WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Patel et al. World Journal of Pharmacy and Pharmaceutical Sciences

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 Patel1*, Rakesh Kaul2 and Ankita Bhavsar1

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.

ABSTRACT
Article Received on
12 Apri l2016, The objective of this study was to assess and mitigate the risk at all
Revised on 03 May 2016,
Accepted on 24 May 2016
stages before the manufacturing process of Ceftriaxone sodium
DOI: 10.20959/wjpps20166-6870 (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
*Corresponding Author
Divyanginee Patel use of early identification and elimination of potential product/process
Sat Kaival College of failure modes. The method used was Failure Mode Effect Analysis
Pharmacy, Sarsa (FMEA). It is a systematic, proactive method for evaluating a process
crossroads, Sarsa-388365
to identify where and how it might fail and to assess the relative impact
Ta. Dist. Anand, Gujarat,
of different failures, in order to identify the parts of the process that are
India.
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.

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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.

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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

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Patel et al. World Journal of Pharmacy and Pharmaceutical Sciences

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

Process Equipment name Capacity
Automatic high speed linear vial 120 vials /min for
Vial washing
washing machine 10 ml to 50 ml vials
Sterilizing & depyrogenating
Depyrogination -
tunnel
Automatic injectable powder
Filling, stoppering and
filling with rubber stoppering 120 vials /min
sealing
machine
Metal detection Metal detector -
Sterilization (Dry) Dry heat sterilizer -
Rectangular double door
Sterilization (Moist) horizontal HPHV steam sterilizer -
(autoclave)
Dehumidification Dehumidifier 1200 cfm

Method
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.

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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

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Fig. 1: Flow diagram for the production of sterile dry powder injection

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Table 2: FMEA of dry powder injection

R
Failure Modes Failure Cause Failure Effects
Sr. No. Severity Occurrence Detectability P
(Risk identification) (Risk evaluation) (Risk analysis)
N
During receipt and Inappropriate quality of
transferring of raw Due to the environment, human raw material which
1 10 3 5 150
material contamination interferation or by the vendor directly affects the quality
may occur of finished dosage form
Quality, quantity and Unqualified and unquantified
Reduced quality of the
2 timing of water supply distilled water due to poor 9 2 8 144
sterility of vials
during washing of vials maintenance of water
Improper treatment of air
Compressed air Air pressure and timing is not
3 to vials causing improper 10 4 7 280
pressure, blowing time maintained properly
sterilization
Improper HEPA filter efficiency,
Checking HEPA filter
4 variations in velocity of air, flow Contaminated product 8 3 6 144
integrity
pattern of air or leaking of the filter
Temperature of air may
Insufficient heat distribution and Improper sterilization of
5 not obtained in 10 3 7 210
heat penetration vials
depyrogeniation
Insufficient time due to machine
6 Depyrogination time Loss of sterility 10 3 8 240
speed fault
Speed of conveyer belt
7 Unoptimum speed of conveyer belt Improper filling of vials 8 3 7 168
during filling
Fluffing of powder in Improper height of filling needle as Harmful to working
8 10 3 7 270
filling area per specification personnel in filling area
Nitrogen flush Pressure required to fill the vials is Filling accuracy is not
9 5 2 7 70
rate/pressure in filling out of the range achieved
Failure in maintenance of area
10 Filling area conditions Loss of sterility 10 4 8 320
classification

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Missing or dispatched Contamination, leakage

11 Improper force of stoppering 9 3 5 135
stoppers and moisture absorption
Missing or dispatched May lead to leakage from
12 Improper Seal strength uniformity 9 3 5 135
seals the vial
Improper checking of labels
including Names and amount of
active ingredients, Storage Misleading labels and
13 Any defect in labeling 9 3 5 135
requirements, Control or lot market complains
number, Appropriate auxiliary
labeling (including precautions)
May lead to harm to the
Improper carton
14 Untrained packing personnel container and market 5 7 7 245
packaging
complain
Mixing up of two
Wrong product storage
15 different types of Improper working of personnel 7 3 5 120
and use
packing material
Storage room
16 Storage room temperature, humidity Degradation of product 9 3 8 216
conditions

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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

RPN Risk level Risk priority
1≥120 Minimum Acceptable risk
125>500 Medium Unacceptable
500-1000 High Intolerable

Table 4: Result of risk acceptability

R
Failure modes Failure effects
Sr. no. P Risk priority Corrective actions
(Risk identification) (Risk analysis)
N
During receipt and Inappropriate quality
transferring of raw of raw material which Take precautions for
1 material directly affects the 150 Unacceptable handling of raw materials,
contamination may quality of finished select approved vendor
occur dosage form
Quality, quantity and
timing of water supply Reduced quality of the Daily water testing from
2 144 Unacceptable
during washing of sterility of vials storage tank
vials
Improper treatment of
Compressed air Maintain proper air
3 air to vials causing 280 Unacceptable
pressure, blowing time pressure
improper sterilization
Maintain proper integrity
Checking HEPA filter
4 Contaminated product 144 Unacceptable of HEPA filter by regular
integrity
testing
Temperature of air
Improper sterilization Check and maintain
5 may not obtained in 210 Unacceptable
of vials temperature as required
depyrogeniation
Maintain and check the
6 Depyrogination time Loss of sterility 240 Unacceptable Depyrogination tunnel
periodically

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Speed of conveyer belt Improper filling of Verify and control the

7 168 Unacceptable
during filling vials speed of conveyer belt
Harmful to working Control the height of the
Fluffing of powder in
8 personnel in filling 270 Unacceptable filling needle to the fill
filling area
area volume
Nitrogen flush Filling accuracy is not Measure and control air
9 70 Acceptable
rate/pressure achieved pressure
Measure and control the
10 Filling area conditions Loss of sterility 320 Unacceptable
area classification
contamination, Check the vials properly
Missing or dispatched
11 leakage and moisture 135 Unacceptable that any vial has missing
stoppers
absorption or dispatched stopper
Check the vials properly
Missing or dispatched May lead to leakage
12 135 Unacceptable that any vial has missing
seals from the vial
or dispatched seals
Misleading labels and Check labels properly and
13 Any defect in labeling 135 Unacceptable
market complains verify all details
May lead to harm to Check primary and
Improper carton
14 the container and 245 Unacceptable secondary containers
packaging
market complain properly
Design label control
procedures based on the
Mixing up of two
Wrong product storage potential for mix-ups
15 different types of 120 Acceptable
and use involving different product
packing material
labels, including different
versions of the same label.
Assess the adequacy of
arrangements to ensure
maintenance of appropriate
Storage room Degradation of
16 216 Unacceptable storage and transport
conditions product
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

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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,
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7. Institute for healthcare improvement, Failure Mode Effect analysis, 2004; 1-7.

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