Author byline as per print journal: Ka-Liong Tan¹, DPhil; Ainoon Othman¹; Irwan Mohd Subri^2,3; Noor Fadzilah Zulkifli¹; Mohd Mahyeddin Mohd Salleh³; Nazariyah Yahaya⁴; Khairun Nain Nor Aripin¹; Shahirah Nadiah Shaharuddin⁵; Seri Azalina Mohd Ghazalli⁶; Muhammad Syazan Sulaiman⁶

Submitted: 4 April 2023; Revised: 22 August 2023; Accepted: 23 August 2023; Published online first: 5 September 2023

Implementation of Halal Management System (HMS) in the manufacturing of solid oral dosage forms

Halal is an integral observance for all Muslims. This concept originates from an Arabic word and can be defined as permissible by shariah law. The consumption of halal foods is mandated under Islamic teachings and includes, water and beverages, meals and snacks, as well as pharmaceutical medicines. Medicines also fall under Islamic dietary law and are required to be halal and Muslims are forbidden to use illicit drugs except in an emergency [1].

In recent years, the global demand for halal pharmaceuticals has been increasing. This comes with the growth of the global population of Muslims which is expected to grow from 1.6 billion to 2.2 billion by 2030 [2]. It is estimated that halal pharmaceuticals now account for 22% of the total value of all halal products [3]. Furthermore, halal pharmaceuticals have also gained increasing acceptability among non-Muslims due to ethical consumption issues such as social responsibility, stewardship, economic and social justice, animal welfare, as well as ethical investment. In addition, many pharmaceutical companies are aspiring towards bigger investment and development of halal-certified products.

The term pharmaceutical refers to both prescription and non-prescription medicinal products in finished dosage forms, i.e. biopharmaceuticals, radiopharmaceuticals, and traditional medicines. The dosage forms can be administered via oral intake, through body orifices, given as injections, implants, or through topical application [4]. Common orally administered drugs can be in the forms of tablets, soft-gel capsules, chewable, orally disintegrating tablets, sublingual tablets, capsules, lipids, and powder. Table 1 shows the classification of oral dosage forms available on the market. According to a recent survey, oral dosage forms are the most popular means of delivering active pharmaceutical ingredients (API) to patients [5]. Oral dosage forms provide better protection against moisture, oxygen, and light before the medication is consumed and released into the body as compared to injectables and topical formulations. Halal pharmaceuticals are better outlined in the supply chain and Table 2 lists the halal-related standards available in Malaysia.

The HMS is an approach used in the detection of non-halal contaminations which incorporates control steps to the production process to ensure that products and services are halal and safe. HMS is crucial to regulate non-halal elements and safeguard the integrity of halal products and services. It covers all aspects of sourcing, manufacturing procedure, packaging, and logistics, see Figure 1. The system provides both guidelines for hazard analysis critical control point (HACCP) and good manufacturing practice (GMP) in product processing to ensure compliance with shariah requirements. Overall, when it comes to halal pharmaceutical production, processes must adhere to local and international standards including: GMP, good hygiene practice (GHP), good clinical practice (GCP), good laboratory practice (GLP), good storage practice (GSP), good engineering practice (GEP), and good distribution practice (GDP). In view of the complexity of HMS, more efforts are required for stakeholders and regulators of the pharmaceutical industry worldwide to understand these features and ensure the adherence of halal-pharmaceuticals.

Medicines are often prescribed in emergencies to treat conditions that may be life-threatening, thus the issue of whether the product is halal issue is not always the highest priority. This can partly explain why the halal pharmaceutical industry remains in a nascent stage. In the absence of strong market demand, halal pharmaceuticals need to rely on governments and industry ­players in Muslim-dominant countries to promote awareness. Suppliers fail to prioritize the halal certification of pharmaceuticals and, to address this challenge, some experts recommend that governments and manufacturers implement the relevant halal management and accreditation processes themselves.

To implement halal management, continuous social science research, clinical experiments, and development initiatives are necessary to identify alternatives to non-halal ingredients. Established international halal regulations are now gaining more recognition, especially those concerning oral dosage forms.

The growth of the halal supply chain to produce solid oral dosage pharmaceuticals presents various challenges. Despite halal’s increasing popularity by both Muslims and non-Muslims, there is a lack of understanding about the halal concept, leading to a poor recognition of its requirements in pharmaceutical preparation. The complexity of ingredients and processes involved makes the implementation of HMS challenging. Non-compliance with halal regulations can result in product recalls, emphasizing the need for systematic traceability and resource utilization to minimize costs during such a crisis. Furthermore, the lack of Muslim human capital in the industry poses an additional obstacle to sustainable HMS implementation. Therefore, there is a need to review the disputes and challenges faced by the implementation of HMS, focusing on the manufacturing of solid oral dosage forms.

