Hedley Rees' Expert Statement on SARS-CoV-2 injections, Written December 17, 2021: PART 2
Licensing drugs
For those who missed PART 1, here it is:
THE PROCESS OF LICENSING
The process consists of licensing companies to undertake clinical studies in humans, and, if successful, licensing the company to sell the approved product(s) under strict terms of the license.
The licenses are awarded by the competent authority responsible for medicines and healthcare products in each country or region. In the United States, it is the FDA (we will use the US as an example, but all are similar or the same).
The license to run a clinical trial is known as a Clinical Trial Application.
The application must include an investigational medical product dossier (IMPD), with details of the supply chain that will be employed to manufacture clinical trial supplies.
1. Preclinical development and Preclinical development supply chain
Patients receive injections that are produced by the supply chain, so it is crucially important that safety testing is carried out on the batches produced.
The diagram below shows the preclinical supply chain required to assess the safety of the compound under development.
The diagram depicts the production of the active pharmaceutical ingredient (API) and onward shipment to the company responsible for carrying out the safety testing (a contract research organisation, or CRO). Even though this appears to be a simple supply-chain to produce 5 – 10 litres of API for testing in animal models, there is already an array of suppliers and service providers involved, often spanning the globe.
Raw and starting materials are sourced primarily from China, so ex-Asian countries are operating a long way from home, limiting the necessary due diligence and oversight required.
There is also the question of supplier/service provider (CDMO/CRO) timeline in selecting suitable companies with the skills, licenses and commercial terms to carry out the work required.
CMC data and safety data must be collected by the company sponsoring the clinical trial and included in the regulatory filing. The sponsor company can then submit a clinical trial application (CTA), and, if approved, they can move onto trials in humans.
2. Clinical development and Clinical development supply chain
When the time comes to submit the regulatory filing (MAA for MHRA/EMA), assuming clinical trials have gone to plan, the Competent Authority mandates the data be submitted using a common technical document (eCTD).
The next diagram shows the clinical supply chain and the three modules of data that must be collected and included in the licence application.
The sponsor company can then submit a marketing authorisation application (MAA), and if approved, they are able to market the product under the terms of the licence.
On approval, the supply chain for all future production must comply with the registered information, as established during phase 3 clinical trials, is as shown in the diagram above. The marketing authorisation holder (MAH) must ensure that all further production meets the terms of the licence and is carried out in compliance with Good Manufacturing and Distribution Practice (GMDP).
For a typical MAA, the regulatory review takes over 12 months, and includes a series of questions and answers that the applicant must satisfy the regulator on before approval. This could not have happened given the accelerated timescale of conditional approval.
The regulatory review also involves assessment of the inspection history of, at the very least, manufacturers (CDMOs) of the active substance and the Product filled into vials, capped, and sealed in unit doses; also, the manufacturing license of the manufacturers need to have that specific product added to their license before commencing manufacture.
Regulatory inspections typically include two scientifically qualified inspectors spending 3 or 4 days at a facility, going through all the critical aspects of the manufacture, then writing a detailed report of observations, categorised under minor, major, and critical.
Because of SARS-CoV-2, the only inspections were carried out virtually. This would be totally inadequate, as regulatory inspectors must observe the physical flow of products and materials within the facility, the condition of equipment, the level of employee training and competence.
Supply chain management
Management of the supply chain begins with the CTS/MAH producing forecasts and orders for finished product required to meet projected sales demand. These are known in the industry as 12-month rolling forecasts. The first 3 months are firm orders and cannot be changed without the supplier’s agreement. The remaining 9 months are forecasts that may be changed within agreed limits defined in the supply agreement. Often, a further 12 months of forecasts are required to help longer term planning, making them available to the finished product manufacturer (CDMO). That information must be cascaded down through the lower tiers of the supply chain – downstream processing, upstream processing, starting and raw material suppliers.
Significant supply lead-times are involved for each tier in the supply chain, and it is not unusual for raw material suppliers to be producing for finished product demand three years into the future. Along with this is all the negotiation of commercial and technical agreements that must be established between actors along the supply chain, including those storing and transporting product around the globe between the various stages of production.
The other thing to bear in mind is that while forecasts can change very quickly, increases in manufacturing capacity takes investment and long lead times to install.
I cannot envisage any circumstances where such a dramatic ramp up in demand and requirement for new facilities, fully compliant with GMDP, could be achieved in anything less than 3 – 5 years.
Supply Chain for Distribution of SARS-COV-2 Injections
The SARS-CoV-2 vaccines are classed as Biologics, which means the active component is a living thing that must be kept alive and in good condition throughout its lifecycle.
Figure 5. shows the stages involved in producing and supplying a biologic. The overall development programme will span continents, with a plethora of companies at widely different geographic locations involved.
Raw Materials: a large number of suppliers and geographic locations will be involved, sourced from anywhere in the world, although typically they come from China and other Asian countries. Examples of the materials are:
Serum, plasma, reagents, commodity chemicals, antibodies, antigens, hormones.
Starting Materials will be animal or human cell lines. This stage is where Regulatory Authorities stipulate the company developing any medicine, including vaccines, must operate to Good Manufacturing and Distribution Practice as set out in the Rules and Guidance for Pharmaceutical Manufacturers Distributors (2017), the Orange Guide. This applies to both clinical trials (development) and the supply of approved Product for sale. Starting materials are therefore difficult and time consuming to source, as the regulations demand significant control over the quality of the processing operations.
Upstream Processing is where biomolecules are grown, usually by bacterial or mammalian cell lines, in bioreactors. Inputs are raw materials and starting material(s). When they reach the desired density, they are harvested and moved to Downstream Processing.
The purpose of Downstream Processing is to isolate, purify and concentrate the drug substance (DS) received from upstream processing, and fill & cap in a primary container, such as a vial.
Conventionally, the filled vials are secondary packaged to form the finished product, ready to ship into the distribution system. With frozen vaccines, this is not possible as they are packaged, part-finished, into trays for shipment to various storage locations that would not have been licensed to carry out GMP operations.
Upstream and downstream processing is being carried out by contract development & manufacturing organisations (CDMOs), working on a fee-for-services basis, under a supply agreement.
A variety of companies are involved in the development and manufacture of COVID vaccines. These include:
All that in less than 12 months!!!
I’ll leave it for readers to judge, but in my book, with an experienced head on, this is treating the world’s population like idiots.
The trail of negligence and culpability is there for all to see.Thanks Hedley.