Good Manufacturing Practice Inspection Research Articles

Analysis of non-compliances identified in GMP inspections between 2013 and 2022

Ensuring the quality and safety of medicinal products is of paramount importance to the pharmaceutical industry. Good manufacturing practice (GMP) regulations are part of a pharmaceutical manufacturer’s quality management system and ensure that medicinal products are manufactured, imported and controlled consistently to quality standards appropriate to their intended use. The aim of the present study is to analyze the non-compliant operations identified during GMP inspections carried out by national competent authorities (NCA) in the EU/EEC between 2013 and 2022. A retrospective analysis of non-compliance reports published in the EudraGMDP database between 2013 and 2022 was performed. Overall, 99 reports by 21 national competent authorities were analyzed presenting the results of inspections in 19 countries. A total of 1458 deficiencies were identified, of which 544 (37%) were classified as major and 127 (9%) as critical. The most common non-compliant operations were the manufacturing of active substances (49 deficiencies) and the preparation of non-sterile products (47 deficiencies). In 41 cases, the NCA recommended suspension or voiding of the certificate of suitability (CEP) and in 36 cases revocation of the GMP certificates. The observed deficiencies highlight the importance and need for continuous monitoring and improvement of manufacturers’ production processes and quality management systems.

Good manufacturing practice in low‐ and middle‐income countries: Challenges and solutions for compliance

AbstractApproximately 2 billion people globally have limited access to essential medicines, particularly those living in low‐ and middle‐income countries (LMICs). In addition, there is a higher prevalence of substandard and counterfeit medicines in LMICs, which may cause antimicrobial resistance and therapeutic failure. Good manufacturing practice (GMP) is key to ensuring access to high‐quality, safe and effective medicines, including active pharmaceutical ingredients and excipients used for manufacturing finished dosage forms. Compliance with GMP standards saves resources for both manufacturers (e.g. avoiding expensive product recalls) and governments (e.g. minimising compliance inspections). Concerted collaborations among different countries to harmonise GMP standards and procedures have occurred, and the World Health Organisation (WHO) GMP is commonly used in LMICs. However, barriers to GMP compliance remain apparent, particularly in LMICs. Pharmaceutical manufacturers in LMICs face several barriers such as inadequate resources and infrastructure, inefficient or weak regulation, a shortage of skilled people and limited training opportunities for manufacturing personnel. Although national regulatory authorities (NRAs) have been established in LMICs, most NRAs are not fully independent and are placed within the health department. NRAs in LMICs are not able to fully utilise international and regional reliance mechanisms and collaborations. Therefore, both NRAs and pharmaceutical manufacturers must be adequately supported through resources, infrastructure and capacity‐building opportunities. NRAs must be suitably empowered with assured functional independence. A comprehensive guideline for managing conflicts of interest among pharmaceutical manufacturers, procurement agencies and NRAs is needed. NRAs must liaise with other NRAs, participate in joint GMP inspections and leverage the expertise of regional or international collaborations. Pharmaceutical manufacturers in LMICs can leverage WHO GMP standards to improve GMP compliance and expand their market. However, as these solutions may have cost implications, prioritising key gaps for GMP compliance and optimisation of available resources are essential.

Characteristics, risk management and GMP standards of pharmaceutical companies in China.

The Good Manufacturing Practice (GMP) is one of the gold standards by which governments worldwide judge modern pharmaceutical companies' production processes and product-safety standards. However, in all the nations, it is difficult to obtain real data about GMP inspection results, so conducting the related research is impossible. Taking advantage of a rare chance to obtain the on-site GMP inspection results in China, we have been able to initiate an empirical analysis of how company characteristics and risk management affect the GMP inspection results of certain pharmaceutical companies. The 2SLS method regression was employed in this study. Our four main findings are as follows. First, compared with Chinese state-owned companies, foreign commercial and private enterprises are held to higher standards. Second, the GMP inspection results tend to be better for those enterprises whose main sources of capital are not dependent on bank loans. Third, enterprises with higher fixed assets tend to receive the better GMP inspection results. Fourth, the longer the quality authorized staff has worked in a company, the better the GMP inspection results expected of that enterprise. These findings offer insights into inspections and production improvements in China and other GMP-compliant countries.

