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Good manufacturing practices for risk management in food safety sustainability: An empirical study

D P Andriani 1 , A P N Aini 1 , M Lestari 2 and P Purba 1

Published under licence by IOP Publishing Ltd IOP Conference Series: Earth and Environmental Science , Volume 733 , International Conference on Green Agro-industry and Bioeconomy 25 August 2020, Malang, Indonesia Citation D P Andriani et al 2021 IOP Conf. Ser.: Earth Environ. Sci. 733 012118 DOI 10.1088/1755-1315/733/1/012118

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1 Department of Industrial Engineering, Universitas Brawijaya, Malang, Indonesia

2 Central Laboratory of Life Sciences, Universitas Brawijaya, Malang, Indonesia

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Food is an essential need for the sustainability of human life so that consumers have the right to get a product that is safe for consumption. However, food poisoning cases due to the risk of biological, chemical, physical, and other contamination still occur frequently. In this study, an empirical investigation was conducted on apple pie production in a food processing SME that is known to have a risk of physical, chemical, and biological. This study used the hazard analysis and critical control point (HACCP) and good manufacturing practice (GMP) approaches to analyze each production process's hazards. This study also identified factors that harm using failure mode and effect analysis (FMEA) and provided recommendations for improving food safety and security for the SME business sustainability.

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Implementation of Food Safety Management Systems along with Other Management Tools (HAZOP, FMEA, Ishikawa, Pareto). The Case Study of Listeria monocytogenes and Correlation with Microbiological Criteria

Jocelyn c. lee.

1 Food Safety Consultant, 836B Southampton Road, Suite 355, Benicia, CA 94510, USA; moc.liartemruog@eelj

Aura Daraba

2 Faculty of Food Science and Engineering, “Dunarea de Jos” University of Galati, 111 Domneasca Street, Build. F, 800201 Galati, Romania; [email protected]

Chrysa Voidarou

3 Laboratory of Animal Health, Food Hygiene and Quality, Department of Agriculture, University of Ioannina, GR47100 Arta, Greece; rg.iou@uoradiovx (C.V.); moc.liamtoh@tevrevelc (G.R.)

Georgios Rozos

Hesham a. el enshasy.

4 Institute of Bioproduct Development (IBD), Universiti Teknologi Malaysia (UTM), Johor Bahru 81310, Malaysia; ym.mtu.dbi@ysahsneh

5 City of Scientific Research and Technology Applications (SRTA), New Burge Al Arab, Alexandria 21934, Egypt

Theodoros Varzakas

6 Food Science and Technology, University of Peloponnese, 24100 Kalamata, Greece

The food industry’s failure in planning and designing of and in implementing a Food Safety Management System and its foundation elements leads, in most instances, to compromised food safety and subsequent foodborne illness outbreaks. This phenomenon was noticed, worldwide, for all food processors, but with a much higher incidence in the medium- and small-sized food processing plants. Our study focuses on the importance of Food Safety Management System (FSMS), Critical Control Points Hazard Analysis (HACCP) and the Prerequisite Programs (PRPs) as the foundation of HACCP, in preventing foodborne outbreaks. For emphasis, we make use of the example of organizational food safety culture failures and the lack of managerial engagement which resulted in a multi-state listeriosis outbreak in USA. Moreover, we correlate this with microbiological criteria. Implementation of food safety management systems (ISO 22000:2018) along with incorporation of management tools such as HAZOP, FMEA, Ishikawa and Pareto have proved to be proactive in the maintenance of a positive food safety culture and prevention of cross-contamination and fraud.

1. Introduction

The two common causes of major food safety incidents and recalls are undeclared allergens and cross-contamination [ 1 ].

In the USA, a majority of an estimated 75 million cases of foodborne illness are reported to have resulted from poor worker hygiene practices. Astoundingly, documentation demonstrates that between 30% and 50% of persons do not wash their hands after using the restroom. The primary means to reduce cross-contamination in a food processing plant is proper employee training [ 2 ]. These good hygiene practices are elements of a Food Safety Management System’s prerequisite programs.

The World Health Organization describes prerequisite programs (PRP) as, “essential food safety practices that need to be implemented prior to and during the installation of HACCP” [ 3 ].

HACCP is the acronym for Hazard Analysis Critical Control Point. HACCP was originally developed by Pillsbury Company USA in the 1970’s (for NASA National Aeronautics and Space Administration). The very well-known principles of HACCP refer to conduction of hazard analysis, determination of critical control points (CCP), establishment of critical limit(s), monitoring control of the CCP, establishment of the corrective action to be taken when monitoring indicates that a particular CCP is not under control, verification to confirm that the HACCP system is working effectively and documentation concerning all procedures and records appropriate to these principles and their application The circulation of HACCP around the world as the foremost system of food safety management was substantially due to the Codex report of 1997 [ 4 ].

Codex, General Principles of Food Hygiene defines Food Hygiene as, “All conditions and measures necessary to ensure the safety and suitability of food at all stages of the food chain; Properly applied prerequisite programmes, including Good Hygiene Practices (GHPs), Good Agricultural Practices (GAPs) and Good Manufacturing Practices (GMPs), along with training and traceability, should provide the foundations for an effective HACCP system [ 4 ].

An increase in food safety legislative demands is the result of widespread food scares related to microbiological hazards (e.g., Salmonella, E. coli ), contaminants (e.g., dioxins) and animal disease (e.g., BSE) [ 5 ]. In sync, the complexity and globalization of food supply chains increased [ 6 ]. Via the robust implementation of various risk-based food safety management systems, food organizations are progressively mitigating and responding to active and risk-managed food safety hazard activities (FSMSs) [ 7 ].

In the last 20 years, a profusion of third-party food safety certification schemes (non-regulatory) has arisen which include public-based FSMSs (International Organization for Standardization (ISO) 9001:2015, Hazard Analysis Critical Control Point (HACCP) and ISO 22000:2018), and industry-based FSMSs (GlobalGAP, British Retail Consortium (BRC), Safe Quality Food (SQF), International Food Standard (IFS) and Food Safety System Certification (FSSC 22000). Notwithstanding, the implementation of these FSMSs has not met the varied expectations and challenges over the years, systems and global supply chains [ 8 , 9 ].

Investigation and research into FSMSs continues with regard to effectiveness and low uptake [ 6 ].

The determinants of market-based food safety management systems (FSMSs) implementation in the Middle Eastern context across Lebanon have been analyzed by Kifle-Abebe et al. [ 10 ]. They found that none of the food processors implemented industry-based FSMSs however, implementation of ISO 22000 (50%), HACCP (40%) and ISO 9001 (25.5%) took place. The key drivers for the increased implementation of market-based FSMSs include economic incentives (market orientation) and firm-specific factors such as organizational readiness, product/process characteristics, company size, and ownership structure.

The development of new, improved standards along with regulations to achieve more and more safe food is imperative and should act as pushing force [ 11 ]. Voluntary rules have been taken forward by many countries. In this context, food safety systems are interrelated with safety, quality, efficiency, reliability, interchangeability, and environmental friendliness coupled with economic factors [ 12 ].

In September 2005, ISO incorporated Hazard Analysis and Critical Control Point (HACCP) principles for food safety into the ISO 22000 quality management system. In this way there has been an integration of HACCP program and principles to quality management systems and prerequisite programs (PRPs) for the improvement of the quality and safety of the food chain in the food industry.

Two ISO technical committees have been formed, ISO/TC34 which developed ISO 22000 family for food products and management systems and subcommittee TC34/SC17 which developed systems for food safety [ 13 ] (ISO). Any party involved in the food chain business directly or indirectly can implement the standard. Now the new ISO 22000:2018 has been running.

ISO 22000:2018 provides a dynamic control method that incorporates recognized key elements, including interactive communication, systems management, prerequisite programs (PRPs) and hazard analysis and critical control points (HACCPs). Various clauses of ISO 22000:2018 are applied to the seven principles and 12 application steps of the HACCP methodology, hence their close relationship. The food safety plan–do–check–act (PDCA) cycle is one of two PDCA cycles and can be found in Operations described in Chapter 8 of the standard. Planning, implementation, regulation, correction, maintenance and updating of the PDCA cycle are described and outlined in the standard [ 14 ].

According to ISO 22000:2018, which was introduced worldwide on 19 June 2018, organizations must conduct hazard analysis to identify significant hazards [ 15 ]. CCPs and prerequisite programs (PRPs) were subsequently not limited to the sole use of the decision tree based on 4 questions. ISO 22000 imparted no detailed PRP-related information and hence was not recognized by the Global Food Safety Initiative as a standardized reference for food manufacturers in the past.

Hence, the revised version of that guideline, ISO 22000:2018, was made more effective. For example, first step is to identify the hazards and analyze them and then determine if they are a PRP, OPRP or a CCP for the significant hazards. Then the HACCP plan be put into action in terms of monitoring, control, and verification. In food industries, this step was considered to be the most critical, and also agrees well with the first principle of CODEX HACCP and ISO 22000:2018 (Section 8.5.2), which calls for the execution of hazard analysis.

Chen et al. [ 16 ] focused on significant hazard analysis, the determination and establishment of prerequisite programs, and the role of critical control point (CCP) based on ISO 22000:2018 in the catering industry. They provided guidelines and practical experiences related to the incorporation of significant hazard analysis and the use of the CCP decision tree approach to determine and update the possible CCPs of seven primary food processes.

It is well known that food chain includes organizations that are either directly involved with food or not directly involved with food processing and come in contact with either food or food ingredients [ 17 ].

The role of the new standard ISO 22000:2018 is to ensure safe food supply throughout the chain and provide a framework of internationally harmonized system.

This standard allows international trading by assuring about reliability, food quality and food safety.

The role of Food Safety Management System (FSMS) in implementation of food safety is reviewed by Panghal et al. [ 18 ]. Global Food Safety Initiative’s theme has announced the goal “once certified, accepted worldwide” in order to help industries and researchers.

Chen et al. [ 19 ], developed a food safety management system for a chaga mushroom biotechnology product manufacturer, to meet the quality demands of customers and enhance the manufacturer’s reputation. The study focused on the identification of the potentially significant hazards present at each stage of the production process for chaga mushroom capsule products, and on the assurance that the biotechnology company in question has fully implemented ISO 22000:2018 and the HACCP methodology.

The aim of this review paper is to show the paramount importance of food safety management systems and their reliance on prerequisite programs for the implementation of effective preventive controls. Even though this may seem to be a very basic principle to practice, there have been incidents that this has been neglected which consequently led to cross-contamination and foodborne illness. The case study in this document is one such incident. Moreover, the implementation of management tools such as HAZOP, FMEA, Ishikawa and Pareto will be described. Finally, correlation with microbiological criteria is discussed in the context of EU regulation 2073/2005.

2. Identified Barriers to Implementing Food Safety Management Systems FSMS

Lack of prerequisite programs is the #1 ranking identified barrier at 92.2%. Lack of knowledge about HACCP is the #2 ranking identified barrier at 83.5% [ 20 ]. Prerequisite GHPs must be in place first, before an effective FSMs, hazard analysis and critical control point HACCP can be implemented [ 21 ]. Nowadays, PRPs include environmental criteria and operational procedures. PRPs are encompassing the entire FSMS now, not only operational GHPs as in the past.

PRPs are recognized to be an established foundation for the implementation of HACCP. Meanwhile, HACCP and PRPs have gone unacknowledged as interdependent. For example, they are often taught separately, with more emphasis on HACCP training and certification than on PRPs. Case in hand, the ISO 22000:2005 on FSMSs contained minuscule guidance on PRP requirements that a supplemental specification for the food industry [ 22 ] on PRPs was developed for it to be benchmarked and approved by the Global Food Safety Initiative (GFSI) [ 23 ]. Thus, the symbiotic significance of PRPs to the manufacture of safe food is predominantly apparent. Recalls associated with pathogens such as Listeria or Salmonella are more often caused by PRP failure (post-process cross-contamination and | or unsanitary production environments) rather than the failure or mismanagement of critical control points (CCPs) in a HACCP plan [ 24 ].

The potential for food and beverages cross-contamination may occur at any and all food processing steps including transportation from the farm fields to processing facilities, processing steps in the food manufacturing facilities (due to deficient SSOPs, lack of personnel training, deficient GHPs, deficient good process practices (GPP), food packaging and storage). Foodborne illness outbreaks are the result of the likely risk of contamination of food products during processing and packaging and storage activities. Therefore, the identification of the root causes of contamination is crucial to understand the likely sources and paths of contamination of foodborne outbreaks and product recalls. Corrective actions and preventive control steps to mitigate their occurrence(s) can only be achieved by identifying the root causes [ 1 ]. Table 1 refers to global food safety incidents/recalls from 2008–2018 based on the type of identified hazards.

Global food Safety incidents and/or recalls according to hazards from 2008–2018 [ 1 , 25 ].

Foodborne illnesses are typically infectious or toxic in nature, caused by bacteria, viruses, parasites or chemical substances entering the body via contaminated food or water. Foodborne pathogens are known to cause severe diarrhea or debilitating infections, including meningitis.

Chemical contamination causes sudden onset of poisoning or long-term diseases, such as cancer. Foodborne diseases may tend to result in long-lasting disability and death. Unsafe food includes uncooked meats, fruits and vegetables contaminated with feces, and raw shellfish contaminated with marine biotoxins.

