Cleaning Validation Program in a Multiproduct Injectable Drug Manufacturing Company

Case study for practical implementation of cleaning validation program in a multiproduct injectable drug manufacturing company

Introduction

Cleaning validation is a perpetual undertaking for multi-product drug manufacturing companies with a dynamic product profile, continuously impacted by altering commercial needs. With the rise in demand of complex molecules or highly potent drugs, manufacturers continue to invest in newer technologies such as containment systems which offer protection to both operators and finished products (1). This causes companies to have multiple production equipment and manufacturing lines ranging from production facilities with antiquated technologies (legacy facilities) to facilities with newer technologies (example – Isolators or RABS).

This case study discusses implementation of cleaning validation program in one such upcoming multiproduct injectable drug manufacturing facility with multiple production lines and unique challenges observed during implementation and evolution of the cleaning validation program to harmonize with current industrial trends.

Understanding the complexity of cleaning validation implementation across multiple production lines

The drug manufacturer has four production lines with unique challenges for product based contamination control, as summarized in Table 1.

Table 1 – Production Lines Profile

A risk matrix to highlight the ranking of each production line with respect to residual contamination, developed based on severity of residual contamination (if residues were transferred to the next batch) and likelihood of equipment retaining residual contamination post cleaning (due to the variability of cleaning operation), is shown in Figure 1.

Figure 1 – Residual Contamination Risk Matrix

Residual Contamination Control in the Legacy Line A

A major risk factor while executing manual cleaning procedures is inconsistency from operator to operator, or the same operator during different cleaning runs. The cleaning process for legacy line A was designed to minimize the likelihood of “inconsistency between operators”. The goal during cleaning process development was to ensure all products with similar solubility were able to be cleaned by one procedure (i.e. constant time, water pressure, temperature, mechanical action, etc.), thereby, markedly minimizing the opportunity of inadvertent errors such as implementing a wrong cleaning procedure. To further prevent contamination between batches, products in the legacy line A are manufactured in dedicated equipment.

If the equipment is to be shared between products, cleaning verification (including swab and rinse sample testing) is completed prior to use of equipment for another batch. Cleaning validation is completed on the worst case product with lower detectability or solubility. Production equipment is visually inspected for presence of any residue on the surfaces at the end of each cleaning event. Additionally, each cleaning event is monitored via rinse sample testing before using the equipment again.

A robustly designed cleaning procedure, trained operators and usage of dedicated equipment provide assurance of risk mitigation with respect to residual contamination in the legacy line A with manual cleaning operations.

Design and Development of Cleaning Validation Program

As the company expanded, new state of the art production lines B and C were added, dedicated to non-cytotoxic and cytotoxic products respectively. Each line is equipped with a dedicated CIP skid and a parts washer for automated cleaning while preventing cross contamination by actives from different production lines. Lines B and C are also equipped with formulation and filling isolators which are critical with respect to contamination prevention of the finished product.

A site wide cleaning validation program was developed and implemented in phases, beginning with Lines B & C, followed by Line D. The program was then extended to dedicated equipment on line A. The program was designed to follow a lifecycle approach shown in Figure 2 (3,5).

Figure 2 -Lifecycle Approach for Process Validation

Stage 1 – Process Design

Design space for cleaning validation program included risk factors associated with the variability of products and cleaning procedures that could lead to residual contamination between subsequent batches. A cause-and-effect diagram highlighting these potential causes of failure of cleaning procedure, is shown in Figure 3.

Figure 3 – Cause and Effect Diagram for Residual Contamination

Cleaning validation masterplan was developed recognizing the risk factors shown in Figure 3, and developing procedures to adequately mitigate these risks, while defining relevant Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) (4,5). The masterplan included establishment of a cleaning validation committee with defined responsibilities of each participating department, deliverables of the cleaning validation program, leading up to continuous process verification program stage.

Lines B and C contain portable process equipment which are cleaned in dedicated cleaning areas using CIP skids for manufacturing tanks and parts washer for smaller equipment. Operations such as equipment disassembly and loading parts in the parts washer are limited to the cleaning area and cleaned and dried equipment is stored in a separate area to avoid any possible cross contamination between unclean and cleaned parts.

Cleaning cycles developed for CIP skid(s) and parts washer(s) consist of three phases – prewash, cleaning and drying, as summarized in Figure 4.

Figure 4 – Cleaning Cycle Development and Critical Process Parameters

Critical Quality Attributes

Cleaning process for every product is evaluated for effectiveness through visual inspection of equipment product contact areas and testing of rinse and swab samples collected at the end of the cleaning cycle.

