Open letter to Ms. Emer Cooke, Executive Director, European Medicines Agency (EMA)

Dear Ms. Cooke,

This is an open letter in relation to a question I submitted via EMAs: Send a question to the European Medicines Agency, on 20/12/2020. This is EMAs acknowledgement of the question:

“We received your question(s) on: 20/12/2020

Subject of your enquiry: GMDP in relation to COVID-19 vaccines that are delivered to vaccination centres bypassing the wholesaler networks

Your question(s):
Dear EMA,

I am an experienced consultant in biopharmaceutical supply- chains. I wish to enquire how the inspectorate with assure GMDP and appropriate quality systems will be maintained with regard to patient safety for the frozen and ultra cold vaccines being assessed for emergency approval? It appears to me that these vaccines are being despatched from manufactures part-finished ie not in the final dosage form for patient administration and there represents a potential risk if untrained personnel, working outside the bounds of a quality system, are employed in ordering, processing and inventory management of the vaccines, also, what is the status in regard to the falsified medicines directive, 2011, in regard to traceability in the case of a serious adverse event of other reason for product recall.

Your, Hedley Rees
This e-mail has been scanned for all known viruses by European Medicines Agency.”

This is the reply I received:

“_Dear Mr. Rees,_

_Thank you for contacting the EMA._

_We would first like to clarify that the EMA rigorous evaluation of Covid-19 vaccines ensures that these medicines meet the necessary quality standards, and this also includes verifying compliance with Good Manufacturing Practice (GMP)._

_In accordance with the requirements of Directive 2001/83/EC, all active substance and finished product manufacturers for Covid-19 vaccines are required to comply with the requirements of EU GMP for medicinal products for human use. Furthermore, Article 80(g) of Directive 2001/83/EC provides that distributors must comply with the principles of and guidelines for Good Distribution Practice (GDP). Having appropriate quality systems to ensure the quality of the product and safety of the patient is a fundamental requirement of both GMP and GDP. Compliance with GDP ensures that medicines in the supply chain are stored in the right conditions at all times, including during transportation._

_Furthermore, as per the requirements of Article 111 of Directive 2001/83/EC manufacturers, located in the Union or in third countries, and wholesale distributors of medicinal products shall be subject to repeated inspections as means of supervision._

_After the product release and distribution, these vaccines are prepared for administration and administered by appropriately trained healthcare professionals using aseptic techniques_ _in line with the detailed handling instructions described in the SmPC (i.e. section 6.6)__. For further details into the arrangements for administration of these medicines, you will need to liaise with the EU National Competent Authority that oversee these operations._

_Lastly, as per requirements concerning biological medicinal products, the name and the batch number of the administered product for each patient is recorded. This allows traceability at batch/lot level should this be required in case or recalls or for pharmacovigilance purposes._

_For further details regarding the authorisation details for the 2 vaccines with require very low transportation temperatures, please see the following links:_



_Kind regards,_

European Medicines Agency

Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
Send us a question. Go to Telephone: +31 (0)88 781 6000″

I am sure you will be concerned, Ms Cooke, that the nature of the question was to address potential patient safety issues, and the answer, at least in my opinion, did not address the concern. I am therefore expanding on the concern here, so that you may decide whatever action you deem appropriate. These are some points I would like to bring to your attention:

  1. The frozen and ultra frozen SARS-CoV-2 sterile injectables could not have been distributed via the established EU pharmaceutical wholesaler network, since the wholesalers only deal with controlled room temperature and refrigerated finished products. It is, therefore, not clear how compliance with EU Good Distribution Practice (GDP), and effective cold chain management, was maintained between the marketing authorisation holders (MAHs) supplying the centres, and the vaccination centres (and other facilities) throughout the various EU locations.
  2. Bona fides of source points would need to be established, orders placed, inventory received and recorded accurately, in-process inventory control carried out, disposition of quarantined and rejected products, etc, etc. As you know, GDP is part of the pharmaceutical quality system. The question arises whether the vaccination centres (and other facilities), were physically inspected by EMA to ensure compliance with GDP and licencing?
  3. In terms of Good Manufacturing Practice for Medicinal Products, the SARS-CoV-2 injectables were to be sterile when received by the user (doctor/nurse/other). This adds an extra level of manufacturing complexity that is dealt with in Annex 1 to basic GMP, titled Manufacture of Sterile Medicinal Products. The Principle of the document states:
  4. “The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination.  Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.”
  5. As you know, this means that only highly skilled operators, working to detailed standard operating procedures, can ensure the product is sterile. There is no way of ‘sterilising’ the product at the end, as this would ruin the product.
  6. Given the above, and in my professional opinion, EMA must prioritise patient safety in considering the above. All production and distribution activities related to the Pfizer/BioNTech and Moderna sterile injectables should be ceased immediately and Article 13: Complaints, product recall and emergency unblinding of Directive 2001/83/EC invoked, which begins:
  7. “In the case of medicinal products, the manufacturer shall implement a system for recording and reviewing complaints together with an effective system for recalling, promptly and at any time, medicinal products in the distribution network. Any complaint concerning a defect shall be recorded and investigated by the manufacturer. The manufacturer shall inform the
    competent authority of any defect that could result in a recall or abnormal restriction on supply and, in so far as is possible, indicate the countries of destination. Any recall shall be made in accordance with the requirements referred to in Article 123 of Directive 2001/83/EC.”

I look forward to you urgent response. If you would like further evidence of the concerns listed above, I would be more than happy to make it available to you and your colleagues at EMA.

Yours sincerely,

Hedley Rees, Managing Director, PharmaFlow Ltd.




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