An overview of current manufacturing guidelines for Ayurveda formulations

Vaibhav Anandrao Charde; Ganesh Dane; Harmeet Kaur; Chandrashekhar Yuvaraj Jagtap; Vijay Kumar; Biresh Kumar Sarkar; G Babu; Bhagwan Sahai Sharma

doi:10.4103/jdras.jdras_1_21

REVIEW ARTICLE

Year : 2021 | Volume : 6 | Issue : 3 | Page : 122-127

An overview of current manufacturing guidelines for Ayurveda formulations

Vaibhav Anandrao Charde¹, Ganesh Dane¹, Harmeet Kaur², Chandrashekhar Yuvaraj Jagtap¹, Vijay Kumar¹, Biresh Kumar Sarkar³, G Babu¹, Bhagwan Sahai Sharma⁴
¹ Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, India
² Shree Lakshmi Narayan Ayurvedic College, Amritsar, Punjab, India
³ Central Ayurveda Research Institute, Kolkata, West Bengal, India
⁴ Central Council for Research in Ayurvedic Sciences, New Delhi, India

Date of Submission	17-Jul-2021
Date of Acceptance	01-Feb-2022
Date of Web Publication	25-Mar-2022

Correspondence Address:
Dr. Vaibhav Anandrao Charde
Central Ayurveda Research Institute, Jhansi 284003, Uttar Pradesh.
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdras.jdras_1_21

Abstract

Good manufacturing practices (GMPs) are the guiding principles, which ensure that products are consistently produced and controlled as per quality standards. This is an important requirement for marketing authorization. At the global and national level, different regulatory authorities work to formulate guidelines and regulations for the manufacturing of product and also work to achieve harmonization of guidelines and quality control of pharmaceutical products. This article provides specific information on contemporary manufacturing guidelines for Ayurvedic formulations especially given by World Health Organization (WHO) and Drug & Cosmetic rules 1945 (Schedule T) and their suitable strategies for practice. Knowledge of such guidelines and practice is helpful to maintain quality, safety, and efficiency to extraordinary heights in the manufacturing of products.

Keywords: Efficacy, GMP, Indian GMP, quality, regulatory authorities, safety

How to cite this article:
Charde VA, Dane G, Kaur H, Jagtap CY, Kumar V, Sarkar BK, Babu G, Sharma BS. An overview of current manufacturing guidelines for Ayurveda formulations. J Drug Res Ayurvedic Sci 2021;6:122-7

How to cite this URL:
Charde VA, Dane G, Kaur H, Jagtap CY, Kumar V, Sarkar BK, Babu G, Sharma BS. An overview of current manufacturing guidelines for Ayurveda formulations. J Drug Res Ayurvedic Sci [serial online] 2021 [cited 2023 Jun 10];6:122-7. Available from: http://www.jdrasccras.com/text.asp?2021/6/3/122/340867

