MHRAs reply to Hedley's FOI request and open letter—it didn't say anything new...

...and it didn't answer the burning question!

MHRA replied on time

Some of you may remember this Freedom of Information request I put in to MHRA on 14th November:

FOI request and open letter to MHRA—please share far and wide...

The reply came back yesterday and I replied today.

It wasn’t very convincing

In spite of the timeliness, it didn’t tell me very much. This is it:

“FOI 22/1125 

Dear Hedley Rees,

Thank you for your email with attachment concerning : PART IV “Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products (ATMPs)”

By way of background it might be helpful if I explain that recitals 17 and 21 of the main ATMP Regulation 1394/2007 reports that:

“(17) The manufacture of advanced therapy medicinal products should be in compliance with the principles of good manufacturing practice, as set out in Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (3), and adapted, where necessary, to reflect the specific nature of those products. Furthermore, guidelines specific to advanced therapy medicinal products should be drawn up, so as to properly reflect the particular nature of their manufacturing process.”

“(21) The operation of this Regulation requires the establishment of guidelines to be drawn up either by the Agency or by the Commission. Open consultation with all interested parties, in particular Member State authorities and the industry, should be carried out in order to allow a pooling of the limited expertise in this area and ensure proportionality. The guidelines on good clinical practice and good manufacturing practice should be laid down as soon as possible, preferably during the first year after entry into force and before the date of application of this Regulation.”

Article 5 of the ATMP Regulation on Good Manufacturing Practice also provides:

“The Commission shall, after consulting the Agency, draw up guidelines in line with the principles of good manufacturing practice and specific to advanced therapy medicinal products.”

As a result of this Annex 2 of the GMP Guide, was revised as a consequence of the adoption of the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products pursuant to Article 5 of the ATMP Regulation  which  came into operation on 26 June 2013.

The second set of changes made to GMP on ATMPs was the creation of Part IV. DG Sante held 2 public consultations in 2015 and 2016 in the lead up to Part IV, which gave opportunities for public comments. The guidance was then finally published in 2017 in Eudralex Volume 4, see also Commission text at https://www.ema.europa.eu/en/news/new-guidelines-good-manufacturing-practices-advanced-therapies

The text on the cover page: reports “These Guidelines are specific to ATMPs. Other documents developing GMP requirements for medicinal products which are contained in Volume 4 are not applicable to ATMPs, unless specific reference thereto is made in these Guidelines.” Clarifying  DG Sante’s intention for Part IV to be a stand-alone GMP guidance so is not aligned with other definitions including reconstitution and is also separate from other GMP updates. Given the above restrictions, the European Commission removed references to ATMPs from Annex 2 through a further amendment of the 2013 version and came into operation in 2018, this is in Eudralex Volume 4 at the above link.

The print version of the 2017 Orange Guide did not contain the PART IV guidelines because they were not adopted. However the guidance went into the online version which is available on Medicines Complete. PART IV was then added to the 2022 print version of the Orange Guide. The Editors note on page 480 provides:

“These Guidelines are specific to ATMPs.

ATMP manufacturers should comply with these Guidelines and relevant paragraphs of Part I of the GMP guide.

In addition, Annex 2A* of PIC/S GMP also provides further advice on GMP standards for advanced therapies, on GMP principles and also specific process controls such as those for vectors.”

See PICS GMP Guide (Annexes) (picscheme.org).

All GMP guidelines are available on  EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

I hope that this information addresses your concerns raised in your questions 1 to 4.

1. Is this change fully aligned with EUs REGULATION (EC) NO 1394/2007 on ATMPs?

2. Since these new regulations, allowing thawing, manipulation of multi-dose products, etc, were only introduced this year, how was it possible to approve frozen mRNA vaccines under The Orange Guide 2017 edition?

3. Has a formal consultation involving UK organisations impacted by the change been undertaken? (MHRA routinely holds consultations, for example “Consultation on how MHRA communicate with healthcare professionals to improve medicines and medical devices’ safety”).

