WHO prequalification of medicines in low- and middle-income countries: Situational analysis of Nepali manufacturers and recommendations

Abstract

Introduction

The World Health Organization (WHO) prequalification (PQ) program is a critical gateway for generic medicine manufacturers in low- and middle-income countries (LMICs) to access the global market. Despite India contributing more than 66% of PQ products, LMIC’s share in manufacturing PQ medicine is less than 22%. Nepali manufacturers fulfilling 50% of domestic requirements of generic medicine are yet to achieve WHO PQ status. This study assesses compliance gaps among six Nepali manufacturers aiming to produce four priority generic medicines (amoxicillin tablets, azithromycin tablets, zinc sulfate dispersible tablets, and oxytocin injections) for WHO PQ and recommends corrections.

Methods and findings

The Department of Drug Administration (DDA) of Nepal, in collaboration with the Promoting the Quality of Medicines Plus program, invited domestic manufacturers for technical assistance towards the PQ of priority products. We shortlisted six manufacturers out of twelve applicants through document review and conducted an onsite inspection using WHO GMP criteria.

Results

We identified systemic deficiencies in pharmaceutical quality systems (>95% major nonconformities), documentation practices, and bioequivalence testing—a cornerstone requirement for generic drug approval. Key barriers included the use of non-prequalified active pharmaceutical ingredients (APIs), lack of Common Technical Document (CTD)-formatted dossiers, inadequate validation of analytical methods, and product development reports.

Conclusion

WHO PQ is a system-strengthening approach targeting overall quality compliance. Our findings mirror challenges faced by manufacturers in LMICs, highlighting the need for regulatory harmonization and targeted technical assistance. We recommend public-private partnerships to establish regional bioequivalence study centers and incentivize sourcing WHO PQ grade API. Success from India leading the manufacturing and exports of WHO PQ and generic medicines could be considered. Strengthening Nepal’s capacity to meet WHO PQ standards will position the country as a competitive player in the global generic market.

Keywords

prequalification low- and middle- income countries good manufacturing practices dossier bioequivalence study generic medicines

Introduction

The World Health Organization (WHO) initiated the prequalification (PQ) program in 1987 with PQ of vaccines and it currently includes four categories, namely, vaccines including immunization device and cold chain equipment, medicines including quality control laboratories, in-vitro diagnostics, and vector control products.¹ The medicines PQ program was initiated in 2001 with the PQ of HIV/AIDS medicines to improve the quality of life-saving medicines used by millions of people in low- and middle-income countries (LMIC).² Medicines PQ program helps combat circulation of substandard and falsified medicines, which covers an estimated 1 in 10 medical products in LMICs thereby ensuring healthy life and promote well-being to meet Goal 3 of the Sustainable Development Goals.^3,4 The medicines PQ program includes active pharmaceutical ingredients (API) and finished pharmaceutical products (FPP) vital for the prevention and treatment of various ailments to ensure accessibility of safe, effective, and affordable generic medicines with proper quality to one-third of the global population.⁵ It covers APIs and FPPs for treatment of twelve therapeutic categories (covid-19, child diarrheal diseases, hepatitis B and C, HIV/AIDS, children pneumonia, influenza, malaria, multidrug resistant bacterial infections, neglected tropical diseases, reproductive health, and tuberculosis), including pilot PQ of biotherapeutic medicines for treating cancer and insulin for treating diabetes.⁶ The PQ process is initiated with an expression of interest published in the WHO website for various product categories. Interested generic medicine manufacturers submit the product dossier and a site master file to the WHO for assessment of product details for safety, efficacy, and quality.⁷ Following satisfactory assessment of the product dossier and the site master file (SMF), WHO conducts a formal inspection of the site for good manufacturing practices (GMP) compliance.⁷ An inspection of clinical testing units or contract research organizations (CROs) performing clinical trials for compliance with good clinical practices and good laboratory practices is also conducted.⁷ The products meeting the requirements of WHO recommended standards from assessment and inspection are listed in WHO list of prequalified products. Similarly, products registered by a stringent regulatory authority (SRA) fulfilling the WHO requirement with desk assessment are also included in the PQ list.⁷

