If a combination of different kinds of surfaces is present on a part, consider the worst case and rate it accordingly. If additional types of surfaces, areas, or sites are present/identified (that are or are not listed in the table above), identify and rate them accordingly (this must be performed by an SME).

IPC areas/parts/sites and NPC areas/parts/sites can be combined and rated, if they are exposed to the same extent of the contaminant residue and/or are of the same type of surfaces/areas.

The inspection, identification of affected surface areas and sites, and risk assessment can be performed for more than one product type and process on a given piece of equipment to capture the impact of different types of residues and processes.

Identification Of Difficult To Clean Areas Using Clean Equipment

When you have a new piece of equipment that has not undergone any usage, you may not be able to assess it in a dirty state.This type of assessment should be rare. Similar to the process described in the previous section, a template can be used to document the equipment name and number, the date the equipment was cleaned, and the date the pictures are taken.

The assessment for SCL can be performed by following the steps below.

Identify the surfaces, areas, or sites that become difficult to clean due to the nature (material of construction), design, geometry, and accessibility of the surfaces of equipment and parts (where residue comes in contact or accumulates, and where residue does not come in contact). Identify these parts/areas/sites as DPC, IPC, and NPC, in accordance with the definitions provided above. You can take pictures of these surfaces, areas, and sites with all the parts disassembled and create a photo log of all the pictures taken. Pictures can be arranged in the order of DPC parts followed by IPC and NPC parts. Use arrows to point to the locations/areas/sites of interest in the picture. Label the identified surfaces, areas, and sites in the pictures of the photo log as described in the previous section.

The SMEs, along with the quality team, should rate the SCL of each of the areas or sites in an increasing order of difficulty to clean in accordance with the ratings provided in Table 2. If a combination of different kind of surfaces is present on an equipment or part, consider the worst case and rate accordingly. If additional types of surfaces, areas, or sites are present/identified (that are not listed in the table), identify and rate them accordingly (this must be performed by an SME).

IPC areas/parts/sites and NPC area/parts/sites can be combined and rated, if they are exposed to the same extent of the contaminant residue and/or are of the same type of surfaces/areas.

The residue level (RL) assessment is performed based on the knowledge of the product processing and type of residue contact and accumulation on each of the DPC, IPC, and NPC surfaces/areas/parts. Rate each of the surfaces/areas/sites, and assign each an RL in an ascending order of difficulty to clean in accordance with Table 1.

Once the SCL and VRL or RL have been assigned or determined for each area or site, calculate the risk level for each area or site using the risk level equation:

Risk Level = Impact (Severity) x Occurrence Probability, where:

Impact (Severity) = Surface Cleanability Level (SCL)

Occurrence Probability = Visible Residue Level (VRL) or Residue Level (RL)

Based on the risk level obtained for DPC, IPC, and NPC parts, independently categorize the risk as low, medium, or high using Table 4.

Table 4: Risk Category Assignment Based on Risk Assessment Performed

Finally, document the risk level in the risk category section of your template. A higher risk category corresponds to greater difficulty in cleaning the area or site, and vice versa.

Conclusion

This article presents a risk-based approach for determining surface areas for cleaning process and cleaning validation. It aids in effective and efficient design of cleaning processes and a cleaning validation program. Practitioners may find it useful as it promotes the use of risk assessment and knowledge of equipment and cleaning processes, thus promoting the principles of ICH Q10: Pharmaceutical Quality Systems.

Glossary:

Risk Assessment: A systematic process for the identification of potential hazards and the analysis and evaluation of risks associated with such hazards.

Direct Product Contact (DPC) Surface: The surface of a piece of equipment or a part that comes in direct contact with the whole batch of a product in processing (for example, the powder hopper of compression and encapsulation equipment).

Indirect Product Contact (IPC) Surface: The surfaces of a piece of equipment that are not directly coming into product contact, but are in close vicinity to where product is being handled/processed and where potential airborne particles may be present on these surfaces (for example, the drying oven trays and chamber).

Non-Product Contact (NPC) Surface: The surface of a piece of equipment or a part that is not involved in functional processing action but that may be soiled with product in the process flow path (for example, equipment exteriors, covers, above and underneath of turret disc of tablet presses, empty hard gelatin capsule handling equipment or parts, oven cart trolleys, fill cam of tablet presses, vacuum connecting tubes, etc.).

Surface Cleanability Level (SCL): A rating system that evaluates the level of difficulty of removing product residue from the surfaces or areas or sites of the equipment and parts based on the nature, geometry, and design of equipment and parts.

Visible Residue Level (VRL): A rating system that identifies the actual physical characteristics and amount or extent of product residue on the surfaces, areas, or sites of equipment and parts based on visual inspection. This rating is only applicable when performing assessment after product has been introduced on the equipment and prior to cleaning of equipment.

Residue Level (RL): A rating system that evaluates the difficulty level of cleaning of a given surface, area, or site based on product nature and extent of residue contact or accumulation that is performed solely based on experiential knowledge and expertise. This rating is only applicable when performing assessment on clean equipment.

References:

• Cleaning Validation for the 21^st Century, Andrew Walsh, and et al., Pharmaceutical Online e-Book.
• PDA Technical Report No. 29 (Revised 2012) – Points to Consider for Cleaning Validation.
• E. Rivera and P. Lopolito, Evaluating Surface Cleanliness Using a Risk-Based Approach – Pharmaceutical Technology, Vol. 41, Issue 12, Page 28-37, Dec. 2017.
• Paul L. Pluta, Ph.D., Global Cleaning Validation Technical Problems – 2018, Pharma Central, May 7, 2018
• Igor Gorsky, “How Clean is Clean in Drug Manufacturing, Part 2,” American Pharmaceutical Review, Volume 18, Issue 1, March/April 2015         
• Igor Gorsky “How Clean is Clean in Drug Manufacturing,” American Pharmaceutical Review, Volume 17, Issue 5, July/August 2014
• Guidance for Industry – Q9 Quality Risk Management, June 2006
• 21 CFR 211. 67 – Equipment Cleaning and Maintenance

About The Authors:

Prakash Patel is the vice president of the Quality Operations Division of Sigmapharm Laboratories, LLC, where he heads the company’s commercial manufacturing, quality assurance, and compliance functions. As the head of Quality Operations, he oversees the division’s Operations, Quality Assurance, and Compliance & Auditing departments. He has participated in, and managed, several successful FDA inspections of the company and other key projects. He has an MS in pharmaceutical manufacturing engineering from the Stevens Institute of Technology and a BS in pharmacy from the Rajiv Gandhi University of Health Sciences, Bengaluru, India.

Igor Gorsky has been a pharmaceutical industry professional for over 30 years. He held multiple positions with increasing responsibility at Alpharma, Wyeth, and Shire. He worked in production, quality assurance, technical services, and validation, including as associate director of global pharmaceutical technology at Shire. He is currently principal consultant at ValSource. He is leading the PDA Water Interest Group and a PDA Task Force for revision of PDA TR 29: Points to Consider for Cleaning Validation. In addition, he is a member of ASTM E55 and one of the authors of ASTM E3106 and E3207. He has a BS in mechanical/electrical engineering technology from Rochester Institute of Technology.