A formidable range of identifiable hazards (biological, chemical, physical) are existent throughout the food supply chain to the point of consumption (farm to fork) [ 1 ].

Table 2 refers to Foodborne Illness Hospitalizations in USA in the decade of 2010–2020 [ 1 , 26 ]. The USA Population growth from 2010 to 2020 was 234.6 million people to 331.4 million people [ 27 ].

Estimations of Hospitalization from Foodborne Illness based on best available data. The average is based on the number of people become ill and later hospitalized because of the severity of illness. For instance: for 10 persons ill with L. monocytogenes , estimated 9 people hospitalized [ 1 , 26 , 28 ].

Listeria monocytogenes (LM) is known to be one of the leading causes of death from food-borne pathogens particularly so in the vulnerable population including pregnant women, newborn babies, the aged and immuno-compromised individuals. LM still is documented to be a relentless challenge for ready-to-eat (RTE) food, cooked meat and fish products and dairy processors. LM is environmentally commonplace in the processing environment as it is able to survive and multiply in resistant and unfriendly conditions such as refrigeration/freezer temperature, and low pH and high sodium chloride (salt) concentration. Several RTE foods such as delicatessen meats, poultry products, seafood and dairy products (such as ice cream) are classified as a high-risk medium for LM because these foods are likely to be refrigerated/frozen thus providing suitable environments for LM to survive and multiply. Listeriosis outbreaks have been linked to seafood, dairy (such as ice cream), meat and vegetable products. However, in the last decade, listeriosis outbreaks have been linked to out-of-the-ordinary food mediums such as raw produce, ice cream and vegetable products [ 1 ]. Table 2 projects estimations of hospitalization from foodborne illness in the decade of 2010–2020.

Deficient recycling/waste disposal and lack of adequate cleaning of equipment and facilities cause the increase in the decomposition and growth of spoiled and contaminated food. This is called environmental hygiene. Inferior sanitary conditions in food processing areas and unhygienic food handling adds to poor food storage and transportation resulting in the sales/distribution of unhygienic/unsafe food. Consequently, adding to increased pest/insect population thereby increasing the risk of food contamination and spoilage [ 1 ].

2.1. Prerequisite Programs (PRPs)

PRPs provide the hygienic foundations for any food operations. The terms prerequisite programs PRPs, Good Manufacturing Practices (GMPs), Good Hygienic Practices (GHPs) and sanitary standard operating practices (SSOPs) are interchangeable in diverse parts of the globe but carry the same applicable definition ( Figure 1 ). “Prerequisite programs” (the term) is now frequently used for systems in support of HACCP principles, all-in written and spoken languages and practices. In other words, “The concept of supporting good practices is widely accepted” [ 29 ].

‘Prerequisite programmes (PRPs) adapted from What is a Management System? Available online: https://images.app.goo.gl/Aqez5sSfpbvjQqmK7 (accessed 20 June 2021).

In Figure 2 the significant systemic importance of PRPs and HACCP is outlined. PRPs are considered the foundation|support upon which HACCP relies. “Systems thinking” can be used to help solve complex food contamination problems, and it can help deliver a structure to model solutions to urgent food safety matters. Systems thinking includes problem solving and critical thinking.

Adapted from Prerequisite Programs Ensure Food Safety Available online: https://images.app.goo.gl/jFnRtoUP3ByyLyn77 (accessed on 20 June 2021).

Many challenges faced today are extremely complex, and cannot be looked at from one perspective only, but they can and should be approached by looking at the system within. Looking at the system within, and having the courage to do so, restructure of the system can take place. By using systems thinking, complex problems can be solved [ 30 ]. Table 3 describes food safety competencies along with safety knowledge and skills and systems thinking.

Food safety competencies along with required safety knowledge and food safety skills and systems thinking approach Source: Adapted from “GFSI Food Safety Auditor Competencies Edition 1” November 2013 [ 31 ].

2.2. Symbiotic Importance of PRPs and HACCP

(PRPs are considered the foundation support upon which HACCP relies).

PRPs are core components of the “world-class food safety program”. They have a significant support role to play as the heavy lifter foundation to other core elements. Traditionally considered as the foundational support for HACCP, we now perceive how PRPs also play an active role (in-direct) in food defense, food fraud prevention and safe food process technology and engineering. They work symbiotically with HACCP as a preventative control (PC) system. PRPs are applicable at all stages of the global food supply chain and in turn, comprise good mitigation practices for growing, harvesting, manufacturing, storage, distribution, retail, food service and cottage industry [ 27 ]. Figure 3 illustrates the interaction between FSMS, necessary good management practices, positive food safety culture and systems thinking.

The interaction between FSMS, necessary good management practices, positive food safety culture and systems thinking Source: (Adapted from “Food Safety for the 21st Century”, Figure 9.2, page 164) [ 29 ].

SSOP and GMP Practices and Programs

GMP regulations guidance are designed to control the risk of food contamination with filth, dirt, scum, allergens, biofilm, chemicals, microbial particulates and other mediums during food processing.

The core GMPs for all FDA-inspected food processing sites are physical site maintenance (including outdoor detached units and portable facilities), equipment (including utensils) cleaning and sanitizing, clean equipment utensils handling and storage, pest control management, proper use and storage of cleansing solution compounds, sanitizers and pesticides, employee training, employee PPE, employee GHP, site and equipment design, and quality assurance audits.

Focused GMPs established regulations for specific food sector industries and products are in addition to the core GMPs. In other words, specific GMPs for processors: meat, poultry, seafood, dairy, feed and pet food. As such, meat and poultry processors are required to implement and maintain SSOP requirements in 9 CFR 416. USDA enforces 9 CFR 416, while FDA enforces 21 CFR 110. These particular processors are responsible for preventing contamination of their products via implementation of their documented SSOP. These processors must understand and become competent on their GMPs, because they serve as a valuable guide and tool when developing and implementing the plant’s SSOPs.

2.3. Current GMPs (cGMPs)

According to the Code of Federal Regulations (CFR) under Title 21 Part 110; and cGMPs in manufacturing, packing and holding human foods the following are described.

2.3.1. cGMPs and Personal Hygiene

The most frequent cause of contamination is Cross-contamination of food by food handlers. Good food worker hygiene (GHP) is necessary because the cleanliness and behavior of workers determine the risk level (low risk or high risk) of cross-contamination from worker to food products and food contact surfaces. Trained, clean, sanitary, good hygiene-minded workers are of the utmost importance to produce safe food.

Several cGMPs concentrate on reducing food handler contamination. View “Code of Federal Regulations (CFR) Title 21, Part 110.10” ( http://a257.g.akamaitech.net/7/257/2422/10apr20061500/edocket.access.gpo.gov/cfr_ (accessed on 20 July 2021)) [ 32 ].

Food processors of all sizes are to instruct proper handwashing to each employee by describing, in detail, how much soap they should use at what water temperature, and the proper lathering time (approx. 20 s). The processor’s employee training program documents and records all training materials. The GMPs on handwashing and facilities—such as sinks, toilets and towel racks—are presented in the SSOP format.

Finally proper maintenance of sanitary facilities and adequate supplies must be carried out including adequate quantities of soap, disinfectant, fully operational sinks supplying potable water, paper towels, toilet paper, paper seat covers, etc.

2.3.2. Employer Top Management Responsibilities

Employer must provide all adequate resources to comply with and implement the above listed best practices, including top management food safety leadership engagement, sufficient labor force, training, maintenance, supplies, necessary food safety consulting, services, etc.

2.4. Compliance with cGMP Regulations

Here is an example of a clearly defined compliance/evaluation-easy regulation: “no pests shall be allowed in any area of the food plant”. When an inspector witnesses a mouse, or evidence of a pest (such as rodent droppings) on the site, then this is a clear regulatory violation. In contrast, other GMPs express terms as such: “clean as frequently as necessary to protect against the contamination of the food.” While some GMPs may use the terms “adequately” or “sufficient”. This unclear regulatory language is subjective. USDA-FSIS has developed more conventional requirements. Their SSOPs require processors to document adequate SSOPs and GHPs to ensure that foods are produced safely in sanitary-hygienic conditions. Whenever there is a modification, replacement or upgrade of sanitizers, cleaning agents, equipment, technologies, methods or practices, these updates and modifications should be documented and accompanied with appropriate validation.

2.5. Sanitation Standard Operating Procedures (SSOPs)

SSOPs are written in order to ensure sanitary conditions in food facilities. The SSOP procedures are specific to a plant but also may be similar to plants of the same or similar food sector categories. All SSOP procedures must be adequately documented and validated. When the facility’s SSOPs are in a developmental stage cGMPs could assist as a guide to the food facility.

Pre-operational “pre-op” (before daily processing begins) and operational (during processing) SSOPs include sanitation requirements to prevent direct product contamination or adulteration. The instructions on the cleaning frequency of the processing line should be addressed in the facility’s SSOPs and supporting documentation.

2.5.1. Pre-Operational SSOPs (Pre-Op)

Pre-Op SSOPs include the cleaning of product contact surfaces of facilities, equipment and utensils to prevent direct product contamination or adulteration. These may include:

“(1) equipment disassembly and reassembly after cleaning, use of acceptable chemicals according to label direction, cleaning utensils, cleaning equipment and cleaning techniques. (2) instructions, and concentrations for sanitizers applied to product contact surfaces after cleaning.” [ 2 ].

2.5.2. Operational SSOPs

Operational SSOPs were established to describe the daily routine sanitary procedures to be performed during operations for the prevention of direct and in-direct product contamination adulteration. Such established operational sanitation procedures must result in a clean sanitary hygienic “environment for the preparation, storage, or handling of any meat or poultry food product”. These operational SSOPs may include: (1) Equipment and utensil cleaning/sanitizing/disinfecting “during production, as appropriate, at breaks, between shifts and at mid-shift cleanup”. (2) worker hygiene procedures for the cleanliness of personal protective equipment (PPE) of outer garments, masks, respirators, Meat and poultry operations’ SSOPs and other prioritized food sector facilities where foodborne illness outbreaks originated must comply with the following regulatory requirements:

• The facility shall have documented SSOPs detailing its daily procedures (both the pre-ops and during-ops) spelling out the steps to prevent direct in-direct product contamination adulteration. At least, these procedures shall focus on the cleaning of food contact surfaces, equipment and utensils. “The SSOPs shall indicate the frequency at which each procedure will be verified”.
• The SSOPs are to be signed and dated by plant management or plant owner. SSOPs shall be reviewed periodically as required.
• The facility shall designate qualified individual(s) (QI) goggles, gloves, hair restraints, handwashing, etc.
• Special food handling in segregated raw and cooked product areas should be carried out. SSOP records shall be maintained on-site administrative storage for at least 48 h as well as maintained for a minimum of six months (appropriate off-site storage).

2.5.3. Food Sector Specific SSOPs

These should be responsible for the implementation and monitoring of SSOPs and daily sanitation activities”. Maintenance of documented records of SSOP activities along with corrective actions for a minimum of six months (48 h on-site) is suggested.

2.5.4. Critical Control Points

CCP is a point in a step or procedure at which a control should be applied for the prevention or elimination of a hazard or reduction to an acceptable level.

The identification of critical control points should ensure that appropriate control measures are effectively designed and implemented. In particular, if a hazard has been identified at a step where no control measure exists at that step, then the product or process should be modified at that step or at an earlier or later stage, to include a control measure. Moreover, a monitoring system per critical point should be established and implemented [ 33 , 34 ].

Detection of CCPs or PRPs in a food processing plant can be depicted with a 4 Q tree diagram as shown in Table 4 . Receiving of raw materials is an OPRP whereas storage of raw materials, e.g., at a frozen room or refrigeration room could be a CCP in parenthesis depicting the microbiological hazard with an M.

Tree diagram for CCP and OPRP detection in food processing for a featured/representative production step according to decision of European Commission (2016/C 278/01) [ 35 ].

2.6. CASE STUDY

Failed PRPs SSOPs GMPs GHPs—Catastrophic Foodborne Illness Case—“Blue Bell Listeriosis Outbreak of 2010–2015 and Recall of 2015”.

2.7. Summary

In early 2015, United States federal/state governmental public health officials formerly served notice to Blue Bell Creameries (BBC), one of the largest US makers of ice cream products, that they were responsible for a listeriosis outbreak originating back 5 years to 2010. The outbreak spread over four US states, 10 persons were sickened and four persons dead, (the Centers for Disease Control and Prevention (CDC) reported). BBC activated a weak performance of recalls intended to minimize its financial damage whilst “limiting the useful and actionable information the company provided to the nation’s consumers”. Only when confronted with extreme convincing evidence (external and internal) of its role in the outbreak did BBC recall all of its contaminated and potentially contaminated products from the US national marketplace. This case study examines the events, systemic food safety failures, and root causes that led to the foodborne listeriosis outbreak and 20 April 2015, complete-market recall wherein BBC’s top executives failed to meet “their moral responsibility to protect consumers” (by concealment, delay tactics and gross negligence).