Specific analytical methods such as HPLC, Ion Chromatography (IC) are used for detection of residues from the production equipment. Swab samples are collected from locations that are either difficult to clean, or are critical for production. Riboflavin studies are conducted to determine areas which might be harder to clean than the rest. Residual limits for swab samples are derived from therapeutic dosages or Acceptable Daily Exposure (ADEs) and calculating Maximum Allowable Carryover (MACO, mg) and Surface Area Limit (SAL, µg/cm²) between two batches. (2)

Additional nonspecific analytical tests such as conductivity and Total Organic Carbon (TOC) are also executed on rinse samples. These tests provide comprehensive evaluation of the tank cleanliness for residues otherwise not analyzed by HPLC/IC etc. Microbial contamination is assessed through bioburden and endotoxin testing.

Product Cross Contamination Assessment

The dynamic product profile of the company includes products of varying solubilities, pH and toxicities. All products are evaluated for their cleanability by the current cleaning cycle and if need be, a newer cycle may be developed to clean a product which cannot be grouped with existing products.

Products filled in Lines B and C are grouped by shared formulation vessel. These products are then ranked based on Surface Area Limit (SAL, µg/cm²) between subsequent batches in any possible combination of production schedule. An example of product matrix is shown in Table 2 below with a ranking system of the products (Products – CP1, CP2, CP3, NP1, NP2 and NP3)

Table 2 – Product Matrix Ranking

Cross Contamination Assessment is done for products as shown in Figure 5, before introducing a product into an existing matrix. Through this cross contamination assessment, conclusions are drawn whether to share equipment, use dedicated or disposable equipment, cleaning validation approaches for direct contact parts and verification and monitoring requirements for indirect and non-product contact surfaces.  

 Figure 5 – Cross Contamination Assessment for a new Product

Coupon studies are executed as a part of cross contamination assessment for all new products to evaluate product cleanability as well as product impact on the intended manufacturing equipment surface. Typically, coupons are soiled with a product and dried in air for a minimum of 72 hours before proceeding with cleanability assessment. For products with low pH, this can result in rouging of the coupons, therefore, resulting in conclusion to clean equipment immediately post production. Table 3 shows an example of coupon studies of three new products (Products 1, 2 and 3) and resulting product cleaning assessment.

Table 3 – Examples of coupon studies for cleanability assessment

Stage 2 – Process Qualification

Cleaning validation runs are routinely scheduled to coincide with production runs. If necessary, equipment may also be soiled artificially and dried for a cleaning validation run. At least one cleaning verification run is executed on each product, depending on the risk profile of the product and the studies executed during process design stage (6). If warranted, a minimum of three cleaning validation runs are performed on the high risk products.

Validation runs are executed on both shared and dedicated equipment. For shared equipment, limits are calculated considering all products manufactured in the equipment and cleaning process is validated for the lowest limit.

Stage 3 – Continuous Process Verification

Risk factors associated with continuous process verification can be seen in Figure 3. A multi-fold approach is implemented to ensure that the cleaning process remains in validated state.

1. Automated cleaning processes are verified periodically through a cleaning verification run. Visual inspection and inline rinse monitoring are performed at the end of each cleaning event.
2. For manual cleaning processes, cleaning is verified through visual inspection and rinse sampling for TOC at the end of each cleaning event, to ensure there are no anomalies in the cleaning process. 
3. All changes to equipment or manufacturing process flow are assessed for their impact on the cleaning process and are captured through change controls to ensure traceability. If cleaning validation/verification is to be executed on a new equipment, a worst case product and manufacturing condition as applicable to the equipment is chosen and the run is executed with rinse sampling for residual and microbial assessment and swab sampling for product specific residual assessment.

Conclusion

Aimed at robust product quality, safety and customer protection, cleaning validation program is implemented through a lifecycle approach, tailored to suit facility design, technological opportunities available in each production line, variability of the product profile and expanding product portfolio in this multiproduct facility. Risk assessments are performed to evaluate the cleanability and detectability of the product and procedures are developed accordingly to ensure prevention of cross contamination between batches.

References

1. F. Mirasol, “Automation Trend in Fill/Finish Reduces Contamination Risk,” BioPharm International31 (6) 2018.
2. Technical Report No. 29 (Revised 2012) Points to Consider for Cleaning Validation, PDA
3. Guidance for Industry, Process Validation: General Principles and Practices, January 2011, FDA
4. ICH Harmonized Tripartite Guideline: Pharmaceutical Development, Q8(R2), Current Step 4 Version, August 2009.
5. Building Blocks of Quality by Design, Snee, R. D., January 2013. (http://www.ivtnetwork.com/article/building-blocks-quality-design)
6. Developing A Science-, Risk-, & Statistics-Based Approach to Cleaning Process Development & Validation, Thomas Altmann, Alfredo Canhoto, Michel Crevoisier, Igor Gorsky, Robert Kowal, Mariann Neverovitch, Mohammad Ovais, Osamu Shirokizawa, and Andrew Walsh, June 2017 (https://www.pharmaceuticalonline.com/doc/developing-a-science-risk-statistics-based-approach-to-cleaning-process-development-validation-0001)
7. Guide to Validation of Cleaning Processes, July 1993, FDA