This article aims to provide justification for the implementation of HMS in the manufacturing of solid oral dosage forms by the pharmaceutical industry. The article also provides some solutions and strategies to improve compliance with halal regulations.

Standardizing halal certification

International organisations, such as the World Halal Council (WHC) and the Standards and Metrology Institute for Islamic Countries, work together to oversee the standardization of halal certification and accreditation processes. Here, stakeholders actively participate in the development process through working groups and public comments [6]. Several countries, including South Korea and ASEAN (Association of Southeast Asian Nations) have set up national halal certification policies in accordance with International Standards Organization (ISO). The development process also complies with the guidelines established by the World Trade Organization (WTO). Table 3 lists the halal certification authorities in Southeast Asia.

HMS is the primary industry standard used to maintain the halal status of products. Table 4 depicts the structure of HMS. The halal procedure is key to ensure that all halal products are produced responsibly [7]. The HMS clauses are established to ­manage the overall quality of an organization in accordance with halal requirements [8]. The certification process may vary based on individual national policies. In Malaysia, medium and large industries can only get halal certification by implementing the complete Halal Assurance System (HAS) [9]. However, small and micro enterprises can obtain the certification via the creation of an Internal Halal Committee (IHC) in accordance with the Malaysian HMS and the Manual Procedure for Malaysian Halal Certification [10-12]. IHC is responsible for designing, monitoring, and assuring the implementation of the six principles of HAS as shown in Table 5. It should consist of at least four members, namely two Muslims at the managerial level, one involved in the acquiring and sourcing process, and the halal executive who is responsible for monitoring the halal affairs of the company [13]. Figure 1 shows an example of the IHC composition.

Regarding halal pharmaceuticals, it is key that guidelines are present to standardize the halal requirements. In Malaysia, this guideline (MS 2424:2019 Halal pharmaceuticals &ndash General requirements) was developed for the production and handling of halal medicines to ensure that pharmaceutical companies comply with shariah requirements. Furthermore, the manufacturers must also establish a dedicated processing line for halal pharmaceuticals.

Figure 3 illustrates the steps of HAS implementation. All materials applied in the manufacturing of halal pharmaceuticals, including API, must comply with halal principles. Materials acquired from suppliers under contracts, any other commercial arrangement, or made in-house must also be subjected to the same requirement. More importantly, all materials must be najs-free, i.e. halal (as described in section 4.0). ‘Najs’ is an Arabic term that means ‘filth’ and is considered non-permissible for consumption according to Islamic law. Finally, companies must use dedicated vehicles with appropriate hygiene and sanitation condition for the transportation of all medicines.

It is key to highlight that, to achieve stainable production of halal pharmaceuticals, manufacturers should employ management and operational team personnel to monitor, identify, record, and report any problems in the halal process based on international standards. This can minimize the risk of contamination, mix-ups, and errors in the production processes, thus protecting consumers from potential risks of sub-standard medicines. Pharmaceutical manufacturers applying for halal certification for their products should comply with all the safety and hygiene requirements and adhere to the requirements of shariah law. Dedicated equipment must be used to avoid cross-contamination of halal by non-halal products [14]. In the cleansing procedure, the equipment must be cleaned using clay to remove any microbial contamination, followed by washing, spraying, and rinsing. Segregation of halal and non-halal products at every stage is obligatory, including storing, displaying, and transporting [15]. Furthermore, primary packaging materials must be customized to prevent contamination post-production. The origin and nature of the paper or plastic packaging, inks, films, and glue are also of concern for halal status. On the packaging, information incorporating the name, brand, minimum content in metrics, name and address of manufacturer/distributor, list of ingredients, code number representing production batch, manufacturers, as well as expiry dates must be outlined.

Non-compliance with halal standards and need for a ­reliable traceability system

With the increasing interest in the halal pharmaceutical market, several problems have emerged, such as non-compliance with halal standards and shariah law and the fraudulent use of halal logo and terms. For instance, a halal product was found to be contaminated with non-halal content, i.e. a pig’s DNA, and certified using a fake halal logo, resulting in the suspension of halal certification for the product [16]. This highlights the importance of a credible system to safeguard the integrity of halal products. For the pharmaceutical industry, a systematic traceability system used by manufacturers is essential to sustain HMS. Table 6 lists the known halal non-conformance cases in pharmaceutical establishments. These incidents are commonly detected by authorities when conducting audit checks.