With a history of more than two decades of medicines PQ, various manufacturers from forty countries have contributed to PQ of 645 FPPs, including medicines prequalified through the SRA route.⁶ Although the PQ program is targeted to ensure the supply of quality assured medicines in LMICs, only one country, Uganda, a low-income country, in collaboration with an Indian manufacturer, has produced five (0.78%) prequalified FPPs. Eight countries from the lower middle-income category contribute to 447 FPPs, with India alone contributing to 427 FPPs (66.20%). Other 31 developed countries contribute to 193 FPPs (29.92%).⁶

In Nepal, an attempt for medicines PQ was made in 2008–2010 to produce zinc sulfate dispersible tablets and chlorhexidine gluconate gel with the support of the United States Pharmacopeia (USP), drug quality and information program implemented by the U.S. Agency for International Development (USAID).⁸ Four Nepali manufacturers (CTL Pharmaceuticals Pvt. Ltd., Deurali-Janta Pharmaceuticals Pvt. Ltd, Lomus pharmaceutical Pvt. Ltd. and Nepal Pharma Lab Pvt. Ltd) initiated the process, but none of them could attain medicines PQ status.⁸ To date, none of the products being marketed by eighty pharmaceutical manufacturers registered with the Department of Drug Administration (DDA), the national medicines regulatory authority of Nepal are prequalified, or SRA approved.

Promoting the Quality of Medicines Plus (PQM+) program under USAID has initiated a process of technical assistance to Nepali manufacturers to meet PQ of selected medicines.⁹ This study highlights the gaps in Nepali manufacturers to produce medicines meeting WHO PQ requirements identified from onsite assessment.

Materials and methods

DDA, in collaboration with the PQM+ program, published an expression of interest in the Kantipur Daily, a national newspaper, for technical assistance to Nepali manufacturers towards WHO PQ of four products: amoxicillin tablets 125/250 mg, azithromycin tablets 500 mg, zinc sulfate dispersible tablet 10/20 mg, and oxytocin injection 5/10 IU/ml.¹⁰ These products are considered by WHO for PQ under different therapeutic categories of children pneumonia (amoxicillin),¹¹ neglected tropical diseases (azithromycin),¹² children diarrhea (zinc sulfate)¹³ and utero-tonic for prevention of postpartum hemorrhage (oxytocin).¹⁴ All products and strengths are included in the WHO model list of essential medicines and the national list of essential medicines, Nepal.¹⁵

Twelve manufacturers showed their interest for technical assistance and submitted their SMF, product dossier, product manufacturing status, and records from previous GMP inspections as requested in the expression of interest. The manufacturers were shortlisted after evaluation of submitted documents on basis of eligibility criteria (Table 1). A detailed assessment of shortlisted manufacturers was performed.

Documents review and shortlisting

The documents submitted by the interested manufacturers were assessed under ten different categories marked as 0–4 scale: 0- nonexistence, 1- some elements available, 2- partly compliant, 3-compliant with some gaps, 4- fully compliant (Table 1).

Table 1.

shortlisting criteria.

S/N	Criteria	Score
1	Currently manufactures or has a potential to manufacture product of interest
2	Marketing authorization is available or justified if not available
3	Manufacturing license /GMP certificate is available
4	Quality management system exist and functional
5	Batch manufacturing instruction and batch release procedures are established
6	Validation master plan and readiness to execute validation
7	Up to date site master file and the intended product of interest
8	GMP inspection history and status (WHO PQ, EMEA, USFDA, PIC/S etc.)
9	Product dossier submitted to regulatory agency
10	Product dossier available but not submitted to regulatory agency
	Total score
	% out of 40

Scoring instruction: 0- nonexistence, 1- some element available, 2- Partly compliant, 3-Compliant with some gaps, 4- fully compliant.

