Quality Risk Management in the Final Operational Stage of Sterile Pharmaceutical Manufacturing: A Case Study Highlighting the Management of Sustainable Related Risks in Product Sterilization, Inspection, Labeling, Packaging, and Storage Processes

Abstract

Quality risk management, commonly known as QRM, is designed to systematically assess, control, communicate, and review potential risks at every stage of the pharmaceutical manufacturing process. The preservation of consistent product quality across the entirety of the product’s life cycle is of paramount importance. The aim of this article is to formulate a best practice guide that will assist pharmaceutical manufacturers in comprehending and implementing the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q9: quality risk management principles. A widely recognized methodology for defining and monitoring risk mitigation strategies within the pharmaceutical sector is the Failure Mode and Effects Analysis (FMEA). ICH Q9 does not, however, offer detailed instructions for applying FMEA to real-world pharmaceutical situations. We previously provided real-world case studies that identify and mitigate risks in the early stages of the manufacturing process of sterile products, such as (1) supply chain and procurement; (2) logistics and warehousing; (3) raw material dispensing; (4) glass bottle washing and handling; (5) product filling; and (6) final product receiving and handling. The final steps of the sterile manufacturing process are the subject of the case study we present in this paper. We identify and control the risks related to (I) product sterilization; (II) product inspection, labeling, and packaging; (III) the finished product’s transfer to storage; and (IV) storing finished products in a warehouse. In order to maximize decision-making and reduce the risk of regulatory noncompliance, this case study describes a proactive strategy for the identification, management, and communication of risks associated with crucial tasks. While each organization’s products and methods are distinct, with varying tolerances for risk, certain stages and associated risks are common. Consequently, the examples provided here offer relevant insights into any pharmaceutical production environment. Managing sustainability-related risks and ensuring the transparency of pharmaceutical company operations are key tasks of success today. These risks, if not managed, will cause serious problems and a negative reputation, as well as environmental and public impact.

1. Introduction

In pharmaceutical manufacturing, quality risk management is identified as a quality management risk-based approach [1,2,3]. It involves the assessment, control, communication, and review of risks facing the quality of pharmaceutical products through their development in a systematic process [4]. It aims to ensure that products remain safe and effective by proactively identifying potential risks and implementing measures to mitigate these risks [5].

While central to the pharmaceutical industry, QRM is also employed in sectors where quality and safety are paramount, such as in banking, insurance, occupational safety, public health, and pharmacovigilance [6]. The biotechnology industry uses QRM to manage risks in complex biological processes [7]. Medical device manufacturers apply QRM to ensure device safety and regulatory compliance [8]. The food industry utilizes Hazard Analysis and Critical Control Points (HACCPs) to prevent hazards associated with food safety [9]. In healthcare, QRM minimizes risks in patient care and clinical procedures [10,11]. QRM has been applied to pharmaceutical and biomedical industries. One study applied QRM to mitigate risks in sterile product supply chains [12], enhancing the storage and dispensing processes [13]. QRM was also applied to sterile manufacturing at the sterile filling and final handling stages of product manufacturing [14]. Cleaning processes were optimized using Risk-Based Cleaning Validation in Pharmaceutical Manufacturing [15]. In addition, Patel, P., et al. improved risk identification for vaccine manufacturing [4]. The use of QRM tools has also addressed risks in temperature-controlled logistics using QRM tools in Cold Chain Management for Biologics [16,17].

QRM is defined as a structured method for identifying, evaluating, and controlling factors that could potentially affect the quality of pharmaceuticals. According to the ICH Q9, risk is the combination of the occurrence probability of harm and the severity of that harm. QRM helps organizations prioritize resources toward critical areas impacting the quality of products and, eventually, patient safety [18].

The ICH Q9 guideline outlines the following steps for effective QRM [2,19]:

1. Risk Assessment: Identifying, analyzing, and evaluating risks to understand the potential risks to product quality.

The initial step is risk identification, whereby potential risks related to the process are identified. Following this, a risk analysis step is performed, in which the potential harms of the risks are assessed for better comprehension and decision-making, either qualitatively, quantitatively, or a combination. The last step is the decision-making step, which determines the risks that are to be mitigated and those that are acceptable.

• 2.. Risk Control: Making a decision to decrease, eliminate, or accept a risk is recommended by the team leader. Risk reduction includes applying measures to reduce risk severity or likelihood. However, risk acceptance determines if residual risks are acceptable.

• 3.. Risk Communication: Sharing risk information among stakeholders.

• 4.. Risk Review: Monitoring and reviewing risks over time.

• 5.. Risk Documentation: Recording all risk management activities.

