It is in the nature of things that when a contract is assigned to a contract manufacturer, a part of the information about the manufacture of the preparation is no longer within immediate daily reach. A considerable level of trust must, therefore, already have been built up between the contract giver and the contract acceptor and the staff of the respective companies. For this reason, it has been proven to be an effective approach to build up close permanent contact with the contract manufacturer from an early stage. The factors required for building trust include readiness to provide information, understanding of audits, transparency regarding errors, sharing know-how and a culture of communication. Practice and dayto- day business will show how the collaboration actually works.

Many contract givers hold marketing authorizations for several preparations with different dosage forms. This often means selecting a number of different contract manufacturers with different core businesses (specialization in particular API, dosage forms and manufacturing technologies).

Factors such as delivery date and quotation price still play a large part in the selection of a contract manufacturer. How the two parties work together during day-to-day business should be considered, particularly if problems arise during manufacture. How does the contract manufacturer handle problems, how quickly is information provided and what solutions are suggested? It is therefore advisable to get to know the relevant responsible person at an early stage to gain a first impression about the contract company's level of understanding of basic pharmaceutical matters and a rough view of the production processes.

Duties of the contract giver

• Selection of one or more contract acceptors
• Definition of the requirements on the contract acceptor
• Handover of the significant documents to the contract acceptor
• Secrecy and contract manufacturer agreement
• Audit and approval of the contract acceptor
• Approval of manufacturing instructions

Selection of one or more contract acceptors

Contract givers are often of the opinion that it is adequate simply to collaborate with one contract manufacturer. In contrast, other contract givers favor assigning a particular preparation to several contract manufacturers. Then if there are problems with delivery reliability or a lot of quality issues, it is possible to switch production to an alternative contract manufacturer quickly. In principle, one can observe that it is always easier for a contract giver to communicate with a manageable number of contract manufacturers. One should bear in mind, when doing this, the considerable investment required for qualification of another, alternative contract manufacturer. Not only must this alternative contract manufacturer be selected, it must also be audited. If the alternative contractor is then commissioned to carry out production, in addition to defining all responsibilities in a contract, it is also necessary to manufacture three validation batches.

When a business relationship functions well, there is normally no question of appointing an alternative contractor. Experience shows that for a contract giver, a contract acceptor is usually a good partner if it only communicates what is absolutely necessary (to the partnership, commission-oriented). That means an order is placed for a defined quantity and by a defined deadline and the goods are delivered in qualitatively faultless condition on the agreed delivery date at the agreed price.

Definition of the demands on the contract acceptor

The contract giver's individual in-house departments set different priorities. So, a commercially and planning-oriented department responsible for purchasing and the assignment of contracts and compliance with the delivery dates makes its assessments based primarily on price and delivery reliability. In contrast, a department dealing with the assessment of contract manufacturers, specifically with audits and approval, will make an assessment based on GMP principles and according to appreciation of quality management issues. Thus, the contract giver must already define in-house the requirements on the contract acceptor in the run up to a product transfer. The contract manufacturer agreement has shown itself to be a beneficial tool for this type of definition. All requirements and arrangements between the contract giver and the contract acceptor should, therefore, be agreed in this contract before the start of production (see chapter 17.A.5 Contract manufacturer agreement).

Handover of the necessary documents to the contract acceptor

The contract giver must hand over to the contract acceptor all documents that are relevant to the transfer of a drug product. On the one hand, the contract giver hands over a large part of its know-how about a preparation, however it is absolutely necessary for the contract acceptor to receive this information and results from the documents for assessment of its in-house manufacture, packaging and analysis. This includes the following documents primarily:

• Sections of the application file for marketing authorization In particular, the contract acceptor needs the sections of the application file for marketing authorization defining the details of the manufacturing, packaging and analytical procedure with their instructions and specifications. Often, as the contract giver sees it, these are the only documents that enable the contract acceptor to compile manufacturing instructions.
• Manufacturing instructions and batch production records If the contract giver has already manufactured a preparation in-house, the relevant manufacturing instructions should be handed over to the contract acceptor. These manufacturing instructions contain both the detailed description of the man-ufacturing procedure and the setting parameters for the facilities and machines used. It is certainly helpful if the batch production records are also handed over or are able to be accessed. All deviations from the specifications and the notes by staff from the manufacturing area should be apparent.
• Test procedures and test protocols As with the manufacturing instructions and records, the documents addressing analysis that are available to the contract giver in-house are needed in order to transfer the analysis of a preparation appropriately.
• Validation documents If the contract giver already has validation documents in-house, it is essential that these are handed over to the contract manufacturer. From these, the contract acceptor can see, for example, an assessment of the limits and setting specifications already determined for the facilities and machines. In addition, the critical processing steps will already have been determined and defined. Using the results that have already been determined, the contract acceptor is therefore able to compile the risk analysis and the validation protocol much more quickly.

Secrecy agreement

The contract giver hands over a large amount of know-how about a particular preparation to the contract acceptor. To prevent misuse of this data, the contract giver must draw up a contractual secrecy agreement with the contract manufacturer before handing over the documents. This contractual secrecy agreement between the contract giver and the contract acceptor is a critical agreement to protect intellectual property and possible trade secrets.

Carrying out an audit and approval of the contract acceptor

The contract giver must carry out an audit of the contract acceptor before the actual start of production. The contract giver must use this audit primarily to assess the contract acceptor's manufacturing operation and quality assurance system. All observations are to be documented in an audit report. The result of the audit and, if applicable, the approval of the contract acceptor, all form the conclusion to the report. (See chapter 17.A.6 Audits of contract manufacturers)

Approval of manufacturing instructions

A working Change Management System starts with the approval of the manufacturing instructions or directions by the contract giver. This ensures that the contract giver is notified of all changes and deviations at an early stage. In addition, it guarantees that production is always carried out in accordance with valid manufacturing instructions approved by the contract giver. All changes must be communicated to the contract giver and documented in a new version of the manufacturing instructions.

You want to get more information about contract manufacturing?

GMP-Logfile-1-2012-contract-manufacture.pdf

About the Author

Max S. Lazar
FDA Regulatory Compliance Consulting, USA