7.4.1 Planning and implementation of plan
The survey showed that all the countries have planned GMP inspections. These plans are generally based on regulatory requirements relating to frequency of inspection. For instance, in the Netherlands, manufacturing plants are inspected at least once every two years. For Venezuela, the plan is activity-based: it is set in terms of the number of inspections to be conducted per month. But most drug regulatory authorities determine statutory frequencies for GMP inspection by considering the number of manufacturing plants.
The TGA uses a more refined system for setting inspection frequency, based on product type and on manufacturer type. The risk-management approach applied to licensing is also applied to GMP inspection. Products are classified according to their relative “risk”, i.e. as high-risk, medium-risk or low-risk. Similarly, manufacturers are classified by their GMP compliance, i.e. acceptable, marginal or unacceptable GMP. The frequency of GMP inspection then depends on which category a particular product or manufacturer belongs to. Frequent inspections are made of plants producing high-risk products, and of manufacturers with marginal or unacceptable GMP compliance. Figure 7.4 shows GMP compliance status in Australia from 1994 to 1998. [The number of manufacturers with unacceptable GMP dropped to almost zero (0.9%) in 1997/98.]
Figure 7.4 Status of GMP compliance in Australia, 1994-98
In Malaysia, inspections are scheduled by the category of product - i.e. whether the product is low-risk, medium-risk or high-risk - and the manufacturer’s GMP compliance status (categorized as good, marginal or low). Schedules for routine inspections are prepared yearly and monitored six-monthly under the Quality Assurance Programme. Malaysia also has a strategy for improving GMP compliance, particularly aimed at those applicants who wish to set up new premises or renovate existing facilities. The DRA has established a one-stop information centre for customer-friendly services. In addition, dialogue sessions are held with the various manufacturers and associations.
Information on implementation of GMP inspection plans is available in only some of the countries. Where data exist, they indicate that plans were successfully followed or even exceeded their targets. This applies to Cuba, Malaysia, the Netherlands, Uganda, Venezuela and Zimbabwe. For Cyprus, however, inspections of domestic plants fell short of the planned values. Cyprus has 10 domestic manufacturers, and nine inspections were planned, but in 1997 only seven were carried out. The Netherlands has 86 manufacturers and 28 inspections were planned in 1998; all of them were carried out. Venezuela has 41 manufacturers and 23 inspections were planned in 1997, of which 35 were carried out. So a low implementation rate does not necessarily indicate a low inspection rate. Enforcement measures are available in case of non-compliance in Cyprus, Estonia, Malaysia, Tunisia, Uganda, Venezuela and Zimbabwe. In Cuba, no enforcement measures are specified for failure to comply with GMP standards. Comparatively speaking, there is less likely to be a workplan for inspection of distribution channels than there is for GMP inspection. Only four countries - Cyprus, Estonia, Uganda and Venezuela - carry out inspection of distribution channels based on such a plan.
The range of enforcement measures following violation of distribution-channel regulations includes: warnings; fines; suspension of licence; closure; and imprisonment. Cypriot inspectors, however, do not have as many options as their counterparts in other countries: they can either issue a warning, or refer violations to the courts (through the police) or to the Pharmacy Board, depending on the seriousness of the offence.
Strategies used by the DRA of Malaysia to improve GMP compliance
• one-stop information centre for customer-friendly services
• technical guidance
• dialogue sessions and regular training for industry personnel
• Technical Working Group on GMP, including NPCB and industry representatives
• recommendation of sources of financial support for manufacturers seeking to improve their GMP status
• encouragement of foreign partnerships for transfer of technology and "smart" alliance
7.4.2 Compliance and law enforcement
Figures 7.5a and 7.5b below provide information on the number of manufacturing plants and distribution outlets monitored, violations found and sanctions imposed. The data indicate the scope of monitoring, the seriousness of violations and the severity of the sanctions imposed.
Figure 7.5a indicates the total number of licensed manufacturing plants, GMP inspection coverage, number of violations detected and number of sanctions imposed. The ratio between the number of manufacturing plants inspected in a given year and the total number of manufacturing plants for these countries indicates a range of approximately 22% of manufacturing plants inspected in Zimbabwe (the lowest) to 100% in Australia and Cuba (the highest). The percentage of violations in the manufacturing plants inspected varied widely, from around 1% in Australia to 60% in Uganda and 83% in Estonia. Although GMP standards and criteria for determining the degree of compliance differ from country to country, these figures reflect the serious problems of GMP implementation in countries such as Estonia, Uganda and Venezuela and the effectiveness of GMP inspection in Australia. As indicated earlier, data on the coverage of distribution-channel inspections, the number of violations detected and sanctions imposed were not readily available for every country. Figure 7.5b gives only a partial picture of the situation. In 1997, for instance, Estonia’s coverage for distribution-channel inspection was relatively high (63% of total licensed channels). Venezuela, on the other hand, inspected only around 14% of its distribution channels. In terms of violations, data from a number of countries show higher figures for sanctions than for violations. This may be due to the fact that one violation leads to more than one sanction. For example, a warning letter may be issued immediately after a violation has been detected, to be followed by other sanctions such as seizure of products or a fine. In addition, since these are cross-sectional figures, they may include carry-over cases from the previous year.
Figure 7.5a GMP inspections, violations and sanctions, 1997
Figure 7.5b Inspection of distribution channels in four countries: coverage, violations and sanctions, 1997*
* Violation data only for importers/wholesalers (data for the other countries not available).
The types of violation found by inspecting distribution channels, and the types of enforcement measure used by countries are summarized in Table 7.2.
Table 7.2 Types of violation and enforcement measures
Types of violation
Types of enforcement measure
• Unlicensed pharmaceutical premises
• Premises operated without professionals
• Unrenewed/expired licence
• Counterfeit products
• Illegally imported products
• Expired products being sold
• Unregistered products on the market
• Products stored under improper conditions
• Sale of those products not authorized in that establishment
• No record-keeping/book-keeping
• Dispensing prescription products without prescription
• Warning letters
• Seizure of products
• Product confiscation
• Product destruction
• Public admonition
• Temporary/permanent closure
• Suspension of licence
• Revocation of licence
7.4.3 Audit system
Only four of the 10 countries-Australia, Estonia, Malaysia and the Netherlands -operate an audit system to evaluate the GMP performance of inspectors or the inspectorate. Auditing of distribution-channel inspection is carried out by Malaysia, the Netherlands, Uganda and Venezuela. In Australia, GMP audit is both internal and external, and involves an extensive review of process and technical approach. Further training, advice, revision of job description, legal proceedings and dismissal of inspectors are some of the means used to correct any weaknesses observed.