Introduction
It has been more than one year ago that the new EU GDP Guidelines came into enforced implementation1. It is an improvement and a step forward over the previous 1994 Guidance2 as the new one better reflects the various changes in the distribution industry which occurred during the last 20 years.
In this article we will present results of the first GDP inspections at companies with a wholesale license based on the new guidelines. During the inspections in the first half of 2014 the focus was on the most important changes related to the previous Guidelines of 1994. The new GDP Guidelines had a lot of impact on the GDP level of most pharmaceutical companies, because of the increased requirements for the quality system, the Responsible Person, qualification and validation, returned goods and the maintaining of temperature during transportation of all temperature sensitive medicinal products. It was not possible to inspect all the new changes of the GDP Guidelines, so a selection of topics was made.
Inspection Practice
A conference in September 2013 was organized in the Netherlands to discuss the most important changes with wholesalers. The pharmaceutical companies were given more time to implement the relevant changes in their quality system and their daily practice. The plan for the 2014 inspections included: What items will be inspected? How far along should companies be with their implementation? Which level of implementation will be reviewed? A list of the most important changes was prepared and which GDP items should be inspected. This included which items should be fully implemented and for which items companies should have made at least a serious start with their implementation such as management review and risk-management. Finally, a risk based list was made of the companies with human medicinal products to be inspected in 2014.
Method/Inspected Companies
A list of companies to be inspected was made based on the date of the last inspection, the magnitude, complexity, and risk of their activities. A risk based system is being built in which the following risks play an important part: the kind and the amount of medicines, how many people are working at the company, cold storage activities, and complexity of the process. Different types of wholesalers were put on the list: full line wholesalers, parallel wholesalers, wholesalers with a lot of medicinal products, warehouses with storage and distribution activities for pharmaceutical companies, and logistics providers. For this article the inspections of 35 companies with a wholesale license were reviewed including the following topics:
- Chapter 1: Quality Management (management review and risk management)
- Chapter 2: Personnel (training/Responsible Person)
- Chapter 3: Premises and Equipment (temperature mapping storage)
- Chapter 5: Operations (qualification of suppliers)
- Chapter 6: Complaints, Returns, Suspected Falsified Medicinal Products and Medicinal Product Recalls
- Chapter 8: Self-Inspections (system for self-inspections)
- Chapter 9: Transportation (outsourcing transportation)
Quality System/Management Review (Chapter 1)
Wholesalers must maintain a quality system delineating responsibilities, processes and risk management principles. The system should include a review process and continued improvement. It is the responsibility of the management to organize this review at least yearly and to be involved in the process. The Responsible Person and other key individuals are also encouraged to participate. As a result of reviewing the quality issues, it will be clear which items have to be improved. Management should give their support and commitment for the implementation of the improvements. Important questions include: Is the quality system working well and what has to be improved? What has been learned from the quality documentations such as complaints, deviations (e.g. alarms, temperature excursions), results of audits and self-inspections?
The results of the inspections showed that a standard operating procedure and management review took place in 52% and 58%, respectively, of the inspections. For a lot of companies it was the first time they followed the evaluation process and conducted a management review. For some companies with an ISO certification it was already a daily practice. The findings ranged from a very good process of evaluating all the quality parameters and involvement of the key personnel, including the management to sometime just being a document of the Responsible Person, with the evaluation of some quality information and without any involvement of the management. Regulatory inspectional remarks were made for these shortcomings
Quality System/Risk Management (Chapter 1)
Another important part of the quality system is risk management. It is a new and relevant requirement as compared to the previous GDP Guidelines. Several activities in the new GDP Guidelines should be based on a risk management basis such as quality systems, validation, and outsourcing.
Each company should ask what are their most important risks? What is their impact? What kind of measures need to be taken to diminish the risks? The questions can be answered during a brainstorming session with key personnel, including management following the ICH principles for risk management3. Thus, a part of the GDP inspections was the question of did you perform risk analyses and what are your most important risks.
The results of the inspections showed that standard operating procedures and risk analyses were performed in 40% and 48%, respectively, of the inspections. In several instances the start of the risk analyses was documented but without measures to reduce and/or mitigate the risk.
Personnel (Chapter 2)
The inspections checked for experienced and GDP trained employees. The availability of a training system, records and continued education were reviewed. The job description of the Responsible Persons and their evaluation against the twelve items referenced in section 2.2 of the new guidelines were assessed.
The results of the inspections showed that there were systems for GDP training, training conducted about the new GDP Guidelines, actual job description for the Responsible Person, and training of Responsible Persons on the new GDP Guidelines in 81%, 54%, 69%, and 70%, respectively, of the inspections. Some of the new responsibilities for the Responsible Person such as training, qualifying suppliers and customers, actions for returned goods were not mentioned in the job description.
