Monday, August 30, 2010

Auditing Process Validation


Validation is required to ensure that a process, system, material, method, product, piece of equipment, or personnel practice, will meet its intended purpose and function or allow functioning in a reliable, consistent manner. A firm derives little benefit if a thorough understanding of validation remains solely within the validation department.

After four decades of existence, validation is little better understood now than when it was first conceived--beyond the concept of "requiring a minimum of three runs". The term "validation" may differ in meaning from company to company. Validation is demonstrating and documenting that something does (or is) what it is purported to do (or be).

Challenge of the Auditor's Role

Resources to support validation may not be the best for adhering to compliance procedures. Start by understanding the SOPs pertinent to validation and, specifically, process validation. The auditor's role will be to examine executed protocols and reports against internal SOPs and external regulations. In addition to the SOPs governing Process Validation, the auditor needs to know if there have been other commitments against which a process validation should be checked.

o Prior internal audit commitments

o Customer audit commitments

o Internal program initiative commitments (e.g., GMP Program)

o FDA commitments (filing or inspection)

When are Process Validations (or Revalidations) Required?

During R&D, physical and chemical performance characteristics should be defined and translated into specifications, including acceptable ranges, which should be expressed in measurable terms. The validity of such specifications is verified through testing and challenge during development and initial production.

Validation of such processes need not be done before the Regulatory Filing (i.e., NDA, ANDA. Validation commitments may be included in the regulatory filing. The Validation Master Plan should include a periodicity (e.g., bi-annual) and specify revalidation when equipment, or other pertinent element, changes. When Annual Process Review (APR) indicates that "drift" is occurring, revalidation must be done.

FDA Regulations for process controls are included in Part 211--Current Good Manufacturing Practice for Finished Pharmaceuticals , Subpart F--Production and Process Controls , Section 211.100 Written procedures; deviations.

In part, these regulations require written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

Validation Types

There are several different types of validation approaches. The best is "Propsective", since it is planned for and is, therefore, most favored by the FDA.


assesses historical performance; traditionally requires more data, not permitted at some companies, but may be necessary for products that have been in production for a long time and pre-dated current requirements for validation.


gathers data as runs are executed; less than ideal due to lack of pre-planning


planned protocol, pre-validation tasks ensured; FDA-favored

Process Validations (Process Qualifications)

Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics. The intent is to demonstrate that a process repeatedly yields product of acceptable quality. A minimum of 3 consecutively successful cycles--on a given piece of equipment using a specific process--constitutes process and equipment validation. Not only is the process under scrutiny, but the piece of equipment used to deliver that process is as well. Process operating limits should be tested, but not edge of failure. "Robustness" and "worst case" are common goals.

Activities that Occur in Advance of Process Validation

Analytical methods must be validated. Processing parameters and conditions must be specified and approved. There must be an availability of clear and detailed SOPs and Manufacturing Batch instruction which avoid the use of subjective criteria and wide processing ranges (e.g., mix gently for 10 - 60 minutes).

Upstream Tasks to Minimize Variability

Check to ensure that tasks are completed which could add variability to the validation, such as:

-Employee training

-Equipment IQ, OQ, Calibration & Maintenance

-Component specifications

-Environmental requirements (temperature, humidity, controlled air quality)

-Qualification of key production materials

Importance of the Protocol

It is a commitment established by the parties involved with the activity. It involves a description of the activity, the proposed and agreed-upon manner to achieve that goal, the number of runs required to achieve that goal, and the acceptance criteria. It is an FDA expectation that all validation protocols be approved before execution. Typical sources for approval are the department responsible for protocol preparation, the department where the equipment will be installed and the quality group.

Protocol & Acceptance Criteria

Product quality attributes must be detailed in the protocol. "Acceptance Criteria" are often the established Product Specifications. Validation should not be used to establish or optimize processing parameters and specifications. Acceptance Criteria may be more stringent, but should never be less demanding, than the Product Specifications. Watch for subjective statements, since they cannot be validated. Example: ...continue to add water until you have a suitable granulation..."

Test conditions should encompass upper and lower processing limits which place the most stress on the system. Key process variables should be monitored and documented. Data analysis should establish variability of process parameters.

FDA's Perception of the Role of the Quality Unit

Those involved in validation must understand what responsibilities the FDA holds the quality unit accountable for. Ensure that any additional requirements from the quality unit have been met by the executed validation--especially additional testing, repeating questionable tests, and providing more rationale.

FDA Regulations for sampling and testing are included Part 211--Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart F--Production and Process Controls, Section 211.110 Sampling and testing of in-process materials and drug products

In part, these regulations require that written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate: tablet or capsule weight variation; disintegration time; adequacy of mixing to assure uniformity and homogeneity; dissolution time and rate; clarity, completeness, or pH of solutions.

Failure to Meet Acceptance Criteria

Unless the acceptance criteria are met, or there is a sound justification for not meeting them, the goal is not achieved and the validation has failed. When protocol failure occurs, it is customary to conduct an investigation. The investigation should: identify the assignable cause, identify corrective actions, and restart the activity. The importance of this investigation and identification of corrective actions cannot be overstressed. If the investigation does not identify an assignable cause for the failure, the validation must be restarted.

Validating a Transferred Process

In the age of multi-national corporations, it is not uncommon for an R&D unit to be located in one part of the nation (or globe) and the manufacturing unit in another. Thus, when a process is transferred from one place to another, a number of technology transfer points and documents are generated as prospective validation in order to proceed with validation through the various steps of product development. There are many departments involved and they are usually isolated units. Confusion results unless communication is good. Often, a project management team approach will facilitate inclusion of all affected units and identification of all of the steps involved.

Validation of Transferred Technology

Audit checklists can be used to ensure that important elements of the transferred process were not overlooked or misunderstood. Appropriate participants should have approved the protocol and also the final report. If it isn't clear to the auditor, it won't be clear to FDA.

Questions Often Asked During Technology Transfer

Raw Materials

Do specifications exist?

Do they make sense?

Are the test methods reliable?

Are the specifications needed?

What should be specified but isn't?

What is the source of raw materials?

Are there more sources?

What is the grade to be used?

Are the grades interchangeable?


Does the plant have the proper equipment?

Are the batch size and equipment matched?

Does an alternate supplier exist?

Can the equipment in the plant be used--even though the principle of operation is not yet specified?

Process Parameters

Are the set points too narrow?

Are the set points too wide?

How were the set points determined?


How do I sample?

What do I sample?

Where do I sample?

Why should I sample?

How much sample should I take?

What does the data mean after it is obtained?

Final Product

How were the specifications set?

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