LOGFILE No. 14/2018 – Inspections & Audits: Pitfalls and Criteria for Success – Part 2
Inspections & Audits: Pitfalls and Criteria for Success – Part 2
A summary of the GMP DIALOGUE at the GMP-BERATER Tage 2017
6 minutes reading time
by Sabine Rabus and Christine Gräßlin
Last week you read in LOGFILE 13/2018 the first part of this summary of the questions and answers that were discussed during a GMP Dialogue at our GMP conference, the GMP-BERATER Tage 2017. GMP inspector Dr Petra Rempe and Annette Könemann, manager of the quality department at the laboratory L+S AG, responded to questions from interested GMP Publishing customers.
In part 2 you’ll read about auditing small-volume suppliers and typesetting studios, as well as about how you should approach known areas of weakness during an inspection.
What is the situation if the machine has a computer? Is a machine qualification sufficient, or is a computer validation also necessary?
This depends on the complexity of the system. Actually, the qualification documents of the supplier need to be verified in advance and approved by the contract giver. In this case, the active involvement of the pharmaceutical company is required.
What are the requirements regarding (most) of the small-volume suppliers? – “Questionnaire” versus “On-site audits”
A variety of options are available. With “small customers” for example, this means a neutral self-disclosure questionnaire which can be presented to authorities. Site Master Files, questionnaires and certificates can also be used. These are normally accepted by the authorities. It isn’t possible for all suppliers to be audited on site, usually it is only the most important and critical ones. The auditing should always be risk-based, and the decision of which supplier is audited on site should also be risk-based. Questionnaires are also an adequate tool with many small-volume suppliers.
A comprehensive system audit is also a possibility. In this context, several companies jointly assign an external auditor. The audit report is provided to all of the participating companies. The payment is shared and the participating companies are known.
If a questionnaire is accepted by a small-scale supplier but an on-site audit is declined, it is always necessary to check whether any other equivalent options are available for gaining more information; audit results from other companies, for example. It is necessary to act on a risk basis in this case as well. Questionnaires only can be used with a supplier of excipients, for example, and not with a supplier of active ingredients. In the latter case, the manufacturer must carry out an on-site audit.
Why is it necessary for external typesetting studios to be audited?
A typesetting studio is a service provider, and qualification of the studio is necessary under all circumstances! The service provider should demonstrate its processes, which must be verified by the contract giver, at least with the first order. This applies to a layout in particular, for which a release also needs to take place. It is necessary to ensure compliance with the appropriate pharmaceutical regulations. The frequency at which an audit should take place is determined by the contract giver and should always be risk-based.
The participants of the GMP Dialogue on audits and inspections
Inspectors from foreign countries tend to target fraudulent processes, especially surrounding the topic of data integrity. But inadvertent errors can also occur. How are the German authorities approaching this topic?
This isn’t a new topic for the inspectors of the CFDA/ US FDA, and depends strongly on the individual inspector. An “investigative search” is a frequent event with foreign authorities. With the German authorities, this isn’t the case. However, if there are indications for fraudulence German inspectors will also go into the matter in further detail.
As one participant reports, the staff from the Chinese authorities (CFDA) are very critical. There have been cases in which the inspectors have asked to enter computer passwords themselves. This is allowed according to Chinese law, and you have to accept this if you want to sell on the Chinese market.
How should I approach known areas of weakness? Discuss them openly or wait and see?
In this case, a proactive approach is right. Ideally, a deadline for the implementation will also be determined. It is also good to point out that the area of weakness has already been identified in the scope of a self-inspection. In this way, you show that this “instrument” is being used and that it works.
If you can demonstrate to the inspector that an adequate plan is already in place and you have a risk assessment at hand, for example, although the problem won’t have been solved, this shows that you have made a start on solving the problem. This will usually be taken into account.
How should I approach areas of weakness that have existed for a very long time but of which we were not aware? Discuss them openly or wait and see?
During the inspection, an intensive error analysis should take place together with the inspector. Potential solutions should be found and discussed. This can also be understood as being an opportunity and a continuous improvement process, i.e. as the practical implementation of “good manufacturing practices”.
In such a situation, dealing openly with areas of weakness and the fastest possible preparation of a concept are very helpful. Authorities aren’t allowed to act as a consultant, and it is naturally the case that inspectors should not solve the company's problems. If a company has prepared a possible solution, however, this document can provide the basis for a discussion with the inspector. Inspectors aren't officially permitted to give advice, but they are allowed to comment on a concept.
It is no longer possible for an old machine (e.g. used for tabletting) to be qualified according to the current requirements. What can be done?
If the manufacturing process is not possible on new machines then the old machine must be sufficiently qualified for the task after all. It is always necessary to check, however, whether the product can’t be made on a new machine as well and a replacement of the old machine is possible, as pharmaceutical manufacturers are always obliged to work according to the state of the art.
Dr Petra Rempe compared an inspection with a play in three acts. This is because an inspection can also be divided into three sections: Preparation – Carrying out – Follow-up.
What should be assumed in the event of an inspection? That the inspectors want to do their work, to do it as well as possible, and to enjoy doing it! This also applies to audits. If your preparations are good, you're half the way there. It’s never possible to identify and rectify every area of weakness in good time, however. Whenever possible, taking a proactive approach, creating an action plan and, of course, good communication, will help. An audit/an inspection should always be viewed as being an opportunity for optimising the processes in the company and for continual improvement. You shouldn't forget that. If a constructive follow-up takes place following the inspection/the audit, the entire “play” should be viewed as being a win-win situation for everyone involved.
GMP and GDP Guidelines:
- EudraLex – Vol. 4 – GMP guidelines
- EU-GDP guidelines for human medicines:
- EU-GDP guidelines for active agents:
Maas & Peither AG - GMP Publishing
Maas & Peither AG - GMP Publishing