Application of Failure Mode Effect Analysis (FMEA) in the traditional medicine Industry: A Case study on Spirulina Capsule Production

doi:10.21203/rs.3.rs-2740070/v1

Spirulina powder is used as a raw material by many traditional medicine industries in Indonesia. Spirulina powder produced in capsule preparations generally has indications for maintaining the immune system. Risk control through quality risk management has been required by the BPOM of the Republic of Indonesia as a consumer security guarantee. The method used to control risk is FMEA combined with fishbone analysis. This research produces several potential risks in the process stages until Spirulina powder is finished. Processes that potentially pose a risk and need to be controlled include receiving raw materials, storing raw materials, mixing, filling, and finishing good storage. The recommended controls to reduce risk are environmental control, machine, equipment, in-process control, and verification of the raw materials' correctness

Health sciences/Medical research/Drug development

Physical sciences/Engineering/Mechanical engineering

FMEA

Fishbone analysis

Spirulina capsule

Traditional Medicine

Risk assessment in the traditional medicine industry to prevent recalls of traditional medicines that cause harm to consumers. Risk assessment in quality management involves identifying hazards and analyzing and evaluating risks associated with hazard exposure. The initial step in quality risk assessment is to determine the problem or risk that must be adequately resolved ^1,2. The next step is that once risks are identified, appropriate quality management tools and required information can be identified more easily to assist in directing questions about risks. Three fundamental questions are often used in an assessment series to assist in clearly describing risks for risk assessment purposes. What is likely to go wrong, how often or likely an error occurs, and the consequences or severity of the error might occur ³.

Spirulina has been used in several medical applications, such as for antibody therapy of E. Coli infections in infants. Spirulina has been clinically tested on humans and used as herbal medicine in several traditional industries ⁴. The Spirulina market is large, with markets in countries like the United States, Belgium, Egypt, Ireland, Argentina, Germany, the Philippines, France, Brazil, Chile, India, Spain, Canada, and African countries. Spirulina, as an ingredient that is widely used as a raw material for food or herbal medicine, is produced by several large companies such as Genix (Cuba), Hainan DIC Microalgae Co., Ltd (China), Earthrise Farms (USA), Cyanotech (USA), Murugappa Chettir Research Center (India), and Solarium Biotechnology (Chile) ⁵.

Spirulina's potential, which will pose a risk to humans if consumed, must be mitigated. Contaminants in Spirulina are raw materials that may be harmful, such as heavy metals, pathogenic microbes, and others ⁶. Another risk that may arise is that the Spirulina raw material used does not match the claims contained in the COA, including the potential for other counterfeits that can harm consumers ⁷.

This research was conducted on the production process of Spirulina capsules in one of the Micro, Small, and Medium Enterprises (MSME/UMKM) of Traditional Medicine in Indonesia. Initial identification to obtain potential risk data is carried out in the pilot scale development process (1/10 production batch) and production batch to evaluate risk using the Failure Mode Effect Analysis (FMEA) method and fishbone analysis.

2.1. Fishbone Analysis

The method used in this study to support FMEA is a causal diagram (fishbone analysis). This diagram is a tool for categorizing possible causes of problems to identify the root causes. Fishbone analysis can identify and classify risks based on their nature. Potential risks in the software development process are identified and then traced back to find their root cause. The risk factors included in this study were obtained from the evaluation results of the production process ⁸.

2.2. Risk analysis and evaluation

Risk analysis and evaluation are carried out by multiplying the parameters in FMEA, which refer to ISO 31000, namely S, O, and D. The value of multiplying the three parameters is called the Risk Priority Number (RPN). The maximum RPN value allowed is 100 (suitable for some applications) ¹.

Table 1. Severity, occurrence, and detectability rating ¹

Severity (S)	Justification	Description
10	Dangerously high	may cause death or serious injury to the consumer
8	Very high	Finish good (FG) unusable
6	Moderate	Partial breakdown in the result and significant dissatisfaction (wrong data)
4	Very low	Performance loss on service parameters (quality, time, reliability)
2	Very minor	Minor consequences on performance
1	None	Not noticed by the user or not affecting the result
Occurrence (O)	Justification	Description
10	Very frequent	Error happening at least once a month
8	Frequent	Error happening between five and ten times in a year
6	Infrequent	Error happening between once and five times in a year
4	Low	Error happening once a year
2	Almost remote	Error happening once every five years
1	Remote	Error sometimes happens every 5–30 years
Detectability (D)	Justification	Description
10	Very remote	Error detection in less than 50% of inspections
7	Very low	Error detection in about 50% of inspections
4	Moderately high	Error detection in 70% of inspections
1	Almost certain	Error detection in more than 90% of inspections

2.3. Product evaluation of Spirulina capsules

Product requirements refer to regulations issued by the Food and Drug Supervisory Agency (BPOM) of the Republic of Indonesia. The evaluation carried out on the analysis of Spirulina capsule production included organoleptic (finish good), capsule weight uniformity (In Process Control and finish good), disintegration time, moisture content (In Process Control and finish good), microbial examination (finish good), heavy metal content, and packaging ⁹. The examination method is carried out according to the procedures described in the Republic of Indonesia Pharmacopoeia version VI of 2020 ¹⁰.

