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Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use PDF Print E-mail
Thursday, 28 November 2013 14:12





of 5 November 2013
on Good Distribution Practice of medicinal products for human use
(Text with EEA relevance)
(2013/C 343/01)


These Guidelines are based on Article 84 and Article 85b(3) of Directive 2001/83/EC (1).

The Commission has published EU Guidelines on Good Distribution Practice (GDP) in 1994 (2). Revised guidelines were published in March 2013 (3) in order to take into
account recent advances in practices for appropriate storage and distribution of medicinal products in the European Union, as well as new requirements introduced by Directive 2011/62/EU (4).

This version corrects factual mistakes identified in subchapters 5.5 and 6.3 of the revised guidelines. It also gives more expla­nations on the rationale for the revision as well as a date of coming into operation.

It replaces the guidelines on GDP published in March 2013.

The wholesale distribution of medicinal products is an important activity in integrated supply chain management. Today’s distribution network for medicinal products is increasingly complex and involves many players. These Guidelines lay down appropriate tools to assist wholesale distributors in conducting their activities and to prevent
falsified medicines from entering the legal supply chain. Compliance with these Guidelines will ensure control of the distribution chain and consequently maintain the quality and the integrity of medicinal products.

According to Article 1(17) of Directive 2001/83/EC, wholesale distribution of medicinal products is ‘all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their deposi­tories, importers, other wholesale distributors or with phar­macists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned’.

Any person acting as a wholesale distributor has to hold a wholesale distribution authorisation. Article 80(g) of Directive 2001/83/EC provides that distributors must comply with the principles of and guidelines for GDP.

Possession of a manufacturing authorisation includes authori­sation to distribute the medicinal products covered by the authorisation. Manufacturers performing any distribution activities with their own products must therefore comply with GDP.

The definition of wholesale distribution does not depend on whether that distributor is established or operating in specific customs areas, such as in free zones or in free warehouses. All obligations related to wholesale distribution activities (such as exporting, holding or supplying) also apply to these distributors. Relevant sections of these Guidelines should also be adhered to by other actors involved in the distribution of medicinal products.

Other actors such as brokers may also play a role in the distribution channel for medicinal products. According to Article 85b of Directive 2001/83/EC, persons brokering medicinal products must be subject to certain provisions applicable to wholesale distributors, as well as specific provisions on brokering.

(1) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67.
(2) Guidelines on Good Distribution Practice of medicinal products for human use, OJ C 63, 1.3.1994, p. 4.
(3) Guidelines of 7 March 2013 on Good Distribution Practice of medicinal products for human use, OJ C 68, 8.3.2013, p. 1.
(4) Directive 2011/62/EU of the European Parliament and of the Council amending Directive 2001/83/EC as regards the prevention of the entry into the legal supply chain of falsified medicinal products, OJ L 174, 1.7.2011, p. 74.

Download this file (GDP rev nov 013.pdf)Guidelines of 5 November 2013
Last Updated on Friday, 27 March 2015 14:06
Guidelines on GDP revised PDF Print E-mail
Thursday, 28 November 2013 13:59

Only eight months after their publication, the Guidelines from 7 March 2013 on Good Distribution Practice of Medicinal Products for Human Use have been revised.

But those who were hoping for major changes and possible less stringent regulations will be disappointed. The new version corrects factual mistakes identified in subchapters 5.5 and 6.3 of the revised guidelines. It also gives more explanations on the rationale for the revision as well as a date of coming into operation. However it completely replaces the guidelines on GDP published in March 2013.

The new text in 5.5. says that "Medicinal products that are nearing their expiry date/shelf life should be withdrawn immediately from saleable stock either physically or through other equivalent electronic segregation." In the old text, also medicinal products that are already beyond their expiry date were included.

The changes in 6.3 were necessary because they might have led to misunderstandings. The revised text requires that "medicinal products returned from a customer (...) should only be returned to saleable stock if they are returned within an acceptable time limit, for example 10 days". The old text required that they "should always be returned to saleable stock if they are returned within an acceptable time limit...".

Here you will find the 5 November 2013 version of the "Guidelines on Good Distribution Practice of medicinal products for human use".

