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The State of Medicine Quality in the Mekong Sub-Region

 | 
Sauwakon Ratanawijitrasin
, 
Souly Phanouvong

2 - The Mekong Subregion Medicine Quality Study

Texte intégral

  • 4 Testing for quality in this documents means testing key quality attributes of medicine samples inc (...)

1The five-country Mekong Subregion study is a research project comprising multiple components and stages, including a series of medicine quality monitoring surveys, laboratory testing, database development, and multi-country comparative analysis. The surveys were conducted in the greater Mekong Subregion by the United States Pharmacopeial Convention – Promoting the Quality of Medicines programme (USP-PQM, formerly USP DQI – Drug Quality and Information) in collaboration with drug regulatory agencies in five countries in the region – namely Cambodia, China (Yunnan Province), Lao PDR, Thailand, and Vietnam. Note that this study did not include medicine samples from Myanmar. Samples of pharmaceutical products were collected from various distribution channels and tested for their quality4. The test results of the samples collected between 2002 and 2008 were then compiled in a database developed in collaboration with the Pharmaceutical System Research and Development Foundation (PhaReD, formerly PSyRIC – Pharmaceutical System Research and Intelligence Center).

2The development of this international medicine quality database and the analysis of the data illustrate an approach for more effective management and utilization of information gained from medicine quality monitoring surveys and quality tests. The following sections describe the survey and analysis methods, as well as database contents, and analyze the test results reflecting the state of the quality of medicines in the region.

2.1 - Methodologies

3Three different designs were employed at the different stages of this study: first, the survey methodology for pharmaceutical product samples collection, which determines which medicines to collect, where from, how to collect, and how many; second, the methods for testing the medicine samples collected, which consist of three test levels – basic screening or field test, national quality control laboratory testing, and confirmatory testing (the requirements and methods of these tests follow the appropriate test procedures and specifications in, where appropriate, the relevant pharmacopoeias), and third, the methodology for data analysis, which applies descriptive statistics to examine results obtained from the tests described above.

4A set of criteria was jointly established by the national health programmes and DQI (PQM) with inputs from other partners, including WHO, to select the anti-infective medicines to be collected. These criteria included:

  1. products used in the national health programme,
  2. products that have testing specifications, and
  3. products with some historical information suggesting their quality problems.

5The main focus was on anti-malarial, anti-tuberculosis and anti-retro viral medicines. The most commonly used antibiotics were also collected. Almost all the medicines collected in this project were those for infectious diseases. These include antibiotics, anti-malarial, anti-tuberculosis (anti-TB), and anti-retroviral (ARV) medicines. Table 1 lists the types of products contained in this database, collected and tested for quality, using generic names. While anti-malarial medicines were collected from all the countries, other medicines were selectively targeted. The range of anti-malarial medicines was perhaps the most comprehensive compared to other product groups. Twelve antibiotics were targeted. These include amoxicillin, ampicillin, benzylpenicillin, phenoxymeth, cefalexin, chloramphenicol, ciprofloxacin, cloxacillin, co-trimoxazole, erythromycin, metronidazole, and tetracycline. Not all the participating countries collected all these medicines.

6The samples mostly came from the border provinces of the surveyed countries, from various types of distribution channels, including hospitals, clinics, health centres, malaria clinics, pharmacies, retail drug outlets, street vendors, distributors, and warehouses. Cambodia, which had the largest number of samples collected in this study, conducted the monitoring in seven border provinces, six of which border Thailand and one with Vietnam. For China, the study covered only two border counties, one with Myanmar and the other with Lao PDR in Yunnan Province. Six provinces in Lao PDR – bordering Cambodia, Thailand and China – were monitored. In Thailand, samples were collected from nine provinces. Among these, five provinces are located near the border with Myanmar to the west – ranging from the northern hilly region to the southern seaboard, one province at the border with Lao PDR, and the rest near the Thai-Cambodian border. Of the eight provinces and one city in Vietnam where samples were collected, seven are border provinces adjacent to Cambodia, Lao PDR, and/or China. Names and locations of the provinces from which samples were collected for testing are displayed in Figure 5.