Considering the resource constraints for the technical assistance, the top two manufacturers for each product were selected as the primary and an alternative candidate.

Onsite inspection

Two PQM+ experts with prior experience of inspection along with two DDA inspectors as observers conducted an onsite inspection of six shortlisted manufacturers for 3 days. Onsite inspection was conducted on basis of WHO main principles and other GMP guidelines considering the PQ requirements.^7,16 Standard requirements for all seventeen elements on basis of WHO main principles¹⁶ and evidence observed during inspection against each requirement formed a basis to list deficiencies.¹⁷ Procedures and practices for each element were observed and verified during the assessment. Observations related to management system, organogram, site master file, quality manual, product quality review, corrective and preventive action, deviation management, and change control were grouped under pharmaceutical quality system.¹⁷ Other areas included GMP for pharmaceutical products, sanitation and hygiene, qualification and validation, complaints, product recall, contract production, analysis and other activities, self-inspection and quality audit, personnel, training, personal hygiene, premises, equipment, materials, documentation, good practices in production, and good practices in quality control. Observations related to personnel, training, and personal hygiene; qualification and validation, and equipment; premises, sanitation, and hygiene; and product complaints, and recall were clubbed together. Thus, total areas of observations were divided under eleven categories.

For each elements observation were classified as critical, major, or minor depending upon the level of potential risk to patient health as a consequence of consuming the product manufactured with the non-conformity.¹⁷

A detailed assessment report following onsite assessment was prepared and shared with the manufacturer. Each manufacturer was requested to prepare a corrective and preventative action plan to close the gaps. PQM+ program would provide technical assistance for overcoming the challenges to fulfil the gaps identified.

To maintain the confidentiality of data, the shortlisted manufacturers were redacted as Company A, B, C, D, E and F.

Results

Initial assessment and shortlisting

A total of twelve manufacturers applied for the technical assistance to PQ of selected products. Highest interest was received for manufacturing azithromycin tablets with eleven applications. Applications received for other products were six, four and two respectively for zinc sulfate tablet, amoxicillin tablet and oxytocin injection. Based on the documents submitted and evaluation criteria (Table 1), six manufacturers for different product category were sorted. Except for oxytocin injection, two manufacturers were shortlisted for each product (Table 2). All shortlisted manufacturers were producing and marketing the product of interest. The manufacturer shortlisted for oxytocin was producing the strength of 5 IU/ml instead of 10 IU/ml as considered by WHO for PQ. The manufacturer was shortlisted based on its capacity to manufacture the required strength.

Table 2.

Initial screening of manufacturers.

Product	Applicant	Shortlisted manufacturer
Amoxicillin tablets	1. National Healthcare Pvt. Ltd.2. Nepal Aushadhi Limited3. SR Drugs Laboratories Pvt. Ltd.4. Chemidrug Industries Pvt. Ltd.	1. National Healthcare Pvt. Ltd.2. Chemidrug Industries Pvt. Ltd.
Azithromycin tablets	1. National Healthcare Pvt. Ltd.2. Nepal Aushadhi Limited3. Deurali-Janta Pharmaceuticals Pvt. Ltd.4. SR Drugs Laboratories Pvt. Ltd.5. Magnus Pharma Pvt. Ltd.6. Ohm Pharmaceuticals Laboratories Pvt. Ltd.7. Omnica Laboratories Pvt. Ltd.8. Quest Pharmaceuticals Pvt. Ltd.9. Panas Pharmaceuticals Pvt. Ltd.10. Universal Pharmaceuticals Pvt. Ltd.11. Chemidrug Industries Pvt. Ltd.	1. Quest Pharmaceuticals Pvt. Ltd.2. Magnus Pharma Pvt. Ltd.
Zinc sulfate tablets	1. Nepal Aushadhi Limited2. Deurali-Janta Pharmaceuticals Pvt. Ltd.3. SR Drugs Laboratories Pvt. Ltd.4. Magnus Pharma Pvt. Ltd.5. Omnica Laboratories Pvt. Ltd.6. Universal Pharmaceuticals Pvt. Ltd.	1. Deurali-Janta Pharmaceuticals Pvt. Ltd.2. Omnica Laboratories Pvt. Ltd.
Oxytocin injection	1. National Healthcare Pvt. Ltd2. Everest Parenteral Pvt. Ltd.	1. National Healthcare Pvt. Ltd.