Introduction

India can emerge as the major country with the spirit of make in India and make for world and play the lead role in production of therapeutically effective Ayurvedic formulations complying with all the international standards. Upsurge demand for Ayurvedic medicines due to high efficacy, safety, and fewer side effects increased the production of Ayurvedic formulations during this COVID-19 pandemic.^[1],[2] Quality and safety of Ayurvedic pharmaceuticals are a top concern for physicians, professionals, the general public, authorities, and industries as the global market expands.^[3] To ensure quality and authenticity of such highly demanded drugs Ayurveda pharmaceutical industry needs better knowledge of guidelines for their implementation in the quality management system. Good manufacturing practices (GMPs) are a set of production and testing procedures that serve to ensure product quality.^[4] cGMP is mainly aimed to ensure that products are constantly manufactured and measured according to predetermined quality standards/parameters.^[4] These guidelines are not strict instructions for manufacturing products but succession of general principles that must be adopted. There are many guidelines to be followed for cGMP in the modern system of medicine such as China cGMP,^[5] WHO-GMP,^[6] PIC/S and EU-GMP,^[7] USFDA Guidelines,^[8] Drug and Cosmetic Act’s Schedule M (D and C act 1940 rule 1945).^[9] In India, commonly practiced guidelines for Ayurvedic formulations are Schedule T of Drugs and Cosmetic (D & C) Act - Rule 157 for Ayurveda, Siddha, and Unani (ASU) drugs^[10] and World Health Organization (WHO) guidelines on GMPs for herbal medicine.^[11] WHO guidelines mainly deal with herbal materials and medicines. These guidelines do not cover combination of herbal materials with metal, mineral, animal, and chemical origin materials. cGMP is essential to maintain the high-quality standard for making drugs safe and efficacious. Here an attempt has been made to overview these guidelines so that the WHO-GMP guidelines for Ayurveda pharmaceutics can be adopted in every ASU pharmaceutical sector. This article aims to map the guidelines for the manufacturing of Ayurvedic drugs which may be helpful to new manufacturers for the establishment or adoption of GMP.

Ayurvedic Formulations

It is well-known fact that various polyherbal combinations are widely used by Ayurvedic physicians to treat many ailments. Mostly Ayurvedic preparations are plant based.^[12] Other substances in these combinations include metals and minerals. Most of the herbal Ayurvedic preparations involve selecting proper plants as well as their parts like flowers, leaves, seeds, and roots. Several methods are mentioned in classical texts of Ayurveda to manufacture the medicine. Conventional pharmaceutical products for therapeutic drug interventions are generally manufactured from synthetic materials using reproducible manufacturing techniques and procedures.^[13] Because medicinal plants have an integrated complexity and a high number of active compounds, their cultivation and handing during manufacture have a direct impact on product quality.^[4],[14] Due to such complexity, adoption of the cGMP in the manufacturing of Ayurvedic formulations become important to ensure their quality.

Drugs & Cosmetics Rules 1945 [Rule 157]

All Ayurvedic pharmaceutical units must comply to GMP standards, comply to Schedule T of the D&C Act describes the GMP for Ayurveda, Siddha, and Unani (ASU) pharmaceuticals. GMP are described under Part I and Part II of rule 157.^[15] Certificate of manufacturing to applicant is issued in Form 26 E-I (under Rule 155-B) for a period of 5 years.^[16] In 2009 supplementary guidelines for the manufacturing of Rasoushadhi (formulation having metal and mineral as an ingredient) have also been added by G.S.R. 157(E).^[17]

WHO guidelines on GMP for herbal medicines

These guidelines are intended only for herbal products in conjunction with the parent guidelines of manufacturing.^[18] These guidelines are specifically related to the production and quality of herbal medicines identifying the important steps which are needed for good quality. These guidelines do not cover combination of herbal materials with metal, mineral, animal, and chemical origin materials.^[18]

Licensing authorities (LAs)

State Government assigns LAs responsible to issue GMP certificate.^[19] WHO-GMP certificate/COPP (Certificate of Pharmaceutical Product) is issued by Drug Controller General of India (DCGI) and Central Drug Standard Control Organization (CDSCO) through inspection of the facilities.^[20]

GMP: The General/Current State (cGMP)

Location, surroundings, and premises

As per Schedule-T and WHO-GMP manufacturing unit location, the surroundings and premises must be free from the contamination from lavatories, drains, open sewerages, and manufacturing units producing obnoxious fumes, smoke, and odor.^{[21],[22],[23]} Building, premises, and facility design should be maintained for manufacturing operations in a clean environment and it should have to confirm the conditions mentioned in Factories Act 1948.^[24] The manufacturing unit should aim to lower the risk of cross-contamination. There should be adequate ventilation in the Bhatti (furnace) area, as well as a tin roof covering to keep flies and dust at bay. Air Handling Unit (AHU) system/ventilation must be suitable to production and for the comfort of the people working. There should be proper flow of material and personnel, and safety measures for fire with proper exit. Proper space for drying must be provided for drying of the raw material, semi-finished and finished drugs before packing. Space for drying should be free from dust, insects, rodents, and flies. There should be adequate space for receiving raw material and its storage, processing area for manufacturing, stores for finished goods and rejected goods/drugs, quality control unit, and office in the manufacturing plant.