In early 2015, BBC (a privately held company), had no food safety mission statement, no plan whatsoever to manage foodborne risks and complications | disputes, no risk-managed Food Safety Management System FSMS, no prerequisite programs, including robust Sanitation Standard Operations Procedures (SSOPs), nor product batch Laboratory Pathogen testing regimens to monitor, verify and validate their products were food safe. Additionally, no one at the operations’ managerial or top executive level was knowledgeable, trained or skilled to prepare | respond to a foodborne outbreak or a recall. After all, for 108 years, the complacent ice cream company had successfully operated without a recall.

The BBC company pled “guilty to two misdemeanor counts of shipping products across state lines” which involved the 2015 listeriosis outbreak and it “agreed to pay $19.35 million in civil charges”. The company also executed “a secret plea agreement (maybe unfavorable to Kruse) with the federal government” [ 36 ].

The 2015 Listeria outbreak sickened 10 people in four states and killed three in Kansas. The listeria spread from inside Blue Bell and the 18-page Grand Jury indictment charges Kruse with conspiracy and wire fraud.

“Rather than send a public notification about the contaminated products to customers and consumers,” the indictment says, “the defendant PAUL KRUSE ordered his sales employees to pull products from customers ‘shelves without disclosing the reason.” He also generated a written statement that BBC “concealed certain Blue Bell products might contain Listeria monocytogenes , and he directed his sales employees to give that statement to customers who asked about the removal of products” [ 37 ].

Consequently, former BBC president “Paul Kruse was charged with seven counts of wire fraud and conspiracy to commit wire fraud” on the grounds of his efforts to conceal from the public what the BBC company had already known regarding the Listeria contamination in certain BBC ice cream products. According to the indictment filed in federal court in Austin, “Texas state officials notified Blue Bell in February 2015 that two ice cream products from the company’s Brenham, Texas, factory tested positive for Listeria monocytogenes, a dangerous pathogen that can lead to serious illness or death in vulnerable populations such as pregnant women, newborns, the elderly and those with compromised immune systems”. Kruse crafted a secret action plan to “deceive certain Blue Bell customers, including by directing employees to remove potentially contaminated products from store freezers without notifying retailers or consumers about the real reason for the withdrawal”. The indictment states, “Kruse directed employees to tell customers who asked about the removal that there was an unspecified issue with a manufacturing machine”. Moreover, BBC concealed deliberately delayed the immediate recall of the BBC products and did not “issue any formal communication to inform customers about the potential Listeria contamination” [ 38 ].

To investigate the source of Listeria monocytogenes contamination, the US FDA environmental assessments were conducted at Blue Bell’s creamery facilities located in three different states: Alabama, Texas and Oklahoma.

Substantial pitfalls in HACCP-based Standard Operating Procedures (SOPs) were identified in all three production facilities as the possible contributors to L. monocytogenes contamination of the product ( Table 5 ).

Violations of HACCP-based Standard Operating Procedures (SOPs) identified by on-site FDA inspections Sources: US FDA Observation Reports on Blue Bell Creameries Facilities [ 39 , 40 , 41 ].

The most prevalent identified violations of SOPs, in all three production facilities, were related to:

• (1) Failure to perform on-site, materials and product microbial testing and to take appropriate corrective actions;
• (2) Failure to maintain clean and sanitized food contact surfaces to avoid cross-contamination either due to lack of performance of the used procedures for cleaning and sanitizing of equipment or due to the defective design of used equipment that does not allow proper cleaning and maintenance;
• (3) Inappropriate design and construction of the production facilities to avoid product’s direct- or cross-contamination.

Additionally, in two of the production facilities, the personnel hygiene was been found being deficient and, thus, representing possible routes for product’s contamination with L. monocytogenes or with soil.

In only one production facility, an additional identified violation was related to the lack of monitoring the temperature—a critical control point (CCP)—a fact which favored the temperature abuse of the product.

Core FSMS Failures: Lack of managerial involvement, lack of organizational food safety culture and deceptive practices—withdrawal of products without using the recall procedure and route, and delay of recall and foodborne illness outbreak alerts.

In Figure 4 all problems related to freezing attributed to the 5 main categories (materials, man, environment, methods and machines) are described in detail. These problems along with the identified violations in the case study could act as preventative measures in the future for food companies that do not act responsibly.

Fishbone diagram for problems during freezing.

The hazard and operability study (HAZOP) [ 42 , 43 , 44 ] conducts most process hazard analysis (PHA) studies today. Proximate physical causes of accidents, also named technical or accident mechanism causes or factors should be taken into account. Causes include equipment failures, human errors by front-line personnel and external events. Chain-of-events model of accident causality is that considered for traditional PHA methods [ 45 ].

Systems theory is the one that current models of accident causality depend on. These models provide a more complete representation of the causal factors involved in accidents. PHA methods such as system-theoretic hazard analysis (STHA) should reflect these models. Another hazard analysis method is the System-theoretic process analysis (STPA) [ 46 ].

Hazop methodology also studies the effects of the deviations from design conditions.

The most common bottom-up HAZID technique is represented by HAZOP [ 47 ], with a widespread use in industry [ 48 , 49 , 50 , 51 , 52 ].

Multi-criteria Decision Making (MCDM) is a problem-solving methodology in various research fields and has shown good results in hazard analysis. Alves Viegas et al. [ 53 ] proposed and conducted a novel MCDM-based HAZOP analysis based on Strategic Options Development and Analysis (SODA), and Intuitionistic Fuzzy Sets (IFS).

Marhavilas et al. [ 54 ] developed and applied an extended HAZOP- Decision-Matrix Risk Assessment (DMRA)—Analytical Hierarchy Process (AHP) approach in process industries for identification of critical points and potential hazards and also prioritization of risks.

A case study in a sour crude oil processing-plant has been presented as a conventional HAZOP study to identify the possible fault causes of deviations in the plant.

Choi and Byeon [ 55 ] proposed HSE-HAZOP for the systematic and efficient application of health, safety and environment (HSE) engineering. They exploited the HAZOP systematic hazard analysis technique and a quantitative risk derivation method. A case study of a solution styrene butadiene rubber (SSBR) plant was used.

The new trend known as the fourth industrial revolution (Industry 4.0 represents the industrial revolution toward automation and artificial intelligence (AI)). Lim et al. [ 56 ] conducted a detailed review of the current state of the palm oil industry development toward Industry 4.0. A novel HAZOP approach is adopted to evaluate the existing problems, and identify potential implementation of Industry 4.0 technologies in the palm oil industry.

4. Other Management Tools in Conjunction with ISO 22000 (Fmea Analysis-Pareto and Ishikawa Diagrams)

In FMEA analysis, risk of contamination and its presence at Hazardous Fraction in the final product, is expressed with the Risk Priority Number (RPN) which is defined as follows:

Where S: Severity of contamination risk, O: Occurrence of contaminated ingredient, D: Detection probability of contaminated ingredient.

where S: severity, O: occurrence, D: detection.

Corrective action is carried out when RPN is greater than 130.

RPN assessment is carried out and corrective actions are proposed per identified hazard. Following calculation of RPN’ (after undertaking corrective actions), a new classification of Hazardous Elements is shown ( Table 6 , [ 57 ]).

FMEA Table of hazardous processing methods for food products for the receiving stage.

Best expert opinion and product history (epidemiological studies) aid the analysis based on the different ways each component or subsystem might fail to comply with its intended function [ 58 , 59 ].

Failure mode and effect analysis (FMEA) model has been applied for the risk assessment of ready to eat vegetables manufacturing. FMEA was attempted in conjunction with cause and effect diagrams. Critical control points have been identified and implemented in Ishikawa diagrams.

Quantification of risk assessment was carried out by determining RPN per identified processing hazard. The highest RPNs (225, 225, 180 and 144, respectively) were correlated with receiving, storage and distribution, packaging and cooling and corrective actions were undertaken. Following the application of corrective actions, RPN values were below the upper acceptable limit of 130 [ 57 ].

Other case studies included FMEA analysis of salmon manufacturing. The highest RPNs (252, 240, 210, 210, 210, 210, 200, respectively) were correlated with fish receiving, casing/marking, blood removal, evisceration, filet-making cooling/freezing and distribution and corrective actions were undertaken. After application of corrective actions, new RPNs were substantially lower [ 60 ].

Another case study involved FMEA model applied in conjunction with cause-and-effect analysis for the risk assessment of octopus processing ( Octopus vulgaris ). The highest RPNs (378, 294, 280, 252, 245 and 144, respectively) were correlated with chemically contaminated product, decomposed raw materials, scombrotoxin presence in the final product, incorrectly labelled product, storage in cans (foreign matter) and defective products, and corrective actions were undertaken. Following the application of corrective actions, new RPN values led to considerably lower values (below the upper acceptable limit of 130) [ 61 , 62 ].

Failure Mode and Effect Analysis (FMEA) has been applied for the risk assessment of snails manufacturing. Quantification of risk assessment was carried out by determination of the RPN per identified processing hazard. The highest RPNs (280, 240, 147, 144, respectively) corresponded to sterilization of tins, bioaccumulation of heavy metals, packaging of shells and poisonous mushrooms, and corrective actions were undertaken. Following the application of corrective actions, new RPNs led to lower values (below the upper acceptable limit of 130). The application of Ishikawa diagram led to converging results thus corroborating the validity of conclusions derived from risk assessment and FMEA [ 63 ].

Varzakas and Arvanitoyannis [ 64 ] applied the FMEA model the risk assessment of corn curl manufacturing. A tentative approach of FMEA application to the snacks industry was attempted in an effort to exclude the presence of GMOs in the final product. This is of crucial importance both from the ethics and legislation aspects. Critical Control points have been identified and implemented in the cause and effect diagram and Pareto diagrams were employed towards the optimization of GMOs detection potential of FMEA.

FMEA model has been applied for the risk assessment of potato chips manufacturing by Arvanitoyannis and Varzakas [ 65 ]. Preliminary hazard analysis was used to analyze and predict the occurring failure modes in a potato processing and potato chips processing plant, based on the functions, characteristics and/or interactions of the ingredients or the processes, upon which the system depends. CCPs have been identified and implemented in the cause and effect diagram along with Pareto diagrams.

Another case study is the application of FMEA model for the risk assessment of strudel manufacturing [ 66 ]. Preliminary Hazard Analysis was employed towards analysis and prediction of the occurring failure modes in a strudel processing plant, based on the functions, characteristics and/or interactions of the ingredients or the processes, upon which the system depends. Critical control points were identified and implemented in the Cause and Effect diagram along with Pareto diagrams.

The FMEA model has been applied for the risk assessment of pastry processing [ 67 ]. The highest RPNs (225, 225 and 144, respectively, were correlated with storage of raw materials and storage of final products at −18 °C followed by freezing and corrective actions were undertaken. New RPN values led to considerably lower values. The application of Ishikawa led to converging results reflecting on the validity of conclusions derived from risk assessment and FMEA.

4.2. Ishikawa-Fishbone Diagrams

Ishikawa or Fishbone diagrams analyze all the hazards at all processing stages where Critical Control Points (CCPs) are incorporated. These diagrams consist of five basic axes: man, machine, materials, methods and environment. In each these axes the hazards are described in detail. Dr. Kaoru Ishikawa, a Japanese quality control statistician invented Ishikawa diagram [ 68 ]. The fishbone diagram is a systematic analysis tool looking at causes and effects at different sub levels. Due to its resemblance to fish skeleton, it is often referred to as a fishbone diagram ( http://quality.enr.state.nc.us/tools/fishbone.htm ) (accessed on 20 July 2021) [ 69 ].

4.3. Pareto

A Pareto diagram is usually constructed, to determine and display high-risk processing steps and their corresponding corrective actions. Then, a second Pareto diagram is drawn focusing on cheese pie processing aiming at the determination of new risk situation (following the suggested corrective actions) ( Figure 5 and Figure 6 ).

Pareto diagram of cheese pie processing prior to corrective actions.

Pareto diagram of cheese pie processing after corrective actions.

5. ‘Process-Based’ Microbiological Criteria

5.1. aspects of microbiological criteria related to foods.

The term «food/foodstuff» covers every unprocessed, semi-processed and processed material which is meant to be used for human nutrition. It also includes any ingredient incorporated into the food and drink, as well as any substance that comes in direct contact with them in the chain of production from start to finish (from producer to consumer). This includes all the raw materials, ingredients, means of processing, packaging and all surfaces in contact with the food or drink throughout the production process.

In recent decades, the issue of food quality and safety has become one of the most fundamental subjects of public debate in global markets and especially in the agricultural and food production industries. This debate has been fueled by many factors, but mainly due to a series of high profile scandals in the food industry, which have increased concerns on the part of consumers regarding food characteristics, production methods and their effects on human health [ 70 , 71 , 72 , 73 ]. Consequently, quality foods are becoming increasingly sought after by consumers globally.

In an effort to become more competitive, food producers are adopting quality and safety systems, either voluntarily or required by law. This is carried out not only so as to ensure health and safety for their products, but also to prevent customer complaints and to build and maintain customer trust/loyalty. In order to apply a given quality system to all stages of the food chain, quality management has a vital role to play [ 74 ].