Onsite inspection

Detailed assessment showed a clear picture about status of Nepali manufacturers and their preparedness towards WHO PQ. Majority of elements of GMP were found practiced and implemented. Although, the manufacturers had major and other observations, none of them were classified as critical (Table 3). Out of 520 nonconformities observed with all six manufactures, 4.81% was other and rest 95.19% was major observations. Company C had 66 observations as minimum and 113 observations for company B was the highest (Table 3). Gaps with other manufacturers lied in between these extreme values.

Table 3.

Category of observations.

Manufacturer	Critical	Major	Other	Total
Company A	0	66	4	70
Company B	0	104	9	113
Company C	0	61	5	66
Company D	0	88	3	91
Company E	0	99	2	101
Company F	0	77	2	79
Total		495	25	520

Majority of observations were related to pharmaceutical quality system; equipment, qualification, and validation; premises including sanitation and hygiene; documentation; and good practices in quality control (Figure 1 and Table 4). Less deficiencies were observed for contract activities, self-inspection, materials, product complaint and recalls.

Table 4.

Observations after onsite inspection.

S. No.	GMP component	Company A	Company B	Company C	Company D	Company E	Company F
1	Pharmaceutical quality system	18	16	12	25	24	20
2	Personnel, training, and hygiene	7	8	2	8	6	4
3	Premises, sanitation, and hygiene	11	23	15	19	20	11
4	Equipment (including utilities), qualification and validation	12	29	17	16	18	21
5	Complaints and recall	3	9	1	4	3	2
6	Contract production, analysis and other activities	0	1	0	1	2	1
7	Self-inspection and quality audit	1	3	1	0	1	1
8	Materials	2	2	2	2	2	2
9	Documentation	8	8	4	6	7	9
10	Good practices in Production	3	3	4	6	2	1
11	Good practices in quality control	5	11	8	4	16	7
	Total	70	113	66	91	101	79

Pharmaceutical quality system

Deficiencies in pharmaceutical quality system was the most lagging component with all manufacturers. Gaps in pharamceutical quality system were related to formal management review, control of documents, organization chart, site master file, quality manual, standard operating procedure (SOP) for quality risk management and stepwise approach, product quality review, trend analysis and process capability index, root cause analysis for nonconformities and follow up for implementation of corrective and preventive actions, SOP for deviation handling, and change control.

Personnel, training, and hygiene

Gaps were identified with respect to training and job description.

Premises, sanitation, and hygiene

Premises faced issues with maintenance and availability of facilities like proper doors and air lock provision, rodent and pest control, management of used containers and scarp.

Equipment, qualification, and validation

All manufacturers had installed GMP grade equipment for manufacturing and testing of products. Good practices related to validation (process, analytical method, cleaning) including validation master plan, validation matrix, and equipment calibration were highlighted during onsite assessment. Preventive maintenance schedule of equipment and utilities was apparent.

Product complaints and recalls

SOPs to address product complaints and handle the recall of products were maintained by all manufacturers. Mock recall was not considered by any. For some manufacturers with history of recall, investigation, handling, and notification to DDA was not properly followed. A detailed investigation on product following a product recall was not conducted.

Contract production, analysis, and other activities

None of the manufacturers had considered contract manufacturing activities to other or by themselves. Some form of contract analysis with external laboratories for product registration purposes as approved by the DDA was practiced by all manufacturers. Other contracted activities like third party contract for pest control, utilities calibration and qualification were not properly maintained by some manufacturers.

