Conference Review on the European Validation Conference, May 4-5 1999, Berlin, Germany

GMP-News Nr. 35

GMP-News No. 35
23 June 1999


Conference Review

European Validation Conference
May 4-5, 1999
Berlin, Germany

The European Validation Conference, organized by the European Compliance Academy (ECA) together with CONCEPT HEIDELBERG took place in Berlin from May 4 – 5, 1999. Here representatives of pharmaceutical companies, supervisory authorities and service providers discussed the current status and trends as regards validation and qualification. Workshops on the topics "Cleaning validation" and "Risk analysis by FMEA" rounded off the conference.

The first paper was presented by Robert DELATTIN, a GMP inspector in Belgium. He gave a general overview of the regulatory requirements in the EU concerning validation. His announcement that the PIC Document PH 1/96 "Principles of Qualification and Validation in Pharmaceutical Manufacture" in the revised version (PIC/S PR 1/99-1) has been valid since March 1 was received with particular interest. Another surprise was Mr. Delattin's announcement that PIC/S PR 1/99-1 will form the basis of a 15th annex to the EC Guide. It is expected that this annex will be available by the end of the year.  

Conference site: Berlin-Köpenick
We would like to thank the UNIVALID company, Amsterdam for supplying us with the photographs on this page.

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Dr. Hermann ALLGAIER from Life Sciences Meissner + Wurst GmbH, who was the moderator on the first day of the conference, outlined the "FDA Requirements for Equipment Qualification and Process Validation". He focussed in particular on the planned changes in the Code of Federal Regulations (CFR) whose paragraphs 210.3, 211.22, 211.220 and 211.222 provide definitions on the topics of validation, responsibilities as regards validation, information on scope and documentation of validations and on method validations. He gave an especially interesting description of the warning letters 97/98 which list the following validation deficits in particular:

  • Failure to apply scientifically sound or appropriate validation principles
  • Deviations from validation protocols or procedures
  • Lack of software validation for automated processing equipment
  • Inadequate documentation

It was particularly remarkable that 75% of all validation deficits concerned active substances (see Fig. 1)  

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Fig 1. Warning Letters Fiscal Year 1997/1998 Percentage of Qualification /Validation Issues

Dr. Stephane BUREAU from Parke-Davis, spoke about Failure Mode and Effects Analysis (FMEA) as a tool for risk analysis. He sees the major advantage of this method in the identification of potential risks and their influence, and that the validation activities focus on those items which have the greatest risk.

An FMEA is based on three questions: 

What happens if a failure occurs?
- Evaluation of the occurrence

What are the possible effects of this failure?
- Evaluation of the significance

Is the failure discovered when it occurs?
- Evaluation of the discovery

Each of these three questions is ranked on a scale of 1 to 5. The individual scores are then multiplied with one another to yield a risk priority number (RPN).

After the average RPN has been calculated, corrective measures are initiated where the RPN exceeds the average. This improves the processes, and validation activities are concentrated on high-risk items, i.e. a streamlining takes place. During the post-conference workshop participants created an FMEA on the basis of practical examples.

Christopher WOOD from Glaxo Wellcome spoke about the status of the ISPE Baseline Commissioning & Qualification Guide. The Baseline is one of two horizontal guides compiled together with the FDA in order to define the basic requirements in consultation with the authorities. C. Wood differentiated between direct and indirect systems, and systems with no influence on product quality. In all three cases Good Engineering Practice (GEP) must be applied. These are established technical industrial standards which are applied in adaptation to the regulatory requirements of the pharmaceutical sector.

In case of indirect systems commissioning takes place. This is a comprehensive approach in which the planning, documentation and project management are structured in order to maintain the prescribed design criteria and user specifications.

According to C. Wood, qualification activities (classical IQ, OQ) are only necessary in the case of systems with a direct influence on product quality.

It is interesting to observe that the ISPE C&Q Guide avoids using the term "Design Qualification" and uses instead the term "Enhanced Design Review". The purpose of this is to avoid mix-ups with regulatory requirements from the medicinal products sector. In this sector "Designing" is strictly regulated.

