Revalidation

A validation status once reached is not static, but is subject to everyday dynamics: all companies develop, undergo restructuring and change their targets. The staff changes, responsibilities change, SOPs are updated, buildings and equipment are adapted and maintenance work is carried out, etc. Even if the influence of each individual measure on the validation status is reviewed as part of a systematic change control program (see chapter 19.C Change control), a conjuction of various events can nonetheless cause processes to become gradually "devalidated". Other factors like compliance erosion in staff, inadequate maintenance work, calibration intervals that are too long due to pressure for time and economy measures, can also mean that the preconditions for the validity of a process are no longer met. To prevent this from endangering the product quality, critical process steps must be revalidated at regular intervals. This means that a completed validation must not be viewed as a one-off exercise, but rather the validation status must be periodically reviewed according to an established review cycle.

Regardless of the periodic revalidation of critical processes, validations (or parts thereof) must always be repeated if changes are to be made to buildings, facilities, equipment, processes, techniques or at the manufacturing site.

1 Time intervals for periodic revalidations

The legal drug product provisions allow the user a certain amount of leeway for carrying out revalidation. Chapter 5, paragraph 5.24 of the EU GMP Guideline says the following on the subject:

"Processes and procedures should undergo periodic critical re-evaluation to ensure that they remain capable of achieving the intended results." The exact definition of "periodic" is left to the manufacturer.

The validation master plan is the appropriate document to establish a company's concept for revalidation. When fixing the revalidation intervals, the following must be taken into consideration:

• the individual process risk and product risk
• the number of batches manufactured per year
• any other control measures used, e.g. SPC (statistical process control)

Depending on the product, the process and the manufacturing frequency, intervals of between two and five years may be advisable. If a process is continuously monitored with other methods, e.g. using statistical process control, then longer intervals may also be justifiable. If no critical change is made to a process during a period under review, an interpretation and evaluation of the process and product data for this period can be accepted as revalidation of the process.

2 Incidences requiring revalidation

2.1 Changes to the manufacturing instructions

Process validation is carried out on the basis of approved manufacturing instructions. If at a later stage these manufacturing instructions are intended to be changed, it is necessary to check, document and possibly show through revalidation, that this change has no effect on the product quality (see chapter 19.C Change control). Examples of changes to the manufacturing instructions are:

Changes to the product composition

If ingredients, like APIs or critical excipients are changed or even if only their percentage of quantity is changed, this can have serious impacts on the reproducibility of the manufacturing process: the original validation result is therefore no longer relevant. Critical excipients are to be understood as those which are either present in the formulation in very large proportions, or whose properties (e.g. particle size, density, moisture) significantly influence the physicochemical behaviour of the batch. This includes excipients that do not have any (or only slight) inherent pharmacological efficacy, but which have a desired effect in the final product (preservative, anti-oxidants, complex formers, polymers with retarding effects on the API).

Before such changes are made, it is necessary to carry out prospective validation studies based on three new batches with the changed product composition. It is important to know that, even if the validation result is favourable, some of these changes must be presented to the regulatory authorities before the changes are implemented in routine production (see chapter 19.C.1 Principles of change control).

Changes in production process or the sequence of operation

Just like the formulation for a validated process, the exact sequence of operation for all subsequent production batches is binding. If it is already planned from the outset to allow different process or sequence variants, these must be taken into account in the validation protocol.

In practice, for operational reasons, there may be a subsequent wish for process changes: for example, it may be suggested, that a drying step is performed in a shelf dryer, since the required fluid bed dryer is constantly in use. Switching between different blending methods is a frequent but very delicate problem as well. In any case, such process changes must be revalidated in the context of a prospective validation.

Apparently harmless variations to be made in the sequence of operation must be highlighted as equally critical: for example, which phase is placed in the vessel and which is mixed in afterwards can be crucial for the quality of a cream.

Changing the chronological order of two processing steps is also a change in the sequence of operation which requires validation (e.g.: first heat then evacuate or first evacuate then heat? Is it permissible to mix in a flow regulation medium before interim storage of the tabletting mass or only immediately before tabletting?).

Likewise, it must first be proven through validation that the quality of a product is not affected if, for example, a manufacturing step is carried out in three sub-batches on equipment with smaller dimensions, for capacity reasons, and these three sub-batches are then combined after successful IPC.

In practice, there are often prolonged holding times for intermediate stages or in-process material because processing has been delayed for planning reasons. These holding times, above all the appropriate packaging, storage, and possibly analysis before further processing, can be critical for sensitive products and therefore require validation.