Self-inspection and quality audit

All manufacturers had either a half yearly or an annual self-inspection plan as guided by the SOP. Self-inspection was performed by a committe formed by the top management with a team comprising of key personnel from all departments. Delayed or missed self-inspection due to covid pandemic was observed for all manufacturers. Except for covid conditions, self-inspection was performed routinely. However, significant variation in implementation of corrective and preventive action plan were observed.

Materials

API used by all manufacturers for all products were not WHO prequalified, not meeting the requirement of Certificate of Suitability of the European Pharmacopoeia (CEP) or stringent regulatory authority approved or not having active pharmaceutical ingredient master file (APIMF) to meet the basic requirements for PQ purpose.⁷ Similarly, excipients not meeting approved pharmacopeial grade (USP, EP, Ph. Eur., JP, BP) for PQ purpose were used by all manufacturers.⁷ Products were not pharmaceutical equivalent (shape and size variation) with the innovator products, the first step to establishing therapeutic equivalency. Use of overages of an API without proper justification was also observed.

Documentation

Standard format for a dossier in the common technical document as required for PQ application was not maintained by all manufacturers, as the format was not mandated by the DDA. Another major gap identified in documentation was related to development, training, implementation, and review of SOPs. Other observations on documentation were related to maintenance of master formula records, batch production records and logbooks.

Bioequivalent studies required for amoxicillin tablets and azithromycin tablets and palatability studies for zinc sulfate tablets to establish therapeutic efficacy with the innovator product had not been considered.^11–13 SOPs related to efficacy evaluation or palatability studies were not maintained. None of the manufacturers had considered engaging contract research organizations for bioequivalence studies.

Good practices in production

Sanitation of production premises was a major gap in implementing good practices that might be a cause of contamination and cross-contamination. Metal detection in tablets was not practiced by all manufacturers on routine basis.

Good practices in quality control

Use of non-traceable and uncontrolled analytical work sheets, non-paginated and unapproved logbooks, and inappropriate microbial limit test and growth promotion test of culture media were common gaps with all manufacturers. SOPs to investigate out-of-specification results were apparent.

Discussion

The study through detailed assessment of shortlisted manufacturers revealed various gaps to meet PQ requirements for the selected products. Strengthening the GMP compliance for pharmaceutical quality system, documentations, equipment qualification, process and cleaning validation, sanitation and hygiene of premises are minimum requirements to move ahead with PQ. This involves streamlining of documents in common technical document format, implementation of deviation handling, change control, sanitation and hygiene of premises, and maintenance of equipment and utilities. Use of proper grade of API and excipients, product development and bioequivalence studies with innovator sample for amoxicillin and azithromycin tablet; and palatability study for zinc sulfate tablets are product related gaps that needs to be fulfilled. Development of oxytocin injection with appropriate strength i.e., 10 IU/ml must be fulfilled. Similarly, personnel development through predefined continuous training program is also required.

Overcoming these challenges requires huge capital investment to improve facilities and qualified and trained professionals to perform PQ related upgrades. Considering the LMIC status and resource limitations of Nepali manufacturers, government support, financial and technical assistance from external partners are required to ensure the quality, safety, and efficacy of generic medicines meeting international standards like WHO PQ. Lessons learned from the journey of Nigeria and Pakistan, LMICs from Africa and Asia, respectively in attaining WHO PQ with PQM and PQM+ technical assistance¹⁸; Nepali manufacturers require continuous support to attain PQ of medicines.

WHO PQ by Nepali pharmaceutical manufacturers will establish their capability to produce generic medicines that consistently meet stringent standards of quality, safety, and efficacy in line with WHO specifications and global standards that increases the trust in healthcare system. Availability of PQ medicines by domestic manufacturer provides an opportunity for international procurement and distribution not only in Nepal but also to international arena.

Conclusion

Fulfilling the gaps through a corrective and preventive action plan generated after the inspection will help the manufacturers meet WHO PQ requirements. All nonconformities should be closed before applying to WHO for PQ. Commitment and demonstration from the manufacturers to close the gaps strengthen the overall pharmaceutical quality system that will improve the quality of all products manufactured, not confined to the PQ of a single product. Strengthening of the overall system thereby produces quality medicines which ensures healthy life and promotes well-being to the public.