The methods and tools of risk management are crucial to locating a risk and to reducing or limiting its impact. Various tools are used to facilitate the QRM processes, including Failure Mode and Effects Analysis (FMEA) [20], Fault Tree Analysis (FTA) [21], Hazard Analysis and Critical Control Points (HACCPs) [9], Risk Ranking and Filtering [4], and others depending on the nature of the application [22]. FMEA is a feasible tool for revealing and evaluating any process failure, its causes, and its impact on a product or system performance [23,24]. It allocates a Risk Priority Number (RPN) to each mode of failure according to its severity, frequency, and detectability. This prioritizes actions to mitigate high-risk failures. In pharmaceuticals, FMEA is used in process design, equipment maintenance, and quality control to prevent defects and ensure patient safety [24,25].

Quality risk management is critical for assuring the quality of pharmaceutical products as well as patient safety. Risk identification can be either prospective or retrospective. In this paper, we use a prospective scenario to determine the various failures in the process/system and its impact on product quality and/or patient safety. By following ICH Q9 guidelines and employing tools like FMEA, organizations can systematically identify and mitigate risks. The application of QRM across various studies highlights its effectiveness in addressing industry-specific challenges. In this article, the cycle of sterile product manufacturing is reviewed. This paper complements our previous work [14,15], where the first and second stages of the drug product manufacturing processes are discussed. This work emphasizes product sterilization, inspection, labeling, packaging, and storage of the finished sterile product. These are critical manufacturing operations requiring robust good manufacturing practice (GMP) and good storage and distribution practice (GSDP). An understanding of the final manufacturing stage of terminally sterilized injectable products (sterilization, inspection, labeling, packaging, and storing processes) enables manufacturers to identify the associated risks to the product and have more effective controls on such processes.

Potential risks could come at any stage of the drug manufacturing process [26,27], especially when it involves the manufacturing of complicated sterile products [18,28]. Examples of potential risks in the operations selected in this study are the risks of handling unlabeled and not yet sterilized products, the presence of particulate/microbial contamination of intravenous (IV) fluids [29], unlabeled finished products passing inspection, incorrect labeling, defective products passing inspection, product mix-ups, and risk of uncontrolled storage of finished sterile products. All these examples are critical types of risks that may happen if manufacturers do not proactively analyze the operations and implement all necessary controls to eliminate or reduce the potential risks.

Risk assessment in the pharmaceutical industry is perceived as important support to build quality into operations (QbD) through the identification and control of potential risks. Building quality into operation means sustainability by design. For example, the identification of sustainability-related risks in processes like sterilization, inspection, storage, and distribution, the assessment of their impacts, and the development of a risk control strategy are becoming critical issues for such processes. All our risk control strategies published in this paper consider major sustainability factors, such as product quality, societal (human/patient) safety, and the viability of the manufacturing facility. Considering the potential risks associated with the sterilization process will lower the damage to the final product and, therefore, reduce the cost and increase the viability of the manufacturer. Conversely, considering risks associated with the product inspection process will reduce the chance of defective products passing inspection and being used by the patient (society safety) [30]

For these reasons, it is required to present a real-life (practical) case study of the critical manufacturing stages for the final product, including the (a) sterilization, (b) inspection, (c) labeling and packaging, and (d) transfer and storage of the finished product in warehouses.

2. Materials and Methods

A group of researchers, including consultants in the sterile pharmaceutical industry with academic instructors, selected a sterile infusion solution product (100 mL glass bottle) and thoroughly reviewed the full product life cycle (Figure 1).

The manufacturing activities of products consist of a few distinct stages. Each stage involves a number of set steps. Each manufacturing procedure starts with procurement and the supply chain and then proceeds to the storage and control of raw and packaging materials, followed by production aspects, including the dispensing of raw materials, formulation, filling, sterilization, inspection, labeling, packaging, palletization, and, finally, distribution and storage. In this paper, we discuss the final stages (stages 5 and 6) of a terminally sterilized infusion solution in the product manufacturing process. This study focuses on three important steps: 1—sterilization of filled bottles; 2—inspection, labeling, and packaging of terminally sterilized products; and 3—transfer and storage of the product in the warehouse. A full risk assessment was performed at each specified step utilizing ICHQ9 guidelines [3] and the FMEA tool [15]. For a simpler approach, we developed the following working method:

• A.. Comprehend the applicable standard operating procedure (SOP) for the specified step.

• B.. Collaborate with the process owner and supervisor to break down the procedure into specific steps.

• C.. Consult with a risk management specialist to identify possible risks related to each step.

• D.. Conduct a risk analysis. Fill in an information table (answered questions) about the risk, such as “What could go wrong?”. What is the likelihood (probability) of it going wrong? What are the effects (level of severity)? What is the ability to detect that harm? This risk assessment tool is referred to as FMEA (Figure 2).

