In the last "Focus on Quality" column (1), I noted that the risk analysis methodology used in the GAMP Good Practices Guide for Validation of Laboratory Computerized Systems (GPG) (2), which was based upon failure mode effect analysis (FMEA), was too complicated. The rationale was that we purchase mostly commercial software in regulated laboratories that already has been tested by the respective vendor. Therefore, why do we need to potentially repeat work that has already been performed?

In this column over the past few years, I have not mentioned in any great detail guidance documents on computer validation but started the discussion on a specific topic from the regulations themselves. This is due to the fact that most guidance has concentrated to a large extent on manufacturing and corporate computerized systems rather than laboratory systems including spectrometers.

This has changed with the publication of the Good Automated Manufacturing Practice (GAMP) Forum's Good Practice Guide (GPG) on Validation of Laboratory Computerized Systems (1). However, this publication needs to be compared and contrasted with the AAPS publication on Qualification of Analytical Instruments (AIQ) (2). Both publications have been written by a combination of representatives from the pharmaceutical industry, regulators, equipment vendors, and consultants.

Overview of the Guide

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"The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose" (International Conference on Harmonisation Guideline Q2A). 1 "Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use" (US Food and Drug Administration Draft Guidance for Industry, 2000 ). 2

So, is your assay fit for the job ?

All pharmaceutical validation projects are labor and capital intensive, and each must be planned and managed carefully. Numerous tasks and activities must be identified early and then scheduled to support the project completion date. Stakeholders such as the Quality Assurance (QA) and Calibration–Metrology departments must be alerted to impending increased workloads under compressed time frames. Standard operating procedures (SOPs) and protocol formats must be developed, test equipment must be purchased or rented, and contractors must be evaluated and hired. Managers must decide whether the US Food and Drug Administration will participate in the design review process, and if so, what will be the agency's exact involvement and participation. Considering the set of activities and programs that require timely completion, pharmaceutical validation projects must be carefully organized, managed, and monitored.

In 1987, when the US Food and Drug Administration issued its Guideline on General Principles of Process Validation, a young FDA reviewer asked her supervisors, "What does this term validation really mean?"

"We don't know," they responded.

Much has changed in the past 18 years. So much has changed, in fact, that the current concept of process validation, once a fresh idea in quality control, and which later became accepted dogma, may now be ready for the trash bin. With companies achieving new levels of process understanding, what does it mean to validate a manufacturing process? Industry leaders and FDA are now examining that question and looking at new models to follow.

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Although the prevalence of IgE-mediated latex allergy has increased over the past decade, the circumstances which culminate in sensitization remain uncertain. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized. BALB/c mice administered latex proteins by the subcutaneous, topical, intranasal, or intratracheal routes exhibited dose-responsive elevations in total IgE. In vitro splenocyte stimulation initially demonstrated specificity of the murine immune response to latex proteins. Subsequently, immunoblot analysis was used to compare latex-specific IgE production amongst sensitization routes. Immunoblots of IgE from subcutaneously sensitized mice demonstrated recognition of latex proteins with molecular weights near 14 kDa and 27 kDa.

WHO- EDM 1/2002 Validation Part 4 : Q.C. related validation

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Validation was hinted in the 1960s, almost four decades ago. What has changed over the last 30 o 40 years? Has the overall understanding of the term improved? Have all responsible firms truly embraced validation? Are they doing everything within their power to make validations a success? Unfortunately not. While validation is a very necessary element of any firm that falls under the scrutiny of the governing regulatory agencies – both United States and foreign – it has not received the recognition it deserves.

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A Statistically Valid Time Frame or Number of BatchesHow large of a sample set is needed of previously recorded data to determine ranges that are truly representative of the process, and will the ranges be useful in the Validation effort and not set o­ne up for failure? This is a difficult question to answer, and it is important to note that the batches selected should have no changes between them, thus be produced with the same processing conditions. The draft FDA Guidance for Industry, Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients from March of 1998 suggests that 10-30 consecutive batches be examined to assess process consistency.


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