Last Updated on Friday, 27 March 2015 14:06
Qualification, Requalification - frequent Obscurities PDF Print E-mail
Thursday, 10 October 2013 09:15

Qualification, Requalification & Monitoring

1. General

The terms qualification, requalification and monitoring are often mixed up, especially if the somewhat different language from ISO standards is used in the GMP environment. Therefore, the three terms will be explained in the following and then differentiated one from the other by way of the examples watersystem and clean room.
General definitions according to GMP:

  • Qualification: ensuring in the case of new equipment/facilities or equipment entering into service that they serve their intended purpose
  • Requalification*: ensuring that the equipment is still in the qualified state after a change AND periodical assessment of equipment within defined time intervals
  • Monitoring: supervision of equipment or a system - this can be performed continuously or discontinuously

But the topic of requalification* needs to be considered in more detail. Strictly speaking, requalification is not mentioned in Annex 15 of the EU Guidelines to Good Manufacturing Practice which is the guidance document for qualification in Europe. But revalidation is described (e.g. article 45) and since qualification is considered to be a subset of validation, a requalification also is required. There is no setting of time standards. But it should be stipulated when a periodically recurring requalification has to be carried out. These requirements should not be taken and met on a general basis but system-related and risk-based. In many cases this is every 3 to 5 years. But in the case of a fully automated system for the visual inspection of parenterals for example, it could be scheduled already every 1 to 2 years. It is very important that this requalification is not understood as a repetition of qualification. Usually, no new tests or measurements are necessary insofar as the equipment concerned was not changed. Here, requalification is rather a review of data from routine operation. Hence, the quality-related equipment or specification parameters are to be considered and analysed as well as the changes in the equipment and the deviations that took place in the period considered. An analysis of the logbook should also be part of this evaluation. The document should end with a conclusion that informs about the equipment's state: equipment still is considered to be qualified: Yes / No. By the way, GMP inspectors don't consider the annual product review (APR) as substitute for the requalification.

2. Example pharmaceutical water

The first variation already arises in the case of a water system. In the course of the (first) qualification the terms qualification and validation become blurred. Usually, so-called dry runs are carried out during the performance qualification (PQ). This means that the equipment is operated with a substitute material instead of the product. Often the substitute material is water. The real product has to be used in the subsequent validation at the latest. In a water system, the product manufactured naturally is water. Therefore, the PQ, at least the later part, also is considered to be a validation. In this case, the qualification in three steps described by the FDA already many years ago, is industry standard. But the single phases differ as concerns the frequency of sampling and the number of sampling points. The complete qualification lasts up to one year in order to prove that seasonal fluctuations of the feed water's quality as well as different operating conditions don't influence the quality of the produced water.
A requalification has to be carried out after changes have taken place at the water system insofar as the change can influence the qualified state of the water system. The risk analysis carried out in the context of qualification should demonstrate if this is the case. This decision making process should be carried out by means of the change control system in order to be able to understand also at a later date why for example no qualification tests were necessary or why which requalification tests had been determined. As a general rule, requalification then consists of the tests that have demonstrated already during the first qualification for the relevant part of the equipment that the equipment was operating correctly. Should there be a risk for the whole system the qualification has to be repeated. Then quality assurance has to decide whether all phases really have to be carried out. The exchange of the water tank with a tank of another size will probably affect the whole system - the installation of an additional valve presumably only the part of the water system that is concerned. It has to be assessed on a case by case basis whether seasonal effects are to be expected.

As already mentioned, the periodically recurring requalification should include the changes, deviations and logbook considerations as well as an overview of the quality data: microbiology, TOC, conductivity etc.

The monitoring partly takes place continuously (for example in the case of online TOC and conductibility measurements) or discontinuously by means of sampling at defined sampling points with the help of a sampling plan (such as microbiology or TOC) if there is no continuous measurement in the system).



3. Example clean room

In the case of clean rooms qualification also takes place after construction or reconstruction. A qualification is carried out for the HVAC system as well as for the premises themselves (for example verification of surfaces of the walls, lighting etc.). As a rule qualification of the HVAC system is much more extensive. Qualification of the HVAC system is also extended over a longer period, again in order to cover seasonal fluctuations (temperature/humidity/number of particles in the intake air). Constructional changes also require a requalification insofar as they may influence the quality or the qualified state.
In the PQ at the latest a further term is added: classification . Classification is part of the qualification and is supposed to show that the clean zones as defined in Annex 1 with regard to the number of particles in the air are actually met in operation as well as at rest. The classification which is also part of the acceptance test has to be carried out according to ISO 14664-1, the particle number limit is defined by Annex 1. Further qualification tests are for example the recovery time, filter leakage tests or the air speed in laminar grade A zones. For the GMP environment Annex 1 always is the binding document. Should there be contradictory statements Annex 1 prevails over statements from the ISO standards. Another part of the qualification is the microbiological examination of surfaces and of the microbial concentration in the air as concerns compliance with the specifications according to Annex 1 - quasi a microbiological classification. But the requirements of Annex 1 are only binding for the production of sterile dosage forms, that is for zones A-D.