4. Why does the change apply to ATMPs only?

In relation to reconstitution, the reference made in GMP is an activity performed at the site of administration after batch certification of a finished ATMP. The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1013) specifically excludes reconstitution from the manufacture:

“manufacture”, in relation to an investigational medicinal product, includes any process carried out in the course of making the product, but does not include dissolving or dispersing the product in, or diluting it or mixing it with, some other substance used as a vehicle for the purposes of administering it; (Regulation 2 Interpretation)

The Human Medicines Regulations 2012 (SI 2012/1916) provides the same clarity:

“manufacture”, in relation to a medicinal product, includes any process carried out in the course of making the product, but does not include dissolving or dispersing the product in, or diluting or mixing it with, a substance used as a vehicle for the purpose of administering it; (Regulation 8 General interpretation)

ATMPs in the UK are regulated under the Human Medicines Regulations 2012 (SI 2012/1916).  The conduct of clinical trials on medicinal products for human use in the UK are regulated under The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031). The manufacture, distribution and other associated activities of an authorised ATMP must be carried under a Manufacturer’s Licence (MIA) and the Marketing Authorisation (MA) granted for that product.  Similarly the manufacture, distribution and other associated activities of an ATMP IMP at clinical trial must be carried under a Manufacturing Authorisation (MIA(IMP)) and the Clinical Trial Authorisation (CTA) granted for that investigational medicinal product. Unlicensed ATMPs can be made available in the UK via the hospital exemption route requiring a Manufacturer’s Licence Exempt Advanced Therapy medicinal Products (MeAT) or the ‘specials’ scheme under a Manufacture’s Specials Licence  (MS).

With regards to question 5,  

5. Given that the change has been implemented, additional urgent questions arise:

a. Under the terms of a Marketing Authorisation (MA), the Marketing Authorisation Holder (MAH) has full responsibility for the safety of its product(s), and the associated responsibility for pharmacovigilance. How will a MAH fulfil its responsibilities to the licence, for an ATMP, when a third-party organisation can make unlicensed changes to the product?

b. The same question applies to sponsors of clinical trials for ATMPs.

Information on the method of reconstitution is detailed in the MAA or CTA submissions, and made available by the MAH or Sponsor to sites involved in administration of ATMPs via the approved SmPC or Clinical Trial documentation such as the Pharmacy Manual.  

Pharmacovigilance is set out in both the Human Medicines Regulations 2012 (SI 2012/1916) (Part 11) and The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) (Part 5).

c. What actions have been taken to ensure that hospital pharmacies (MHRAs example), provide equivalent controls over product quality compared with Good Manufacturing Practice (GMP)? For example, provision of staff training, standard operating procedures, equipment validation, and investigation of quality deviations?

d. What provisions are there for hospital pharmacies to comply with Good Distribution Practice (GDP) also?

e. What is the alternative Quality System for hospital pharmacies?

A hospital pharmacy operates under section 10 of the 1968 Medicines Act and Regulation 4 of the Human Medicines Regulations 2012. They are regulated by the Care Quality Commission (CQC) in England and their equivalent bodies in Scotland, Wales and Northern Ireland who inspect to ensure standards are met.  MHRA only regulate those required to hold a manufacturing licence or authorisation referred to above.

EU guidelines on Good Distribution Practice is applicable to the licenced wholesale dealers and manufacturers  (WDA(h), MIA, MS and MeAT holders)

f. Aside from hospital pharmacies, what other organisations will be allowed to reconstitute ATMPs according to the change?

Any healthcare institution that can meet the requirements of UK medicines legislation and is regulated to provide such healthcare.

We hope that this clarifies matters for you.

If you have a query about the information provided, please reply to this email.

If you disagree with how we have interpreted the Freedom of Information Act 2000 in answering your request, you can ask for an internal review. Please reply to this email, within two months of this reply, specifying that you would like an Internal Review to be carried out.

Please remember to quote the reference number above in any future communications.

If you were to remain dissatisfied with the outcome of the internal review, you would have the right to apply directly to the Information Commissioner for a decision. Please bear in mind that the Information Commissioner will not normally review our handling of your request unless you have first contacted us to conduct an internal review. The Information Commissioner can be contacted at:

Information Commissioner’s Office

Wycliffe House

Water Lane

Wilmslow

Cheshire

SK9 5AF

Yours sincerely

MHRA Customer Experience Centre

Communications and engagement team

Medicines and Healthcare products Regulatory Agency

10 South Colonnade, Canary Wharf, London.”

It was the usual reference to websites and other bodies—this is my reply

“Dear MHRA Customer Services,

Thank you for this timely response to the FOI submitted on 14th November 2022 – much appreciated. Unfortunately, however, it does not provide convincing answers to the questions raised, explained as follows:

The questions relate to a substantial change in the 2022 edition of Rules and Guidance for Pharmaceutical Manufacturers and Distributors (The Orange Guide). This is in regard to reconstitution activities applicable to ATMPs only from January 2022 onwards.