However, the question as to what exactly is a quality food cannot be answered as easily as one might think, and the vagueness in the definitions of what constitutes quality has been noted by researchers such as Deming: «The difficulty in defining quality is in translating the future needs of the user into quantifiable characteristics, in a way which enables a product to be designed so as to provide satisfaction to the consumer at the price they will pay» [ 75 ].

Generally, there is agreement among academics and researchers that there are two main aspects to food quality; Objective and subjective. The former regards the physical features of a product and is related to quality control and food technology. The latter reflects the evaluation and judgments of consumers regarding perceived product quality characteristics. In any case, while food quality is an inherently complex and multifaceted concept it definitely has food safety at its core. Being the most essential variable for food quality, food safety is regulated by state legislation, in order to ensure that consumers purchase food products that fulfill their expectations regarding safety. In order to implement food quality and safety controls it is necessary to have real-time monitoring at critical points in the process. Rapid and precise methods of analysis are vital to guarantee product quality and safety, as well as compliance with labeling. The fast detection of spoilage agents such as bacteria, pathogens and other microbial contaminants in food production and processing is necessary, to reduce spoilage and secure a safe supply of food [ 76 , 77 ].

The food we consume is not sterile but carries a microbial load which differs from product to product due to the fact that it originates from plant and animal sources. The end microbial load of the food we consume is the sum of the natural microflora of its raw material and the microorganisms which are introduced during its harvest, processing, storage and distribution. Food related illnesses and spoilage stem from a failure to control microorganisms, in one or more stages of food production. The consequences of a mass case of food poisoning or a batch of spoiled food product can be quite serious not only for producers and sellers but also for consumers and regulatory authorities. It is therefore easy to conclude that we need a way to assess and determine the microbial quality of food in order to prevent illness caused by food unfit for human consumption, whether caused by introducing pathogens or by undesirable spoilage due to the influence of its natural microflora.

These are Microbiological Criteria which provide the guidelines we need regarding what is acceptable and safe in food and its production. These criteria determine the acceptability of a product, production lot or process based on the absence, presence or number of pathogens or/and on the quantity of toxins (or metabolites) per unit of mass, volume, surface or per batch.

Monitoring/controlling microorganisms in a food requires constant microbiological testing of samples from various stages of its production. The evaluation of this testing is made according to the predetermined Microbiological Criteria which set the acceptable range of values to which the microbiological parameters must comply. Different Microbiological Criteria are applied in each stage of production in order to ensure food is safe and will retain suitable quality to the end of its shelf life.

Given the above, food microbiology is a scientific field which, today more than ever, is essential in the effort to guarantee the efficient monitoring of microbiological parameters in the «new type» of food products being produced today. Products which undergo minimal processing while simultaneously having maximum shelf life. Microbiological analysis is the most valuable scientific tool of food microbiology in this effort and its efficiency can be optimized when used in conjunction with quality control/hazard analysis systems (ISO/HACCP).

The determination and development of Microbiological Criteria initially came about through consultation with the WHO/FAO [ 78 ] and continued to evolve through many revisions, following the contribution of the International Commission on Microbiological Specifications for Foods (ICMSF) [ 79 ]. Significant effort and funds are required for the development of effective Microbiological Criteria for a food or ingredient. Therefore Microbiological Criteria must be developed and put in place only when it is necessary and can prove effective and practical. In reality Microbiological Criteria have been set for specific bio hazards in specific food products by regulation 2073/2005 of the ICMSF [ 80 ]. Generally, Microbiological Criteria must be able to assess (1) the microbial quality of a food; (2) compliance to GHP (Good Hygienic Practices); (3) the suitability of a food or ingredient for a specific purpose and (4) the acceptance of an imported product originating from a country or region where production conditions are unknown or uncertain.

Microbiological criteria for lot acceptance determinants fall into three categories based on regulatory consequences [ 81 , 82 ]: (1) microbiological standard, a compulsory criterion incorporated into law or regulation; (2) a microbiological guideline, an advisory criterion to inform food operators of the microbial content that is expected in a food when best practices are applied; and (3) microbiological specifications, part of a purchasing agreement between a buyer and a supplier of a food. The state puts in place microbiological standards only when they are seen as necessary to guarantee the safety of food products subject to government regulatory control. Therefore, government bodies controlling food/food production manage the risk involved and through risk evaluation, may conclude that a microbiological criterion is necessary for a food, at different places in the food chain. Standards need to be based on tolerable level of risk and FSO for the biological hazard in question. Different types of microbiological testing (e.g., within lot, process control, investigational) may be used by industry and government). Lot microbiological testing represents one of the most common types, which compares a given microbial hazard detected in a food, to a pre-determined safety limit/range, i.e., a microbiological criterion. Microbiological Criteria can be classified into two categories, according to EU regulation 2073/2005, as modified and in effect today, as well as relevant Guidelines issued by the European Commission, regarding official microbiological sampling and testing [ 83 ]. These are «food safety» and «production process hygiene», and have the following features:

• ▪ Food safety standards/criteria determine lot acceptance and apply only for products for sale in the market (including finished products in storage facilities and during distribution and sale, according to Section 8, article 3 of Regulation 178/2002) [ 84 ]. These apply not only to products produced within the EU, but also to those imported to EU markets from third countries.
• ▪ Production process hygiene standards/criteria are an indication that a production process is functioning within acceptable limits. They are applied to specific phases of production or at its very end and contribute to the assessment of production processes, mainly for internal use by company supervisors. They are not applied to finished products already on the market and as such are not applicable to products exported within the EU or imported to EU markets from third countries.

When an official regulatory authority wishes to assess the acceptability of a product it can sample, analyze and compare the results to predetermined acceptable ranges, as stated in relevant legislation. If the sampling and analysis concerns Production process hygiene standards/criteria, then in the case of results outside normal ranges, the regulatory body focuses its actions on investigating the cause of this failure and on evaluating the impact of this discrepancy on the finished product. In any case noncompliance to production process hygiene standards/criteria is considered a failure in food safety management processes in general.

Finally, regulation (ΕU) 2073/2005 {14} applies but official regulatory authorities reserve the right to conduct sampling and microbiological analysis for microorganisms, toxins or metabolites not mentioned in said regulation. This may be deemed necessary when there is suspicion of unsafe food products in the context of hazard analysis (article 14 Reg. (ΕU) 178/2002) [ 84 ].

5.2. Issues Concerning Microbiological Sampling and Testing

For every category of food, the following implements, which are part of Microbiological criteria, must be determined:

• The microorganisms for which it should be tested.
• The sampling plan (number of units, frequency of testing etc.).
• Acceptable limits/ranges for every unit tested.
• The standard benchmark method of analysis to be used.
• The phase at which the criterion is applied (e.g., end product or any production stage where maximum microbial levels are expected).
• Measures in case of unsatisfactory results.

5.3. Results

When testing results are not satisfactory for whichever type of criteria, food producers must apply the measures determined by the regulation. If there is a tendency towards repeated unsatisfactory results, food production companies must immediately take steps to prevent the occurrence of microbial hazards.

5.4. Sampling Frequency

Minimum sampling frequency for products during official inspection should be based on risk/hazard analysis.

5.5. Testing and Scope of Application

Depending on the particular characteristics of each food, food producers must guarantee compliance of a given product to relevant criteria which must have been set by authorities, without fail. These criteria regard the following products ( Table 7 captures the main micro-organisms, their toxins, metabolites found in selected food categories).

The main microorganisms, their toxins, metabolites found in selected food categories.

• Food ready for consumption (ready-made or ready to eat RTE).
• Fresh poultry meat.
• Minced meat and products containing meat.
• Meat products.
• Mechanically separated meat.
• Gelatin and collagen.
• Dairy products.
• Egg products.
• Living bivalve molluscs.
• Boiled crustaceans and molluscs.
• Chopped fruit and vegetables, ready for consumption.
• Sprouting vegetables and seeds.
• Non-pasteurized fruit and vegetable juices, ready for consumption.
• Slaughtered animals.

6. Discussion

The case study above highlights the critical importance of the successful implementation of a food safety management system and its reliance on prerequisite programs such as hazard analysis, SSOPs, microbiological criteria testing, management commitment and leadership, etc. BBC’s standing in the communities it operated in was similar to an untouchable “celebrity status” with its products popular throughout the USA for the past century. Outstandingly, the abovementioned food safety process failures in 2015 were not reported in the years before. This complicit behavior by BBC founders, management and workers went unchecked by presumably “star-struck” inspectors auditors. In fact, the recent whole genome sequencing (WGS) technology traced the L.M clone back to BBC’s products produced and consumed in 2010 establishes the aforementioned presumption.

Leadership is essential for positive food safety culture. Leaders must demonstrate ideal model behavior. The top damaging characteristic in food safety management is a food safety culture which nurtures fear. Amidst this “fear culture”, employees are disparaged from reporting potential incidents; they may cover up errors mistakes oversights, thereby increasing opportunities for incidents. We may presume this case study is one of toxic-negative-fear culture wherein there were no indications of any form of food safety management nor the important prerequisite programs [ 84 ].

Foodborne illness outbreak incidents, such as this case study, in the last decades have deteriorated consumers trust and have understandably generated a growing negative misperception on the enormity of food safety management systems [ 85 ].

We strongly believe that the implementation of food safety management systems along with other management tools such as Ishikawa, FMEA, Pareto, HAZOP could help the food industry to avoid the lack of good hygiene practices issues and to effectively and proactively monitor the critical control points (CCPs) and operational prerequisites (oPRPs). Training of all employees will play a catalytic factor in this direction and the adaptation of a positive food safety culture will minimize any likely risks, hazards, obstacles and constraints. These steps will be beneficial not only for the company but also for the consumers who will enjoy a safe, healthy, delicious and nutritious food.

7. Conclusions

In this review we have managed to describe the prerequisite programs as part of a food safety management system that need to be implemented for food safety and security reasons. This proves to be an excellent preventative management system that if applied along with other management tools such as FMEA, HAZOP, Ishikawa and Pareto can help the food industry protect its products from cross contamination, fraud, maintaining their authenticity, making them more traceable and improve the safety culture. A very good case study is explained from the US regarding a listeriosis outbreak and the violations that took place. Finally, the implementation of microbiological criteria is a prerequisite for all manufactured foods, especially those of animal origin and is well correlated with the case study and the implementation of FSMS.

Author Contributions

Conceptualization, T.V., C.V.; methodology, J.C.L., A.D., C.V., G.R., H.A.E.E.; validation, J.C.L., A.D., C.V., G.R., H.A.E.E.; formal analysis, J.C.L.; investigation, J.C.L.; resources, J.C.L., A.D, C.V., G.R., H.A.E.E.; data curation, J.C.L., A.D., C.V., G.R., H.A.E.E.; writing—original draft preparation, J.C.L., A.D., C.V., G.R., H.A.E.E.; writing—review and editing, J.C.L., A.D, C.V., G.R., H.A.E.E.; supervision, T.V.; project administration, T.V.; funding acquisition, T.V. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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cGMP: A Guide to Current Good Manufacturing Practices

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What is cGMP?

From gmp to cgmp, the importance of cgmp in pharmaceutical manufacturing, requirements of cgmp, using software to remain cgmp compliant, how tulip is used in pharmaceutical manufacturing, share on social.

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If food and drug manufacturers ever need a lesson on why they must uphold the highest production standards, they can study the 2012 New England Compounding Center tragedy where poor practice at a compounding pharmacy resulted in a meningitis outbreak that cost more than 100 lives.

Any company making goods for human consumption has especially high standards to meet. In the US, manufacturers of pharmaceuticals, supplements, and certain foods, must adhere to what the FDA terms Current Good Manufacturing Practices (cGMP).

Current Good Manufacturing Practices regulations are defined by the FDA as systems that assure proper design, monitoring, and control of manufacturing processes and facilities.

For pharmaceutical production, for example, cGMP regulates manufacturing controls aimed at ensuring the identity, strength, quality, and purity of drug products. This is achieved through strong quality management systems , obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.

Through its authority under the Federal Food, Drug, and Cosmetic Act , the FDA has promulgated the Good Manufacturing Practices (GMP) regulations.

The FDA adds the “c” to the GMP acronym to emphasize to manufacturers that they need to stay “current” or up-to-date in the way they comply with the regulations.

“The flexibility in these regulations allows companies to use modern technologies and innovative approaches to achieve higher quality through continual improvement,” the FDA says. “Systems and equipment that may have been ‘top-of-the-line’ to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today's standards.”

All consumables—from food to pharmaceuticals—need to be produced to the highest standards because the population has the right to expect not to be harmed by anything they ingest.

While Good Manufacturing Practices are vital for all types of products consumed by the public, the FDA points out that pharmaceuticals can present a challenge that is often not found with food and drink. While a shopper can observe if the loaf of bread they pick up at the store has turned moldy, it is not possible for that same consumer to detect (through smell, touch, or sight) whether a drug product is safe or if it will work.

Product testing is required under cGMP, but the FDA warns manufacturers that they cannot rely on testing alone to ensure quality. Because only a small sample of any manufactured batch of pharmaceuticals is tested, it is important the drugs are produced under conditions and practices required by the cGMP regulations to assure that quality is built into the design and manufacturing process at every step.