It is often asked which of the measurements have to be repeated regularly, respectively how often and to which extent requalification has to take place. As already explained in Chapter 1 a requalification is required. It does not necessitate a repetition of measurements however, but can be carried out by means of an evaluation of operation or monitoring data - excluding, of course, a requalification after changes. But, other than in the case of water (see 2) recurring measurements certainly are required in clean room areas (analogously to qualification). Such information can be found in ISO 14644-1-3 or rather in the annexes: classification of rooms (according to zones) for example has to be repeated every 12 months, the leakage tests after 24 months at the latest and the recovery test as well. Since Annex 1 requires the application of ISO 14644, strictly speaking, these requirements are valid only for sterile areas (zones A-D). Problems arise, when these recurring tests are termed. In the ISO environment the terms used are qualification or requalification measurements. But this is not quiet correct since then there ought to exist a qualification protocol as is customary in the GMP environment, with an analogous release procedure such as in the original qualification. Sometimes, at this point, the terms 'monitoring' even better 'technical monitoring' are used. But it would also be possible to talk about verification or revision. The term "periodic performance evaluation" also is used. Maybe the review of Annex 15 could be optimised by giving clear definitions.

Monitoring of clean rooms is rather extensive. Apart from the obvious values such as particle concentration in the air and microbiology of the surfaces and the air, differential pressures between different clean room zones, the temperature and if necessary, relative air humidity and the air speed under laminar flow (A) areas are monitored, too. Monitoring can take place continuously or discontinuously. A permanent monitoring is required only for particles in clean room zones A and B. This has to be carried out according to ISO 14644-2. Monitoring of the air pressure differential between two different cleanliness classes has to take place continuously, at least in the zones for the manufacture of sterile products classified according to Annex 1. For solid pharmaceutical production (tablets) for example, there are no defined requirements. They have to be defined by the manufacturer himself. Microbiological monitoring only is possible offline, whereas it is carried out quasi continuously for example by means of so-called settle plates during the filling process in grade A. It is not sufficiently possible to use particle measurement values of the air to assess the microbiological quality.

Last Updated on Friday, 27 March 2015 14:09
Cleaning Validation Requirements in Asia PDF Print E-mail
Thursday, 10 October 2013 09:13

Since the nineties, cleaning validation has been one of the main validation topics discussed by the pharmaceutical industry and APIs manufacturers. Because of growing globalisation, countries in East Asia (Tiger States and Panther States) have also become interesting as consumer countries of APIs and/ or medicinal products. What about requirements on cleaning validation there?
On Singapore's Health Authority site you can find a "Regulatory Guidance" from the beginning of 2013 which specifies the requirements on cleaning validation.
What's new? How similar or different is this guideline from other European or US guidelines on cleaning validation?
The good news is that there are practically no significant differences. The content of the guidance refers entirely to the PIC/S document PI 006, see PIC/S website. Annex 15 of the EU GMP Guide is based on the former version of the PIC/S document PI 006. It also covers the requirements of the Guide to Inspections on Cleaning Validation of the US FDA.

In a word, the taking over of passages from the PIC/S PI 006 document about cleaning validation makes Singapore's requirements directly comparable to the European and US ones.
The guidance document can be found on Singapore's Health Sciences Authority website.

Last Updated on Friday, 27 March 2015 14:10
FDA publishes current list of Drug Master Files (Type II) PDF Print E-mail
Thursday, 10 October 2013 09:12

All holders of a Drug Master File (DMF) for the US market are required to pay a DMF fee when first authorizing the reference of their DMF in a generic application. In addition, Type II API DMFs must undergo an FDA initial completeness assessment. This assessment is described in the FDA Draft Guideline "Initial Completeness Assessments for Type II API DMFs under GDUFA" which was published in October 2012.

If the DMF passes the initial Completeness Assessment, the DMF number will be made publicly available on FDA’s website. The list of Drug Master Files is now available for download.

Last Updated on Friday, 27 March 2015 14:09
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