Validated water system: The water used in the manufacturing of the product shall be pure and as per the manufacturing requirement.^[21] For washing the premises there should be adequate provision of water. Wastewater and materials should be adequately and safely stored for awaiting disposal in accordance with the standards of the Environment Pollution Control Board manufacturing divisions and laboratories. Biomedical waste should be disposed of according to regulations. Additional measures for the disposal of flammable and hazardous items should be taken in accordance with state and federal legislation.

Containers cleaning: Containers such as glass and stainless steel (SS) equipments that are used in the manufacturing operation should have separate arrangements for washing, cleaning, and drying.^{[21],[22],[23]}

Raw materials (RM): All the procured RM should be stored in the store section specified for the RM in proper condition and in container specified for the material so as to avert from contamination by microbes, insects, and rodents infestation, dampness and to maintain quality of the raw material The raw materials should be stored category-wise such as fresh herb, dry herb, metallic origin, mineral origin, animal sources, volatile oils and flavors, excipients, plant extracts/concentrates and resins/exudates. As per WHO GMP guidelines, technical series report 986 (chapter 14.15) mentioned that within the shelf-life period, RM released by the QC department should be used for various procedures.^[21] Storage area: A separate sampling area for starting materials should be there. [WHO GMP guidelines (Chapter 12 “Premises” subchapter 12.22, TRS 986)]^[21]

Warehousing area: The quarantine status of the material should be marked. For storage of the recalled materials and rejected materials, a separate area should be made available. (Para 2.5, Part-I of Schedule M) The printed material should be kept in a separate room in safe and secure storage conditions. Separate weighing and sampling areas should be available for the starting material. RM and excipients should have a specified sampling area. Different dispensing areas for special categories of products are required. Regular quality checks for leakage, breakage, and spillage of the containers. Pest control management for warehouse area is essential regularly.

Production area:^{[21],[22],[23]} Different sections of production area should be linked in a sequence order conforming to the sequence of the operation which will lead to minimizing the risk of cross-contamination. There should be adequate space for working and in-process storage. Cracks should not be present in ceilings, walls, and floor and they should be smooth. Drainage system should be well designed which can prevent backflow. The production section should be properly ventilated having facilities of air control. Packaging materials: The packaging materials should be properly stored. Before packing the products, closures and containers should be well cleaned and properly dried.

Finished goods stores: Following adequate packing, finished goods transferred from the production area must be housed in finished goods stores within a quarantined area. After the QC laboratory and experts have verified that the completed items are correct in terms of packing/labeling and finished product quality, they will be relocated to the Approved Finished Goods Stock Area. Quality-approved final goods must be dispatched in accordance with marketing requirements. For each dispatch, a distribution record must be kept as necessary. If a medicine necessitates particular storage conditions, the finished goods store must be outfitted to meet those criteria.

Working space: Enough space (manufacturing and quality control) for the installation and placement of equipment and materials used in any of the operations, as well as the operational space for the technician or operator to facilitate easy and safe work and reduce the risk of drug and raw material mix-ups. It also eliminates the risk of cross-contamination from another medicine produced, stored, or handled in the same location. Worker’s hygiene, health, clothes, and sanitation: All personnel and employees should undergo health checks before and during employment, as outlined in chapter 11 of personal hygiene under sub-point 11.1 of WHO-GMP recommendations. Worker clothing should be clean and consist of uniforms that are appropriate for the nature of the work and the climate. Wherever possible, it should also include head, hand, and foot protection. Processing rooms should not be connected to lavatories, and a separate facility should be provided at a distant site. Workers would also have access to facilities for changing clothes and storing personal belongings.