The goal is to submit the complete Guide to the FDA for review in November 1999 so that it can be published as an official document in the first quarter of the year 2000.

"Streamlining validation" and therefore also cost reduction was also the topic of the second talk by Dr. Hermann ALLGAIER from Life Sciences Meissner + Wurst GmbH. Using a complexity matrix, he demonstrated how extensive the validation and qualification activities within a company are.

Overlooking the conference hall

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For Dr. Allgaier the integration of qualification and validation activities is the key to increasing the efficiency of validations.

This also includes in particular:

  • The avoidance of duplication of work
  • Focusing responsibilities
  • Integrating and coordinating activities

He illustrated this using an Engineering Turnover Package Approach.

Dr. Hans H. SCHICHT of Contamination Control Consulting presented an overview of the current and future regulatory requirements in Europe and the USA concerning clean zones. He said that, in addition to the European body of regulations (EC-GMP Guide) and the FDA aseptic Guideline and the U.S. Pharmacopoeia Draft Proposal, the ISO standards play an important role. Particularly ISO 13408-1 gives particle limits for rooms in which aseptic production takes place. A classification of rooms is also found in ISO 14644-1. Information on the qualification of rooms is found in ISO/DIS 14644-4, while requalification requirements are described in ISO/DIS 14644-2.

A proposal of Dr. Schicht's for the classification of rooms for non-sterile manufacture was also discussed.

The last talk of the day was held by Walter TRAMPEDACH of CONCEPT HEIDELBERG. His topic was entitled "The qualification of water systems in accordance with the current GMP requirements". After a brief introduction to the options for water systems W. Trampedach described the individual qualification stages (DQ, IQ, OQ, PQ) in detail and provided practical examples as regards documentation.

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Table Top Exhibition

 

In his first presentation W. Trampedach placed very great importance on the correct compilation of a DQ. Not only does this reduce complaints as regards the executed shipment but it also simplifies the IQ. He named the minimum SOP's necessary for operating a water system as follows:
  • operation SOP
  • inspection SOP
  • calibration SOP
  • cleaning SOP
  • maintenance SOP
  • sterilization SOP
  • filter control SOP

and  

  • the machine logbook

In full agreement with the PIC/S PR 1/99-1 W. Trampedach sees the PQ as the first step in the validation of the system.

W. Trampedach's statement that as of 1 July '99 the European Pharmacopoeia, like the USP, will require conductivity measurements (at 20 °C not more than 1.1µS ž cm-1) and TOC measurements (not more than 0.5 mg/l) was received with astonishment. Some wet chemical and physical tests, however, will be dispensed with. 

The first talk on the second day was held by Dr. Helmut BENDER of Boehringer Ingelheim Pharma KG. He described what requirements from the point of view of qualification and validation are placed on pharmaceutical development and production of clinical samples. Dr. Bender dealt in depth with the "FDA Guideline on the preparation of investigational new drug products". This states clearly that in the production of batches for early clinical phases, the implementation of process validation is only possible to a limited extent. For this reason, an expanded in-process and finished product control is required. He named risk analysis as a decisive factor for being able to implement validations economically. He considers possible tools to be FMEA (see above), HACCP (Hazard Analysis and Critical Control Points) and HAZOP (Hazardous and Operability Analysis).

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Discussing during lunch:
W. Trampedach, Concept Heidelberg;
Anthony Trill, MCA

 

On the topic "Streamlining Validation" Dr. Bender recommended in addition to compiling a master validation plan, also combining IQ and OQ to form an "IOQ Plan". This reduces the amount of documentation and improves the legibility of the documents since repetitions are no longer. Some participants criticized, however, that this combined document presents the inspector with very much more data during an inspection, with the danger of intensifying the inspection.  

 
Dr. Paolo VERARDI from Glaxo Wellcome described in his talk the remodelling activities in his sterile powder filling plant. Dr. Verardi described how a new building with new installations would have been distinctly more expensive than the remodelling. The remodelling included arranging the installations in cubicles, a new laminar flow concept, improved filling units and controls, and a new instrumentation with a computer connection (PLC). All of these measures not only contributed considerably improved process and work safety but also had economic effects. For instance, the improved filling installation has saved $ 83,000 in costs.