Harmonization of medical products regulation: a key factor for improving regulatory capacity in the East African Community

BackgroundLimited capacity to regulate medical products is associated with circulation of products which do not meet standards of quality, safety and efficacy with negative public health and economic outcomes. This study focused on assessing the effect of the East African Community (EAC) medicines regulatory harmonization initiative on the capacity of national medicines regulatory agencies, with a focus on registration and inspection systems.MethodsAn exploratory mixed-method design using both qualitative and quantitative data to access data from six national medicines regulatory authorities (NMRAs) and the EAC Secretariat. Data was collected using a combination of semi-structured interviews, questionnaires, and checklists for the period 2010/11–2015/16 with 2010/11 data serving as baseline. Heads of NMRAs, regulatory and monitoring and evaluation experts, and the EAC Secretariat Project Officer were enrolled in the study. A set of 14 indicators grouped into 6 categories were used to assess NMRAs performance.ResultsPolicy and legal frameworks provide a foundation for effective regulation. Collaboration, harmonization, joint dossier reviews and inspections of manufacturing sites, reliance and cooperation are key factors for building trust and capacity among NMRAs. Five out of six of the EAC Partner States have comprehensive medicines laws with autonomous NMRAs. All the NMRAs have functional registration and good manufacturing practice inspection systems supported by regional harmonised guidelines for registration, inspection, quality management and information management systems with four NMRAs attaining ISO 9001:2015 certification.ConclusionsThe EAC regulatory harmonization initiative has contributed to improved capacity to regulate medical products. The indicators generated from this research can be replicated for evaluation of similar initiatives across and beyond the African continent and contribute to public health policy.

Assessing the Correlation Between GMP Deviations and Potential Quality Defects of Medicinal Products: the Result of the Survey of Qualified Persons

Introduction. One of the key issues in the field of assessing the conformity of drug manufacturers with the requirements of good manufacturing practice (GMP) is a systematic methodology for classifying revealed deficiencies (deviations, non-conformities) by their level of criticality. Today the information included into regulatory documents regarding the definitions of critical, major and minor (other) deficiencies is not always sufficient for the use in GMP inspection practice, as well as in quality management systems of the pharmaceutical manufacturers. In terms to study approaches to the classification of GMP deviations applied in the practice of the Qualified persons of drug manufacturers in the Russian Federation, a survey was conducted in the form of a questionnaire. This work became a logical continuation of a previous study among employees of the pharmaceutical inspectorate of the Russian Federation.Aim. To identify the correlation between the classification of critical and major GMP deviations and potential class I and II quality defects of medicinal products.Materials and methods. The study was based on a survey of Qualified persons of drug manufacturers (56 respondents) using a questionnaire specially designed. The main hypothesis of the study is that specialists (Qualified persons) who make decisions on the classification of GMP deviations are guided by potential quality defects that may be caused by the indicated deviations. In the framework of the study, authors used the model of gradation of quality defects of the medicinal products into 3 classes (class I, II and III) according to the rate of their significance as indicated in the PIC/S and EMA guidelines. At the same time, for GMP deviations a three-level gradation system is also used: Critical, Major and Minor (Other). In designing of questionnaires for the survey, the focus was made on examples of quality defects of classes I and II and, accordingly, Critical and Major GMP deviations.Results and discussion. The results of the processing and analysis of questionnaires summarize the opinion of the majority of respondents about the direct relationship between product quality defects of the high risk (class I) and critical GMP deviations. Respondents also expressed the opinion that deviations that could trigger the occurrence of the class II quality defects in most cases will be classified as critical. The results obtained during the study also indicate the similarity of existing approaches of the classification of GMP deviations (deficiencies) between QPs of the drug manufacturers and pharmaceutical inspectors.Conclusion. The results of the study show that for the purpose of classifying (determining the criticality) of GMP deviations (deficiencies) , it is possible to use the rating system for the quality defects of medicinal products by the rate of their significance for the patient which is presented in EU regulatory documents and PIC/S guidelines. The results of the study also will facilitate the drawing of conclusions that today, not only from the position of regulatory authorities, but also for the pharmaceutical industry, there is a need to develop methodological guidelines with a focus on a risk-based classification of GMP deviations (deficiencies). These guidelines should take into account the potential impact of the mentioned GMPdeviations on the occurrence of the quality defects of medicinal products and, as a result, threats to the life and health of patients.