• E.. Use the FMEA risk evaluation to rate severity, probability of occurrence, and likelihood of detection on a scale of 1–5, with 1 representing the lowest risk and 5 representing the highest risk to product quality and/or patient safety. In order to calculate a Risk Priority Number (RPN), multiply all three numbers for each possible risk: (Severity of the effect) × (Likelihood of occurrence) × (Unlikelihood of detection) (Table 1). Then, assign levels according to a risk priority matrix (Figure 3).

• F.. Complete risk control by implementing updated policies/standards, physical enhancements, and changes to procedures to remove or reduce risks.

3. Results and Discussion

The three SOPs illustrating the major processes are 1—sterilization of filled bottles; 2—inspection, labeling, and packaging of the terminally sterilized product; and 3—finished product transfer and storage in a warehouse. Each SOP was broken down into straightforward, clearly defined steps. In the present study, the total number of steps required to transform each SOP varied between 12 and 32 (because of the large volume of information, the SOPs steps are not shown in this paper). The breakdown of each SOP helps with risk identification. As a result, risks related to each step were identified, and an FMEA table was created with all of the information required for the entire risk assessment, as shown in Table 2, Table 3 and Table 4. The process step description is shown in column 2, what can go wrong when carrying out the step is stated within (column 3), and the failure effect outcomes, i.e., the effect if the step goes wrong, is shown in (column 4). In addition, column 6 shows the potential causes of failures, and any existing/current controls available to avoid these outcomes are shown in column 8. According to the initial input and team discussions, numerical rankings were allocated to severity (column 5), probability (column 7), and detectability (column 9). The Risk Priority Number was determined and is displayed in column 10. Based on the risk score, the related risk was classified as low, moderate, or high (column 11), as well as what action or decision was necessary (column 12). The FMEA tables define the person/s in charge of taking the action (column 13) and the date of action completion (column 14), followed by the recalculation of a new RPN by members of the team after the action was applied (column 17). From the team’s experience and the determination of risk severity, it was found that the influence of such control measures implemented in the process step to mitigate risk is only visible in the probability and detectability of risk. This clarifies why the risk severity score in all FMEA tables remained the same despite adopting the control.

The risk analysis of the three crucial steps chosen in this study reveals that many risks are in the green area, indicating that the RPN is less than 18 (not demonstrated in this study), and hence, no action or control measures are required. The research presented here provides some examples of risks in the yellow and red regions, as well as the actions taken to mitigate the risks associated with those steps. The FMEA tables present the risk analysis followed by the interpretation of the data and conclusions.

3.1. Risk Assessment Associated with the Sterilization of Filled Bottles

RPNs were calculated for all possible risks associated with the processes considered within Table 2. The simplification of this process shows that there are 26 steps. A full risk assessment was performed for each step, and it was found that there are 22 steps with risks in the green area (low risk) and 4 steps with risks in the yellow area (moderate risk). No step was associated with a critical risk (red area).

Table 2 shows that four risks were associated with steps # 1, 3, 12, and 13 in the sterilization process. Generally, risks with RPNs less than 64 are moderate and, if left with current controls, would be acceptable. However, any additional control or adjustment of the current control would be highly recommended to mitigate further risk without compromising overall product quality. As can be seen in Table 2, the RPN values of all steps were reduced to ≤ 18 (which puts the risk in the green area). It typically works best to lower the risk as much as practically possible in order to protect product quality and patient safety. The main responsibility of the risk team is to suggest all control measures for a particular step to eliminate (if possible) or reduce the risk magnitude (the RPN). Step # 1, with an RPN value of 24, reflects the effect of human error and the effect of such an error on the overall sterilization cycle success. Suggesting mandatory double checks (e.g., using the fingerprint of the supervisor) on the autoclave operator work before proceeding to the next step in the process reduces the risk magnitude to 8 (green area). This double-check strategy is one of the elements of cGMP that ensure the performance accuracy of the critical processes, such as sterilization. Table 2 shows more clearly that further control measures on personnel activity in any process are necessary and can reduce the risk magnitude to more acceptable values. Automation remains the best possible solution to avoid human error. For example, in step 3, a regular washing cycle is a mandatory requirement in autoclave operation. Implementing auto warning signals if a washing cycle is not completed increases the detection of such a discrepancy and, therefore, reduces risk.

Table 2

Risk assessment associated with the sterilization of filled bottles.