Dr. Verardi also presented the bioluminescence method for determination of bacteria counts as part of monitoring. This method, which is based on photoemission by released bacterial ATP by activation with luceferin/luciferase proved very practicable. This was confirmed by comparison measurements using the "classical" agar method.

According to Dr. Verardi, the great advantage of the bioluminescence method lies in its rapidity. A significant result can be obtained already after only 10 minutes. 

 

Pat JEATER from Validation in Partnership explained critical aspects in the validation of solid and semisolid dosage forms. At the beginning of his presentation he spoke about the FDA Guide to Inspections of Oral Solid Dosage Forms of May 1994. Using the hypothetical example of " Dr. Faust's Tablets" he explained critical aspects of validation, with reference to examples from GMP Trends in all cases. The process steps are weighing-in, grinding, mixing, grinding, tableting, packaging (see Fig.) 

Fig.

Process for manufacturing "Dr. Faust's Tablets".

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During mixing he considers it important that the validations include determinations of mixing speed, mixing time and degree of filling. The data is confirmed by means of samples taken at critical points. The content uniformity and the bulk and tamped volume are examined. P. Jeater explained that it is important that a plan define when, where and how samples are taken. The handling of the samples is also very important. The more handling takes place, the more potential errors there are.

During grinding the analytical validation should also include distribution of particle size. It should also be defined in the manufacturing specification. The samples are taken after grinding, from the drums into which the ground material is filled. Samples are taken from the bottom, the middle and the top of each drum. The samples are, however, taken at different sites (north, south, west, east and centre).

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Fig.  Sampling after grinding

He considers critical parameters during tableting to be the type of press, type of transport and transport rate of the bulk product, pre-pressing, tableting speed, de-dusting and computerization. Parameters analysed are tablet weight, thickness, friability, hardness, disintegration time and dissolution.

In blister packing a possible adhesion of tablets and the temperature and duration of sealing (possible degradation of the active substance) are aspects relevant for validation. The ISPE baseline "Oral Solid Dosage Forms" may be helpful in the qualification/validation of new production rooms.

As far as semi-solids are concerned, an expansion of the qualification activities may need to be extended to the rooms (HVAC). Since the packaging is an integral part of the product, particular attention should be paid to demixing during packaging.

Dr. Clemens RUFER, formerly of Schering AG, talked about "The requirements for process validation in the active substance production sector". At the beginning he explained the relevant bodies of regulations and pointed out that there is currently no other GMP area in which so much change is taking place. Until now three organizations (FDA, ICH, PIC/S) have compiled drafts on active substance GMP, all of which also contain information on qualification/validation. As regards the necessary steps which should be included in the validation Dr. Rufer showed a highly illustrative pyramid.

"Manufacturing Pyramid"

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Validation activities should start with the step (= critical step) from which influences on the quality and purity of the finished product cannot be ruled out. Dr. Rufer quoted an old Berlin saying to illustrate the term "critical": Critical is when if something goes wrong the end doesn't go right either!

Dr. Rufer also provided examples of the structure of validation plans and reports at Schering. He also pointed out the problems of retrospective validation which is receiving less and less acceptance from the authorities. If, however, retrospective validation is to take place, the mode of procedure must also be described in a validation plan. As regards revalidations, Dr. Rufer said that they are necessary after process changes – in accordance with the changes – and of course in the case of results indicative of a process change (e.g. within the framework of the annual product review). This is why a functioning change control system is very important. Along with SOP´s, the validation documentation and the annual product reviews this is also frequently checked during inspections. 