The halal traceability framework was established to maintain the integrity of halal products and ingredients throughout the production and supply chain [17]. The IHC and HAS been put in place to facilitate recall procedures for any products that have been recognized as non-compliant [17]. In Malaysia, the National Pharmaceutical Regulatory Agency (NPRA) regulates halal products, manufacturing plants, and work methods, to expand the production and supply of halal products for the global market. The traceability HMS requirement is in tandem with the existing international standards, i.e. the Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP Guide. This document is also adhered to by the NPRA. The existing traceability system requirements outlined in the PIC/S standard facilitate the implementation of HMS. With outlined traceability practices in place, minimal integration is needed for the adoption of the HMS guideline. Table 7 compares the traceability for HAS, HACCP and GMP.

Product recall management is the final step in traceability systems. In general, this refers to the process of removing defective medicines from the supply chain, ideally before they reach consumers. For example, these will be products that may cause illness or harm, i.e. unsafe food products, products with potentially adverse effects, or contaminated pharmaceutical products. All manufacturers are required to have effective product recall management systems in place to ensure consumer safety. This is also key for halal products and for ensuring their halal status. A product recall can damage the reputation and financial standing of a company. As a damage control strategy, companies must have a good recall management system in place that include checks for halal compliance.

During a recall crisis, a systematic traceability system and efficient utilization of resources can cut down cost. For example, an individual transportation network is vital to reduce transportation costs and to ensure the halal status during transportation. Overall, preventing the occurrence of product recalls will lead to a high level of customer confidence in halal integrity in the halal industry, particularly in terms of halal assurance.

Halal disputes and proposed solutions

Overall, there is increasing awareness among consumers, health experts, and various organizations of the need for solid oral dosage formulations that are safe, efficacious, high quality, hygienic, and compliant with religious obligations. More pharmaceutical manufacturers are exploring new values in their production process, especially in terms of identifying suitable alternatives that can substitute non-halal ingredients in the process of halal pharmaceutical production, see Table 8.

To achieve that, comprehensive scientific knowledge of all aspects of pharmaceuticals, including production, transport, and storage is a prerequisite to support halal requirements. Ideally, pharmaceuticals should be developed through various research and development programmes that will facilitate the creation of more alternatives for non-halal ingredients in halal pharmaceutical production. These include intoxicants, pork and its by-products, the meat of dead animals, and blood. Muslims are also prohibited from consuming animals that are grouped as carnivores and predatory birds such as dogs, tigers, owls, and hawks. These ingredients are termed &ndash najs and are thought to be ritually unclean. Despite the criteria for halal being fairly clear, halal pharmaceuticals do present some grey areas in terms of manufacturing processes. Below is a summary of a number of components of pharmaceuticals that are not halal compliant.

Alcohol
The use of alcohol in producing API. Although the use of ethanol derived from the manufacturing of alcoholic beverages is not allowed, the use of alcohol compounds as processing aids and stabilising agents is permissible as its trace amount in the final product (0.01%v/v) will not be intoxicating [18].

Gelatine
A long-standing issue affecting Muslim consumers is the use of gelatine from pigs (porcine) and cows (bovine) that are not slaughtered according to Islamic shariah law [19]. With the rise in demand as well as religious concerns surrounding gelatine, there is a need to search for affordable, abundant, and sustainably accessible alternatives [20].

One potential alternative to conventional gelatine (non-halal porcine and bovine) is to ensure that gelatine is derived from animal waste produced in Muslim countries [21]. It is estimated that about 24% of all gelatine originates from bovine and other cattle waste products [22]. Ovines, i.e. sheep and goats are other mammalian sources to extract gelatine [23]. In addition, gelatine derived from chicken by-products can also be considered and used as there is a large amount of chicken waste that includes chicken skin, bones, and shanks. Lastly, fish-sourced gelatine is acceptable to people of all religions.

Glycerine
Glycerine, also referred to as glycerin or glycerol, is used in various products including cosmetics, pharmaceuticals, and foods. Glycerine sourced from animal fat needs to be regulated under the shariah rulings of slaughters to be considered halal. It is not acceptable if the ingredient is extracted from animals that are alive. On the other hand, Halal glycerine can be derived from plants such as palm oils and soybeans.

Lecithin
Lecithin is a fatty substance that occurs naturally in the body tissues of humans, animals, and plants. It can be found naturally in soybeans and yolk. However, it is considered non-halal if obtained from the fatty tissues of non-slaughtered animals. Lecithin functions as an emulsifier by suspending fats and oils to prevent mixing with other substances. It has a variety of medicinal and commercial uses with extensive health benefits. Lecithin supplements are often prescribed to supplement the treatment of high cholesterol, ulcerative colitis, and Alzheimer’s disease.