To ensure the safety and efficacy of the drugs they produce, pharmaceutical manufacturers need to comply with a range of cGMP requirements aimed at ensuring their facilities are in good condition, equipment is properly maintained and calibrated, employees are qualified and fully trained, and their processes are reliable and reproducible:

Facilities and equipment: A manufacturer’s buildings and facilities must be properly maintained to ensure pharmaceuticals are produced in safe and effective conditions. Equipment used within the plant must be well-maintained and calibrated.

Raw materials and products: Manufacturers are required to maintain a master formula for each of the pharmaceutical products they produce. The master formula must be followed, without deviation, through the entire manufacturing process.

Staff: Staff involved in every step of the manufacturing process are required to be suitably trained for the tasks they carry out.

• Procedures and Processes: Standard operating procedures (SOPs) are required for all aspects of the manufacturing process and must be kept up to date. This means manufacturers must regularly review all procedures to ensure they are based on the latest science and technology applicable to the pharmaceutical being manufactured.

Effective software solutions have become indispensable tools for all manufacturers, and these solutions are particularly important for pharmaceutical producers needing to comply with cGMP requirements.

The Pharma 4.0 era of drug manufacturing has seen the industry embrace a range of digital solutions that have enabled significant advances in all aspects of the production process, resulting in significant improvements to overall product quality and production efficiency.

Software plays a multifaceted role in enabling pharmaceutical manufacturers to achieve cGMP compliance and enhance their overall operations:

Data analytics: The analysis of data gathered from the various production line operations is an invaluable resource when it comes to ensuring equipment, and the plant as a whole, is operating effectively and compliantly.

Product traceability: Electronic logbooks make product tracing more efficient and accurate, and enable manufacturers to compile more comprehensive product information.

Interactive staff training: Interactive digital training guides workers through relevant processes more effectively than paper instructions or meetings. One of the emerging technologies in this sphere is computer vision, a solution that trains workers as they perform a given task.

• Media-rich SOPs: In the same way interactive training is more effective than paper-based instructions, digital SOPs can provide a more media-rich, interactive outline of operating procedures than an SOP outlined in the pages in a physical manual. Digital SOPs can provide staff with a clearer picture of how to do things, and what to do in case something goes wrong.

Tulip is currently being used by some of the largest pharmaceutical manufacturers to help streamline processes, improve quality, and automate data collection and compliance procedures.

Using Tulip, manufacturers are able to create a system of apps that address any number of different challenges a pharmaceutical producer might face. Some of the most common use cases we see manufacturers leverage our platform for include digital work instructions , machine monitoring, electronic batch records , and documentation around activities such as equipment use, line clearances , and changeovers.

By connecting systems and processes to a centralized, digital solution, pharmaceutical manufacturers are able to ensure data integrity and traceability in accordance with FDA 21 CFR Part 11.

If you’re interested in learning more about how Tulip can help streamline cGMP compliance in your production facilities, reach out to a member of our team today !

Simplify your Good Manufacturing Practices with Tulip

Learn how Tulip's operations platform can streamline your compliance efforts and enable your business to adhere to GMP regulations.

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Good Manufacturing Practices (GMP)

An in-depth introduction to GMP for pharmaceuticals.

About this Course

This course provides an introduction to GMP for pharmaceuticals and the current U.S. FDA regulations. It reviews a brief history of GMP regulations and discusses the regulatory requirements for the quality management system, equipment, batch records, validation, packaging, labeling, holding, distribution, and audits.

There are many components to the GMP regulations, and this course provides a general introduction to many of these key elements. This course reviews manufacturing regulations 21 CFR 210 (Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding Drugs) and 21 CFR 211 (Current Good Manufacturing Practice for Finished Pharmaceuticals 2021). It also discusses FDA guidance and applicable question and answer (Q&A) documents intended to assist industry.

Course Preview:

Language Availability: English

Suggested Audiences: Distribution Staff, Labeling Staff, Other sponsor organization representatives that contract to GMP vendors and need to understand the regulations., Packaging Staff, Production and Manufacturing Technicians, Quality Professionals, Validation Staff

Organizational Subscription Price: $675 per year/per site for government and non-profit organizations; $750 per year/per site for for-profit organizations Independent Learner Price: $99 per person

Course Content

History and overview of good manufacturing practices (gmps).

To best understand the Current Good Manufacturing Practice (CGMP) requirements, it is helpful to review the history and evolution of the regulations. This module covers key cases that helped form current GMPs, then reviews each section from key manufacturing regulations 21 CFR 210 and 211. It also describes the importance of the term “current” in the regulations.

Recommended Use: Required ID (Language): 20408 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Requirements of the Quality System

A quality system is the foundation that allows an organization to adhere to Current Good Manufacturing Practices (CGMPs), which in turn allows it to consistently meet or exceed its customer’s specifications. This module describes the purpose and organization of a quality system in manufacturing, differentiates quality assurances and quality controls, reviews SOPs for key processes, and describes roles and responsibilities for individuals focused on quality.

Recommended Use: Required ID (Language): 20409 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Personnel Requirements

Personnel are essential to the production of pharmaceuticals; without them the drug product would not be produced.  Staff must be properly trained and qualified. An organization adhering to CGMPs should clearly define, develop, demonstrate, and document all staff competencies working in the CGMP environment.

This module provides an overview of personnel requirements for CGMP. It discusses staff training, job descriptions, and qualifications. It also explores key personnel roles along with hygiene and wellness program considerations.

Recommended Use: Required ID (Language): 20410 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Facility, Equipment Calibration, Maintenance, and Cleaning

A Good Manufacturing Practice (GMP) facility’s design is critical to the overall functioning of the manufacturing process. There are many different components to consider: from flow of staff and equipment, to the water system plumbing, as well as the electrical system and lighting.  Proper environmental monitoring is also critical to continuously verify microbiological and particulate counts. The heating, ventilation, and air conditioning (HVAC) system design must also be considered to ensure adequate air flow and filtration to ensure no cross contamination occurs.

This module reviews the FDA’s GMP requirements related to facility design, HVAC controls, facility cleaning, environmental monitoring, water systems, validation master plans, equipment and instrument calibration and maintenance, and cleaning programs and cleaning validation.

Recommended Use: Required ID (Language): 20411 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

There are specific regulatory requirements for the validation of software, processes, and analytical methods used in manufacturing. In this module, we will explore the procedures for software validation, process validation, and analytical method validation according to Current Good Manufacturing Practices (CGMPs). This module also reviews key regulations and requirements for validation and pitfalls to avoid.

Recommended Use: Required ID (Language): 20412 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Batch Records and Other Documentation

Batch production records (also known as batch records) provide step-by-step instructions on how to manufacture a product, while also collecting the detailed information for the specific lot being made. A batch is synonymous with the lot produced.  There are many important parameters involved when making a batch following Current Good Manufacturing Practices (CGMPs). Each step is important and must be followed as prescribed.  Sampling instructions, time limits, and other sequences are typical of the detailed instructions captured within a batch record.  Once the batch is complete the quality unit reviews all the documentation to verify the product meets the pre-approved specifications and was manufactured according to the CGMPs.  Many documents and other records support the batch record and are reviewed and approved by the quality unit to release a product.

This module reviews the purposes and key components of batch records, and the associated CGMPs’ documentation requirements. The module concludes with a discussion on good documentation practices and document storage.

Recommended Use: Required ID (Language): 20413 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Packaging, Labeling, Storage, and Distribution of Product

After manufacturing, the regulations require proper packaging, labeling, storage, and distribution of the drug product or substance. Standard operating procedures are necessary to define the operations and quality control parameters essential to maintain a state of control. Clear documentation within the batch record will assure regulatory agencies (such as the FDA) that regulatory requirements were upheld during the manufacturing process.

In this module, we examine the GMP requirements and procedures for packaging, labeling, storage, and distribution processes. The module highlights the required standard operating procedures, reviews typical FDA inspectional observations to avoid, and reviews requirements for stability testing and expiration dating.

Recommended Use: Required ID (Language): 20414 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

" role="button"> Audits and Inspections

Audits and inspections are a essential elements of the quality system. While being audited or inspected can create anxiety, it also promotes assurance that an organization adhering to current GMP regulations is following the regulations and procedures.

This module describes the purpose of an internal audit program and differentiates internal audits from external audits and inspections. It focuses on the various types of quality audits used in the GMP environment. It also discusses mock inspections and what an inspection preparedness program should include.

Recommended Use: Required ID (Language): 20415 (English) Author(s): Susan Leister, BS, MBA, PhD, CQA, CSSBB - Technical Resources International, Inc. and University of Phoenix

Who should take the Introduction to Good Manufacturing Practices course?

This course is designed for quality professionals; production and manufacturing technicians; packaging, distribution, and labeling staff; validation staff; and, any other sponsor organization representative that contract to GMP vendors and needs to understand the regulations. This course is also for any other staff looking to enter the GMP sector.

This course is an introduction to GMPs, so no previous experience with GMP is required prior to taking the course.

Which regulations does this course cover?

This course covers the key elements of the U.S. Food and Drug Administration (FDA) regulations for good manufacturing practices at 21 CFR 210 and 211.

How long does it take to complete the Introduction to Good Manufacturing Practices course?

This course consists of eight modules. Each module contains detailed content and quiz as well as images, supplemental materials, and case studies (when appropriate).

Modules vary in length, and learners may require different amounts of time to complete them based on their familiarity and knowledge of the topic. However, modules are each designed to take about 30 minutes to complete.

Is this course eligible for continuing medical education credits?

This course does not currently have CE/CME credits available.

What are the standard recommendations for learner groups?

This course is designed to be completed in its entirety and sequentially. A recommendation is to set all modules as “Required” for initial completion.

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Privacy Overview

• Open access
• Published: 14 June 2015

Aid conditionalities, international Good Manufacturing Practice standards and local production rights: a case study of local production in Nepal

• Petra Brhlikova 1 ,
• Ian Harper 2 ,
• Madhusudan Subedi 3 ,
• Samita Bhattarai 4 ,
• Nabin Rawal 5 &
• Allyson M. Pollock 1  

Globalization and Health volume  11 , Article number:  25 ( 2015 ) Cite this article

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Local pharmaceutical production has been endorsed by the WHO as a means of addressing health priorities of developing countries. However, local producers of essential medicines must comply with international pharmaceutical standards in order to be eligible to compete in donor tenders. These standards determine production rights for on-patent and off-patent medicines, and guide international procurement of medicines. We reviewed the literature on the impact of Good Manufacturing Practice (GMP) on local production; a gap analysis from the literature review indicated a need for further research. Over sixty interviews were conducted with people involved in the Nepali pharmaceutical production and distribution chain from 2006 to 2009 on the GMP areas of relevance: regulatory capacity, staffing, funding and training, resourcing of GMP, inspectors’ interpretation of the rules and compliance.

Although Nepal producers have increased their overall share of the domestic market, only the public manufacturer, Royal Drugs, focuses on medicines for public health programmes; private producers engage mainly in brand competition for private markets, not essential medicines. Nepali regulators and producers state that implementation of GMP standards is hindered by low regulatory capacity, insufficient training of staff in the industry, financial constraints and lack of investment for upgrading capital. The transition period to mandatory compliance with WHO GMP rules is lengthy. Less than half of private producers had WHO GMP in 2013. Producers are not directly affected by international harmonisation of standards as they do not export medicines and the Nepali regulator does not enforce the WHO standards strictly. Without an international GMP certificate they cannot tender for donor dependent health programmes.

Conclusions

In Nepal, local private manufacturers focus mainly on brand competition for private consumption not essential medicines, the government preferentially procures essential medicines from the only public producer while donor funded programmes rely on international manufacturers compliant with international GMP standards. We also found evidence of private hospitals bypassing national medicines approvals process.

Policies in support of local pharmaceutical production in developing countries as a source of essential medicines need to examine carefully how GMP regulations impact on regulators, local industry and production of essential medicines in practice.

Introduction

The Global strategy and plan for action on public health, innovation and intellectual property adopted by the 61st WHA in 2008 identified local pharmaceutical production as one of the key building blocks required for needs-based essential health research and development addressing health priorities of developing countries [ 1 ]. Initiatives calling for local pharmaceutical production are not new. Local production has been on the WHO’s agenda since 1978 and in the 1970s and 1980s governments, UN and other international organisations supported the development of local pharmaceutical production in many low-income countries on the grounds that it would promote self-sufficiency in the medicine supply; reduce dependency on imports and improve foreign trade balances; and create employment opportunities [ 2 – 4 ]. Although questions were raised about economic feasibility and product quality [ 5 ] many developing countries succeeded in building a viable pharmaceutical industry satisfying more than 70 % of their national requirements of essential medicines [ 6 , 7 ]. A robust evidence base on the positive impact of local production on access to medicines is limited and mixed, with the majority of studies focusing on the affordability of local products compared to their imported counterparts [ 8 ]. In a recent study, the locally produced essential medicines in Tanzania showed an overall higher availability across the country over imported products, which were more likely to be available in urban areas [ 9 ].

Post TRIPS, the strategic importance of local production was again brought forward as a way to benefit from public health flexibilities specified in the Doha Declaration [ 4 ]. However, the viability of local production depends on several factors including effective regulation, funding, technology transfer, economies of scale, and procurement policies. The procurement of essential medicines, especially for donor funded programmes, has been accompanied by a shift from national governments to international public-private partnerships so that local producers must comply with international pharmaceutical standards if they are to be eligible for tenders.