Good Manufacturing Practice for Medicinal Products in Bulgaria: an Analysis of Regulatory Inspection Findings.

The manufacture of medicinal products for human use in the European Economic Area is governed by European Directives and Regulations stipulating the relevant principles and guidelines of Good Manufacturing Practice, describing the minimum standard to be fulfilled in the production processes. To present analysis of the deficiencies reported following Good Manufacturing Practice inspections in Bulgaria in two consecutive years (2016, 2017) and to compare them with results from similar inspections reported by other EU member states. A retrospective study was carried out by reviewing the complete Good Manufacturing Practice inspection reports of all manufacturers conducted by the Bulgarian Drug Agency in 2016 and 2017, according to relevant requirements and applicable local legislation. The items reviewed were scope of inspection, type of companies, classification of deficiencies – ‘critical’, ‘major’ and ‘other significant deficiencies’, their nature and reference to EU Good Manufacturing Practice. The analyzed data included 55 inspections, revealing 460 various deficiencies, of which 2 were critical and 102 – major. Twenty inspections were performed in 2016 vs. 35 inspections in 2017. The pattern of deficiencies was similar to the findings of other EU regulatory agencies, showing that equivalent requirements were applied. Our analysis showed that Bulgarian Drug Agency inspectors rarely raised deficiencies related to Computer Systems, Qualification/Validation, Personnel and Qualification of Suppliers unlike other EU regulators agents. Our analysis of Good Manufacturing Practice inspection findings in 2016 and 2017 showed that the Bulgarian Drug Agency demonstrated its ability to detect non-compliances and take necessary regulatory actions. Quality related issues constitute the main reasons for non-compliances with the requirements.

Perdagangan Bebas Produk Farmasi dan Alat Kesehatan serta Kesiapan Memenuhi Persyaratan Cetak Biru Masyarakat Ekonomi ASEAN

The implementation of the ASEAN Economic Community (AEC) as an Indonesian Government’s strategic step has an impact on economic globalization. The study on pharmaceutical products and medical devices free trade was done using qualitative and quantitative methods. The data were collected from a round table discussion about "Free Trade in Health Goods and Services in ASEAN" which involved the Ministry of Health (MoH), Ministry of Trade (MoT), and National Agency for Drug and Food Control (NADFC). The discussion aimed to obtain information on the readiness to meet the AEC blueprint. Secondary data on export and import of pharmaceutical products and medical devices were obtained from the MoT. The results of the study show that between 2013 and 2017 there were 70-72 product items exported to 9 ASEAN countries with a value much greater than the import. The tariff measure (TM) requirements included the Most Favored Nation (MFN) assessment and regulation of the trade remedy procedure by MoH and MoT. The implementation of ASEAN Common Technical Dossier (ACTD) and Good Manufacturing Practice inspection agreements, Bioequivalence reporting agreements, agreements related to traditional medicines and health supplement have been done by NADFC and industry. The simplification of Certificate of Origin, operation certification procedures and realization of ASEAN self-certification have to be specified. MoH must coordinate with NADFC and MoT in deciding and implementing regulations

Pharmacopeial specifications and analytical data from post-marketing quality sampling and testing programs: A perspective beyond out-of-specification results