	Risk Assessment										Risk Control
	Risk Identification		Risk Analysis					Risk Evaluation			Risk Reduction and Acceptance		Compliance of Action	Risk Re-Evaluation
Step #	Process Step/Input	Potential Failure Mode	Potential Failure Effects	Severity (S) (1–5)	Potential Occurrence	Occurrence (O) (1–5)	Current Controls	Detection (D) (1–5)	RPN (S × O × D)	Risk Acceptance	Action Recommended	Resp.	Actions Taken	Occurrence (O)	Detection (D)	RPN (S × O × D)	Risk Acceptance
							What Controls Exist That Either Prevent or Detect the Failure?				What Are the Recommended Actions for Reducing the Occurrence of the Cause or Improving Detection?	Who Is Responsible for Making Sure the Actions Are Completed?	What Actions Were Completed (and When) with Respect to the RPN?
1	Ensure that autoclave operator is trained on autoclave operation and related instruction to the sterilization process.	Operator is not trained or does not correctly perform the procedure.	Product damage. Failed sterilization cycle. Operator injured.	4	Untrained operator. Lack of proper training. Does not follow instructions. Lack of double check by supervisor.	2	Approved training SOP is available. All autoclave operators are well-trained and qualified, and their performance is checked and documented.	3	24	NO. Risk mitigation is required.	Implement proof of physical checking by supervisor through fingerprint. Maintain current control.Annual review for risk or whenever there is change.	Production, Engineering, and QA	Completed	1	2	8	Yes
3	Ensure that trolleys, the autoclave internal chamber, and autoclave nozzles are cleaned as prescribed in the related SOP.	Some trolleys are not cleaned. Internal chamber of sterilizer is dirty. Some autoclave nozzles are rusted.	External surface of sterilized product may have some dirt. Sterilizer function may be affected with time. Returned autoclave water is dirty.	3	Untrained operator. Operators do not follow instructions. Lack of autoclave cleaning status check list/logbook. Lack of sufficient autoclave periodic maintenance schedule and follow up.	3	Operators are trained on the SOP. The cleaning process is documented in an autoclave logbook. A physical checking process is used to confirm autoclave cleaning status. Review of autoclave cleaning records by the supervisor.	3	27	NO. Risk mitigation is required.	Additional control must be added, like auto-warning through autoclave PC if a regular washing cycle was not performed, indicating the absence of a cleaning process.	Production, Maintenance, and QA	Completed	2	2	12	Yes
12	Take manual intervention immediately in the case that the temperature sensors of the autoclave or chamber pressure exceeded the defined action limit.	Delay in manual intervention. No intervention and sterilization cycle proceeded until end.	Product damage and cost involved. Concern about proper supervision.	4	Untrained or insufficient training offered to autoclave operator on manual intervention. Lack of area supervision. Absence of clear instruction about manual intervention in autoclave malfunction.	3	Well-written and approved instruction on what to complete in the case of any malfunction. Emergency contacts with higher authority are available whenever needed. Operators are trained on manual intervention.	3	36	NO. Risk mitigation is required.	A specific troubleshooting check list for all cases of autoclave malfunction is required to be available beside all sterilizers, and operators are well-trained on it.	Production, Maintenance, and QA	Completed	2	2	16	Yes
13	Ensure that autoclave operators are well-trained on the manual intervention during electric power failure.	Delay of manual intervention.	Product damage or sterilization cycle failure.	4	Untrained or insufficient training offered to autoclave operator on manual intervention during power failure. Lack of area supervision. Absence of clear instruction about manual intervention in power failure situation.	3	Well-written and approved instruction what to complete in the case of any malfunction. Emergency contacts with higher authority are available whenever needed. Operators are trained on manual intervention during power failure.	3	36	NO. Risk mitigation is required.	A specific troubleshooting check list for all cases of autoclave electric power failure is required to be available beside all sterilizers, and operators are well-trained on it.	Production, Maintenance, and QA	Completed	2	2	16	Yes

In steps 12 and 13, implementing troubleshooting strategies and having all possible autoclave operational errors (malfunction or electric power failure) on hand will help the autoclave operator(s) make the correct decision and take action without delay. Based on all newly implemented changes for each risk, decision makers can adjust or revise the existing SOP and/or add additional instructions and controls. The effectiveness of all new controls must be monitored for at least 6 months. Every modification made to an existing GMP document (e.g., SOPs, forms, software, etc.) related to the stated risks must be revised, reviewed, and authorized. Risk communication must be discussed with all responsible personnel. An annual risk assessment is required if there is a significant modification in the process.

3.2. Risk Assessment Associated with the Inspection, Labeling, and Packaging of Terminally Sterilized Products

Potential risks associated with the processes in Table 3 were evaluated, and RPNs were calculated. The simplification of this process shows that there are 32 steps. A full risk assessment was performed for each step, and it was found that there are 28 steps with risks in the green area (low risk) and 4 steps with risks in the yellow area (medium or moderate risk). Table 3 shows that all risks fall into the medium or yellow area. It is very common in risk management that any step associated with moderate risk must be reduced to as low as practically reasonable by taking all possible control measures, for example, eliminating the step, modification, control, etc.

