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Questions & Answers


Official and industrial experts regularly answer questions frequently asked during courses and conferences. The first volume of this series covers questions and answers relative to pre-filled syringes.

Questions on Inspection of pre-filled syringe lines Dr. Daniel Müller, Regierungspräsidium Tübingen

If the manufacturer of drug products (pharmaceutical manufacturer) is responsible for processing the packaging material, also called bulk process, a sufficient number of in-process controls need to be performed to monitor the processing process. Do the regulations/guidelines require in-process controls concerning sterility and endotoxin burden in the packaging material to be carried out at appropriate steps during the process (after cleaning, sterilization, depyrogenation)?
On the one hand, GMP guidelines require that processes are accompanied by sufficient and appropriate in-process controls. This "monitoring" shall help to guarantee process stability and therefore also product quality.
On the other hand, critical (quality-defined) production processes - and this also includes the processing process for packaging materials - need to be validated to indicate their suitability. Validated processes should then produce reproducible products of good quality.

Safeguarding all steps of the process with IPC "despite validation" would be an exaggeration. But disregarding IPC totally would be just as pointless. A risk analysis should display the critical steps of the process. For safety reasons those steps are then accompanied by IPC. A classical example for such an IPC carried out generally by the industry involves control of the filling quantity accompanying the batches which is realized regardless of qualification of the filling machine.

Do risk-based classification of possible mistakes and limitation of such mistakes suffice for designing an SOP for the visual control of pre-filled syringes? Are there any differences between routine production of products for the market and the production of clinical control samples?
This is an important step in the right direction. But it should be accompanied by a limitation of the sum of all defect classes in order to maintain the total waste at a reasonable level. An accurate defect description or even better (digital) photos of defect samples or real visual samples should of course round off the defect list. Line clearance of the workstation (clearance of foreign or precursor products) is equally important in the case of each visual inspection. But this is unfortunately lacking in some cases in the SOP for the visual control.

Are there any special requirements for the design of media fills in lines of pre-filled syringes, defining which manipulations must be carried out and which can possibly be omitted? (E.g. changing the filling needles)?
No, because the principle that all operations/manipulations authorized in the routine operation also need to be carried out in the case of a media fill is valid in this case, too. This must also be respected for the aseptic filling lines of pre-filled syringes as well as for vials or ampoules. It is primarily the decision of the firm as to what operations it authorizes for the routine operation. But a media fill can not be misused as justification for unnecessary risks of contamination. That's why a risk based decision is also necessary in this case. And it will certainly be closely scrutinized by the authorities during inspections.

In the case of ready-to-use packaging materials (ready-to-use syringe bodies, stoppers) do the German authorities inspect the manufacturers of these primary packaging materials?
No, there is no corresponding legal basis in place. The Drug Law stipulates the control of manufacturers of drug products and those of active pharmaceutical ingredients. To date the manufacturers of primary packaging materials as well as the manufacturers of pharmaceutical excipients (starting materials) are not controlled or inspected by the authorities. Responsibility for this control lies with the manufacturer of drug products who is obliged to qualify his suppliers - and an audit is certainly part of this process.

Are the authorities inspecting a manufacturer of pre-filled syringes also allowed to view the audit reports, e.g. the reports of an audit concerning the qualification of suppliers of packaging materials?
Yes, and they will certainly do so. These reports are of paramount importance especially in the case of the use of ready-to-use packaging materials (ready-to-use syringe bodies, stoppers) because in these cases the quality-defining process steps such as cleaning (including endotoxin reduction) and sterilization are carried out by the manufacturer of the packaging material and therefore beyond the reach of regular inspections by the authorities. The remaining possibility to inspect in order to achieve consumer protection involves observing the qualification - and the audit reports - of the suppliers by the manufacturers of drug products. In the case of gross violation of the GMP, the authorities would be obliged to have a regulating influence on the suppliers through the manufacturer of drug products.

The production of pre-filled syringes/From glass barrel … to needle syringes

Dr. Stefan Kettelhoit, Gerresheimer Bünde GmbH

How does a manufacturer of syringes define a "batch"?
The definition of a batch differs for bulk and ready-to-use syringes and it may also differ between the individual manufacturers of syringes. At Gerresheimer Buende (GB) a bulk batch represents a manufacturing section with equal manufacturing conditions over a period of about 10 days which means up to 950,000 syringes. In the case of readyto- use syringes the size of a batch is defined by the size of the EtO sterilization chamber and amounts today to 270,000 - 430,000 syringes.

Can each tray be traced back individually?
No. In the case of ready-to-use syringes each box can be traced back individually with the help of the imprinted production date and time. Trays of a bulk syringe batch can of course be traced back according to the batch.

Do manufacturers of syringes control for inclusions and how sensitive is this control?
At present they manually control 100% for inclusions.

The importance of innovative elastomere components

Dr. Mike Schäfers, West Pharmaceutical Service Deutschland GmbH & Co. KG

Can the formation of wrinkles be reduced in the case of fluoropolymere stoppers by using a different form of stoppers?
Yes, there are ideas and tests to redesign the Fluro Tec plunger rod so as to make it less sensitive to wrinkles. But it will not be possible to omit them totally. May I point out to you the very different material properties of the coating (plastic material) and the elastomere (elastic and flexible). The efforts referred to above are still in an experimental phase. Furthermore I would like to mention the fact that the use of the vacuum method of installation has proved itself successful in order to omit folds while installing the plunger rod.

Compiled by Dr Andreas Mangel

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