This paper is particularly concerned with GMP (Good Manufacturing Practice) which is a requirement for international procurement of medicines for donor and publicly funded health programmes. Although compliance with GMP is a condition of market entry, as well as conferring production rights for many essential medicines procured though international donors, there has been little analysis of the impact of international GMP standards on local production for public health systems and government use.

This in itself is of concern as the growth in international pharmaceutical standards and the process of their harmonisation, specifically through the International Conference on Harmonisation (ICH), has been criticised for raising standards and compliance costs with insufficient attention being paid to whether they improve research on medicines and the safety of end products [ 10 – 12 ]. The WHO has warned that the standard setting process of the ICH is dominated by Western governments and their research-based pharmaceutical industry, describing the process as exclusive, non-consultative and lacking in local knowledge [ 13 ]. It also noted that the standards are too high for local production. Closures of small and medium producers as well as public vaccine producers due to stricter GMP requirements have been observed, for instance, in India [ 14 ].

Despite the WHO’s criticisms and the importance of the GMP standards for the availability of affordable and high-quality medicines and viability of local pharmaceutical production it is not clear from the literature to what extent local production in low- and middle-income countries has been affected by the international harmonisation of the regulations. In this paper we provide a brief background to GMP reported studies on the impact of GMP on local production before using the case study of Nepal to explore GMP implementation and enforcement from regulators’ and producers’ perspective in the context of development aid and aid conditionalities.

Background to GMP standards and their international harmonisation

According to the WHO, GMP “is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by marketing authorization” [ 15 ]. They apply to producers and other parties involved in labelling and packaging pharmaceutical products. GMP standards are intended to reduce the risks in production process including cross-contamination and mix-ups (e.g. confusions because of false labelling). GMP guidelines represent minimal standards that are a necessary condition for marketing authorization.

The WHO prepared its first version of GMP in 1967 at the request of the Twentieth World Health Assembly [ 15 ], but these are not legally binding on member states. The WHO has made clear that the implementation and enforcement of GMP is a matter for individual states and their respective drug regulatory bodies which can specify different sets of requirements.

In 1975 the WHO attempted to implement the rules at the global level through the Action Program on Essential Drugs and the Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. In the Certification Scheme, exporting countries certify domestic pharmaceutical companies as manufacturers of drugs authorized for the domestic market and that their compliance with the WHO GMP is checked on a regular basis [ 16 ].

Western industry, quite separately established its own standard setting initiative. The European Free Trade Association (EFTA) introduced a Pharmaceutical Inspection Convention (PIC) in 1970 and complemented it with Pharmaceutical Inspection Co-operation Scheme in 1995 with the aim of developing and harmonising GMP and inspection standards and to promote cooperation among participating authorities including exchange of information and experience. 44 EFTA and non-EFTA countries are participating in PIC/S [ 17 ].

The most recent and prominent harmonisation effort via the International Conference on Harmonization (ICH) is led by pharmaceutical regulators and industry representatives of the EU, Japan, and the US, and accepted by other developed countries. In 1999, the ICH brought GMPs for Active Pharmaceutical Ingredients, which apply to production of APIs for on-patent and off-patent medicines in ICH signatory countries and in other countries such as Australia and Canada. These guidelines were also adopted by PIC/S in 2001 and, despite the earlier criticism of ICH by WHO, formed the basis for the 2010 WHO GMP guidelines for APIs [ 18 ]. ICH standards are thus of growing importance in policing and regulating the global pharmaceutical industry and none more so than GMP. Given their global impact it is worth noting several features of the ICH harmonisation process for its implications for market consolidation and developing countries:

Industry driven harmonisation of regulation

In 2000, the WHO warned that the ICH represented interests of drug regulatory authorities and representatives of pharmaceutical industry of 17 high-income countries; the negotiation processes excluded nongovernmental organizations, patient and consumer groups and lacked consultations with academics and medical practitioners; and “the additional safety benefits from these rigorous standards have not yet been demonstrated but the costs incurred by manufacturers in meeting these requirements are significant” [ 13 ]. The WHO representing developing countries has only observer status on ICH.

GMP enforcement in developing countries

Regulatory authorities in developing countries have been under increasing pressure to adjust their domestic regulatory systems in response to various international political issues. Whether it be WHO or ICH or FDA GMP standards, their implementation and enforcement is not a low cost exercise, as pharmaceutical companies and governments must develop capacity to implement and enforce the regulation. Although most sub-Saharan Africa countries have a legal basis for medicine registration, guidelines and assessment procedures, regulatory authorities have limited economic and human resources, and the enforcement of regulations is often discretionary so that many public and most local manufacturers do not meet WHO standards [ 19 ].

The enforcement of GMP standards, however, is not just a problem for low- and middle-income countries. Recent safety concerns over medicines and APIs imported by developed countries illustrated difficulties of regulatory agencies to monitor production facilities of foreign suppliers [ 20 ].

medicine procurement and aid conditionalities

GMP standards are enforced through government drug procurement systems at international, national, and local level and in particular through aid conditions. International procurement agents including GDF and UNOPS require compliance with WHO GMP standards as a necessary condition for participation in a tender and may impose other conditions. Donors may also have their own requirements: the Global Fund requires compliance with WHO GMP ensured by the WHO Prequalification Programme and/or compliance with the US or EU rules [ 21 ]; PEPFAR requires US FDA GMP standards [ 22 ].

These conditions may lock out local companies from their domestic market. For instance, producers in Tanzania complying with Tanzanian GMP guidelines have access to government tenders but cannot participate in more profitable international tenders requesting international GMP standards [ 2 ] and may be unable to tender for donor contracts within the country. Ugandan producers argue that the increased donor funding towards essential medicines combined with the requirement of WHO-GMP compliance means that “they are slowly being pushed out of the local essential medicines market” and some suggest that this “might be the single biggest threat to the survival of local pharmaceutical manufacturing” [ 23 ].

Another factor that inhibits local producers is size. Large MNCs argued for the size criterion to be included as a necessary condition for participation in international tenders. Their key argument is that small companies are not reliable in that they will not be able to supply drugs as promised [ 24 ].

Survival of local pharmaceutical production under international GMP rules ultimately depends on strength of drug regulation and access to sufficiently large markets. Stricter rules and related compliance costs need to be associated with additional safeguards ensuring medicine safety, efficacy and quality to be accepted by producers and, perhaps more importantly, in line with the access to affordable high quality medicines agenda. Trust in regulatory authorities and processes is a necessary condition for the rules to be accepted by purchasers of pharmaceuticals [ 25 ] thus securing demand which in turn provides incentives for producers to adopt the rules.

Impact of GMP on local production

Our PubMed search identified only three studies on the issues of GMP in relation to local pharmaceutical production in low- and middle-income countries; these concerned the production of vaccines [ 26 ], antiretrovirals [ 27 ], and anti-malarials [ 28 ]. All three studies emphasize the need for local producers to invest in their production facilities and comply with GMP. The two public vaccine producers in Iran found it difficult to keep up with changing GMP requirements and although they satisfy the local needs, the informants identified the need for WHO prequalification and insufficient capacity as the key barriers to the export [ 26 ]. Abdo-Rabbo et al. examined the quality of animalarials at various levels of the distribution chain in Yemen and concluded that the problems with quality were not limited to a specific level of distribution chain and concerned locally produced as well as imported medicines [ 28 ]. None of the identified studies assessed the impact of GMP and their international harmonisation on local production.

A limited search of grey literature to check for additional studies and projects yielded two reports by MSF/DND Working Group which were concerned with the impact of ICH standards on the development and availability of medicines in developing countries [ 29 , 30 ]. A comparison with the ICH and WHO GMP requirements concluded that although there were differences between the two sets of standards, they were ‘often marginal or formal’. The report further noted that ‘the main difference between ICH and WHO specifications is the interpretation of data submitted by applicants and the enforcement by DRAs’ [ 30 ].

In addition to regulatory capacity building, institutions such as UNIDO, WHO (Prequalification Project), and DfID support specific local pharmaceutical producers of, primarily, antiretrovirals, anti-TB and antimalarials in achieving WHO prequalification [ 31 – 33 ]. As of April 2015 only three out of 419 WHO prequalified medicine products were produced by a low-income country producer (119 HIC, 297 MIC) and none of prequalified APIs were produced in a low-income country (3 in HICs, 75 in MICs) [ 34 , 35 ].

Background to pharmaceutical production and regulation in Nepal

Allopathic medicine in Nepal has a relatively recent history. The limited supply of medicines to Nepal was via India, and the British Embassy for the elite (Interview, Kathmandu University, April 2007) until the first “people’s movement” of 1950. The more systematic development of the health sector began with increasing development aid assistance and the country’s roll over five year plans. Nepal government started to manufacture its own drugs in government facilities from the 1950s, focusing initially on medicinal plants and herbal forms and was located under the Ministry of Forests. The Royal Drugs Laboratory was set up as a pilot production site in 1965, and then converted to Royal Drugs Limited (RDL) in 1972 - the first production unit in Nepal (Interview, APPON, December 2006). The first private company, Chemidrug Industries Pvt. Ltd. was opened in 1971 (Interview, Kathmandu University, April 2007). The drug Act of 1978 resulted in the Department of Drug Administration (DDA) being set up in 1979 (where it was still part of the Ministry of Forests). Precursors to the Drug Act included the Black Marketing and other Social Offences Act, 2032 BS (1975), and the Drug Abuse Control Act, 2033 BS (1976) (see [ 36 ] for a full list of all the Acts pertaining to health, and their development in Nepal). By 1979 there were two Nepalese companies but around 1000 Indian ones; Nepal was an extension of the Indian market. It was not till after the late 1980s, however, that the nascent Nepalese industry started to mushroom. Relocated to a part of the Ministry of Health and Population, the DDA has overseen this growth of the Nepal pharmaceutical industry to its size of 58 registered companies in July 2014 (personal communication), and been responsible for the regulation of the industry.

Nepali pharmaceutical companies focus on the secondary and tertiary production (formulation and packaging) and supply medicines only to the local market. They had a 25-27 % share of the Nepali pharmaceutical market in 2004 while the import was dominated by Indian pharmaceutical producers (170 Indian companies out of nearly 250 importers) [ 37 ]. In interviews, Nepali producers talked of the 30:70 split in the market between Nepali and Indian products, and their aims of reversing this percentage. For 2006–2009 the share of local manufacture increased to 40 %; with domestic producers mainly catering to rural areas, where they have about 80 % of the market, and having about 20 % of the urban market [ 38 ].

In Nepal, although there is local production of some essential medicines, the majority are imported. Of the 537 products in various strengths and dosage forms listed on the 2011 National List of Essential Medicines, Nepali companies were producing less than one third, 176 products [ 38 ]. Fifteen drugs accounted for just over half (52 %) of local production in 2005 [ 37 ]. Of these eight were listed on the national essential medicines list and included amoxicillin (the highest selling drug), ciprofloxacin, iron preparations, paracetamol and metronidazole. The public manufacturer, Royal Drugs, focuses on medicines for public health programmes while the private producers engage mainly in brand competition in the private market [ 39 ].

The DDA is located in Kathmandu, and aims to “make available safe, efficacious and quality drug to the general public by controlling the production, marketing, distribution, sale, export–import, storage and use of drugs” through the selection of essential medicines and support of pharmaceutical industries to comply with WHO-GMP and to “achieve self-reliance in the production of essential drugs” [ 40 ]. (For a comprehensive overview of regulations in place see [ 41 ].)

This paper uses a broadly ethnographic approach combining interviews, observations and a review of international and national literature collected within a broader research project ‘Tracing pharmaceuticals in South Asia’ [ 42 ]. In Nepal, from 2006 to 2009, the team undertook more than 170 transcribed semi-structured interviews, the majority of which were in Nepali and then translated into English. The interviewees were people involved in the pharmaceutical production and distribution chain including producers, medical representatives, pharmacists and providers with some having overlapping roles. Information was collected from four further categories: international donors, activists, regulators and scientists. The topics were based on an interview schedule and included the everyday working practices of the interviewees, with particular focus on the three main drugs of the research (rifampicin, fluoxetine, and oxytocin) and reflecting the broader issues of regulation, production, access to and rational use of medicines. In line with the iterative and reflexive qualitative research methodology, topics discussed reflected the empirical concerns and issues that emerged from the research. In addition extensive participant observation was conducted in a number of areas in and around Kathmandu, and in Western Nepal (in clinics, pharmacies, OPDs, with Medical Representatives on their rounds, and visits to two production plants.

Regulatory and policy documents were collected from the interviewees and from the websites of the Nepal medicine regulatory agency, WHO and donors.

Ethical review for the project ‘Tracing pharmaceuticals in South Asia’ as a whole was obtained from the School of Social and Political Science at the University of Edinburgh, and for the Nepali element from the Nepal Health Research Council (NHRC).

Issues with GMP implementation in Nepal

Rules are subject to local discretion and regulatory capacity and not updated in line with WHO standards

The rules and standards themselves are subject to a great deal of local discretion and interpretation and this in itself depends on the role of the enforcers and the staff who are employed.

