EU GMP, Annex 15

5.3. Manufacturing processes may be developed using a traditional approach or a continuous

verification approach. However, irrespective of the approach used, processes must be shown to be
robust and ensure consistent product quality before any product is released to the market.
Manufacturing processes using the traditional approach should undergo a prospective validation
programme, wherever possible, prior to certification of the product. Retrospective validation is no
longer an acceptable approach.

Concurrent validation
5.16. In exceptional circumstances, where there is a strong benefit-risk ratio for the patient, it may be
acceptable not to complete a validation programme before routine production starts and concurrent
validation could be used. However, the decision to carry out concurrent validation must be justified,
documented in the VMP for visibility and approved by authorised personnel.

5.17. Where a concurrent validation approach has been adopted, there should be sufficient data to
support a conclusion that any given batch of product is uniform and meets the defined acceptance
criteria. The results and conclusion should be formally documented and available to the Qualified
Person prior to certification of the batch.

Health Canada
Concurrent Validation: A process where current production batches are used to monitor processing
parameters. It gives assurance of the present batch being studied, and offers limited assurance
regarding consistency of quality from batch to batch.

Process Capability: Studies conducted to identify the critical process parameters that yield a resultant
quality, and their acceptable specification ranges, based on the established +/- 3 sigma deviations of
the process, under stressed conditions but when free of any assignable causes.

Prospective Validation: Conducted prior to the distribution of either a new product or a product made
under a modified production process, where the modifications are significant and may affect the
product's characteristics. It is a pre-planned scientific approach and includes the initial stages of
formulation development, process development, setting of process specifications, developing in-
process tests, sampling plans, designing of batch records, defining raw material specifications,
completion of pilot runs, transfer of technology from scale-up batches to commercial size batches,
listing major process equipment and environmental controls.

Process Validation: It would normally be expected that process validation be completed prior to the
distribution of a finished product that is intended for sale (prospective validation). Where this is not
possible, it may be necessary to validate processes during routine production (concurrent validation).
Processes which have been in use for some time without any significant changes may also be validated
according to an approved protocol (retrospective validation).

a) Prospective Validation:
In prospective validation, the validation protocol is executed before the process is put into commercial
use. During the product development phase the production process should be broken down into
individual steps. Each step should be evaluated on the basis of experience or theoretical considerations
to determine the critical parameters that may affect the quality of the finished product. A series of
experiments should be designed to determine the criticality of these factors. Each experiment should
be planned and documented fully in an authorised protocol.
All equipment, production environment and the analytical testing methods to be used should have been
fully validated. Master batch documents can be prepared only after the critical parameters of the
process have been identified and machine settings, component specifications and environmental
conditions have been determined.
Using this defined process a series of batches should be produced. In theory, the number of process
runs carried out and observations made should be sufficient to allow the normal extent of variation and
trends to be established to provide sufficient data for evaluation. 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 these data.
Some considerations should be exercised when selecting the process validation strategy. Amongst
these should be the use of different lots of active raw materials and major excipients, batches produced
on different shifts, the use of different equipment and facilities dedicated for commercial production,
operating range of the critical processes, and a thorough analysis of the process data in case of
requalification and revalidation.
During the processing of the validation batches, extensive sampling and testing should be performed
on the product at various stages, and should be documented comprehensively. Detailed testing should
also be done on the final product in its package.
Upon completion of the review, recommendations should be made on the extent of monitoring and the
in-process controls necessary for routine production. These should be incorporated into the batch
manufacturing and packaging record or into appropriate standard operating procedures. Limits,
frequencies and actions to be taken in the event of the limits being exceeded should be specified.
Matrix or "Family" approaches to prospective process validation:

It may be possible and acceptable in particular circumstances for a manufacturer that uses the same
process for several related products to develop a scientifically sound validation plan for that process
rather than different plans for each product manufactured by that process.

The matrix approach generally means a plan to conduct process validation on different strengths of the
same product. However, discrete manufacturing steps such as compression, and coating that involve
different tools, equipment, and process conditions for the different dosage strengths can not be
generally validated using the matrix approach. It should be recognized that the matrix approach has
limitations when there are concerns with respect to physical characteristics such as flow properties,
particle size distribution, homogeneity.

The "family" approach means a plan to conduct process validation on different products manufactured
with the same processes using the same equipment.

The validation process using these approaches must include batches of different strengths or products
which should be selected to represent the worst case conditions or scenarios to demonstrate that the
process is consistent for all strengths or products involved.

b) Concurrent Validation:

Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being
the "norm". In using this approach there is always the risk of having to modify process parameters or
specifications over a period of time. This situation often leads to questions regarding disposition of the
batches that had already been released for sale, subsequently known to have undesired quality
characteristics.