Figure 5: Map of countries of the Mekong Subregion with dots illustrating the locations of pharmaceutical sample collection sites

Figure 5: Map of countries of the Mekong Subregion with dots illustrating the locations of pharmaceutical sample collection sites

7In each country, samples were collected using two techniques: formal inspection and ‘mystery shopping’. The former was carried out by sampling team(s) that consisted of representatives from a medicines regulatory agency, national QC lab, disease programme, and local health agencies; while the latter was performed by ‘disguised’ consumers and/or by the provincial or district health authority personnel who were not known by the sellers in the sampling area. Each country collected two rounds of samples per year.

8A sample consisted of a minimum of 20 units for tablet or capsule dosage forms of single API preparations; 30 units for two or more APIs formulations; and 10 units for injectables. If fewer units were found (i.e. in informal sector), samples with less than 20 units were also collected. Every effort was taken by the sample collectors to record necessary information about the samples in the standardized sampling form. Special precautions were taken to ensure sample integrity and quality and to protect them from physical damage during the sampling, transportation, and testing phases. Samples were kept and stored according to the manufacturer’s recommended storage conditions. The source of a sample should be traceable, i. e., samples that had the ‘identifiable’ name of the drug product and its API (s) and the manufacturer’s address on the label. Where possible, samples should have been in their original container or package.

Figure 6: Methodological framework on medicines quality monitoring applied in the GMS by the United States Pharmacopeia Promoting the Quality of Medicines Program

Figure 6: Methodological framework on medicines quality monitoring applied in the GMS by the United States Pharmacopeia Promoting the Quality of Medicines Program

Source: United States Pharmacopeia Drug Quality and Information Program.
Ensuring the Quality of Medicines in Resource-Limited Countries: An Operational Guide. Rockville, Md.: The United States Pharmacopeial Convention. Available online: www.usp.org/worldwide/dqi/resources/technicalReports

Figure 7: Three levels of testing for checking the quality of the samples

Figure 7: Three levels of testing for checking the quality of the samples

9As described earlier, three levels of testing were designed for checking the quality of the samples collected: field, QC lab and confirmatory. For the field level testing, samples collected from the various distribution channels were first subjected to field testing using the Global Pharma-Health Fund (GPHF) Minilab® kit that can be carried out with a simple setup and without a laboratory.

  • 5 The GPHF-Minilab® - Protection Against Counterfeit Medicines. Accessed Nov 20, 2011. http://www.gp (...)

10The kit provides all necessary basic screening test tools and supplies which can help early detection of substandard and counterfeit drugs for some 50 essential medicines. The test procedures and techniques consist of a physical/visual inspection, a simple disintegration, and a thin-layer chromatography (TLC). A person with general scientific knowledge in analytical chemistry and pharmaceutical sciences who participated in a week-long proper training programme would be able to conduct such a test5.

11Physical/visual inspection of pharmaceutical products is the first step in any quality control activities, as it helps ensure the authenticity of the package. Visually inspecting the integrity of the packaging, the appearance of tablets, or other dosing forms may help to identify potentially poor quality products. An examination of remaining shelf-life and compliance with approved labelling, packaging, and shipping instructions is also important. The physical appearance of a medicine dosage form – shape, size, colour – can provide an important clue in identifying suspicious and potentially counterfeit medicines. Visual inspection may also indicate substandard manufacturing, such as crumbling, chips, or cracks in solid dosage forms.

Figure 8: Basic tests used in the medicines quality monitoring programme in the Mekong Subregion

Figure 8: Basic tests used in the medicines quality monitoring programme in the Mekong Subregion

Source: GPHF Minilab ® Manual, 2008 update

12Simple disintegration is a test to determine whether a pharmaceutical solid dosage form (tablet or capsule) will disintegrate within the specified time when placed in a liquid medium at a temperature between 35° and 39° C. All immediate release tablets or capsules should disintegrate within 30 minutes. In the field, where the Minilab kit is used, disintegration can be performed using tap or distilled water in a 100–150 ml. wide-neck bottle.