Ensuring that marketed medicines meet acceptable standards (safety, quality, and efficacy) involves aspects of product development, compliance with good manufacturing practices, and monitoring and testing of these products already on the market. Pharmacopeias are one of the main tools used by regulatory authorities in the analytical testing for quality assessment; there are almost 60 pharmacopeias in the world. Thus, this research evaluated the potential impacts of the differences between the pharmacopeial specifications in the quality assessment of these products. It also assessed the use of analytical data to strengthen these surveillance systems. The pharmacopeial specifications for assay determination and dissolution test from United States Pharmacopeia (USP), British (BP), Brazilian (FB), Portuguese (FP), Argentine (FA), and International (Ph. Int.) Pharmacopeias were compared. The quality control reports and results of the Brazilian conformity assessment program were used to support the research. The possibility of selection of medicines or manufacturers for monitoring, sampling, and testing, as well as good manufacturing practice inspections based on analytical data were observed, even considering compliant cases or those within the tolerance limits. An important impact of acceptance criteria given in the individual monographs of different pharmacopeias regarding quality testing was also observed. Strengthening of the pharmacopeial harmonization projects and universalization of the requirements provided by the individual monographs can help in supporting the internationalization of the pharmaceutical market and improving access to medicines.

The Turkish Medicines and Medical Devices Agency: Comparison of Its Registration Process with Australia, Canada, Saudi Arabia, and Singapore

Introduction: Regulatory agency comparisons can be of more value and facilitate improvements if conducted among countries with common challenges and similar health agency characteristics. A study was conducted to compare the registration review model used by the Turkish Medicines and Medical Devices Agency (Türkiye Ilaç ve Tibbi Cihaz Kurumu; TITCK) with those of four similar-sized regulatory agencies to identify areas of strength and those requiring further improvement within the TITCK in relation to the review process as well as to assess the level of adherence to good review practices (GRevP) in order to facilitate the TITCK progress toward agency goals.Methods: A questionnaire was completed and validated by the TITCK to collect data related to agency organizational structure, regulatory review process and decision-making practices. Similar questionnaires were completed and validated by Australia's Therapeutic Goods Administration (TGA), Health Canada, Singapore's Health Science Authority (HSA), and the Saudi Arabia Food and Drug Administration (SFDA).Results: The TITCK performs a full review for all new active substance (NAS) applications. Submission of a Certificate of Pharmaceutical product (CPP) with an application is not required; however, evidence of approval in another country is required for final authorization by the TITCK. Pricing data are not required by the TITCK at the time of submission; however, pricing must be completed to enable products to be commercially available. Mean approval times at the TITCK exceeded the agency's overall target time suggesting room for improved performance, consistency, and process predictability. Measures of GRevP are in place, but the implementation by the TITCK is not currently formalized.Discussion: Comparisons made through this study enabled recommendations to the TITCK that include streamlining the good manufacturing practice (GMP) process by sharing GMP inspection outcomes and certificates issued by other authorities, thus avoiding the delays by the current process; removing the requirement for prior approval or CPP; introducing shared or joint reviews with other similar regulatory authorities; formally implementing and monitoring GRevP; defining target timing for each review milestone; redefining the pricing process; and improving transparency by developing publicly available summaries for the basis of approval.

Dietary supplements quality analysis tools from the United States Pharmacopeia.