Step 3 in Table 3 shows the risk associated with line clearance of inspection, labeling, and packaging. The impact of whether the line clearance was completed or not completed, the presence of the QA inspector, and whether the line clearance check list was not properly developed or documented will be very high. The degree of risk increases when the detection value is high. The total RPN was calculated to be 30 (yellow). At this point, the team made the decision to lower this intolerable risk by updating the line clearance SOP to include a few essential components in the procedure, such as using batch reconciliation data as an assurance criterion for proper line clearance activity, avoiding consequent inspection and packaging of very similar products using the same inspection line, and considering time calculation when finishing or starting a new lot. With such controls, the remaining risk is reduced when the detection score (detection low number) rises and the probability of risk falls, resulting in a calculated RPN of 10 (green).

In step 16, the risk associated with the product inspection process can be very high if proper instructions are not followed or in the absence of all possible control measures to ensure that the inspection activity is performed correctly. Because the product inspection process is virtually 100% manual, and the decision to accept or reject any bottle depends on the inspectors, significant attention must be paid to this step. Potential failures at this step can include inspectors who do not follow proper instructions, e.g., inspection time per bottle. The potential causes of such failures can include negligence by inspectors, lack of inspection line supervision, lack of attention to the inspection process by the inspector, no frequent/routine checking of inspected units, and the absence of QA inspection activities. Whatever the possible failures are, a thorough investigation and the implementation of all control measures are required to ensure that only good bottles are accepted on the line and are passed to the labeling and packaging stage.

The risk level in step 16 is high because the harm caused by accepting defective bottles is high (severity = 5) and detection level is insufficient (detection score is high). It was determined by risk management members that the overall RPN is 45 (yellow). Here, the members made the decision to lower this unacceptable risk by establishing new rules, such as prohibiting the use of cellphones by inspectors during an inspection, carefully monitoring and recording the inspection time, enforcing a penalty for violation of the new rules, random sampling of inspected bottles and reinspection by the line supervisor and recording the results. With this control, the increase in the detection level (detection low score) and decrease in the probability of risk lead to a reduction in the residual risk, and the calculated RPN becomes 20 (green).

The detected risk in steps 20 and 24 places them in the yellow area. The Risk Assessment team highlighted three major potential failure modes. The potential failures include discrepancies in lot quantity reconciliation (mix-up issue), packaging unlabeled bottles, and incorrectly printed labels. For these two steps, the most important control measure should be in place to detect such failures if they occur. The Risk Assessment team decided to add further control measures to reduce the RPN to more acceptable values.

For step 20, the recommended actions for reducing the occurrence of the cause or improving detection were to (i) add control access to inspection area; (ii) improve the design of inspection lines so that similar inspection lines are separated with sufficient space to avoid potential mix-ups; (iii) fix partitions between similar inspection lines; and (iv) avoid inspection of similar products at the same time. The implementation of all these control measures led to a reduction in the RPN from 30 (yellow area) to 10 (green area).

For step 24, the recommended actions for reducing the chance of unlabeled bottles passing to the cartooning stage (increasing detection level) were (i) adding an auto-detection sensor to the labeling line to detect and reject any unlabeled bottles and (ii) performing software checking of batch code data by a PC program to ensure the printing of correct information on all labels. The implementation of all these control measures led to the reduction in the RPN from 45 (yellow) to 20 (yellow). In both steps, the significant change/modification placed in the process was to increase the detection of failure and, therefore, reduce the occurrence probability. All changes made in any GMP documents, e.g., SOPs, formats, software, etc., associated with the discussed risks should be revised, reviewed, approved, and communicated with key personnel annually.

Table 3

Risk assessment associated with the inspection, labeling, and packaging of terminally sterilized products.

