Validation is a key element of the quality assurance system in a pharmaceutical company. For a long time, our understanding of pharmaceutical quality was such that one relied solely on the control of raw materials and final products. The intermediate process was guaranteed by established experience and the professional honesty of longtime employees. Today, our understanding is almost the reverse. Well-tested raw materials from qualified suppliers are used in a process that must be so well controlled that, theoretically, absolutely nothing can result other than a product that conforms to the specifications. In contrast, the place of manufacture and staff carrying out production are interchangeable, as long as they are qualified.

The new approach is conclusive, reasonable, sensible, since if a serious defect is identified at the final product quality control, irreparable damage has already occurred. For drug products, reprocessing is prohibited in most cases or is only possible with a great deal of additional expenditure (see chapter 11.L Reworking). Since modern drug substances and innovative preparations are also becoming ever more expensive, it is, therefore, necessary to avoid the final product being rejected using preventive measures, such as validation. The assessment of a process within the framework of a validation is important, moreover, because staff stay with companies for ever shorter periods of time, which prevents the gathering of a pool of experience and with it continuity of information and quality. Even more - it is intended to have production processes relocatable between different manufacturing sites - even worldwide. Therefore, to guarantee a reproducible quality, processes must be validated.

The term "reproducible quality" in this context means more than the reproducible fulfilment of final product specifications (cf. also EMEA Note for Guidance on Process Validation, paragraph 1). Or to put it the other way round: even if drug product specifications are repeatedly complied with, it is still not permissible to conclude that a process is under control.

Therefore, quality in a product is spoken of in terms of being "produced into" and not simply "tested into". "Quality" is the sum of properties of a product, not only those that are covered in the specifications.

At the same time, process validation is only a part of a broad concept which includes qualification of equipment, facilities, computers, buildings, building and utility services engineering, staff and suppliers, and demands systematic documentation, archiving and change control.

For pharmaceutical manufacturers, validation should be understood not as a discretionary rule, but as a mandatory requirement that must be complied with. Thus validation is addressed regularly in regulatory inspections as well as in supplier audits and there are still numerous deficiencies observed: about 10 % of all GMP complaints are in the context of validation - at fourth place in the ranking for all GMP complaints.

Common deficiencies include:

• Validation protocols have not been compiled or are not being followed
• Information about the equipment used, the critical process parameters, sampling data, number of validation batches or acceptance criteria is missing from the validation documentation
• Changes to validated processes are not being adressed

Given the enormous amount of time and effort required for validation activities, it is not easy, initially, to appreciate that validation should also be a tool for saving materials, making cost-savings and saving time. The new demand by the PIC (cf. PIC/S PI 006) for permanent validation seems, therefore, to conflict with international cost reduction efforts in health care.

However, observing other industries, such as the electronics or automobile industries, one can ascertain that in these - solely for economic interest - even more wide-ranging process requirements are fulfilled such that final inspections can be completely waived to some extent. With the aid of statistical process control (SPC) and Continuous Improvement Processes (CIP), the manufacturing processes there are not only permanently monitored, they are also continuously optimised.

By comparison, the concept of validation currently practised in the pharmaceutical field is only a small beginning - it is not possible to determine normal process variability nor process capability on the basis of only the required three batches.

Thus, the suggestion of the PIC is understandable: "a series of batches ... should be produced ... It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data." (PIC/S PI 006).

Recognising this fact, appendix 15 of the EU guideline states that; "in theory the number of process runs carried out ... should be sufficient to allow the normal extent of variation and trends to be established ... It is generally considered acceptable that three consecutive batches/runs ... would constitute a validation of the process".

The significance of the process validation has taken on a new emphasis, since over the past months a series of new rules and regulations on this subject have been published, notably appendix 15 to the EU GMP Guideline "Qualification and validation", the EMEA "Note for Guidance on Process Validation" and the aide mйmoire from the ZLG (German central authority of the Laender for health protection regarding medicinal products and medical devices) "Inspection of qualification and validation in pharmaceutical manufacture and quality control". Last but not least, chapter 12 of the ICH Q7A guideline, "Good Manufacturing Practice guide for active pharmaceutical ingredients" covers the topic of validation more extensively than most other rules or regulations. For excipients, the topic of validation is described in the IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients.

The objective of the EMEA "Note for Guidance on Process Validation" is standardisation of the validation documents that must be submitted with the submission file for marketing authorisation. This guideline is directed at manufacturers of pharmaceutical products; to some extent, though, the procedure is also transferable to the manufacture of active pharmaceutical ingredients, excipients, biotech or blood products.

This paper describes very thoroughly what validation data is expected at the point of submission of the application file for marketing authorisation.