Senior DDA officials told us they have developed regulations in the following areas: Drug registration regulations, Drug standard regulations, Drug Inquiry and Inspection Regulation and Drug manufacturing code.

Drug manufacturing code of 1984 is written in Nepali and published along with the WHO GMP code of practice (in English). Despite the WHO revising their GMP codes in 1998 and 2003, this part has not been updated in the DDA’s publication. We were told by a senior drug administrator that the DDA is in the process of publishing a new code as the 1984 DDA code does not explain certain things clearly; for example, it is written in the code that “fresh air” is necessary while producing drugs but it does not explain what is meant by this. When asked about overlap between the DDA code and WHO GMP code, he replied in vague terms, saying that most of the WHO GMP standards are incorporated in the DDA code (Interview, Senior Drug Administrator, DDA, June 2007).

From the 1990s the DDA made the upgrading of facilities to WHO GMP standards mandatory. The deadline was set for April 2007, but by the end of the data collection period in 2008 only eight companies had managed this. The then director of the DDA described that the WHO GMP certification for Nepali companies remained “optional”, with the DDA’s own Code on Manufacturing of Drugs the only legally binding requirement. As of 2013 26 of the 58 Nepali companies were compliant with the WHO GMP (personal communication, 2013).

GMP certification was described by the DDA as necessary only for export [ 43 ], although the WHO does inspect for drugs and products linked to their “own purposes” (for example vaccination programmes, TB drugs for DOTS, and ARVs). The WHO role is mainly indirect, through the DDA. While the Association of Pharmaceutical Producers of Nepal (APPON) are supposed to be assisting with this process, and doing trainings around GMP they are deemed by many to be of little help (as one company director stated: “they take our money and drink whisky”!). During the fieldwork period, they had a volunteer pharmacist from Japan helping them with this process of developing guidelines and trainings. APPON was more involved in lobbying for dollar rates for imports from India and for non-tariff barriers such as labelling of all foreign imports in Nepali.

GMP training and capacity

The Director of the DDA described the GMP certification process as part of the Essential Drugs and Medicines Programme. The DDA conducted the initial training in country, with support from the WHO which is “technical and financial”. However, the difficulties they face in implementing the GMP process were described to us as three fold. Firstly, regulatory capacity relating to the staff issues and their lack of expertise; this is not only DDA staffing problems (they had only five staff members who checked that rules were being followed), but the lack of expertise in the company staff. While there are increasing numbers of graduates now coming out of the universities, to date they have little experience. Pharmacy is a relatively new discipline in Nepal (Kathmandu University started their Pharmacist training course in 1994; the Institute of Medicine set up their School of Pharmaceutical and Biomedical Sciences in 1997; Pokhara University started in 2000; and Purbanchal University in 2005). By March 2014 there were 1400 pharmacy graduates registered with Nepal Pharmacy Council (personal communication) while the DDA register, in addition to the existing quality control laboratories and producers, reported 1688 wholesalers and 8800 retailers of allopathic medicines [ 44 ].

Secondly there are difficulties with understanding the concept. Some manufacturers say that they already sell well, so why do they need GMP? They have a “market perspective”, and as their drugs pass their own tests, why do they need it? They complain about the investments required for upgrading when they see little benefit. Thirdly, the GMP concepts themselves are changing and becoming more stringent.

Regulatory requirements and associated costs

An interview with a senior member of the of the quality control division of Nepal Drug Limited, the state run pharmaceutical company, which was struggling to remain in competition with the new private companies, reveals the issues they face with GMP (Interview notes, May 2007). He stated that they did not have the infrastructure to fulfil GMP standards; that the laboratory was not well equipped; there was not enough physical space; human resources were inadequate; there was no R&D budget; little administrative support; and that the location of the factory was wrong, due to the poor air quality in Kathmandu.

“If we have to go to GMP, we need the budget to improve some of the existing facilities, update them, and establish a new department to fulfil the requirement of WHO-GMP…. We have been discussing to hire consultants from outside to do feasibility study for focusing on IV Fluid (saline) WHO-GMP certificate”.

One group of senior management workers for one of the GMP certified companies described the sheer production of paperwork required for monitoring as overwhelming, besides the prohibitive costs. In addition, the director of one of Nepal’s largest pharmaceutical companies said that initially their production dropped after implementing GMP standards. They used to have “quality control”, but now this has shifted to “quality assurance” with greater stringency. This shift was described to us by another company’s senior manager as follows:

“Quality control is not in common use now. We call it quality assurance. Before while checking quality, they used to check at the end. But now they say that if we check it right from the beginning then quality is assured right from the beginning. The quality of excipient, whether the raw material is mixed properly or not, whether it is weighed properly or not, coating, punching, if everything is done properly, all this is checked. This is called SOP (Standard Operating Procedure)” (Interview, Kathmandu, April 2007).

One of the larger more established pharmaceutical companies had recently upgraded to GMP certification standards. The director of the company told us that the initial cost outlay had been 4 crore rupees (That is 40 million rupees, or a little over £300,000 at 2007 exchange rates). This had spun them from a profit making business into one with large debts. An ex-employee of Royal Drugs Nepal, stated that there was no way that this company could afford to upgrade to GMP standards. One particular complaint was that despite this initial outlay, the Nepal market was small and it would be difficult to recoup costs (the size of the Nepal market is stated to us a particular difficulty for Nepal to develop its own injectables; the market is just too small). Not one person we interviewed in the business thought of export as a possibility, and all were concentrating on the Nepal market.

A senior pharmacology professor referred to the problem in Nepal as one of quality versus cost. He referred to amoxicillin, which is now produced by nearly all the Nepali companies. It costs around 4–5 rupees, but if you find it for less than this then in his opinion the quality must be compromised. He reckoned that the then director at the DDA was good at his job, and working hard at trying to keep prices low while maintaining quality; he was working at trying to get GMP certification implemented. It was difficult, he said, as smaller companies used to send “goondas” around to him to ask why GMP was being put into place, claiming that it was driving up their costs and the prices of affordable medicines.

We were further told that the concepts themselves have changed a lot. An employee at one company explained to us how they had shifted to the AHU (air handling units) which are stricter, and of the use of “reverse osmosis” having replaced “demineralisers” for the water they use. The costs to run these new units had increased as well, and the size of the backup generators required to keep manufacturing standards up with the regular power cuts have increased. This was a particular problem in Kathmandu where during the time of the research power cuts of up to sixteen hours a day were frequent.

The GMP process was described to us by senior staff at one company where we were shown around the production site, and they bemoaned the sheer volume of recording necessary at every level of production. GMP certification considers many elements: the premises; personnel; quality control; production; sanitation and hygiene and finally, documentation. As they phrased it all the GMP process “should be done per documentation and documented”. Each and every activity is prescribed in detail through Standard Operating Procedures (SOPs), which are strategically displayed in Nepali and English throughout the site. The DDA was described as responsible for the guidelines that are set up for this end, and then responsible for their implantation (Interview, Kathmandu, April 2007).

Impact on local industry and market

Less than half of currently operating companies achieved the WHO-GMP certification, perhaps due to the rise in costs. Stricter measures taken in the case of imported products have resulted in some Indian companies being unable to import their products, and their products not being re-registered by the DDA (Interview, wholesaler, April 2007). The producer of “strepsils” (BOOTS) entered into a contract with a Nepali company to make this in Nepal, but because the company does not have GMP certification Strepsils are no longer available on the Nepal market.

Aid conditionalities and GMP

Although health expenditure from the general government has been steadily increasing the foreign aid remains a significant source of health care financing in Nepal (19 % of total health expenditure in 2008/09). The dependence is more pronounced in certain areas such as safe motherhood, immunisation, family health and planning, TB and leprosy control and STDs [ 45 ].

Government regulation currently states that any tender for the government procurement of drugs must be accompanied by the appropriate paperwork, which includes GMP certification. Despite the old state run Nepal Drugs (ND) not having GMP certification, contracts for public procurement are awarded as a priority to ND.

In the 1990’s ND was formulating rifampicin and supplying the National Tuberculosis Programme with about 1.1 million capsules annually (Interview, ND, February 2007). This was prior to the development of the WHO prequalification and the GDF), through which Nepal and other developing countries are currently supplied anti-TB drugs paid for by the Global Fund and other donors. After several years ND lost the contract and although it was not possible to ascertain the key reasons it was suggested that change in management and bribery caused the loss of contract (Interview, ND, February 2007). In addition, donors and conditions for international procurement of medicines changed. Currently, even with the capacity, ND would not be able to supply rifampicin to the national programme without WHO prequalification or other international GMP certificate.

During an interview with a senior advisor to the Ministry of Health and Population, we were told that the J-Vaccine (for Japanese Encephalitis) for Nepal was paid for by Japan and procured by the Nepal government from a company in China. The Chinese company was not GMP certified but the Japan government was happy with the quality and willing to give money. In 2007 the money for the vaccine was no longer given directly to Nepal but to UNICEF. Since the WHO, and other UN agencies, cannot procure any drugs without GMP certification the Chinese company, which had not applied for GMP by then, could not supply the product.

In 2005 MoHP launched a zinc programme in the public health sector procuring zinc from Nutriset in France. Local producers were also interested in supplying zinc. The POUNZ project introducing the zinc programme in the private sector assisted three local manufacturers with achieving the GMP audit and the three producers started supplying zinc in 2009. This would not be possible without the government commitment to this large scale programme and technical assistance offered by POUNZ. MoHP is planning to change procurement to the local suppliers who continued working with US Pharmacopeia representatives towards WHO prequalification with the view of reaching to international markets [ 46 , 47 ]. As of May 2015 no Nepali manufacturer has achieved WHO prequalification [ 34 ].

These examples show some of the issues that arise from GMP certification in a heavily aid dependent state like Nepal.

Getting around registration: drugs and therapeutics committees?

Some (private) hospitals have established Drugs and Therapeutics Committees (DTCs) to get around market registration. One private hospital director explained that their committee – established in February 2006 - allows them to procure from any part of the world, even if that drug is not licensed in Nepal with the DDA. He explained that the DTC formation has been encouraged by the DDA who “don’t have physicians”, although the government says what the makeup of the committee should be. The DTC then can “import” medicines not registered, for example important drugs for their hospital cardiac medicines (the hospital specialised initially in cardiology – and has expanded from that). They have to produce “documents” – studies and outcomes from these drugs. Thus they are able to provide data for later registration.

A communication in the Kathmandu University Medical Journal suggested that these committees have a supportive function for the DDA:

“In developing countries like Nepal, where the pharmacovigilance programs are in its primitive stage, the DTC has immense responsibility in ensuring drug safety. This committee can also act as an advisory committee to the policy makers and drug regulatory authority of Nepal for drug safety matters based on their experiences” [ 48 ].

GMP and export

By 2012 no Nepali company had yet exported any pharmaceutical product [ 38 ]. However, GMP certification is also required for Ayurvedic products. Shakya documents the experience of a Nepali Ayurvedic company (Gorkha Ayurved Co.) with exporting medicinal herbs. The company had no idea that GMP certification was necessary (or that buyers could also ask for other internationally harmonised standard of Sanitary and Phytosanitary Measures (SPS). When the company set about the process of heading towards GMP certification, they found the RDRL (and the Department for Food Technology and Quality Control) “without any plan of policy regarding SPS standards, including GMP certification procedures”, particularly for Ayurvedic products [ 49 ]. Shakya is critical that the DDA had not prepared itself for accreditation processes, nor determined the basic mechanisms that companies should take. Businesses were pretty much on their own, suggested the author, with the company having huge outlays, including hiring a foreign expert to assist in the process.

It seems apparent that one consequence of attempting to harmonise its regulatory capacity will be a greater dependence on foreign assistance (both technical and financial) for this process.

Our research highlights several issues with implementation of international GMP standards in a country like Nepal and how international standards linked to foreign aid determine production rights of generic medicines where governments are dependent on aid. Domestic producers report that compliance with the stringent standards of GMP is a major obstacle for domestic production of affordable pharmaceutical products. The lenient approach to the enforcement of the GMP rules by the Nepali drug regulator, however, allows the growth of the industry which remains poorly regulated. These findings are relatively undocumented and unexplored in the literature.

The literature and our interviews highlight the issue of regulatory capacity building and the interpretation of standards by inspectors. International institutions and development agencies offer technical assistance to developing countries in the form of teaching GMP linked to capacity building [ 24 , 50 ] yet, interviewees were concerned that since adherence to GMP standards is subject to individual experience and interpretation, inspectors from developed countries may impose more stringent rules than intended by regulators in developing countries (interviews with producers in India, [ 2 ]).

Our Nepali case study documents problems with GMP implementation and enforcement due to low regulatory capacity, insufficient training of staff in the pharmaceutical industry as well as financial constraints. Nepali producers do not produce APIs and target only the domestic market and to that extent they are not directly affected by internationally harmonised GMP requirements, but this also limits their market and their ability to recoup costs of investment in GMP related upgrades of manufacturing facilities. Nepali health programmes funded by international aid largely bypass government regulators and local producers as international agencies procure through large companies with an international GMP certificate. This impacts on local production through reduced economies of scale for some classes of medicines as Nepali companies do not have access to this part of the domestic market. This perhaps also explains the limited focus of the local industry on essential medicines.