13Thin-layer chromatography (TLC) test technique in the GPHF-Minilab® kit comes with ready-to-use TLC plates with essential labware and chemicals, as well as authentic tablets and capsules for reference purposes. TLC is a simple and effective test for identification and semi-quantification of the API(s) contained in the formulations. The GPHF-Minilab® has been developed for rapid quality verification for counterfeit medicines.

14A pre-determined subset of samples were then analysed using the so-called ‘level two or QC lab test’ at the respective national quality control laboratories whose analysts were trained by the USP PQM experts. Samples from Lao PDR were tested at the Food and Drug Quality Control Center; those from Vietnam were tested at the National Institute of Drug Quality Control (NIDQC); those from Thailand were analysed at the laboratory of the Bureau of Drug and Narcotic; and those from Cambodia were tested at the National Quality Control Laboratory of Drug and Food (now know as National Health Product Control Laboratory). Due to logistical and technical reasons, samples from Yunnan were tested at the NIDQC.

Figure 9: Officers conduct a simple disintegration test of oseltamivir tablets in Cambodia

Figure 9: Officers conduct a simple disintegration test of oseltamivir tablets in Cambodia

Photo: S. Phanouvong

15The QC lab tests were used to determine whether the samples’ quality conformed to pharmacopoeial specifications for appearance, identification of API(s), assay for content of API (s), and, in certain cases, dissolution property. High-performance liquid chromatographic (HPLC) and ultraviolet (UV) spectrophotometric methods were used for most identification and assay tests at the QC lab level. Dissolution serves as a quality control test by providing evidence of the product’s physical consistency and manufacturing process. It is a critical regulatory and compendial requirement in the testing of solid dosage forms and quantitatively determines the in-vitro biological availability. If a product fails the dissolution property test, it is most likely that the product will not be absorbed by the body, thus it will not produce any therapeutic effect. The following pharmacopoeial methods and procedures were used in this project, namely: the International Pharmacopoeia, the United States Pharmacopeia, the Chinese Pharmacopoeia, and the Vietnamese Pharmacopoeia, of their latest edition. Confirmatory tests were conducted on some samples at reference laboratories with ISO-IEC 17025 accreditation. These included the USP Research and Development Laboratory in Rockville, Maryland, USA; the NIDQC in Vietnam. These laboratories used pharmacopoeial specifications to test the samples.

Figure 10: Training on basic testing for field monitoring of anti-infective medicines in Thailand, 2009

Figure 10: Training on basic testing for field monitoring of anti-infective medicines in Thailand, 2009

Photo: BND staff

Figure 11: Training on quality control technique and procedures to detect counterfeit and substandard medicines to central and field laboratory staff in Vietnam

Figure 11: Training on quality control technique and procedures to detect counterfeit and substandard medicines to central and field laboratory staff in Vietnam

Photo: S. Phanouvong

Table 1: Types of medicine samples in USP-PhaReD database

Table 1: Types of medicine samples in USP-PhaReD database

2.2 - Medicine Quality Database and Analysis of Test Results

16The USP-PhaReD Medicine Quality Database, which is the first international database on medicine quality, is a web-based searchable database of drug quality test results. The database was developed between 2007 and 2009. It contains information on the results of quality testing on more than 3,000 drug samples collected between 2002 and 2008 from the five countries.

17Altogether, 3,669 samples of pharmaceutical products, covering 2,728 production batches, were collected from multiple survey rounds conducted over seven years. The numbers of samples collected from each of the five countries in different years are listed in Table 2.

Table 2: Number of Samples Collected by Country by Year

Table 2: Number of Samples Collected by Country by Year

18This data set is of great value for revealing the state of medicine quality in the Mekong Subregion due to a number of attributes, as described below:

19Firstly, large numbers of samples in wide ranges of categories were included. A total of 31 types of medicines (by International Nonproprietary Names) in 3,669 samples covering 2,728 production batches were monitored. The samples were in various dosage forms – the majority of which were tablets with a small number of capsules, injections, and syrups. Secondly, the large geographical distribution covered multiple countries with border area locales – 33 provinces/counties in five countries. Thirdly, it was a multi-year study with a follow-up of one to seven years. And fourthly, all participating countries employed the same basic methods in sample collection and testing.