	Risk Assessment										Risk Control
	Risk Identification		Risk Analysis						Risk Evaluation		Risk Reduction and Acceptance		Compliance of Action	Risk Re-Evaluation
Step No.	Process Step/Input	Potential Failure Mode	Potential Failure Effects	Severity (S) (1–5)	Potential Occurrence	Occurrence (O) (1–5)	Current Controls	Detection (D)(1–5)	RPN (S × O × D)	Risk Acceptance	Action Recommended	Resp.	Actions Taken	Occurrence (O)	Detection (D)	RPN (S × O × D)	Risk Acceptance
							What Controls Exist That Either Prevent or Detect the Failure?				What Are the Recommended Actions for Reducing the Occurrence of the Cause or Improving Detection?	Who Is Responsible for Making Sure the Actions Are Completed?	What Actions Were Completed (and When) with Respect to the RPN?
3	Line clearance process should ensure that all previous products, packaging materials, samples, and documentation are totally removed from the line and such activities are recorded in BMR.	Line clearance is not performed. Line clearance not completed. QA inspector is not present or does not attend line clearance. The line clearance checklist is not properly designed.	Different product mix-ups on the line during the inspection/packaging process. Patient safety is compromised. GMP guideline violation. Regulatory authority concern.	5	Untrained inspection line supervisor. Lack of production supervision. Line clearance performed but not completed. No line clearance check list is available, or it is not in use. Failure in QA site inspection. Weakness in QMS.	2	Clear SOP states that no start up inspection line before review and approval of line clearance by QA inspector. Inspection line operators and QA inspectors are well-trained and qualified to perform line clearance. Updated and approved line clearance check list is available and in use.	3	30	NO. Risk mitigation is required.	Use batch reconciliation data as assurance criteria for proper line clearance activity. Avoid consequent inspection and packaging of very similar products using the same inspection line. Consider time calculation when finished and when starting new lot.	Production and QA	completed	1	2	10	Yes
16	Take uninspected bottles from feeding conveyer and inspect as per approved instruction (all inspection criteria should be considered for every single bottle). Bottle inspection time shall be from 5 to 10 s.	Inspectors do not follow instructions, e.g., inspection time per bottle.	Overall product quality may be compromised. Patient safety is questionable. GMP guideline violation and regulatory authority concern.	5	Negligence by inspectors. Lack of inspection line supervision. Lack of attention to inspection process by inspector. No frequent/routine checking of inspected units. Absence of IPQA inspection activities.	3	Inspectors are supervised frequently. All inspectors are well-trained on what to complete and not to complete. IPQA inspectors check inspected bottles randomly and frequently. Any discrepancies are documented and investigated.	3	45	NO. Risk mitigation is required.	New instruction is implemented that no mobiles should be available with inspectors during inspection. Penalty is enforced for violation of the new rules. Random sampling of inspected good bottles is reinspected by line supervisor and results are recorded.	Production and QA	completed	2	2	20	Yes
20	Any discrepancies between the quantity of bottle per trolley and feed conveyer counter should be recorded and investigated with the involvement of a production pharmacist.	Discrepancies are not documented.	Inaccurate batch reconciliation. Product safety is questionable.	5	Ineffective quality management system. Lack of proper production supervision. Untrained inspection line supervisor.	3	Inspection line staff are well-trained on the SOP as well as on GDocP and data integrity. Presence of IPQA inspectors at production inspection lines.	2	30	NO. Risk mitigation is required.	Control access to inspection area. Similar inspection lines should be separate with enough space to avoid any mix-ups. Fixing partitions between similar inspection lines. Avoid inspection of similar products at the same time.	Production, Engineering, and QA	completed	2	1	10	Yes
24	All inspected and accepted bottles should be passed to a labeling machine and labeled as per the approved format with batch coding details.	Unlabeled bottle passes to the cartooning step. Wrong batch code data printed on the label.	Unlabeled products reach customer. Loss of product traceability. Customer complaint. Patient safety is affected. GMP violation and regulatory authority concern.	5	Absence of inspection process at labeling stage. Unqualified inspector at labeling stage. Absence of review and double check of batch code information.	3	Presence of inspectors at the labeling process stage to detect unlabeled bottles. Manual review and check of printed batch code data. Manual inspection at cartooning stage.	3	45	NO. Risk mitigation is required.	Implementation of auto-detection sensor is fixed on the line to detect and reject any unlabeled bottle. Implementation of software checking of batch code data by the PC program.	Production, Engineering, and QA	completed	2	2	20	Yes

3.3. Risk Assessment Associated with Finished Product Transfer and Storage in a Warehouse

All possible risks associated with the processes within Table 4 were considered, and RPNs were calculated. The simplification of this process shows that there are 12 steps. A full risk assessment was performed for each step, and it was determined that there were nine steps with risk in the green area (low), two steps with risks in the yellow area (moderate), and one step with a risk in the red area (high). Table 4 shows that all risks fall into the yellow and red areas. It is very common in risk management that any one step associated with critical risk must be carefully investigated and all possible control measures implemented, e.g., eliminate the step, modify, change, control, etc.

In steps 2 and 7, the level of all detected risks falls between 18 and 63, categorized in the yellow area (moderate risk). The Risk Assessment team highlighted several potential failure modes. Generally, all potential failures are categorized under noncompliance with Good Documentation Practice (GDocP) and Good Manufacturing Practice (GMP). Noncompliance examples include the instructional SOP is not clear, the SOP cannot be followed, critical data are not recorded or saved, and an expired SOP is only available in the work place. Although some current controls are in place, they are insufficient to protect processes and result in a low RPN. The Risk Assessment team decided to add more control measures or to modify the current control measures to reduce the RPN.