Temperature Mapping of Storage Facilities (Chapter 3)
The premises of the wholesaler should be clean, dry, and maintained within acceptable temperature limits. To fulfill the last requirement it is necessary to know the temperature behavior in the storage area, monitor the temperature and control it. An appropriate alarm system should be in place to warn when there are excursions from pre-defined storage conditions. After an alert, a corrective action should be taken. There could be temperature differences in the storage area such as near heaters and at the sunny side of the building where the temperatures may be higher. The new guidelines require that a mapping exercise should be performed on the storage area before use, under representative conditions and periodically based on a risk assessment. Because of the climate in the Netherlands and the differences between the outside temperature in winter and summer a mapping in both seasons is essential. A temperature mapping is an exercise in which temperature sensors are placed on the points identified as most critical through a risk analysis and the temperature is measured for at least 48 hours. During the inspections the following items were checked: the availability of a good system for monitoring and controlling temperature, alarms, follow-ups, and was temperature mapping performed in the summer and winter. The results of the inspections showed that the availability of a system for monitoring, documentation, and controlled temperature were 94%.
Weak systems were 18%. The performance of one temperature mapping inspection were 62%. Temperature mapping in summer and winter were 27%. The availability of temperature alarm system were 65%, and the follow-up of alarms were in 50% of the inspections. Two companies did not have storage areas because of outsourcing. The 18% weak systems were due to the presence of too few analog thermometers with a daily registration of the temperature by hand on a paper in the storage area during working days. One reason for the low (27%) temperature mapping in summer and winter is that a lot of companies waited for cold weather and low temperatures. Because of the very warm winter (2013/2014) low temperatures did not occur and the winter mapping was postponed one year. SMS was used to alarm key personnel for action. However, 50% of companies did not take or had an insufficient documentation of an action including the evaluation of the stability of the medicines at higher temperatures.
Qualification of Suppliers (Chapter 5)
Based on the new GDP Guidelines it is not sufficient to only check if the supplier has a wholesale license. It is also necessary to check if the supplier complies with GDP and has a good and reliable reputation. In practice mostly a questionnaire is used to verify such items as the quality system, and results of inspections. The final decision if a supplier can be used is the responsibility of the Responsible Person. Only approved and qualified suppliers should be used. Part of the GDP inspections was the system for checking the suppliers. One question was if they checked the license yearly of the suppliers. Another question was if the Responsible Person approved suppliers based on complying with GDP and reliability. A selection of the suppliers used was reviewed to check on their controls, evidence of a license, and that the decision was based on their quality information such as by the outcome of a questionnaire.
The results of the inspections showed that qualification based on license of suppliers, remarks about the system, and qualification based on a questionnaire were 94%, 35% and 24%, respectively. Two inspected logistic provider companies did not perform this task. It was the responsibility of their clients. Some remarks were made about the low frequency of checking the license system at once every three years, and insufficient involvement of the Responsible Person.
Handling Returned Goods (Chapter 6)
There is a certain risk when returned goods are placed again in the sealable stock. Thus, returned goods must be handled according to a written, risk-based adequate process taking in account how the returned product was stored and the time from its original delivery. An acceptable time limit recommended by the new guidelines is 10 days. Five criteria are mentioned in section 6.3 of the GDP Guidelines. They should be part of the process and the SOP. Additionally, medicinal products requiring specific temperature storage conditions such as low temperature should meet the six criteria mentioned in section 6.3. The Responsible Person is responsible for the system and for the decision if products are put back in stock again. Checking of the system for returned goods was part of the inspection. Companies were asked questions about having an adequate system based on the new guidelines such as: Is there a standard operating procedure? And how is the Responsible Person involved?
The results of the inspections showed the availability of a system for handling and judging returned goods, a system and SOP based on new GDP Guidelines, and uncertainty about following the new criteria in 90%, 20%, and 24%, respectively, of the inspections. These results illustrate that nearly each company had a system for handling of returned goods. However, most of the systems were not based on the criteria of the new GDP Guidelines. In several cases the role of the Responsible Persons and their involvement in the process were not mentioned in the standard operating procedure. Similar results were seen for the criteria of the guidelines. Some companies did not use the criteria for delivery or qualified how they accepted returned goods with a delivery time of several months.
Self-Inspection (Chapter 8)
Self-inspections should be periodically performed to verify implementation of GDP and to improve GDP compliance if necessary. All the GDP aspects should be covered. They should be done by trained and authorized employees of the company. The value of these inspections is to know GDP level, to comply with its requirement of continued improvement and to increase the quality awareness of employees. The inspections verified if there was an operational system for self-inspections in place, including planning, conducting, reporting and improvements if there were shortcomings. The availability, content, and a CAPA follow-up of a self-inspections standard operating procedure were examined.