Importance of local production capacity for the supply of essential medicines and availability of safe, efficacious and high quality medicines is high on the DDA’s agenda but there are few incentives for local manufacturers to produce essential medicines and the relatively long transition period before the compliance with WHO-GMP standards is mandatory challenges the acceptance of the stricter GMP requirements. Producers who already upgraded their production facilities have to absorb the cost of GMP compliance (resulting in higher prices of their products) without gaining recognition of high quality drug producers (as should be signalled by the GMP certificate). Some manufacturers question the need for GMP when their products sell well and there is no evidence to show that the GMP certificate guarantees high quality and GMP non-compliance results in low quality end products. It is, however, difficult to determine whether this is caused by weak enforcement or inadequacy of GMP standards in ensuring high quality of end products. These conditions are likely to perpetuate the ‘business’ practices of bonuses, gifts and substitution to push specific products as opposed to ‘ethical promotion’ [ 51 ].

The Nepali local pharmaceutical industry has been growing significantly over the last decade. Many local producers are not affected by international quality standards as they do not export medicines and the DDA does not enforce the WHO GMP standards strictly. The evidence suggests that local private manufacturers focus on brand competition in private consumer markets and their production of essential medicines is limited to a few high-volume medicines as the government preferentially procures medicines from the only public producer and the donor funded health programmes rely on manufacturers compliant with international GMP standards.

Further research into access to affordable medicines via local pharmaceutical production in developing countries should consider the extent to which international standards assure quality, safety and efficacy and the capacities of national drug regulatory authorities to enforce standards where regulators have considerable interpretive license over standards and their implementation. As things stand, when aid conditionalities are linked to international standards the combined effect is to both determine and confer production rights and thus affect viability of local pharmaceutical industry and their incentives to produce essential medicines within low-income countries.

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Acknowledgements

This work was supported by the Economic and Social Research Council and the Department for International Development [RES-167-25-0110] through the collaborative research project Tracing Pharmaceuticals in South Asia (2006–2009). In addition to the authors of this paper, the project team included: Soumita Basu, Gitanjali Priti Bhatia, Erin Court, Abhijit Das, Stefan Ecks, Patricia Jeffery, Roger Jeffery, Rachel Manners, and Liz Richardson. Martin Chautari (Kathmandu) and the Centre for Health and Social Justice (New Delhi) provided resources drawn upon in writing this paper but are not responsible for the views expressed, nor are ESRC or DFID.

Ethical review was provided by the School of Social and Political Science at the University of Edinburgh, and ethical approval in Nepal for the study granted by the Nepal Health Research Council (NHRC).

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PB and AMP conceived of the study, PB, AMP and IH drafted the manuscript. PB carried out literature reviews. IH coordinated data collection in Nepal. IH, MS, SB, NR participated in the design, data collection and analysis. All authors read and approved the final manuscript.

Petra Brhlikova, Ian Harper and Allyson M. Pollock contributed equally to this work.

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Brhlikova, P., Harper, I., Subedi, M. et al. Aid conditionalities, international Good Manufacturing Practice standards and local production rights: a case study of local production in Nepal. Global Health 11 , 25 (2015). https://doi.org/10.1186/s12992-015-0110-3

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Industry 4.0 was introduced early in the last decade. That introduction spawned related concepts like “Smart Manufacturing” and digitalization, as well as a proliferation of digital manufacturing technologies for supporting systems. The industry experienced widespread puzzlement over how to apply these concepts in practice and which roles “Manufacturing Executions Systems” play and will play in this context.

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Acknowledgment

This work was carried out with the knowledge and experience gathered from the project “Road to Digitalization” (R2D), which was supported by the Bavarian state ministry of economy, media, energy and technology and several companies.

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Good Manufacturing Practices for the 21st Century for Food Processing (2004 Study) Section 1: Current Food Good Manufacturing Practices

August 9, 2004

Table of Contents

Current food good manufacturing practices (GMPs) are published in Title 21 of the Code of Federal Regulations, Part 110 (21 CFR 110). GMPs describe the methods, equipment, facilities, and controls for producing processed food. As the minimum sanitary and processing requirements for producing safe and wholesome food, they are an important part of regulatory control over the safety of the nation's food supply. GMPs also serve as one basis for FDA inspections.

The current GMPs are the result of an extended rulemaking process that spanned decades. The following section (Section 1.1) describes when, why, and how the food GMPs were developed and some of the obstacles that were overcome. Table 1-1 summarizes the major events that led to the development of GMPs as they are today. Section 1.2 provides a detailed discussion of the requirements in each of the five subparts of the GMP regulation, and concludes with a table (Table 1-2) outlining the main requirements.

1.1   The Development of Food GMPs

Food safety has been regulated since the mid-1800s and was mostly the responsibility of local and state regulators. However, the Pure Food and Drugs Act, passed by Congress in 1906, marked the first major federal consumer protection law with respect to food processing. The 1906 law prevented interstate and foreign commerce in misbranded or adulterated foods, drinks, or drugs. The intent of the Act was to prevent poisoning and consumer fraud. As more food products were manufactured in subsequent years, however, poor-quality food products and deceptive packaging continued to be produced due to loopholes in the law. Consumers were often unaware of what they were buying until products were opened. Therefore, in 1933, the FDA decided to overhaul the 1906 Act.

In 1938, after a battle about USDA jurisdictions with respect to the Act's enforcement, the Food Drug, and Cosmetic Act (FDCA) replaced the 1906 Act. The FDCA provided the necessary identity and quality standards to protect consumers from fraud. The FDCA provides the regulatory basis for today's food GMPs. Two sections of the FDCA are directly related to conditions in a facility where food has been manufactured.

• Section 402 (a)(3) specifies that food has been manufactured under such conditions that it is unfit for consumption.
• Section 402 (a)(4) considers that food may be adulterated if it is prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth or rendered injurious to health.

These provisions are unlike other parts of Section 402, in that they relate to the conditions of a facility where food is produced or stored. Thus, instead of having to prove that the food is adulterated, insanitary conditions are considered sufficient to show that the food might have become adulterated.

Given the FDCA's vagueness in establishing violations and thus, the difficulty of enforcing it, FDA began working on draft GMP regulations by the mid-1960s (although others had made the suggestion to do so as early as 1948). The objective of the GMP regulations was to describe general rules for maintaining sanitary conditions that must be followed by all food processing facilities to ensure that the statutory requirements of Section 402(a)(3) and (4) were met. After much industry involvement, including much debate about FDA's authority to adopt rules to carry out the provisions of the FDCA, the GMP regulations for food processing facilities were finally proposed in 1968 (see Table 1-1).

Three broad categories of interrelated issues arose during the development of the GMPs (Dunkelberger, 1995):

• Concern that the regulations were unduly stringent and especially burdensome for small food companies without necessarily improving the quality or safety of foods.
• Contention that the GMP regulations must prescribe conditions that "reasonably" relate to insanitary conditions that may contaminate food and render it injurious to health.
• Assertions that the regulations did not have the force of law.

These first two issues were resolved mostly through the use of more general terms, such as "adequate," "sufficient," and "suitable," rather than hard-line standards. FDA also used "shall" when the agency felt compliance was necessary and "should" when practices in the rule were less obviously related to the statutory requirements of the Act. The third issue became inconsequential when it was proved that FDA did have the statutory authority to promulgate the GMP regulations. The GMP regulations were finalized in April of 1969 and published as Part 128 of the Code of Federal Regulations (CFR). In 1977, Part 128 was recodified and published as Part 110 of the CFR.

The final GMP regulations were very broad, not specifying what exactly a facility must do to comply. This naturally created enforcement problems for the FDA. To address the ambiguity created by the umbrella GMPs, FDA next tried to develop industry-specific GMPs through the mid-1970s. By the late 1970s, however, FDA decided to improve the umbrella GMPs rather than adopting industry-specific GMPs. The revisions were finalized in 1986 and printed in 21 CFR 110. Specific GMPs were also included and printed in 21 CFR Parts 100 through 169 for:

• Quality control procedures for nutrient content of infant formula (21 CFR 106).
• Thermally processed low-acid canned foods in hermetically sealed containers (21 CFR 113).
• Acidified foods (21 CFR 114).
• Bottled drinking water (21 CFR 129).

In July of 2002, FDA formed a Food GMP Modernization Working Group to examine the effectiveness of current food GMPs given the many changes that have occurred in the food industry since 1986. The Working Group has been researching the impact of food GMPs on food safety, as well as on the impact (including economic consequences) of revised regulations. Part of the group's current effort, as of June 2004, is to find out which elements of the food GMPs are critical to retain and which should be improved. FDA is now holding public meetings to obtain the public comments to assist in this effort.

Table 1-1: Food GMP Development Timeline

1.2   Key Provisions of Food GMPs

The current GMPs consist of seven subparts, two of which are reserved. The requirements are purposely general to allow individual variation by manufacturers to implement the requirements in a manner that best suit their needs. Table 1-2 summarizes the five written subparts, which are discussed in further detail below.

1.2.1   General Provisions (Subpart A)

The general provisions in Subpart A of the food GMPs are divided into four sections. The first section defines much of the terminology used in describing GMPs. The terms "shall" and "should" are also defined to differentiate between when compliance is necessary ("shall") and when procedures and practices are not directly related to insanitary conditions as specified in Section 402(4)(a) ("should").

The section on personnel delineates plant and employee responsibilities with regard to personal hygiene. For example, personnel with diseases or other conditions that could contaminate food are to be excluded from manufacturing operations. The section also outlines expectations with respect to personal hygiene and cleanliness, clothing, removal of jewelry and other unsecured objects, glove maintenance, use of hair restraints, appropriate storage of personal items, and restrictions on various activities, such as eating and smoking. The section discusses the need for appropriate food safety education and training in very general terms. The subpart further mandates the assignment of supervisory personnel to ensure compliance.

Currently, establishments that only harvest, store, or distribute raw agricultural commodities are exempt from the requirements of Subpart A, although FDA reserves the right to issue special regulations to address this sector.

1.2.2   Buildings and Facilities (Subpart B)

Subpart B of the food GMPs outlines requirements for the maintenance, layout, and operations of food processing facilities.

Section 110.20 outlines the requirements for adequate maintenance of the grounds, including litter control, waste removal and treatment, and grounds maintenance and drainage. The subpart requires that plants be designed and built to reduce the potential for contamination. Some detail is provided on how to achieve this, but the requirements are largely focused on the end result of a sanitary facility rather than specific practices. The language also includes many general terms to allow flexible implementation of the requirements.

Section 110.35 describes sanitary operations. Physical facilities, equipment, and utensils are to be sanitized in a way that protects against food contamination. Storage of cleaning materials and toxic materials permitted are outlined to prevent contamination with chemicals. The section also briefly addresses pest control and cleaning of various food contact surfaces, as well as the frequency of cleaning.

Section 110.37 describes the requirements for adequate sanitary facilities and controls, including the water supply, plumbing, toilet and hand-washing facilities, and rubbish and offal disposal.

Some of the requirements of the section are fairly specific, such as the requirement of self-closing doors for toilet facilities, whereas others remain general, such as plumbing of adequate size and design.

1.2.3   Equipment (Subpart C)

Subpart C describes the requirements and expectations for the design, construction, and maintenance of equipment and utensils so as to ensure sanitary conditions. It also adds a specific requirement; an automatic control for regulating temperature or an alarm system to alert employees to a significant change in temperature. Other requirements of the subpart are fairly general and intended to prevent contamination from any source.

1.2.4   Production and Process Controls (Subpart E)

The first section of Subpart E lists the general sanitation processes and controls necessary to ensure that food is suitable for human consumption. It uses more general words (e.g., "adequate," "reasonable," etc.) and covers many aspects not discussed in previous subparts. This section also addresses the monitoring of physical factors (critical control points), such as time, temperature, humidity, pH, flow rate, and acidification.

The second section outlines very general requirements for warehousing and distribution. The section requires finished foods to be stored and distributed under conditions that protect against physical, chemical, and microbial contamination. The container and the food must also be protected from deterioration.

1.2.5   Defect Action Levels (DALs) (Subpart G)

The last subpart of the food GMPs allows FDA to define maximum defect action levels (DALs) for a defect that is natural or unavoidable even when foods are produced under GMPs as set out in the other subparts of the regulations. Generally, these defects are not hazardous to health at low levels; they include rodent filth, insects, or mold. The DALs are defined for individual commodities and may be obtained by request from FDA, which produces a Handbook on Defect Action Levels for Food. They are also available from the FDA Web site Defect Action Levels handbook . Table 1-3 provides examples of the maximum DALs for select food products. Manufacturers are expected to use quality control operations that reduce the level of the defect to the lowest possible levels. Those exceeding maximum DALs will be considered in violation of Section 402 (3)(a) of the FDCA.

The section bans blending of food with a defect level above a maximum DAL with other food. It also stresses that compliance with DALs does not excuse violations of Section 402(4)(a) of the FDCA or that of the other subparts of 21 CFR 110.

Table 1-2:  Summary of 21 CFR Part 110: Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Human Food

Table 1-3: Maximum Defect Action Levels for Selected Food Products

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