You will know that The Orange Guide has a long history of being the GMDP ‘bible’ for practitioners operating in pharmaceutical supply chains (of which I am one). That is confirmed in the Preface to the 2022 Edition written by Dr Laura Squire OBE Chief Healthcare Quality and Access Officer, dated January 2022:

“Although much of the text of this book is available in its original form in other places, including various websites, I am pleased that the Orange Guide continues to satisfy a demand for information in one authoritative and convenient place.”

Under those circumstances, it would seem reasonable for MHRAs authoritative publication to alert practitioners in the pharmaceutical supply chain to such a sweeping change that would allow hospital pharmacies to carry out the following activities mentioned in my original FOI:

• Thawing, washing, buffer exchange, centrifugation steps necessary to remove preservation solution (e.g dimethyl sulfoxide [DMSO]), removal of process related impurities (residual amount of preservation solution, dead cells) including filtering

• (Re)suspension, dissolution or dilution with solvent/buffer, dispersion;

• Mixing the product with patients own cells, with an adjuvant and/or other substances added for the purposes of administration (including matrixes). However, the mixing of a gene therapy vector with autologous cells is a manufacturing activity that should be conducted under GMP;

• Splitting the product and use in separate doses, adaption of dose (eg cell count);

• Loading into delivery systems/surgical devices, transfer to an infusion bag/syringe.

This compares with the 2017 Edition of The Orange Guide, which defines ‘reconstitution’ as:

Reconstitution should be understood as a simple process of:

• Dissolving or dispersing the investigational medicinal product for administration of the product to a trial subject,

• Or, diluting or mixing the investigational medicinal product(s) with some other substance(s) used as a vehicle for the purpose of administering it,

• Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product.

• An investigational medicinal product must exist before a process can be defined as reconstitution.

• The process of administration must commence as soon as practicable before administration.

• This process has to be defined in the clinical trial application / IMP dossier and clinical trial protocol, or related document, available at the site.”

Please note bullet 3: “Reconstitution is not mixing several ingredients, including the active substance, together to produce the investigational medicinal product.”

Given this is such a major change to the Orange Guide, it would be expected that it should be mentioned with the other changes flagged up in the Preface, described by Dr Squire. There is no mention of the change whatsoever, as far as I can detect.

I do note, however, receipt of an email from UKs Advanced Therapies Network, dated 28/11/2022, the text of which is below:

“Dear Hedley,

The Advanced Therapy Treatment Centres, Cell and Gene Therapy Catapult and London Advanced Therapies are collaborating on a training needs analysis of NHS staff involved the supply chain of Advanced Therapy Medicinal Products (ATMPs) in hospitals – this work being undertaken by Ernst and Young. Given the different perspectives of the people involved with these treatments, it is important to understand the learning and education needs of those involved in order to attend to the needs of the present, and prepare the development of the future, ATMP NHS workforce.

 As part of this analysis, we have created a survey to gain more insight into the diverse needs across the different roles involved.  If your role is involved anywhere in the ATMP supply chain, we kindly ask you to participate, you may access the survey here.

 The survey will take approximately 10 minutes to complete. If possible, please aim to complete this survey in the next 5 days. Your time and participation is much appreciated. 

 Please feel free to circulate to your colleagues who work with ATMPs”.

This makes it very clear that training for NHS staff to comply with this new definition of ‘reconstitution’ activities for ATMPs is in the early stages of planning, while the regulations have been changed to allow it to happen in spite of no training being given to NHS staff. Would you therefore provide clarification of what action MHRA would be able to enforce if a hospital pharmacy undertook ‘reconstitution’ of an ATMP, in patient treatment and administration during either clinical trials or commercial supply?

If you require further clarification of these questions, I would be pleased to oblige.

Kind regards,

Hedley Rees”

Please do let me know what you think: