WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Patel et al. SJIF Impact Factor 6.041 Volume 5, Issue 6, 1143-1153 Research Article ISSN 2278 4357 MANUFACTURING RISK ASSESSMENT STUDY FOR STERILE DRY POWDER INJECTION OF CEFTRIAXONE SODIUM Divyanginee Patel 1 *, Rakesh Kaul 2 and Ankita Bhavsar 1 1 Sat Kaival College of Pharmacy, Sarsa crossroads, Sarsa-388365 Ta. Dist. Anand, Gujarat, India. 2 Pharmanza (India) Pvt. Ltd. 70/1, G.I.D.C. Estate, Kansari-388630, Khambhat, Gujarat, India. Article Received on 12 Apri l2016, Revised on 03 May 2016, Accepted on 24 May 2016 DOI: 10.20959/wjpps20166-6870 *Corresponding Author Divyanginee Patel Sat Kaival College of Pharmacy, Sarsa crossroads, Sarsa-388365 Ta. Dist. Anand, Gujarat, India. ABSTRACT The objective of this study was to assess and mitigate the risk at all stages before the manufacturing process of Ceftriaxone sodium (CFTX) dry powder injection was initiated. To evaluate the current controls and decide the future actions to be taken for the improvement of product/process reliability and quality of the product for commercial use of early identification and elimination of potential product/process failure modes. The method used was Failure Mode Effect Analysis (FMEA). It is a systematic, proactive method for evaluating a process to identify where and how it might fail and to assess the relative impact of different failures, in order to identify the parts of the process that are most in need of change. Subjected a sterile dry powder injection to a failure mode effect analysis, including technical risks as well as risks related to human failure, which break down the formulation into the process steps and identified possible failure modes for each step, each failure mode was ranked on the estimated frequency of occurrence, detectability and severity. Failure risks were calculated by Risk Priority Number (RPN). Results were predicted by a risk priority number that the risk is acceptable, unacceptable or intolerable. According to the results, corrective actions are taken.this article describes practical ways to analyze the risks to the quality system, providing the way to achieving effective and efficient quality management and compliance. Risk management improves decision making if a quality problem arises. KEYWORDS: FMEA, dry powder injection, risk assessment, RPN. www.wjpps.com Vol 5, Issue 6, 2016. 1143
INTRODUCTION To ensure the quality is built into pharmaceutical products, the most up to date technologies and concepts of and concepts of risk management should be incorporated into the manufacturing process. As part of this new approach, work was done to evaluate the filling process of CFTX dry powder injection in order to reduce its associated risks. Risk is understood as the combination of the probability of occurrence of harm and the severity of that harm. [1] CFTX is the semi synthetic 3rd generation cephalosporin drug of antibiotic/anti bacterial class. During manufacturing, especially in filling of the powder, the powder may exposed to an environment which may cause allergic reactions and potential health effects. It is carcinologic also. Conditions like humidity, warming and light should be avoided due to instability. [2] The manufacturing of sterile medicinal products is subjected to special requirements in order to minimize risks of microbiological contamination and particulate or pyrogen contamination. That depends on the skill, training and attitudes of the personnel involved. Quality assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods for preparation. [3] Sterility of CFTX dry powder injection produced by aseptic processing should obtained guarentting the conformity of processes different factors. To obtain sterile products, it is essential that all processing should be done in a way that minimizes the risk of contamination hazard. [4] A facility for the filling of a sterile dry powder antibiotic comprises the tunnel concept for washing and sterilization of the product containers, a filling unit under laminar airflow with localized vacuum exhaust, a changing room suite, autoclave, airlock, and conventional clean room containing the filling equipment. The need is to reduce the possibility of sensitization and other allergic reactions. Particulate contamination represented as a function of starting materials, container, and closure contribution was assessed. [5] Due to the aforementioned difficulties related to the manufacturing process of CFTX dry powder and the high risk of producing a poor quality product, a risk based analysis was performed to improve the understanding of the filling process and reduce its associated risks before manufacturing. www.wjpps.com Vol 5, Issue 6, 2016. 1144
Risk assessment Risk assessment of CFTX dry powder consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Quality risk assessments begin with a well-defined problem description or risk question. As an aid to clearly defining the risks for risk assessment purposes, three fundamental questions are often helpful. 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)? Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the What might go wrong? question, including identifying the possible consequences. This provides the basis for further steps in the quality risk management process. Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk. Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations consider the strength of evidence for all three of the fundamental questions. Severity It is the impact on patient safety, product quality and data integrity. Occurrence It is the likelihood of the fault occurring. Detectability The ability to determine the existence, presence, or fact of a hazard. [1,6] FMEA was developed to assess risk of failure and harm in processes and to identify the most important areas for process improvements. The main objective was the prevention of www.wjpps.com Vol 5, Issue 6, 2016. 1145
problems and errors by reducing the RPN. FMEA is a systematic, proactive method for evaluating a process to identify where and how it might fail and to assess the relative impact of different failures, in order to identify the parts of the process that are most in need of change. [7] MATERIALS AND METHODS Material (Ceftriaxone sodium) and equipments used for this study were obtained from Pharmanza (Ind.) Pvt. Ltd., Khambhat, Gujarat, India. Table 1: Equipments used in various unit operations Method Process Equipment name Capacity Vial washing Automatic high speed linear vial 120 vials /min for washing machine 10 ml to 50 ml vials Depyrogination Sterilizing & depyrogenating tunnel - Automatic injectable powder Filling, stoppering and filling with rubber stoppering sealing machine 120 vials /min Metal detection Metal detector - Sterilization (Dry) Dry heat sterilizer - Sterilization (Moist) Rectangular double door horizontal HPHV steam sterilizer - (autoclave) Dehumidification Dehumidifier 1200 cfm The steps someone has to go through to design an FMEA form are described below: 1. Selection of the process The importance of the process in terms of the impact of potential failures was taken into account as selection criteria. Evaluation using FMEA works best on processes that do not have too many sub processes. 2. Review of the process The process was analyzed and described in a flow chart and the process design was studied thoroughly for the efficient output. 3. Brainstorm potential failure modes Each stage of the process was studied and identifies the ways it could potentially fail or the things that might go wrong. www.wjpps.com Vol 5, Issue 6, 2016. 1146
4. List of potential effects of each failure mode List of the potential effects and their probable failure were prepared. Cause and effects analysis (Fishbone diagram) was used for this step. [4] 5. Assign a severity rating for each effect Each effect was given its own severity rating (from 1 to 10, with 10 being the most severe). 6. Assign an occurrence rating for each failure mode After collecting data on the factors responsible for the failure of the product, the failure frequency was determined and they were rated appropriately (from 1 to 10, with 10 being the most likely). 7. Assign a detection rating for each failure mode and effect List of all controls currently in place to prevent each effect of a failure from occurring was prepared and a detection rating was assigned for each item (from 1 to 10, with 10 being a low likelihood of detection). 8. Calculation of the RPN for each effect RPN was calculated by multiplying the severity rating with that of occurrence rating by the detection rating. 9. Prioritize the failure modes for action Depending upon calculation and analysis carried out, the priority order was decided. 10. Taken action to eliminate or reduce the high risk failure modes: The action to be taken for each high risk failure was determined and a person was assigned to implement the action /change. The FMEA of dry powder injection is described in Table 2. The flow chart for the manufacturing of CFTX dry powder injection is shown below www.wjpps.com Vol 5, Issue 6, 2016. 1147
Fig. 1: Flow diagram for the production of sterile dry powder injection www.wjpps.com Vol 5, Issue 6, 2016. 1148
Table 2: FMEA of dry powder injection Sr. No. 1 2 3 4 5 Failure Modes (Risk identification) During receipt and transferring of raw material contamination may occur Quality, quantity and timing of water supply during washing of vials Compressed air pressure, blowing time Checking HEPA filter integrity Temperature of air may not obtained in depyrogeniation 6 Depyrogination time 7 8 9 Speed of conveyer belt during filling Fluffing of powder in filling area Nitrogen flush rate/pressure in filling 10 Filling area conditions Failure Cause (Risk evaluation) Due to the environment, human interferation or by the vendor Unqualified and unquantified distilled water due to poor maintenance of water Air pressure and timing is not maintained properly Improper HEPA filter efficiency, variations in velocity of air, flow pattern of air or leaking of the filter Insufficient heat distribution and heat penetration Insufficient time due to machine speed fault Failure Effects (Risk analysis) Inappropriate quality of raw material which directly affects the quality of finished dosage form Reduced quality of the sterility of vials Improper treatment of air to vials causing improper sterilization Severity Occurrence Detectability R P N 10 3 5 150 9 2 8 144 10 4 7 280 Contaminated product 8 3 6 144 Improper sterilization of vials 10 3 7 210 Loss of sterility 10 3 8 240 Unoptimum speed of conveyer belt Improper filling of vials 8 3 7 168 Improper height of filling needle as per specification Pressure required to fill the vials is out of the range Failure in maintenance of area classification Harmful to working personnel in filling area Filling accuracy is not achieved 10 3 7 270 5 2 7 70 Loss of sterility 10 4 8 320 www.wjpps.com Vol 5, Issue 6, 2016. 1149
11 12 Missing or dispatched stoppers Missing or dispatched seals 13 Any defect in labeling 14 15 16 Improper carton packaging Mixing up of two different types of packing material Storage room conditions Improper force of stoppering Improper Seal strength uniformity Improper checking of labels including Names and amount of active ingredients, Storage requirements, Control or lot number, Appropriate auxiliary labeling (including precautions) Untrained packing personnel Improper working of personnel Contamination, leakage and moisture absorption May lead to leakage from the vial Misleading labels and market complains May lead to harm to the container and market complain Wrong product storage and use 9 3 5 135 9 3 5 135 9 3 5 135 5 7 7 245 7 3 5 120 Storage room temperature, humidity Degradation of product 9 3 8 216 www.wjpps.com Vol 5, Issue 6, 2016. 1150
RESULTS The key activities performed during risk analysis include understanding the impact of risk, to rank the significance of risk (by scoring 1 to 10), to calculate the risk score (RPN). After the calculation of risk score, the results of the level or priority of the risk were estimated. If the RPN is between 1 and 120, then it is minimum risk and considered as acceptable risk. If the RPN is higher than 120 and lower than 500, then it is medium risk and considered as unacceptable risk. If the RPN is above 500, then it is higher risk and considered as intolerable. Table 3: Risk level and acceptability criteria Table 4: Result of risk acceptability RPN Risk level Risk priority 1 120 Minimum Acceptable risk 125>500 Medium Unacceptable 500-1000 High Intolerable Sr. no. 1 2 3 4 5 Failure modes (Risk identification) During receipt and transferring of raw material contamination may occur Quality, quantity and timing of water supply during washing of vials Compressed air pressure, blowing time Checking HEPA filter integrity Temperature of air may not obtained in depyrogeniation Failure effects (Risk analysis) Inappropriate quality of raw material which directly affects the quality of finished dosage form Reduced quality of the sterility of vials Improper treatment of air to vials causing improper sterilization R P N Risk priority 150 Unacceptable 144 Unacceptable 280 Unacceptable Contaminated product 144 Unacceptable Improper sterilization of vials 210 Unacceptable 6 Depyrogination time Loss of sterility 240 Unacceptable Corrective actions Take precautions for handling of raw materials, select approved vendor Daily water testing from storage tank Maintain proper air pressure Maintain proper integrity of HEPA filter by regular testing Check and maintain temperature as required Maintain and check the Depyrogination tunnel periodically www.wjpps.com Vol 5, Issue 6, 2016. 1151