Dr. Rufer also spoke on the "Current state of the cleaning validation". He began with an outline of the relevant bodies of regulations and pointed out that with the revision of the PIC PH 1/96 paper its chapter on cleaning validation was also revised. Dr. Rufer also considers an SOP or guideline to be necessary which describes the policy and the execution of the cleaning validation in a company-specific form. It should contain the following: 

Objectives

  • General principles (When cleaning validation is/is not necessary)
  • General "Bracketing Concept"
  • Description of the fundamental mode of procedure and the responsibilities

Information on

  • Validation plans
  • Sampling and test methods
  • Selection and definition of limits
  • Validation implementation
  • Validation report

Procedure after completion of the validation (monitoring, review, revalidation)

Dr. Rufer paid special attention to several aspects:

When is validation of cleaning required? The requirement includes all steps in pharmaceutical production and in active substance production at least from the "final intermediate" state (possibly also earlier if residues might be carried on). In the case of campaign production, cleaning is not necessary after every batch, but the cleaning intervals should be defined (numbers of batches and times). For material which is difficult to clean (e.g. filters) Dr. Rufer recommends "dedicated equipment". The standing time between process end and cleaning or until renewed production should also be defined.

  Social Event: Dr. Allgaier, Dr. Verardi, Pat Jeater

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As regards the topic of "Bracketing" Dr. Rufer explained that identical product groups can be combined to form product families if they are really comparable as regards their chemicophysical properties (e.g. solubility). Identical equipment can be combined into equipment families if they are comparable as regards their cleanability (e.g. surface, material). As regards sampling technique (e.g. swabbing) Dr. Rufer urgently recommended that recovery rates be determined.

Dr. Rufer sees the 0.1-% criterion, which is also given in the ICH Impurity Guideline, as a suitable cleaning limit for active substances.

The changes to the chapter on cleaning validation resulting from the new document PIC/S PR 1/99-1 were discussed in detail during the post-conference workshop.

Anthony J. TRILL, Senior Inspector of MCA, spoke on the GMP requirements with respect to computerized systems. A. Trill sees the V-model as a general condition for specification and testing.

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Fig..  V-Modell 

According to A. Trill, attention is paid in inspections to whether the computerized system has a direct influence on the safety and/or quality of the pharmaceutical product. Since computerized processes and data records may also have a direct influence on product quality these are also verified during the inspection.

The GMP regulations mention only very general requirements as regards computerized systems and are therefore open to interpretation, as A. Trill explained. In order to be in compliance, computerized systems should be fully described, documented and their functions defined. They should also be subject to quality-assuring measures, be validated and be in a controlled state. Inspectors therefore pay attention to whether computerized systems are:

  • valid
  • safe
  • accurate
  • reliable  

in the areas of R&D, manufacturing, quality control and along the supply chain, that is up to distribution.

As well-known and useful bodies of regulations on compliance, A. Trill recommends – in addition to the GMP regulations – in particular GAMP 3 and the British document BS 7799.

A. Trill lists the following inspection topics:
  • Non-compliance in supplier audits/QA and product certification
  • Legacy system: retrospective validation and documentation of systems
  • Project management and staff awareness training (QA staff and general)
  • Year 2000 compliance

A. Trill complained that there is presently too little harmonization as regards electronic signatures and reports. In the PIC/S an attempt is made to change this. 

The last talk was by the moderator for the second day, Dr. Norman C. FRANKLIN of Interactive Consulting GmbH i.G. Dr. Franklin began his talk with a historical outline and the current requirements on the topic of changes and deviations, and explained the differences between these two terms. After that he illustrated how the specifications of the CFR can be applied to validation. How should one proceed in the case of deviations? Basically there are four things to bear in mind when a deviation occurs:

  • Determine that a deviation has occurred
  • Examine the deviation
  • Eliminate fault
  • Repeat test

In case of a deviation in validation experiments in the laboratory and in production a fault search should be initiated in order to determine whether

  • a defective device
  • an operating/processing error
  • or other explainable fault
  • was the cause. In these cases a repetition is allowed.

Dr. Franklin also mentioned the draft of the Guidance for Industry on the topic of "Investigating out-of-specification (OOS) test results" which reflects the FDA opinion on this topic.

 

Source: ECA Event European Validation Conference and Post-Conference Workshop ,
5 - 7 May 1999, Berlin

Would you like more information? You can obtain the comprehensive conference documents in English for DM 330.00 plus VAT and postage from CONCEPT HEIDELBERG, Postfach 10 17 64, 69007 Heidelberg, Telephone 06221 / 84 44 0, Fax 06221 / 84 44 84

Author: S. Pommeranz, Project Manager, CONCEPT HEIDELBERG

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