In step 2, the recommended actions to reduce the potential occurrence of the failure and/or to increase detectability of that failure were to (i) conduct frequent GS&DP training sessions with all staff; (ii) conduct annual training on the preparation of effective SOPs; (iii) review SOP operation twice per year; and (iv) conduct surprise QA audits. The implementation of such control measures led to a reduction in the RPN from 30 (yellow area) to 10 (green area).

In step 7, the recommended action to reduce the potential occurrence of failure and/or increase detectability of failure was adding independent QA inspections of saved data loggers’ temperature readings in the system. Such an inspection increases the detectability of failure and reduces the detection score from 2 to 1. The potential occurrence was reduced from 3 to 2. The total RPN of this risk changed from 30 to 10.

In step 10, the level of detected risk is more than 63, which is in the red area or high risk. The Risk Assessment team highlighted several potential failure modes. Most (if not all) potential failures are related to the principles and guidelines of Good Storage and Distribution Practices (GS&DPs). One example of noncompliance is having congested storage, whereby pallets of different lots or different statuses (quarantined and released lots) are stored together. Storage capacity is an important requirement of good storage practice and should be considered early in the warehouse design stage. This failure can cause an increase in the chance of product mix-ups, mishandling of products, wrong deliveries, regulatory noncompliance, and customer complaints. Although some current controls (especially manual control) are in place, these controls are insufficient to further protect the process, resulting in a low RPN. The Risk Assessment team decided to add more control measures or to modify the current control measures to reduce the RPN to more acceptable values. The use of computer-generated selection ensures products go to the correct customer. Computer software complies with data integrity and 21 CFR part 11 and should be used only by authorized staff. Applying qualified and validated software in the process of selecting released lots during the dispatching process will ensure the correct selection of released products to the correct customer.

Table 4

Risk assessment associated with finished product transfer and storage in a warehouse.

	Risk Assessment										Risk Control
	Risk Identification		Risk Analysis						Risk Evaluation		Risk Reduction and Acceptance		Compliance of Action	Risk Re-Evaluation
Step No.	Process Step/Input	Potential Failure Mode	Potential Failure Effects	Severity (S) (1–5)	Potential Occurrence	Occurrence (O) (1–5)	Current Controls	Detection (D) (1–5)	RPN (S × O × D)	Risk Acceptance	Action Recommended	Resp.	Actions Taken	Occurrence (O)	Detection (D)	RPN (S × O × D)	Risk Acceptance
							What Controls Exist That Either Prevent or Detect the Failure?				What Are the Recommended Actions for Reducing the Occurrence of the Cause or Improving Detection?	Who Is Responsible for making Sure the Actions Are Completed?	What Actions Were Completed (and When) with Respect to the RPN?
2	Stores should operate with proper storage temperature and lightening at all times. All operations should be performed accurately and safely by well-trained staff and according to the approved SOPs.	Absence of some store operation SOPs, unclear content of SOPs, or use of obsolete SOPs.	General store operations are not conducted properly. Mistakes may be observed. GMP noncompliance.Product safety may be affected.	5	Poor quality assurance system. Lack of proper store operation management. Insufficient documentation control.	3	Presence of competent QA staff and supervision. Presence of competent and well-trained store manager and supervisor. Store passes SFDA GSDP guideline inspection.	2	30	Acceptable but further control may be needed	Frequent GSDP training of store and QA staff. Conduct annual training on how to prepare an effective SOP.Semiannual review of store operations SOPs.QA conduct surprised store audits.	Area owner, QA department, and training department	completed	1	2	10	Yes
7	Temperature recordings from data loggers should be saved and kept for no less than one year.	Data logger temperature recording is not saved or is lost.	Lack of GMP documents for store temperature recording.Regulatory concern.Product quality concern.	5	Data logger software is not efficient.Poor or negligence of store supervision/review.Poor QA system	3	Data loggers used in the store are certified, and the software is in compliance with data integrity requirements.Routine review of data logger recording by store management. Manual temperature recording is in place.	2	30	Acceptable but further control may be needed	QA audit of store should cover reviewing randomly saved data loggers’ temperature readings in the system.	Warehouse and QA	completed	2	1	10	Yes
10	All pallets of the same batch should be stored near each other within the same rack.	Store is congested and some pallets of different lots or different statuses are stored together.	Chance of product mix-ups. Mishandling of products.Wrong deliveries.Patient safety may be affected. Regulatory noncompliance. Customer complaint.	5	Poor storage system.Store design is not efficient.Poor store management.Lack of QA audits. Insufficient SOPs or SOPs are not followed.Untrained store staff.	4	Stores are designed based on the approved layout. Physical separation using chains of different color for identification is in place.SOPs for the process of stacking pallets is in place. Store staff trained on all SOPs.	4	80	Risk is unacceptable	Apply computer-generated selection and control of products intended to go to the customer. Software complies with data integrity and is used by only authorized store staff.	Warehouse, IT, and QA departments	Completed	2	2	20	Yes