20Even with these strengths, there are certain aspects that do not allow for generalization, and render some cross-country data within this set not entirely comparable, thus limiting the range of possible analyses. Since the pharmaceutical samples were collected on a non-random basis due to availability and feasibility, the surveys were not based on random sampling design. Therefore, the data cannot be generalized as country-level data. In terms of medicine types and time, because not all five countries collected the same types of medicine and conducted follow-up sample collections every year during the seven years of the survey period, analyses to compare the whole range of results could not be made. In addition, the legal definition of counterfeit pharmaceuticals and the methods to identify them in the survey vary from country to country (Annex I). As a consequence, some analyses may have to rely on data from fewer than five countries.

21Descriptive statistics are used to examine the patterns of quality testing results. The following aspects of medicine quality are examined in the analysis, with a focus on substandard and counterfeit products, both at the regional and country levels, where existing data are amenable:

  1. overall picture,
  2. medicine quality trends by country,
  3. quality of medicines by group,
  4. counterfeit medicines,
  5. quality by distribution channels,
  6. risks to consumers.

Notes

4 Testing for quality in this documents means testing key quality attributes of medicine samples including the appearance (visual/physical examination of the packaging and labelling), identification of the active pharmaceutical ingredient(s) (API), assay of content of the API(s), disintegration and dissolution for certain samples in solid dosage forms.

5 The GPHF-Minilab® - Protection Against Counterfeit Medicines. Accessed Nov 20, 2011. http://www.gphf.org/web/en/minilab/index.htm

Table des illustrations

Titre Figure 5: Map of countries of the Mekong Subregion with dots illustrating the locations of pharmaceutical sample collection sites
URL http://books.openedition.org/irasec/docannexe/image/1207/img-1.jpg
Fichier image/jpeg, 302k
Titre Figure 6: Methodological framework on medicines quality monitoring applied in the GMS by the United States Pharmacopeia Promoting the Quality of Medicines Program
Légende Source: United States Pharmacopeia Drug Quality and Information Program. Ensuring the Quality of Medicines in Resource-Limited Countries: An Operational Guide. Rockville, Md.: The United States Pharmacopeial Convention. Available online: www.usp.org/worldwide/dqi/resources/technicalReports
URL http://books.openedition.org/irasec/docannexe/image/1207/img-2.jpg
Fichier image/jpeg, 86k
Titre Figure 7: Three levels of testing for checking the quality of the samples
URL http://books.openedition.org/irasec/docannexe/image/1207/img-3.jpg
Fichier image/jpeg, 81k
Titre Figure 8: Basic tests used in the medicines quality monitoring programme in the Mekong Subregion
Légende Source: GPHF Minilab ® Manual, 2008 update
URL http://books.openedition.org/irasec/docannexe/image/1207/img-4.jpg
Fichier image/jpeg, 80k
Titre Figure 9: Officers conduct a simple disintegration test of oseltamivir tablets in Cambodia
Légende Photo: S. Phanouvong
URL http://books.openedition.org/irasec/docannexe/image/1207/img-5.jpg
Fichier image/jpeg, 94k
Titre Figure 10: Training on basic testing for field monitoring of anti-infective medicines in Thailand, 2009
Légende Photo: BND staff
URL http://books.openedition.org/irasec/docannexe/image/1207/img-6.jpg
Fichier image/jpeg, 83k
Titre Figure 11: Training on quality control technique and procedures to detect counterfeit and substandard medicines to central and field laboratory staff in Vietnam
Légende Photo: S. Phanouvong
URL http://books.openedition.org/irasec/docannexe/image/1207/img-7.jpg
Fichier image/jpeg, 64k
Titre Table 1: Types of medicine samples in USP-PhaReD database
URL http://books.openedition.org/irasec/docannexe/image/1207/img-8.jpg
Fichier image/jpeg, 279k
Titre Table 2: Number of Samples Collected by Country by Year
URL http://books.openedition.org/irasec/docannexe/image/1207/img-9.jpg
Fichier image/jpeg, 109k

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