Footnotes

ORCID iD

Achyut Bikram Thapa

Funding

This work was made possible by the generous support of the American people through the U.S. Agency for International Development (USAID) through the Promoting the Quality of Medicines Plus (PQM+) Program via Cooperative Agreement number 7200AA19CA00025 implemented by the United States Pharmacopeia (USP). The views and opinions expressed in this paper are those of the authors and not represent the views and opinions of USAID or the U.S. government or the USP.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author biographies

Achyut Bikram Thapa, PhD scholar, Kathamndu University, Senior Technical Advisor, United States Pharmacopeia, PQM+ Program, Kathmandu, Nepal.

Professor Rajani Shakya, PhD, Department of Pharmacy, Kathmandu University, Dhulikhel, Nepal.

Robhash Kusam Subedi, PhD, Technical Director, Meera Biotech Private Limited, Bhaktapur, Nepal.

Professor Panna Thapa, PhD, Department of Pharmacy, Kathmandu University, Dhulikhel, Nepal.

References

WHO prequalification of medical products, general information - WHO list of prequalified medicinal products. World Health Organization. https://extranet.who.int/prequal/medicines/general-information-who-list-prequalified-medicinal-products (accessed 15 November 2023).

WHO prequalification of medical products, medicines, overview – history and mission. World Health Organization. https://extranet.who.int/prequal/medicines/overview-history-mission (accessed 15 November 2023).

https://sdgs.un.org/goals/goal3 (accessed 15 November 2023).

WHO substandard and falsified products. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/substandard-and-falsified-medical-products (2018, accessed 12 January 2024).

A study on the public health and socioeconomic impact of substandard and falsified medical products. World Health Organization, 2017.

WHO prequalification of medical products, medicines, prequalified lists. World Health Organization. https://extranet.who.int/prequal/medicines/prequalified-lists (accessed 25 November 2023).

Procedure for prequalification of pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-fifth Report. Annex 10. World Health Organization WHO Technical Report Series, No. 961, 2011.

Edwin Toledo, USP DQI good manufacturing practices assessment for manufacturers of zinc sulfate tablets and chlorhexidine, 2009.

https://www.usp-pqmplus.org/where-we-work/nepal (accessed 25 November 2023).

10.

Invitation to manufacturers in Nepal to submit an expression of interest for technical assistance, Kantipur national daily, 2021.

11.

1st invitation to manufacturers of medicinal products for treatment of infections in newborn and young infants and childhood pneumonia, to submit an expression of interest (EOI) for product evaluation to the WHO prequalification unit. World Health Organization, 2020.

12.

7th invitation to manufacturers of medicinal products for treatment of neglected tropical diseases, to submit an expression of interest (EOI) for product evaluation to the WHO prequalification unit. World Health Organization, 2020.

13.

1st invitation to manufacturers of zinc products to submit an expression of interest (EOI) for product evaluation to the WHO prequalification team: medicines. World Health Organization, 2016.

14.

9th invitation to manufacturers of reproductive health products to submit an expression of interest (EOI) for product evaluation to the WHO prequalification team: medicines. World Health Organization, 2019.

15.

National list of essential medicines Nepal (sixth revision), department of drug administration, ministry of health and population, government of Nepal, 2020.

16.

WHO good manufacturing practices for pharmaceutical products: main principles. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: Forty-eighth Report. World Health Organization; 2014 Annex 2 WHO Technical Report Series, No. 986. https://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/TRS986annex2.pdf?ua=1

17.

Guidance on good manufacturing practices: inspection report. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fiftieth Report. World Health Organization, 2016 Annex 4 (Appendix 1) (WHO Technical Report Series, No. 996).

18.

https://www.usp.org/news/nigeria-pharmaceutical-company-first-to-receive-who-prequalification-in-west-africa (accessed 22 February 2024).