4. Conclusions

Almost all regulatory authorities view quality risk management (QRM) as a mandatory requirement for pharmaceutical industries to be in a state of compliance and for continued improvement. In August 2022, annex 1 of the EU GMP regulatory standard was revised and released for review. It has been in operation since August 2023. In this revised version of annex 1, a new section discusses and identifies quality risk management (QRM) as a central principle to defining processes, operations, and limits.

Throughout the development of good manufacturing practices, we know that quality control is a reactive approach and quality assurance is a proactive approach. However, it is proven that understanding and implementing ICH Q9 is a perspective approach. Risk assessment supports management in defining company objectives and in having better decision-making processes. This will provide regulators and stakeholders with the assurance of the company’s ability to deal with potential risks.

Manufacturing processes of terminally sterilized infusion products present several associated risks, including contamination during the manufacturing process and damage to packaging or the product that occurs in shipping, which can contaminate the drug and render it dangerous [7]. These issues can harm the patient receiving that injectable and have financial impacts and liability for the manufacturer. Because sterile injectable products have stringent quality requirements over oral pharmaceutical products, risk assessment should cover all potential risks to the products’ critical quality parameters, such as sterility, particulate (viable and non-viable) contamination, damage causing leakage, and improper storage temperatures. These are considered the most critical risks of sterile products that manufacturers can face.

The case study highlighted in this paper focused on three different stages of sterile infusion product manufacturing. These three stages are considered critical, requiring continuous compliance with good manufacturing practices, good documentation practice with data integrity, and good storage and distribution practices. The aim of this study was to highlight what events created unacceptable risk to product quality and/or patient safety during the sterilization, inspection, labeling, packaging, and storing processes. The case study presented in this paper places emphasis on the principles of ICH Q9 guidelines—QRM and how they can be effectively applied in practice.

The issue of environmental impact and risk assessment of such impact is applied to pharmaceutical products with well-identified hazards to the environment and people. In our case study, sterilized pharmaceutical infusion has no environmental impact. The nature of raw materials/API, excipients, or any material present in the formulation is safe for the environment as well as for operators. The environmental impact of some pharmaceutical products is seen with the presence of hazardous APIs like hormonal, cytotoxic, and cephalosporin in the drug products. These products pose a medium to high risk of harm to human health and the environment. Manufacturers must take extra steps to eliminate or reduce these risks through the use of dedicated isolated production areas, controlled and dedicated HVAC systems, educated and trained personnel, etc. Having such a design, the potential hazards shall be uncovered, identified, and put under control.

There is no right or wrong technique to perform a risk analysis. There are various acceptable methods. All pharmaceutical companies must implement an efficient risk management program within their quality management systems. Ineffective programs may lead to inaccurate risk analysis with time-consuming and costly prioritization. It is important to save resources for managing important risks and to allocate the required resources to high-priority risks. Using the FMEA tool for assessing failure modes, identifying failure causes, and calculating the potential probabilities of such failures lowers all risks to tolerable levels.

Author Contributions

Conceptualization, B.E., R.A. and F.B.; methodology, B.E. and R.A.; writing—original draft preparation, B.E. and R.A.; writing—review and editing, B.E., R.A. and F.B. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

The data presented in this study are available on request from the corresponding author due to privacy reasons.

Acknowledgments

We appreciate the participation of all process owners and supervisors of the glass production line and the glass inspection, labeling, and packaging line and their valuable input and feedback in defining all potential failures in the process of sterile product sterilization, inspection, labeling, packaging, and storing.

Conflicts of Interest

Author Bassam Elmadhoun, was employed by the Pharmaceutical Solution Industry CO. The remaining authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures and Tables

Figure 1. Stages of manufacturing for 100 mL of a sterile drug product in a glass bottle.

Figure 2. Risk identification questions of FMEA.

Figure 3. Risk Priority Number matrix. (Green: low; Yellow: Medium; Red: High).

Table 1

Risk Priority Number levels.

Risk Priority Number(Severity × Occurrence × Detection)	Level	Action
RPN ≤ 18	Low	Risk is acceptable.
RPN 20–63	Medium	Risk may be acceptable. Reduce risk to as low as practically reasonably.
RPN ≥ 64	High	Risk is not acceptable. Risk reduction/mitigation is required.

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