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
- 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
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
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.
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