Concurrent validation may be the practical approach under certain circumstances. Examples of these
may be:

when a previously validated process is being transferred to a third party contract manufacturer
or to another manufacturing site
 where the product is a different strength of a previously validated product with the same ratio
of active / inactive ingredients
when the number of lots evaluated under the retrospective validation were not sufficient to
obtain a high degree of assurance demonstrating that the process is fully under control
when the number of batches produced are limited (e.g. orphan drugs).

It is important in these cases however, that the systems and equipment to be used have been fully
validated previously. The justification for conducting concurrent validation must be documented and
the protocol must be approved by the validation team. A report should be prepared and approved prior
to the sale of each batch and a final report should be prepared and approved after the completion of all
concurrent batches. It is generally considered acceptable that a minimum of three consecutive batches
within the finally agreed parameters, giving the product the desired quality would constitute a proper
validation of the process.

Process Re-Validation:
Re-validation provides the evidence that changes in a process and /or the process environment that are
introduced do not adversely affect process characteristics and product quality. Documentation
requirements will be the same as for the initial validation of the process.
Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes
necessary in certain situations. The following are examples of some of the planned or unplanned
changes that may require re-validation:
Changes in raw materials (physical properties such as density, viscosity, particle size
distribution, and moisture, etc., that may affect the process or product).
Changes in the source of active raw material manufacturer
Changes in packaging material (primary container/closure system).
Changes in the process (e.g., mixing time, drying temperatures and batch size)
Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment
which involve the replacement of equipment on a "like for like" basis would not normally
require a re-validation except that this new equipment must be qualified.
Changes in the plant/facility.
Variations revealed by trend analysis (e.g. process drifts)
A decision not to perform re-validation studies must be fully justified and documented.

FDA

Concurrent Validation

FDA considers concurrent validation to be a subset of prospective validation. The Agency recognizes
that in a limited number of cases it may be impossible to complete validation of an API process in a
timely manner when data from replicate production runs are unavailable because: - Only a limited
number of API batches intended for clinical or orphan drug products have been produced; - API
batches are produced infrequently (e.g., limited market demand, complex multi-step API processes
with long completion times); or - APIs batches are produced by a modified process (e.g., a validated
process goes outside the proven acceptable range of a critical operating parameter and the batch is
subjected to intensive analytical tests).

In such cases, firms should do all of the following: - Document the reasons for not completing process
validation before shipment of the API; - Perform all of the elements of prospective validation, as
discussed in Section XIII.C., exclusive of replicate production run testing, before releasing any batch
for distribution; - Conduct intensive in-process monitoring and testing, along with intensive testing of
each API batch, to show that each production run resulted in an API meeting its predetermined quality
characteristics and specifications (such data should also be assessed under the validation protocol to
determine consistency of the process);.

- Provide for the Quality Control unit to evaluate batch production records, in-process controls, and
analytical data from each process run to determine whether each batch should be released.

The level of intensive in-process and final API testing should be greater than levels for validated
routine production runs, and should only be reduced to routine levels after the process has been
determined to be validated. In addition, data from production runs that are evaluated as part of the
validation studies should encompass the operating ranges that are approved for use during routine
process control.

The Agency cautions that this validation approach should be applied with discretion so as not to: -
Unduly delay completion of, or avoid performing, meaningful validation; or - Distribute API batches
manufactured before completion of validation for a prolonged period of time.

This approach should not be viewed as a viable alternative where the number and frequency of API
production runs permit timely completion of validation prior to API distribution. If analysis of data
shows that the process used to manufacture the distributed batches was not, in fact, validated, no
additional batches should be distributed until corrections have been implemented and the process has
been determined to be validated.

Hong Kong
4.7. For concurrent validation, what are the examples of exceptional circumstances? What
level of documentation is expected to justify a concurrent validation?
PIC/S PI006-3, Sections 6.4.1 and 6.4.2, provide some examples of circumstances where
concurrent validation may be justified:
process undergoing transfer to third party;
where the product is a different strength of a previously validated product;
where the product is a different tablet shape; and
where the process is well understood.

The following are also generally regarded as examples of exceptional circumstances when
considering concurrent validation:
Limited demand (e.g. orphan drugs); and
Very short shelf life products (e.g. radiopharmaceuticals).

The use of concurrent validation is usually justified within rationale statements in validation
plans and protocols and should rely on prior process experience and validation, as well as
risk to the product.

4.9 How often should a production process be re-

validated periodically if there is no significant change? How frequently should processes be evaluated
to confirm they remain valid?