The results of the inspections showed that availability of an operational self-inspections program, a standard operating procedure, and followup in 72%, 90%, and 45%, respectively, of the inspections. Most of the companies had an operational system for self-inspection and a standard operating procedure in which important aspects of self-inspections are described. The majority of companies performed around 5 self-inspections each year with a limited scope to one or two chapters of the GDP guidelines, as a deficiency the Quality Assurance department was not always part of the self-inspections. In some cases the frequency was not adequate such as less than one self-inspection every two years. More than 50% of the companies did not have a good follow up CAPA system necessary to improve the shortcoming and monitor their progress.
Outsourcing Transportation (Chapter 7 and 9)
Outsourcing of GDP activities such as storage and transportation is commonly widespread nowadays for pharmaceutical companies. Thus, it was necessary to have a separate chapter in the new guidelines about its principles and the way of handling it. Outsourced activities should be correctly defined, agreed and controlled to protect the integrity of the medicinal product. In practice there must be a written and signed contract between the contract giver and the contract acceptor which clearly establishes the duties of each party. An audit of the contract acceptor should be performed before the commencement of outsourcing and should be repeated periodically based on risk analysis to control the outsourced activities. During the inspections, the focus was on the outsourcing of transportation. In Chapter 9 of the guidelines several special requirements are mentioned including maintaining of storage conditions, reporting of temperature excursions and product damage, written procedures for all GDP activities, temperature mapping of vehicles, containers, and the use of packaging. There should be a written contractual Quality Agreement specifying these details. The inspections investigated if wholesalers had outsourced transportation, performed an audit and if they had a written and signed agreement.
The results of the inspection showed that transportation was outsourced by wholesalers, contracts were available for outsourced transportation, and audits were performed by wholesalers in 77%, 84% and 64%, respectively, of the inspections. These results confirm the current practice of outsourcing transportation and the availability of a contractual agreement. However, not all contracts described the required GDP responsibilities, and specific transportation items such as communication about temperature excursions, and qualification of vehicles. Some contracts were based on the old GDP (1994) guidelines and others were not signed. The use of sub-contractors was sometimes possible without concerns about GDP and without permission from the contract giver. Auditing of the logistics providers by the wholesalers were confirmed by checking their audit reports. It is recommend to have a list of the GDP responsibilities of the contract giver and the contract acceptor and which topics of the new guidelines they covered as part of the contractual agreement .
Conclusions
Many inspected companies have made a good start with the implementation of the changes according to the new GDP Guidelines. However, some 24% of companies did not perform any or only a few activities. Thus, they still have to do a lot of work to comply with the new GDP Guidelines. In general all of the discussed GDP topics are necessary improvements. Some items have been implemented by around half of the inspected companies such as management review, risk management assessment, the follow-up on alarms in case of temperature excursions, the follow up on self-inspection gaps, and the performing of audits on outsourced transportation activities. On the other hand, some categories were very weak and were mostly not compliant with the new GDP guidelines:
- Training of employees and the Responsible Person based on the new GDP Guidelines. Only about 50% and 70%, respectively, are trained.
- Performing of temperature mapping especially in the winter.
- The qualification of suppliers based on the quality status and not only the license.
- The handling of returned goods based on the new criteria with justification of the results.
Similar results have been reported by D. Churchward and S. Ronninger from the GMP inspection data of the MHRA. The top five deficiencies listed include: investigation of deviations, quality management, investigation of CAPA, chemical/physical contamination (or potential for), and supplier and contractor audit. The inspectorate has identified the following additional focus areas: data integrity, implementation of new supply chain requirements according to Falsified Medicines Directive (FMD), and cross-contamination. The data shows areas of commonality between the findings by inspections conducted by MHRA and those from other agencies such as the U.S. FDA4.
Note
A summary of the GDP inspection results were presented at the IQPC Cool Chain Europe Conference, January 26–29, 2015, Frankfurt, Germany.
References
- EU Guidelines on good distribution practice (GDP) of medicinal products for human use. European Commission, 23 November 2013 ( 2013/C 343/01
- EU Guidelines on good distribution practice (GDP) of medicinal products for human use 23 March 1994; European Commission ( Ref 94/C 63/03)
- ICH Q9 Quality Risk Management
- Churchward, D. and Ronninger, S., Group Yields New MHRA Inspection Data Report Format. PDA Letter, November / December, 2014, page 43.
Riekert Bruinink is a Senior GMP/GDP inspector at the Dutch Healthcare Inspectorate. He was Chairman of the PIC/S GDP Working Group and a member of the EMA GDP Drafting Group. This group was responsible for making the new EU GDP Guidelines. ([email protected])
Rafik H. Bishara, Ph.D., is a Technical Advisor, and the Leader of the Parenteral Drug Association (PDA) Pharmaceutical Cold Chain Interest Group (PCCIG), US Branch. ([email protected]).