The United States Food and Drug Administration (FDA) issued the dietary supplement (DS) current good manufacturing practice (GMP) regulations in compliance with the mandate from the Dietary Supplements Health and Education Act (DSHEA), with the intention of protecting public health by ensuring the quality of DS. The GMP regulations require manufacturers to establish their own quality specifications for identity, purity, strength, composition, and absence of contaminants. Numerous FDA‐conducted GMP inspections found that the private specifications set by these manufacturers are often insufficient to ensure adequate quality of dietary ingredients and DS. Wider use of the public standards developed by the United States Pharmacopeial Convention (USP), in conjunction with GMP compliance, can help ensure quality and consistency of DS as they do for medicines. Public health protection could be enhanced by strengthening the GMP provisions to require conformance with relevant United States Pharmacopeia–National Formulary (USP–NF) standards, or in the absence of USP standards, other public compendial standards. Another serious concern is the presence of synthetic drugs and drug analogues in products marketed as DS. Use of the new USP General Chapter Adulteration of Dietary Supplements with Drugs and Drug Analogs <2251> may reduce the exposure of consumers to dangerous drugs disguised as DS. © 2016 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.

Good Manufacturing Practice: The Role of Local Manufacturers and Competent Authorities

In every country, a manufacturer of medicinal products for either human or veterinary use is required to operate in compliance with local legislation. In all EU Member States, legislation is approximated to the effect that they are committed to abide by the same standards. The candidate countries transpose the acquis into their national legislation, including the good manufacturing practice (GMP). Consequently, the local manufacturer is required to strictly comply with GMP and the manufacturing licence, including for medicinal products exclusively intended for export. A vital role is also played by national regulatory authorities, in Croatia by the Agency for Medicinal Products and Medical Devices which issues the manufacturing licence, GMP certificate, and the Certificate of a Pharmaceutical Product (CPP) and conducts laboratory control of products. GMP inspection is carried out by the Pharmaceutical Inspectorate with the Ministry of Health and Social Welfare. Both authorities are responsible only for human medicines. There are legislative issues not yet harmonised with the acquis, but as a country aspiring for the EU membership, Croatia is expected to demonstrate that its industry and competent authorities are able to conform to current requirements and thus fully adhere to the integrated European regulatory network. Hence the importance of strengthening the institutional capacity of the competent authorities, as insufficient resources may have a direct bearing on patients by limiting their access to affordable treatment.

CHINA-ASEAN RELATIONS, APRIL 2007 TO SEPTEMBER 2007: CHRONOLOGY OF EVENTS

APRIL 2009 7th Thailand's Director General of Department of Trade Negotiations (DTN) Chutima Boonyapraphatsorn says the Ministry of Commerce will sign two acts under the ASEAN Pharmaceutical Examination Act in order to avoid repeated checking, making trade more convenient. Thailand ranked only second to Singapore in the export of pharmaceutical products. 8th 13th ASEAN Finance Ministers' Meeting convenes. Finance ministers from ASEAN agree on the allocation details of a USD120 billion regional reserves pool in which China, Japan and South Korea will make a joint pledge up to 80 per cent. They also agree to set up a regional fund to develop transport infrastructure. ASEAN will seek a contribution from the Asian Development Bank, which has an existing infrastructure development programme. fund, to be managed by a Special Purpose Vehicle, will also mobilise resources from private firms. fund supports member countries in transport infrastructure development projects, says Thai Finance Minister Korn Chatikavanich. size of the fund and lending criteria are subject to further study at the next ministerial meeting in Vietnam next year. Vietnam Government statistics reveal that Sichuan Province shipped USD330 million worth of goods to Vietnam last year, rising 60 per cent from the year before. Sichuan Province's main exports to Vietnam are apparel, steel, bags, semiconductors and electronic products. 10th ASEAN economic ministers sign The Sectoral Mutual Recognition Arrangement for Good Manufacturing Practice Inspection of Manufacturers of Medicinal Products aimed at ensuring the safety, quality, efficacy and lower prices of drugs sold in the region. 11th Anti-government protests in Thailand cause the summit between ASEAN and China to be postponed to June. protests also cause the cancellation of a meeting between the Foreign Ministers of Japan, China and South Korea. 12th Chinese Foreign Minister Yang Jiechi meets envoys from ASEAN in Beijing and unveils a multi-billion-dollar package of aid and credit to enhance China-ASEAN cooperation. Over the next three to five years, China plans to offer credit of USD15 billion to ASEAN countries including loans with preferential terms of USD1.7 billion in aid for cooperation projects. 14th A seminar for trade union leaders from China and ASEAN countries opens. Wang Zhaoguo, member of the Political Bureau of the CCP Central Committee, vice-chairman of the Standing Committee of the National People's Congress and president of the All-China Federation of Trade Unions, gives a speech. 29th Philippines Peso and New Taiwan Dollar add to ADB's USD10 billion Asian Currency Note Programme (ACNP). MAY 2009 1st ASEAN invites China, Japan and the Republic of Korea to the Health Ministers Meeting scheduled on 7 May to discuss a common regional response against the threat of Influenza A/H1N1. 3rd Finance ministers from ASEAN+3 finalise an expanded regional scheme of bilateral currency swaps known as the Chiang Mai Initiative (CMI). First established in 2000 in response to the Asian Financial Crisis of 1997-8, the CMI is aimed at enabling participating ASEAN+3 countries to draw on one another's foreign reserves in the event of external financing difficulties. 4th Economic ministers from ASEAN meet in Siem Reap to participate in the Economic Ministers' Retreat to formulate economic strategies to alleviate the worst effects of the global economic crisis in the region with a USD370 billion fund contributed by G20 Nations, China, Japan, South Korea and ASEAN. 6th 7th mid-term review of the ASEAN Regional Forum on Counter Terrorism and Transnational Crimes is launched. Representatives from 27 countries including China, Japan, India, Canada, Australia and the European Union participate in the event, which calls for closer cooperation among ASEAN nations and partners to fight against terrorists crimes. …