Equipment and machinery: Depending on the nature and operation size of product to be manufactured, suitable equipment and machinery shall be made available which can be operated manually, semi-automatically, or can be fully automatic. Crushing, powdering, grinding, mashing, burning, boiling, roasting, and labeling packing are some of the machineries used in the manufacturing process. The suitable space shall be made available to ensure ease in orderliness in the operations, in movement of workers and in between the machines and rows of machines. Under Part II A (Rule 157), for manufacturing of different categories of Ayurvedic drugs, the required minimum manufacturing premises and list of equipment and machinery is indicated.^[22] Equipments should be installed properly and there should be proper maintenance with proper cleaning. For each machine Standard Operational Procedures (SOPs) should be laid down for maintaining, cleaning, and performing. The finished product should be avoided coming into contact with materials that are used for pest control, cleaning, and equipment lubrication. According to [chapter 14.3, WHO-GMP guidelines (TRS 986)], such materials should be of an appropriate food grade to avoid health risks.^[21]

Batch manufacturing records (BMRs): Regardless of the type of product manufactured (classical preparation/patent and proprietary medications), the company should keep a BMR for each batch of manufactured drugs. These are required to provide an account of the list of RMs used and amounts obtained from the central store, as well as other tests performed during the manufacturing or performance phases, such as physical attributes, color, taste, and chemical testing.

Distribution records: Sale and distribution records of every batch shall be kept to ease the prompt and comprehensive recall of the batches. The record should be kept until the date of expiry of the batch. Records need to be preserved up to five years of stocks exhaust.

Record of market complaints: Manufacturers/licensees are required to retain a register of market complaints received after products have been marketed. All such data obtained by market complaints must be entered by the manufacturer, investigations into the complaint’s compliance must be conducted by the manufacturer, and corrective action should be implemented to prevent similar recurrences or complaints. Manufacturer should give such record of complaints to the LA. The register of such complaints should be made available during inspection of premises.

Quality control (QC): Every licensee should provide a facility for QC section in own premises or through government-approved testing laboratories. The quality control section shall verify all RM, in-process quality checks, monitoring as well as finished product which will be released to the finished goods store or warehouse. Non-wooden equipment/instruments should be used unless and until tradition demands wooden material. If the use of wooden equipment is inevitable, special attention must be given for cleaning because wooden materials easily contaminate, easily discolor and retain odors.

Discussion on significant differences in the guidelines

Each license applicant/holder must develop suitable procedures and methodologies which is to be maintained and documented for inspectional purpose or reference. No other manufacturing activity should be carried out in the same manufacturing facilities that is dedicated to the production of pharmaceuticals.^[25] All of the rules must be followed if any necessary adjustments to the general requirements in part one of schedule T (related to GMP requirements) for pharmaceutical product premises and materials do not influence the major points.^[26]

The water used in the manufacturing process must be pure and potable. It is mentioned under Para 1.1 (C), Part-I of schedule T under subheading water supply whereas according to WHO-GMP, water used in the manufacture or production of herbal products should be suitable for its intended use. (Chapter 14 of WHO-GMP guidelines)^[21]

Schedule T Part-I under Para 1.1 F (A), subheading Raw Materials, Different categories of RM like fresh herbs, Dry herbs, animal source, metallic, mineral origin, volatile oils, exudates, and excipients. The status of RM such as approved or rejected or under test should be clearly mentioned.^[22] Normally, separate sampling area should be made available for raw material. If sampling is done in the storage area, cross-contamination or contamination should be prevented as mentioned under WHO-GMP guidelines, TRS-986, premises subchapter 12.22-Storage Areas.^[21]

All manufacturing personnel must be free of infectious diseases, according to Schedule T^[22] and in WHO-GMP guidelines, under chapter 11 of personal hygiene (11.1), health examinations should be conducted on all the employees prior to and throughout the employment.^[21]