The organoleptically tested results of Spirulina capsules were bluish-green fine powder. The organoleptic characteristics are by the research characteristics of spirulina powder ^11,12. The capsules used are hard gelatine size 0 capsules. The capsule body color and capsule cap color are blue TR.

3.1. Quality Target Product Profil (QTPP)

Table 2. QTPP Product Spirulina capsule

QTPP element	Target
Route of administration	Oral
Dosage form	Capsule
Dosage strength	450 mg per capsule
Drug product quality attributes	It does not contain heavy metals
Drug product quality attributes	Product stability for two years
Container closure system	Suitable for storage in normal conditions (Temperature 25-30 °C & avoid direct light)

QTPP is obtained based on consideration of the company and market needs. The oral route for products that act as immune boosters is highly favored. The dosage of capsule dosage forms by industry requirements is included in the MSME classification with a simple manufacturing process. Dosage strength was obtained from the market leader for Spirulina capsule products, which have indications of maintaining endurance based on consideration of several pre-clinical studies^13–15.

3.2. Pilot scale evaluation

Table 3. Pilot-scale evaluation of Spirulina capsules

Stage	Problem
Receiving Raw Materials	Spirulina powder raw materials have substandard quality
Raw Material Storage	The expiration date of the product decreases due to storage
Mixing	Recall the product because it poses a danger to humans
	Spirulina content in the capsule is not homogeneous.
	The flowability of granules in the filling process could be better.
	The product Expired Date decreased
Filling	Weight uniformity & Disintegration
Finished Product Storage	Uncontrolled environment (temperature, Rh, and rodents)

3.2. Fishbone analysis

3.4. Evaluation of failure mode effect analysis

Table 4. Risk assessment

CPP	Potential Failure Mode		Potential Effect of Failure	S	Potential Cause	O	Current control	D	RPN
Receiving Raw Materials	MAT		The raw material for Spirulina capsules is of substandard quality	9	Weak Inspection method of raw material specifications	6	Raw material inspection checklist (Visual Inspection and comparing COA documents with standard specifications)	7	336
	Raw materials received do not meet the specifications.
Raw Material Storage	MET		ED of the product decreases due to storage	10	Unsuitable Raw Material Container	6	Pack in a paper drum and two plastic bags inside.	7	420
	Spirulina raw material is unstable.
	ENV		The ED of the product decreases due to storage	10	Extreme temperature changes (> 30 °C) and humidity (≥70%).	6	Checking Temperature and Rh during storage	7	420
	Spirulina raw materials are chemically damaged.
Mixing		MAC	Recall the product because it poses a danger to humans	10	Mixing equipment (Scop) is not clean	10	Equipment cleaning before use	10	1000
		There is metal and microbial Contamination.
		MET	The product is not homogeneous	6	Mixing time and method is not good	8	Mixing mixture 1 (Spirulina + MCC 101) 20 minutes (60 Hz/18 rpm) Mixing Mix 2 (Mixture 1 + Mg Stearate)	10	480
		Un-homogeneity
		MET	Weight uniformity	8	Spirulina obtains moisture content from the air	8	Checking water content	4	256
		Moisture content >10%
		ENV	The product ED decreased	10	Room temperature > 30 °C	6	Checking Temperature and Rh during the mixing process	7	420
		Spirulina raw materials are chemically damaged.
Filling		MAC	Weight uniformity & hardness	6	Improrer compression force	8	Setting up the capsule weight control pin on the capsule filling machine	10	480
		Unstable pin
Finished Product Storage		ENV	Uncontrolled environment (temperature, Rh, and rodents)	10	Temperature and rodent control is not carried out	6	Checking Temperature and Rh	7	420
		Product damaged during storage

Notes: COA (Certificate of Analysis); LOD (Loss on drying); As (Arsenic); Pb (Lead); Cd (Cadmium); Hg (Mercury); MAC (Machine); MAT (Material); MET (Method); ENV (Environment); EQU (Equipment); NA (Not Avalaible); IPC (In Process Contol); ED (Expired Date); Rh (Relative humidity)

Risk control functions to control risks that arise during the process so that the RPN value meets the standards. Risk control in this study is divided according to the stages of risk that may arise. Risk control is correlated with the root of the problem obtained from the analysis results using the fishbone analysis method and described in the risk assessment ¹⁶.

