Here you will find answers to the following questions:
Purpose of the supplier inspection
Supplier inspections or audits are used to verify on-site whether the supplier is in the position to manufacture and supply starting materials, labeling or packaging materials of the desired (ordered) quality.
Chapter 5.26 of the EU GMP Guideline requires that starting materials should only be purchased from "approved" suppliers. The same also applies, according to Chapter 5.40, to primary and printed packaging materials. The pharmaceutical manufacturer is responsible for the starting materials, labeling and packaging material used and must control their quality.
In this respect, inspections offer a way of deciding whether to approve the supplier and about the level of inspection effort required.
The EU GMP Guideline does not give any more precise specifications regarding the scope of the inspection of starting materials. However, at least the identity should be checked. The extent to which the customer chooses to rely on the supplier's quality control and the resulting certificates therefore depends on the result of the inspection of the supplier. Thus, the result of the inspection of a supplier leads to more than simply the decision whether a supplier is able to supply a product or not. The inspection also makes an important contribution to the mutual trust between supplier and customer. An inspection can help to build such mutual trust so both sides get to know and appreciate the situation at the outset and the specific problems of the other, and are thus in the position to improve the quality of the product together.
The pharmaceutical manufacturer must, therefore, recognize that it is not simply a case of purchasing starting materials, labeling and packaging material as cheaply as possible. A medicinal or drug product of consistent and reliable quality can only be achieved with high-quality starting materials.
In addition to these "classic" supplier inspections, the inspections of equipment manufacturers as part of design qualification, and the inspection of software manufacturers are becoming important. The purpose of these inspections is the same: the pharmaceutical manufacturer, as the customer, wants to ascertain on-site, before placing an order, that the goods will satisfy the requirements he has established.
Carrying out the supplier inspection
Before carrying out the initial inspection of a new supplier, the pharmaceutical manufacturer should compile the basic information about the future contract partner. As for contract acceptors, this can take the form of a questionnaire to be filled in by the supplier and to be considered during the inspection.
The inspection is carried out on the basis of a checklist. The pharmaceutical manufacturer should first establish what it considers to be the principal considerations regarding the starting materials and/or packaging material to be supplied in the form of "mandatory" and "optional" requirements.
1 Supplier quality assurance system
1.1 Is there certification in accordance with DIN/ISO 9000 ff.?
1.2 Is a quality assurance instruction manual available, and is it kept up to date?
1.3 Is quality defined on all levels of the system?
1.4 Is the responsibility of the upper management stipulated?
1.5 Are an organizational structure and job descriptions available?
1.6 Are change control and OOS procedures established?
1.7 Does the supplier contract work out to third parties? If it does, are there contractual regulations?
1.8 Do appropriate approval procedures exist?
2.1 Number and qualification of personnel in manufacture and quality control?
2.2 Is there a company training scheme?
2.3 How are personnel clothing and health monitoring controlled?
3 Rooms and facilities
3.1 Is the standard of hygiene of the rooms and facilities defined and is it monitored?
3.2 Is the maintenance/calibration of the machines controlled and carried out?
3.3 Are measures in place to prevent cross-contamination and misidentification?
4 Manufacturing procedure
4.1 Are the substances/materials used specified?
4.2 Are written process instructions in force?
4.3 Is the suitability (reproducibility) of the procedure verified?
4.4 Are in-process controls being carried out?
4.5 How is batch size established?
4.6 Is documentation batch related?
4.7 How are deviations dealt with?
5 Quality control
5.1 Is suitable analytical apparatus available?
5.2 Is the analytical apparatus maintained and calibrated?
5.3 Do written analytical procedures exist?
5.4 Does a sampling plan exist?
5.5 What is the procedure for issuing certificates?
5.6 Are control tests of third parties transferred to the certificate and declared accordingly?
6.1 Who is responsible for dispatch from supplier to customer?
6.2 Are the supporting sales documents relating to the customer and the batch retained?
6.3 How are the accuracy of the delivery and adherence to delivery dates guaranteed?
7.1 Is there an established procedure for handling complaints?
7.2 Are complaints recorded and evaluated in relation to the product?
7.3 How is the customer involved in dealing with complaints?
Supplier inspections have been carried out by customer partnerships, in particular for primary packaging material manufacturers. These reduce the cost to suppliers and similarly to customers. For this type of joint inspection, however, all the parties involved must first be in agreement about the requirements. It is essential to draw up a joint checklist and agree on the classification of deficiencies, particularly if companies not involved in the inspection wish to forego their own inspection on the basis of the inspection report.
Samples of the starting materials and/or packaging materials in question should be investigated before the inspection. If this has been agreed with the supplier, sampling from the production underway during the inspection can provide valuable additional information. Evidence of the comparability of the analytical investigations carried out by the supplier and by the customer must be demonstrated in order to justify the pharmaceutical manufacturer reducing the controls it carries out later. This presupposes that the supplier, as specialist for the products it distributes, discloses to the pharmaceutical manufacturer the analytical procedures used, which unfortunately cannot be taken for granted in practice.
The pharmaceutical manufacturer will not always have the required knowledge in-house to control the supplier sensibly. This applies, for example, to starting materials manufactured biotechnologically, starting materials of human or animal origin and also to software (compare Figure 18.G-2). In these cases, people with expert knowledge (consultants, experts) must be called in, if the pharmaceutical manufacturer does not want to hazard purchasing the goods "blind".
An important point to check during the inspection is how the supplier handles changes. This applies to changes initiated by the pharmaceutical manufacturer and to those made by the supplier. The inspection should control by means of selected examples whether the processes (who is responsible for which tasks, who assists, who should be informed?) are clearly established and, in particular, whether there are smooth supplier-customer interfaces.
The issue of how the supplier handles complaints it receives is also important for maintaining mutual trust between supplier and the pharmaceutical manufacturer. The inspection can be used, at the same time, to trace previous complaints on-site and in particular, what measures the supplier has taken to determine the cause of failure and prevent errors in future.
Supplier inspections reinforce the mutual trust between customer and supplier and are the deciding pre-condition for reducing investigation effort.
For special products (biotechnology prepa-rations, software, etc.), it may be logical to call in people with external expert knowledge to enable an effective audit to be carried out.
Dr. Michael Hiob
Ministry for Health of Land Schleswig-Holstein, Germany
Max S. Lazar
FDA Regulatory Compliance Consulting, USA