To assign shelf life to the material at the stipulated storage circumstances, the QC department should conduct stability studies of the products; for such stability studies, part I of Schedule M under para 16.10 must be referred to. The results of all stability tests must be kept on file. Stability testing of raw material and finished drugs/product should be conducted. WHO guidelines must be referred for stability testing studies [TRS 953, Good Practices in Quality Control, Chapter 17, subparts 17.22–17.25 Annex-2]. Incoming herbal materials/raw material/containers should be processed on principle of FIFO-first in, first out basis. If suitable, they should be stored between temperature 2°C and 8°C. Production area: When heating or boiling of the materials like operations is needed, a suitable air exhaust facility should be employed to prevent accumulation of vapors and fumes.

The herbarium sample of utilized part of the medicinal plant, such as the blooming or fruiting top, should be made for reference if herbal drug is not defined in published pharmacopoeia. To avoid degrading, reference standards must be kept in appropriate conditions. The reference standard drug’s expiration and revalidation dates should be identified and indicated. Foremost critical stage of production should be clearly mentioned over the preserved sample. (WHO guidelines on herbal medicine para 14.3 under subheading Reference sample and standards).^[27]

In chapter 12, Ancillary Areas is mentioned in the subheading 12.11 of WHO GMP guidelines which state about separate area with separate entries should be designed for rest and refreshment rooms. No such ancillary area is mentioned in schedule T.

Requirements for sterile product has been mentioned in separate heading para 1.2 under general requirements. The WHO-GMP rules make no mention of such a specific requirement (TRS 986). Pathogens such as Salmonella ^{More Details}, Pyocyanea, and Escherichia ^{More Details} coli must be absent from products. (Subheading of Manufacturing operations, Para 8.1, part I of Schedule M.).^[28]

Materials used for cleaning and lubrication of equipment should not come directly in contact with the product or raw material. To avoid health risks, these materials must be of an acceptable grade like food-grade wherever feasible. (WHO-GMP-TRS 986 Chapter 14.3).

There is a detailed description of important requirements in schedule T with reference to Ayurveda formulations like space for each section, and equipment to efficiently prevent contamination and mixing-up (Part II of Rule 157 of Schedule T). No such specific information was provided in WHO-GMP.

Schedule T of Indian GMP, is to be revised or amended from time to time with WHO-GMP guidelines so as to incorporate things like Suppliers Audit and Approval, Quality Management System (QMS), Quality Risk Management (QRM) and Pharmaceutical Quality System (PQS) of the product.^[29]

Documents required to obtain a license

Application for WHO-GMP certification and issuance of COPP requires List of products applied for issuance of COPP and their composition, Site Master file, Data on Finished Formulation, Master manufacturing formula, manufacturing process, finished product specification, Stability study evaluation, process validation report, list of SOPs and STPs (standard testing procedures), Manufacturing Plant layout, Schematic diagram of water system, labels of the products applied for WHO-CoPP, Proof of safety and effectiveness, List of Reference standards/ marker for all active ingredient /formulation, undertaking regarding the absence of any non-herbal ingredients including metals/minerals in the products applied for WHO-CoPPs.^[30]

Conclusion

WHO guidelines for herbal medicine provide some relaxation otherwise the parent guidelines are to be adopted as that of modern pharmaceutical industries. All the basic requirements of WHO-GMP are mentioned in Indian cGMP. In addition to WHO-GMP, Schedule T also invoked guidelines for the manufacturing of metals and mineral origin products. GMPs have to be adopted and understood along with other Rule 158 B, Schedule M and other acts and rules like Factories Act 1948, biomedical waste, good clinical practice (GCP), good storage practices (GSP), good agricultural practices (GAP), and good hygiene practices (GHP). However, the Indian GMP needs apprising of their requirements as per varying trends in GMP globally and rules and regulations in other countries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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