7 8 9 Speed of conveyer belt during filling Fluffing of powder in filling area Nitrogen flush rate/pressure Improper filling of vials Harmful to working personnel in filling area Filling accuracy is not achieved 168 Unacceptable 270 Unacceptable 70 Acceptable 10 Filling area conditions Loss of sterility 320 Unacceptable 11 12 Missing or dispatched stoppers Missing or dispatched seals 13 Any defect in labeling 14 15 16 Improper carton packaging Mixing up of two different types of packing material Storage room conditions contamination, leakage and moisture absorption May lead to leakage from the vial Misleading labels and market complains May lead to harm to the container and market complain Wrong product storage and use Degradation of product 135 Unacceptable 135 Unacceptable 135 Unacceptable 245 Unacceptable 120 Acceptable 216 Unacceptable Verify and control the speed of conveyer belt Control the height of the filling needle to the fill volume Measure and control air pressure Measure and control the area classification Check the vials properly that any vial has missing or dispatched stopper Check the vials properly that any vial has missing or dispatched seals Check labels properly and verify all details Check primary and secondary containers properly Design label control procedures based on the potential for mix-ups involving different product labels, including different versions of the same label. Assess the adequacy of arrangements to ensure maintenance of appropriate storage and transport conditions (e.g., temperature, humidity, container design) DISSCUSSION Different risk acceptability was found according to RPN. Corrective actions should be taken to improve risk levels. When the risk is intolerable, then work to eliminate the negative event or introduce detection controls is required as a priority. When the risk is unacceptable, work to reduce the risk or control the risk to an acceptable level is required. When the risk is acceptable, then the risk is acceptable and no risk reduction or detection controls are required. Corrective actions are taken to reduce the risk to an acceptable level. CONCLUSION From the above evaluation of risk assessment based on FMEA, it was concluded that various critical steps that were expected to occur at each stage of the manufacturing process, were www.wjpps.com Vol 5, Issue 6, 2016. 1152
adequate to reduce the associated risks at a very early stage. This method helped us to focus the various critical steps that were critical to the product quality and process. Also, it eliminates the need of validation of all parameters of the aseptic manufacturing process and just includes few which are found critically. Results can be used to identify high vulnerability elements and to guide resource development for best benefits. So, by early identification and elimination of potential product/process failure modes we can improve product/process reliability and quality of the product for commercial use. AKNOWLEDGEMENT We are grateful to thank Mr. Rakesh Kaul and Mrs. Trupti Dawavala from Pharmanza (Ind) Pvt. Ltd. (Khambhat) for research fellowships. REFERENCES 1. Q9 Quality Risk Management. ICH, 2005; 3-6. 2. Medicines and Healthcare products Regulatory Agency, UKPAR Ceftriaxone 250mg, 1g and 2g Powder for Solution for Injection PL 24598/0006-8. 3. Guide to good manufacturing practice for medicinal products annexes, Annex 1 Manufacture of sterile medicinal products, 2009; 1. 4. Quinto A, Mmenezes C. Design, Validation and control of sterile manufacturing facilities: A brief overview from the perspective of Risk Management and existing Regulations. Pharm Eng, 2010; 30(2): 1-9. 5. Gerald Prout. Validation and Routine Operation of a Sterile Dry Powder Filling Facility. J Parenter Sci Technol, 1982; 36(5): 199-204. 6. Lotlikar MV et al. Quality Risk Management (QRM): A Review. J. Drug Delivery Ther, 2013; 3(2): 149-54. 7. Institute for healthcare improvement, Failure Mode Effect analysis, 2004; 1-7. www.wjpps.com Vol 5, Issue 6, 2016. 1153