Changes in primary packaging material

The primary packaging material for which sufficient long term stability data is already available, is defined in the approved and validated manufacturing instructions. In practice, it is also usual (but not compulsory) to store long term stability samples from the three validation batches, in order to support or supplement the available data.

A change in the primary packaging material may, on the one hand, influence the validation status of the packaging process, as the changed packaging material may require different machine settings and can have different processability properties (e.g. changing the film thickness of a blister film or of a sachet bag, changing the dimensions of ampoules, vials, stoppers, changing the material of films, stoppers, closures, etc.). On the other hand, the influence on the stability of the product must also be reviewed.

Before such a change is introduced, extensive clarifications are first required which extend far beyond the scope of revalidation. Ultimately, changes to the primary packaging materials must be indicated to the regulatory authorities in advance.

Planned changes of raw material suppliers

The quality of the raw materials determines not only the stability of a product, but also the technological behaviour during processing. Unfortunately, it is not yet possible to exhaustively describe raw materials in the specifications in terms of their quality attributes and requirements, meaning that there may be some surprises during processing if the supplier is changed, despite the raw material being in line with the specifications (see chapter 17.A Contract manufacture).

Qualified raw material suppliers must be defined at the time of validation of an approved formulation. As the validation is to be carried out in conditions as close to reality as possible, it is advisable to use the different suppliers' raw materials in the validation batches.

If a further supplier is to be approved at a later date, he must first be qualified (see chapter 3.1 Selection of one or more contract acceptors), and the production process concerned (or sub-step) must be revalidated.

For contract manufacturers, it is also important to obtain the approval of the customer before the change is implemented.

2.2 Extension of the ranges of critical process parameters

During a validation study, the operating ranges for critical process parameters within which the process is valid, are verified. If it is planned to extend these ranges at a later time, it must be proven that the process still reproducibly leads to a product with the desired quality. However, justifying the planned extension of the limits soon leads to a crisis in the line of argumentation - ultimately the processing step in question was originally designated as "critical", i.e. a slight change would have a big influence on the product quality. In contrast to this, however, it must be proven that the processing step is not so critical after all, before extending the ranges.

As the extension of the acceptance limits for critical processing steps can have a far-reaching influence on all subsequent steps, it is generally not sufficient to validate only the processing step in question - rather, all subsequent processing steps must also be validated either prospectively or concurrently.

2.3 Changes in manufacturing site

Revalidation is required if the manufacturing site is changed to a different, possibly newly constructed manufacturing unit of the same company, for example, or to a subsidiary or contract manufacturer, as the results of the original validation cannot be compared with manufacturing conditions in a changed environment. The same facilities or equipment are not generally available at the new manufacturing site (at best they are constructed in the same way). In the case of relocation to a new manufacturing hall, the original equipment will have been disassembled in the meantime, and must be qualified again and started up at the new site. Not only that, but usually the manufacturing, sampling and IPC tasks at the new manufacturing site will be carried out by different staff and possibly different raw materials suppliers will also be permitted.

All these aspects show why a process must be revalidated when the manufacturing site is changed (prospectively or concurrently). However, before validation studies are performed, the following basic requirements must be fulfilled at the new manufacturing site:

• Qualification of the facilities and equipment
• Calibration and maintenance performed according to standard operating procedures
• GMP-training of all staff involved
• Environmental monitoring
• Effective change control system implemented

2.4 Serious quality problems

If out of specification results (OOS results) occur during the quality control, the underlying error must be searched for based on a written, OOS-SOP (see chapter 14.H Out-of-specification results). If it comes to light that the error occurred during the manufacturing process, then measures must be taken to prevent the error from occurring again. In particular if the same error occurs repeatedly, the corresponding manufacturing step can no longer be considered to be validated. Corrective measures must therefore be taken (e.g. changing the manufacturing instructions, adding additional control steps, staff training, adjusting the frequency of calibrations or maintenance). Validation should then show that these measures have been successful - namely, that the manufacturing process is again running in a controlled manner.

The same applies if repeated problems or quality deviations have already been observed during routine manufacturing, e.g. during IPC. The causes of trends, which are observed during a retrospective batch assessment (e.g. during the Annual Product Review (see chapter 15.F Annual product review)), must also be investigated critically, even if they have not yet lead to OOS situations. Both point to the fact that changes in the manufacturing process have occurred, which is why it must be revalidated.