Inspection of contract manufacturers
Here you will find answers to the following questions:
- Why must contract manufacturers be inspected?
- What are the considerations with regard to inspections when formulating contracts with contract manufacturers ?
- What is the procedure if deviations are observed?
1 Purpose of the inspection of contract manufacturer
The contract giver must ascertain that the contract acceptor manufactures and tests the medicinal product in accordance with regulations and manufacturing and testing procedures.
Chapter 7.3 of the EU GMP Guideline states that the contract giver must, moreover, assess whether the contract acceptor is competent to carry out the work required successfully.
To fulfil these obligations, the contract giver must also ascertain this themselves on-site and carry out inspections of the contract acceptor.
2 Carrying out inspections of contract manufacturer
The inspection of the contract acceptor should be done by an inspection team of qualified persons from the contract giver. If the contract giver is also in possession of a manufacturing authorisation, the responsible head of production and head of quality control and, if applicable, the sales manager are represented in the inspection team. Otherwise, the contract giver must use other qualified persons, who are in a position to assess the relevant manufacturing and testing activities.
The exact procedure for the inspection of the contract acceptor should be specified in the agreement on the manufacturing contract. This applies, in particular, to the issues listed in figure 18.F-1 on which the partners to the contract should agree.
Figure 18.F-1 Contractually required arrangements for an inspection within the conditions of a contract
Contractual arrangements for inspection related to a contract manufacturers
- Who from the contractual partners can/must participate in the inspection? Can external experts be called in?
- How often can/must the inspection be carried out and how long can/must it last?
- (When) Can inspections be carried out without prior warning?
- Is the contract giver authorised to do sampling on-site?
- Which documents is the contract giver allowed to see at the contract acceptor? Can the contract giver make copies of these documents?
- Who receives a copy of the inspection report?
- What is the procedure regarding the follow-up inspection in the event of deficiencies?
- Who decides about the type and scope of remedial actions and deadlines?
- To what extent is the contract giver permitted to forward the results of the inspection to other contract giver to avoid repeating inspections?
Before carrying out the initial inspection of a new or potential contract acceptor, the contract giver should make a review of the manufacturing and/or testing operation, in particular the staff and instrumentation. To this end, a corresponding questionnaire should be sent to the contract acceptor to complete (see chapter 17.A Contract manufacture). The company description of the future contract partner can, of course, also be reverted to if this is available (site master file) (see chapter 15.E Site master file).
The scope of the inspection is determined according to the subject of the contract and the contract work. This requires there to be a manufacturing order contract, in which the individual operations are described in detail and the responsibilities of the contract partners are clearly established. On this basis, the contract giver can ensure that the contract acceptor performs all operations in conformity with the legal regulations, the principles of GMP and other requirements laid down in the contract (see chapter chapter 17.A Contract manufacture).
For inspections of the contract acceptor, as for self-inspections, the inspections should be set at shorter intervals until such time sufficient knowledge has been acquired about the reliability of the contract partner. The frequency and scope of inspections must also be made contingent on the type and scope of the contract (parenteral product manufacture or packaging; two to three batches/year or 20-30 batches/year). The important factor is not whether the interval chosen is six months longer or six months shorter, but whether the contract giver has made the decision as to how often to conduct inspections for good reasons, or arbitrarily (see chapter 6.1 Frequency of audits).
The results of the inspection are recorded by the contract giver. If deficiencies are observed during the inspection, the measures being taken to remedy these, including deadlines, should be included in the record. If the contract giver and contract acceptor hold different opinions regarding the grade of the error or the remedy, these positions should also be noted in the record. The inspected company receives a copy of the inspection protocol, or an extract of it, and should comment on it within a defined period.
3 Handling of changes and deviations
For the relationship between the contract partners to run smoothly, it is important to have a jointly agreed change control program (see chapter 19.C Change control). It must be ensured that all major changes (e.g. procedure parameters, specifications or provenance of the starting material and packaging material) are communicated between the contract partners and the measures required for this are established (e.g. revalidation, amendment). The inspection should check the operability of the change control program and make proposals for improving its effectiveness.
Where deficiencies are observed during the inspection, these should be discussed between the contract partners on-site as far as possible, and measures should be established to remedy the deficiencies and prevent them occurring in future. The contract giver can use their own error classification for this, described in figure 18.E-5 and figure 18.E-6, provided nothing else has been agreed contractually.
Any party who concludes contracts with third parties must ascertain that operations are carried out in accordance with the regulations by carrying out inspections of the contract acceptor.
The frequency and scope of the inspection depends on the size of the order and the level of risk of the manufactured products.
The rights and duties of both parties should be recorded in a written and approved contract.
In the course of the audit, compliance with the principles of GMP is reviewed, in particular the handling of changes and their authorisation.