Questions and answers: GMP compliance for active substances (Annex 1: Manufacture of sterile medicinal products)

Questions and answers

EU GMP guide annexes: Supplementary requirements

Annex 1, paragraph 85 states, ‘the integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble-point, diffusive-flow or pressure-hold test.’

The filter-sterilisation process may be physically stressful for the filter. For example, high temperatures during the process may cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater than 0.2 µm in size. The performance of a filter can improve with use, as particles begin to block individual pathways and remove larger pathways that smaller particles could successfully navigate. For these reasons, filters should be tested both before use but after sterilisation and again after use.

Furthermore, testing should be performed in situ in order to verify the integrity of the filter complete with its housing.

2. What are the sampling requirements for sterility testing when a finished product batch of a terminally sterilised medicinal product is made up of more than one steriliser load? H+V October 2008
The sampling plan for sterility testing should take account of the definition of a batch as stated in the glossary of the GMP guidelineExternal link icon together with the recommendations of annex 1 section 93 (section 127 in the February 2008 revision). Each steriliser load is considered to be an independent sub-batch. Consequently, one sterility test should be performed per sub-batch. The number of samples per steriliser load should conform to European PharmacopoeiaExternal link icon requirements, section

Can there be any exceptions to this rule?

For large-volume parenterals where the sterilisation cycle has been qualified with an overkill level, an alternative sampling plan in accordance with a specific internal procedure agreed with the supervisory authority can be accepted (unless already specified in the marketing authorisation).

This procedure should state the need to sample from each steriliser load including the coolest location identified during the steriliser qualification. The number of samples per load should be defined based on a risk-based approach and the overall number of samples per batch should conform to European PharmacopoeiaExternal link icon requirements, section An alternative option, which would require a variation to relevant existing marketing authorisations, would be to introduce a system of parametric release, thereby avoiding the need to carry out the sterility test.

3. What are the key changes in the 2008 revision of annex 1 of the EU GMP? H+V January 2010
The revision provides updated guidance on:

  • classification of the environmental cleanliness of clean rooms;
  • guidance on media simulations;
  • guidance on capping of vials;
  • bioburden monitoring prior to sterilisation.
4. The new revision to the annex includes a number of revised requirements. What steps are being taken by EU authorities to assure the consistent interpretation of the requirements of the revised annex by EU GMP inspectors during inspections? H+V January 2010
GMP inspectors from the EU have worked together with inspectors from SwissmedicExternal link icon to prepare harmonised guidance on the interpretation of the revised annex to be used during the inspection of manufacturers by their Inspectors. This document has subsequently been proposed and adopted as draft guidance by the Pharmaceutical Inspection Cooperation SchemeExternal link icon (PIC/S): GMP annex 1 revision 2008: Interpretation of most important changes for the manufacture of sterile medicinal productsExternal link icon.
5. For an aseptically produced product, where should bioburden monitoring take place? H+V May 2013
According to the EU GMP guidelineExternal link icon (annex 1), the bioburden should be monitored before sterilisation and testing should be performed on each batch.

For routine commercial manufacturing, bioburden testing should be performed on the bulk solution, immediately before its sterile filtration. If a presterilising filter is additionally installed, then sampling for bioburden testing may be performed prior to the prefiltration, provided that no holding time is scheduled for the solution between the two filtration steps.

6. What is the maximum acceptable bioburden level? H+V May 2013
The specification limits for bioburden should be NMT 10 CFU/100 ml, in line with the human and veterinary notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).

When a prefilter is installed, unless otherwise justified, a bioburden limit of 10 CFUs/100 ml before first filtration is achievable in principle and is strongly recommended from a GMP point of view. Higher bioburden limits should not be justified by the high capacity of two consecutive bacteria retaining filters.

However, when appropriate justification is submitted (processes involving fermentation or other biological or herbal components, use of purified water for ophthalmic preparations, etc.), a bioburden limit of higher than 10 CFUs/100 ml before prefiltration may be acceptable. In such cases, it should be demonstrated that the first filter has the capability to achieve a bioburden prior to the last filtration of NMT 10 CFUs/100 ml, in line with the notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).

7. Do I need to follow the requirements of the updated ISO 14644 part 1 standard?
Annex 1 of the EU GMP guide is currently under revision and will take account of the updated ISO standard. In the meantime, for qualification or re-qualification of clean room facilities, medicinal product manufacturers may apply the updated ISO standard with reference to Annex C (counting of macroparticles), or may continue to follow the previous ISO standard. Routine monitoring, however, should continue to be carried out in accordance with the existing Annex 1.
8. Water for injection by reverse osmosis


 limit test for DEG will be performed on each container as a matter of routine.
5. The European Pharmacopoeia limit test for DEG involves a gas chromatographic method, which may be difficult to perform on a large number of containers. H+V December 2007
This point is acknowledged and currently, alternative tests are under consideration with a view to work up a possible change to the identity tests in the monograph. The European PharmacopoeiaExternal link icon DEG limit test remains the official method for confirmation of compliance with the monograph.
6. Are there any considerations applicable to the pharmaceutical assessment of marketing-authorisation applications? H+V July 2008
In application dossiers for new marketing authorisations (MAs), or in case of relevant variations for existing MAs (for example, replacement of an excipient with glycerol) for medicinal products containing glycerol, confirmation of the tests applied on receipt of batches of glycerol to control the risk from potential DEG contamination in relation to the specific intended use of the product should be provided. A test for DEG content should be conducted in addition to identity testing for glycerol. A suitable control for DEG is included in the European PharmacopoeiaExternal link icon monograph for glycerol.

Sufficient information regarding satisfactory control of this risk will be required in the dossier before approval of the MA application or variation.

For existing approved medicinal products, no variation application is required, except for those few specific types of variationsreferred to in the first paragraph. However, as a minimum, the specific European PharmacopoeiaExternal link icon control for DEG should be conducted along with the identity test at receipt of each batch of glycerol. The excipient is required to comply with the current European PharmacopoeiaExternal link icon glycerol monograph, and as the specification approved in the dossier will have been that of the European PharmacopoeiaExternal link icon, the risk of DEG contamination will have been appropriately controlled. Compliance with this requirement will be verified during GMP inspections.

7. My company manufactures products for external use. Does this guidance apply? H+V July 2008
Where a company manufactures products for external use, and when it has justified that the presence of DEG in these products poses a low risk, the omission of the test for DEG on each container may be accepted by the supervisory authority.
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Referance : European Medicines Agency’s answers to frequently asked questions, as discussed and agreed by the Good Manufacturing Practice (GMP) / Good Distribution Practice (GDP) Inspectors Working Group

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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