Quality medicines for the poor: experience of the Delhi programme on rational use of drugs

Prior to 1994, most Delhi hospitals and dispensaries experienced constant shortages of essential medicines. There was erratic prescribing of expensive branded products, frequent complaints about poor drug quality and low patient satisfaction. Delhi took the lead in developing a comprehensive Drug Policy in 1994 and was the only Indian state to have such a comprehensive policy. The policy's main objective is to improve the availability and accessibility of quality essential drugs for all those in need. The Delhi Society for the Promotion of Rational Use of Drugs (DSPRUD), a non-governmental organization, worked in close collaboration with the Delhi Government and with universities to implement various components of the policy. The first Essential Drugs List (EDL) was developed, a centralized pooled procurement system was set up and activities promoting rational use of drugs were initiated. In 1997, the Delhi Programme was designated the INDIA-WHO Essential Drugs Programme by the World Health Organization. The EDL was developed by a committee consisting of a multidisciplinary group of experts using balanced criteria of efficacy, safety, suitability and cost. The first list contained 250 drugs for hospitals and 100 drugs for dispensaries; the list is revised every 2 years. The pooled procurement system, including the rigorous selection of suppliers with a minimum annual threshold turnover and the introduction of Good Manufacturing Practice inspections, resulted in the supply of good quality drugs and in holding down the procurement costs of many drugs. Bulk purchasing of carefully selected essential drugs was estimated to save nearly 30% of the annual drugs bill for the Government of Delhi, savings which were mobilized for procuring more drugs, which in turn improved availability of drugs (more than 80%) at health facilities. Further, training programmes for prescribers led to a positive change in prescribing behaviour, with more than 80% of prescriptions being from the EDL and patients receiving 70-95% of the drugs prescribed. These changes were achieved by changing managerial systems with minimal additional expenditure. The 'Delhi Model' has clearly demonstrated that such a programme can be introduced and implemented and can lead to a better use and availability of medicines.

Good Manufacturing Practice Inspection in Europe, in Light of the New Central Agency and Current International Agreements

This paper covers good manufacturing practice (GMP) inspection in Europe. Inspections within the European Union and in other countries are discussed. Excerpts of Council Regulation No. (EEC) 2309/93 are provided. Topics covered include coordination of inspections, supervisory authority, the Pharmaceutical Inspection Convention, mutual recognition with other countries, and more.