Table 5. Risk Control

Step of process	Control Methods	S	O	D	RPN
Receiving Raw Materials	Checklist of Raw Materials: Documents (Halal Certification & COA) Visual inspection (the condition of the raw material container is in good condition, and shipping transportation complies with regulations (GTP)) QC inspection for all containers with the following parameters: Description Moisture Content (Max 8%) Solubility (Method of dissolving in water) Microbiology (TPC ≤10000, Yeast & Mold ≤1000)	4	4	4	64
Raw Material Storage	Placement of raw materials on shelves, available segregation between raw materials	6	4	4	96
Raw Material Storage	Study of the placement of thermohygrometer in critical locations Check the room temperature three times a day	6	4	4	96
Mixing	Examination of heavy metal contamination on the finished product (AAS) Cleaning Validation	2	2	4	16
	Visual Inspection	4	6	4	96
	Bulk density using the tap density method	4	4	4	64
	Environmental control (Temperature 20-27 °C, Rh ≤70%, and pressure 5-20 Pa) Study of the placement of thermohygrometer in critical locations	6	4	4	96
Filling	Weight Uniformity Disintegration tester Environmental control (Temperature 20-27 °C, Rh ≤70%, and pressure 5-20 Pa) Study of placement of thermohygrometer in critical locations	4	6	4	96
Finished Product Storage	Eliminate rodents once every two weeks, provide a rat trap program, and provide insect killer Study of the placement of thermohygrometer in critical locations	4	4	1	8

Notes: GTP (Good Transportation Practices); AAS (Atomic Absorption Spectrophotometer); TPC (Total Plate Count)

3.4. Product Evaluation of Spirulina capsules

The evaluation results of the finished goods show that the product meets the standards set by QTPP and the quality standards set by BPOM. The weight uniformity test meets the standard (± 10%), illustrating that the filling machine's granule size and set-up can produce a stable and uniform weight in one production batch. The capsule disintegration time describes the compression force at stable machine settings, and the moisture content in evaluating Spirulina capsule granules describes the environment during a controlled production process. The results of the evaluation of the growth of microorganisms in the product fulfill the requirements with the justification that the Spirulina capsule product during the production process does not get microbial Contamination either from equipment, the environment, or other things during the production process.

3.4. Evaluation of heavy metal content

The evaluation results of checking the heavy metal content in the finished good showed that the Spirulina capsule product met the requirements. These results illustrate that there is no heavy metal contamination from raw materials or Contamination during the production process from the equipment and machines used. The potential risk of heavy metal contamination is caused by Contamination of the equipment and machines used because they contain metal elements. The potential is quite significant for both flakes.

Table 7. Results of testing for heavy metal content

Batch Number	As	Cd	Hg	Pb
01	ND	ND	ND	ND
02	ND	ND	ND	ND
03	ND	ND	ND	ND
04	ND	ND	ND	ND

Notes: ND (not detected)

Spirulina is a raw material widely used by the food or traditional medicine industry. Spirulina has been scientifically proven to help to maintain a healthy body ¹⁷. Security considerations are one of the main factors that need to be reviewed for quality risk management. Risk assessment starts from the raw materials used and during production until they become finished goods ready to be marketed. The methodology used to manage risks at each stage combines the FMEA method with fishbone analysis. The method compiles and ranks risks and reduces risks through risk control. The results of this study resulted in several recommendations for managing the risk to be as low as possible, among others:

Verify the correctness of raw materials both in terms of document completeness and testing (moisture content, microbiology, solubility, and organoleptic)
Control of storage of raw materials, especially in environmental conditions (temperature and humidity) and storage
In Process Control, the mixing process is controlled visually, bulk density, no heavy metals are detected in the final product, and environmental control (temperature, humidity, and air pressure)
The capsule-filling process is controlled by testing the uniformity of weight, disintegration time, and environmental conditions (temperature, humidity, and air pressure).
Finish goods stored in the finished goods warehouse must be controlled from rodent hazards and a controlled environment during storage.

Conflict of Interest

The author ensures that this article is unrelated to a company or is commercial with other parties, causing the resulting article to be biased.

Author Contributions

TDR & DEA contributed to the concept and development of the framework for this article. TDR and FAH contributed to the literature study, data extraction, confirmation, and synthesis to become a manuscript. FAH sends the manuscript to the publisher and ensures that the manuscript is approved, and coordinates if there is a revision to be corrected

Funding

There was no funding from any source in the making of this article

Acknowledgments

Tantan Institute assisted this work in verifying the data and validity.

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Table 6 is available in the supplemenary files section.

There is NO Competing Interest.

Table6.docx

Application of Failure Mode Effect Analysis (FMEA) in the traditional medicine Industry: A Case study on Spirulina Capsule Production

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Abstract

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1. Introduction

2. Materials and Methods

3. Results And Discussion

4. Conclusion

Declarations

References

Tables

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Supplementary Files

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