Glutamic acid
Glutamic acid is an α-amino acid involved in the production of proteins of all living things. Pharmaceutically, glutamic acid supplements have been used to treat behavioural problems and as a supportive treatment of cognitive diseases. It has also been prescribed to prevent nerve damage in chemotherapy patients. In addition, it is also widely used in a variety of cosmetic products.

Glutamic acid can be found naturally in poultry, fish, and all high-protein foods. However, glutamic acid from non-slaughtered animals and pigs are not acceptable for use in halal products.

Disputes of the use and non-halal nature of these components of pharmaceuticals have sparked disputes and constructive discussions in the industry for a long time. The labelling of gelatine, glycerine, lecithin is compulsory to ensure its source of origin is clearly stated. The relevant authorities ensure that all related activities for the manufacturing and handling of halal pharmaceuticals are properly recorded. All businesses must maintain halal control points to ensure that chemicals, reagents, equipment, and other necessities are approved as halal [24]. To date, the scarcity of information remains a key constraint when it comes to the global halal pharmaceutical industry. Most suppliers are not aware of the opportunities in local and global markets. They are also not well versed in the importance of halal certification. In addition, most consumers also have a low level of concern about the content of medications and their halal status. Currently, there is no obligation for the clinics or pharmacy departments to label the micro packaging of medicine. As such, Muslim patients who are not informed of the presence of non-halal materials in the drugs would have unknowingly consumed the prescribed medicinal goods instead of sourcing halal substitutes of the same medicines. This factor contributes to the narrow exploration of the halal market and the difficulty that pharmaceutical manufacturers face in sourcing halal ingredients. The creation of a larger demand from the Muslim population is essential to sensitize the involved stakeholders and push them to undertake more halal product development.

Moreover, at present, the lack of human capital continues to act as a deterrent to the development of the halal pharmaceutical industry. The production of medicines with desirable pharmaceutical qualities that also satisfy religious obligations requires the participation of all involved parties in the manufacturing process. While the halal pharmaceutical industry is growing globally, there is still a lack of understanding of the halal concept, with most of the population associating it with religious matters. Even though religion plays a significant role in halal pharmaceuticals, more awareness about halal products should be instilled to facilitate their widespread production and uptake. Halal education programmes should be developed to educate the producers and the public about the role of halal pharmaceuticals in providing healthy, hygienic, and safe pharmaceutical drugs.

Conclusion

This article has outlined that HMS is an extension of HACCP and GMP guidelines in oral dosage processing to ensure compliance with shariah requirements. It highlights that it is important for manufacturers to uphold their moral commitments and safeguard the concerns of consumers when it comes to halal. This will allow local and international halal commerce to flourish. Non-compliance with halal regulations can result in oral dosage product recall. To reduce the cost during recall, a systematic traceability system is vital. Good HMS implementation can assure the quality and safety of oral dosages to embolden the trust and confidence of patients toward halal pharmaceutical products.

Acknowledgements

Contributors: We thank Maria Arshad for technical editing the manuscript for grammar and syntax. This manuscript underwent proofreading service by Proofreading by A UK PhD (Registration: NS0163592-K).

Funding sources

This work was financially supported by the Duopharma R&D fund (A2-5-21-804111-16).

Disclosure

KL Tan, A Othman, I Mohd Subri, NF Zulkifli, MM Mohd Salleh, N Yahaya, and KN Nor Aripin are affiliated to Universiti Sains Islam Malaysia (USIMs). SN Shaharuddin is affiliated to Kolej Universiti Islam Perlis (KUIP). All received consultation fee from Duopharma Biotech Berhad, Malaysia.

Competing interests: The authors have no declared conflicts of interests.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Ka-Liong Tan¹
Ainoon Othman¹
Irwan Mohd Subri^2,3
Noor Fadzilah Zulkifli¹
Mohd Mahyeddin Mohd Salleh³
Nazariyah Yahaya⁴
Khairun Nain Nor Aripin¹
Shahirah Nadiah Shaharuddin⁵
Seri Azalina Mohd Ghazalli⁶
Muhammad Syazan Sulaiman⁶

¹Faculty of Medicine and Health Sciences, University Sains Islam Malaysia (USIM), Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia
²Institute of Fatwa and Halal (IFFAH), University Sains Islam Malaysia (USIM), Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia
³Faculty of Syariah and Law, University Sains Islam Malaysia (USIM), Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia
⁴Faculty of Science and Technology, University Sains Islam Malaysia (USIM), Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia
⁵Faculty of Islamic Studies, Kolej Universiti Islam Perlis (KUIPs), Kuala Perlis, 02000, Perlis.
⁶Duopharma Biotech Berhad, Suite 18.06, Level 18, CIMB HUB, No. 26, Jalan Sultan Ismail, 50250 Kuala Lumpur

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