Trends in validation - News from PIC/S and FDA -

GMP-News Nr. 49

12 December 1999

Trends in validation

News from PIC/S and FDA

At the beginning of 1996 the document PH 1/96 "Principles of Qualification and Validation in Pharmaceutical Manufacture" of the Pharmaceutical Inspection Convention (PIC) appeared. This document defined for the first time information for the production sector on the following topics:
  • Validation Master Plan
  • Installation and Operational Qualification
  • Non-sterile Process Validation
  • Cleaning Validation

This document was to undergo "testing" for two years before undergoing revision on the basis of this trial period.

So far, this is probably nothing new.

But is might be news that the document PH 1/96 has already been in effect as a revised document known as PIC/S PR 1/99-1 since March 1999 and also forms the basis for a 15th supplementary guideline to the EC-GMP Guideline. A draft of this 15th supplementary guideline, which will contain GMP requirements for qualifications and validations is to be expected at the end of the year.

The introduction clearly points out that the document PR 1/99-1 was drawn up as a guideline for inspectors but is also to be used by the pharmaceutical industry and active ingredients production. In particular the chapter on cleaning validation has been modified to the effect that reference is also made to active ingredients manufacture.

And what's new from FDA?

The planned changes (Proposed Amendment of Certain Requirements for Finished Pharmaceuticals dated May 3, 1996) of the Code of Federal Regulations (CFR) are still in the air. Paragraphs 210.3, 211.22, 211.220, and 211.222 provide for definitions on the topics of validation, responsibilities as regards validation, information about the scope and documentation of validations and on method validation. The separate subchapter "Process Validation" describes validations in very general terms. The purpose of this is, inter alia, that all manufacturers use the same standards. To make even more sure that validations are "up to date", the manufacturers are to be obligated to name one or more staff member(s) who will be assigned the responsibility and the competence for carrying out process and method validations, etc. for the enterprise. There is no information yet, however, as regards the date of the coming into effect of these planned changes.

But a draft of a guidance for process validation in the area of medical products is new. This very extensive draft (36 pages) also contains examples for qualification reports in its annex.

In addition to a general introduction (chapter 1) and the description of the rationale for process validation (chapter 2) chapter 3 contains definitions. Here FDA stays by Performance Qualification as in the still valid "Guideline on General Principles of Process Validation" of May 1987 and does not regard it as synonymous with process validation, as the PIC/S document PR 1/99-1 does.

In chapter 4 a "process validation decision tree" gives assistance as to whether a process is relevant for validation. This chapter also particularly mentions the need for the validation of software used in the manufacturing process or in a test process.

Chapter 5 describes in great detail what methods and aids can be part of a validation. It deals in particular with control charts and capability indexes (Cpk values) as well as "Failure Mode and Effects Analysis" (FMEA) and "Fault Tree Analysis" (FTA). All in all, the FDA draft pays much attention to statistical aids for risk analysis at the beginning of a validation.

Remark: Interestingly, the PIC/S document PR 1/99-1 also sees the possibility for using capability indexes in validations.

Chapter 6 deals directly with the Master Validation Plan both as a time-related and an organizational planning instrument. It shows relatively extensively what should be contained in validation protocols and in the qualification stages IQ, OQ and PQ. The chapter is rounded off with a short "Review" checklist.

In chapter 7 the FDA draft deals with the topic of revalidation and describes, among other things, when revalidation is necessary. Revalidations do not have to encompass the same inputs as an initial validation but should be carried out on the basis of the situation. The document considers suitable monitoring to be much more important than periodic revalidation, since it allows problems which are developing and changes to be rapidly identified and a revalidation carried out if necessary.

Retrospective process validation is still described (chapter 8). Here it is important that the necessary requirements (stable process without changes) are adhered to and an adequate documentation takes place. This also mean retrospective validations, like all other validations, should be planned in writing and summarized in a report.

The summary (chapter 9) points out that the "Guidance" is to be understood as an everyday tool and therefore very extensive examples (16 pages) for IQ, OQ and PQ reports are to found in the annex.


Although it is only a draft and is aimed towards the validation of medical products the Guidance is well worth reading in order to familiarize oneself with trends in the area of FDA validations. Especially since many of the requirements listed in the document can be applied to drugs, too.



ECA event European Validation Conference and Post-conference Workshop May 5 - 7, 1999, Berlin

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