Revalidation is mentioned in both PIC/S Guide to GMP Annex 15 (Clause 45) and PI006-3
(Section 6.6 and 6.7). Revalidation does not mean that all processes and equipment need to be underg
o routine retesting. In both documents, the term revalidation is intended to prompt assessment of when
such retesting may be appropriate.
If there is no significant change to a process, and the process is regularly evaluated as
remaining valid, there is usually no need to routinely re-validate periodically.
For most processes, it is a requirement that processes be evaluated routinely (for example, annually as
part of periodic product review) to establish that they remain in a
validated state. Depending on risk, it may be appropriate to perform evaluations more frequently.

4.10 What changes are considered significant and require a revalidation?

Refer to PIC/S Guide to GMP Annex 15 (Clause 43 and 44) and PI006-3 (Section 6.7.4).

The need for revalidation should be considered when change is proposed to a starting
material, product component, process equipment, process environment (or site), method of
production or testing or any other change that may affect product quality or reproducibility
of the process.
The likely impact of the change on the product should be evaluated, including risk analysis
and the need for, and the extent of, requalification and revalidation should be determined.
Changes that are likely to require revalidation include:
Changes of raw materials (physical properties such as density, viscosity, particle size distribution m
ay affect the process or product);
Change of starting material manufacturer;
Changes of packaging material (e.g. substituting plastic for glass);
Changes in the process (e.g. mixing times, drying temperatures);
Changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment w
hich involve the replacement of equipment on a 'like for like' basis would not normally require a re
validation;
Production area and support system changes (e.g. rearrangement of areas, new water treatment met
hod);
Transfer of processes to another site; and
Unexpected changes (e.g. those observed during selfinspection or during
routine analysis of process trend data).

4.11 What type of quality risk management is expected for process validation?
PIC/S Guide to GMP Annex 15, Clause 1 requires a risk based approach to determining the
extent and scope of validation.
PIC/S Guide to GMP Annex 20, Appendix ll, Section ll.6 provides guidance on the
application of risk management to validation:
To identify the scope and extent of verification, qualification and validation activities (e.g. analytic
al methods, processes, equipment and cleaning methods);
To determine the extent for follow-up activities (e.g., sampling, monitoring and re-
validation); and
To distinguish between critical and non-critical process steps to facilitate design of a validation stu
dy.
A risk assessment should form part of all validation projects and include:
Significance/severity and likelihood/probability of a failure;
Consequences (associated risk to product quality);
Other factors (as applicable), including the level of risk due to: level of process knowledge, thorou
ghness of control strategy, level of process fit with facility/equipment; and

4.13 How is process capability determined?

Many product non-conformities are not due to errors but are a result of excessive variation
and off-target processes. Reducing variation and proper targeting of a process requires
identifying the key input variables and establishing controls on these inputs.
A capability study may be used to demonstrate that the process consistently conforms to
requirements and is appropriate for measuring characteristics where non-conformities are
due to variation and off-target conditions.
There are several statistics that can be used to measure the capability of a process -
the most commonly used is Cpk (process capability adjusted for centeredness).

A Cpk of 1 implies that 99.7% of all data points will occur within the specification limits.
The most common acceptance criterion for a capable process is Cpk 1.33, which implies
that 99.99% of all data points will occur within the specification limits. The specific method
for determining process capability is available in texts and online.
Most capability indices estimates are valid only if the sample size used is large enough.
Large enough is generally thought to be about 50 independent data values.

Articol indieni

TYPES OF VALIDATION
Prospective validation

The objective of the prospective validation is to prove or demonstrate that the process will work in
accordance with validation protocol prepared for the pilot production trials. Prospective validation
should normally be completed prior to the distribution and sale of the medicinal product. In
Prospective Validation, the validation protocol is executed before the process is put into commercial
use. During the product development phase the production process should be broken down into
individual steps. Each step should be evaluated on the basis of experience or theoretical considerations
to determine the critical parameters that may affect the quality of the finished product. A series
ofexperiments should be designed to determine the criticality of these factors. Each experiment should
be planned and documented fully in an authorized protocol.

Concurrent validation
It is aprocess where current production batches are used to monitor processing parameters. It gives of
the present batch being studied, and offers limited assurance regarding consistency of quality from
batch to batch. Concurrent Validation means establishing documented evidence a process does what it
is supposed to based on data generated during actual implementation of the process. Concurrent
validation may be the practical approach under certain circumstances. It is important in these cases
when the systems and equipment to be used have been fully validated previously.
Pharmout

Concurrent validation
The draft Annex indicates that concurrent validation may be acceptable in exceptional circumstances
"where there is a strong risk benefit to the patient" but the decision must be justified and documented
in the VMP and approved by authorised personnel.
The current US FDA Process Validation Guidance document provides greater detail on the potential
benefits to concurrent validation. It indicates that concurrent release might be appropriate for
processes used infrequently for various reasons including limited demand drugs,
radiopharmaceuticals with short half-lives or drugs that are medically necessary and are being
manufactured in coordination with the Agency (US FDA) to alleviate a short supply.