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Industries · Advanced therapy medicinal products

Advanced therapy medicinal products step by step.

Gene, cell and tissue therapies. Below: the path of one batch as the rules describe it, what MALUTI records at each step, and every record type these documents ask for — built or not yet.

The path of a batch

Advanced therapy · EU GMP Part IV · 23 steps

Your certificate, line by line →

An authorised product

On the market, with a marketing authorisation. The emergency plan for a modified organism belongs to its risk management plan, the assembly in the hospital has to be validated, and when a failing product is supplied at a physician’s request, the authorisation holder and the supervisory authority are told.

A product in a trial

Two signatures instead of one: the authorised person certifies, and then the sponsor releases it for use at the trial site. The certification is kept five years, and when a failing product goes out at a physician’s request it is the sponsor who hears first and the authority next.

The person it is made for

  • Two codes, and the link between them never breaks

    1 of 2 built

    Bidirectional tracking from donation to the recipient, with the donation code from the tissue establishment, the internal code the manufacturer generates, and a link between them that can always be established — kept thirty years after expiry.

    Part IV §6.35, §6.37

  • The answer comes fast, because a patient reacted

    Built in MALUTI

    Traceability data kept as auditable documents, unequivocally linked to the product, and stored so they can be reached rapidly in case of an adverse reaction.

    Part IV §6.39

  • The product and the patient are matched before it is released

    Built in MALUTI

    For autologous or donor-matched products, the match between the origin of the starting material and the recipient verified as part of certification, with the information on the origin of the cells or tissues checked.

    Part IV §11.27

  • The batch documentation outlives the batch by years

    1 of 2 built

    Batch documentation kept one year after the expiry of its batch or five years after certification, whichever is longer; for investigational products the period is set separately.

    Part IV §6.32

Before production

  • Conformity is checked before anything enters the process

    3 of 4 built

    Conformity of starting and raw materials to their requirements checked before they enter manufacture; antimicrobials used to reduce bioburden removed as soon as possible, and not left to stand in for aseptic work.

    Part IV §7.10, §7.11

  • What is grown comes from a bank, and the passages are counted

    Built in MALUTI

    A master and working seed lot or cell bank system where it can be used, with the number of generations consistent with the specifications in the authorisation.

    Part IV §8.10, §8.12

  • The bank is sealed, labelled, cold and released

    1 of 2 built

    Storage containers sealed, clearly labelled and kept at an appropriate temperature; quarantine and release procedures followed after a bank is established.

    Part IV §8.16, §8.17

  • Premises and equipment are qualified in stages

    Built in MALUTI

    Operational and performance qualification showing the premises and equipment do what they are meant to, with a report summarising the results and the conclusions.

    Part IV §10.21, §10.22

Making it

  • A modified organism gets a risk category and containment to match

    1 of 2 built

    A risk assessment placing the product in a category — negligible, low, moderate or high risk to the environment — and containment measures established to match, covering the design of the premises, the organisation of work and the treatment of residues.

    Part IV §15.10, §15.11

  • There is a plan for the day something escapes

    1 of 3 built

    An emergency plan adapted to the risk covering containment, protection of personnel, cleaning, decontamination and waste, and the notification of the local authorities; for an authorised product it is part of the risk management plan.

    Part IV §15.14, §15.15

  • Nobody carries the modified organism out with them

    Not built yet

    Decontamination when personnel or materials move from an area holding modified organisms to one that does not, or between areas holding different ones, with unidirectional flows where possible.

    Not built: entries and exits are recorded per room, and the order of them is not: nothing here refuses the next room because of the last one, and no decontamination stands between them.

    Part IV §15.13

  • When it is made in several places, one of them answers for it

    1 of 2 built

    A central site identified in the EU, a written agreement with each decentralised site, and the steps of certification and release laid down in writing with no gaps or unexplained overlaps in anyone’s responsibility.

    Part IV §11.46, §11.48, §11.49

  • A deviation far away is approved in writing and reported at once

    2 of 3 built

    A deviation at a decentralised site approved in writing by a responsible person after assessing its impact, investigated to root cause, and every quality defect, deviation or non-conformity reported to the central site immediately.

    Part IV §11.51

  • The transport conditions are shown to work

    Built in MALUTI

    The adequacy of the defined transport conditions — temperature, type of container — demonstrated.

    Part IV §10.52

Releasing it

  • Certification is recorded in a register as it happens

    Built in MALUTI

    The authorised person certifies that each batch was made and checked to the authorisation, and records that certification in a register or its equivalent as the operations are carried out.

    Part IV §11.30, §11.31

  • An investigational product waits for two signatures, not one

    1 of 3 built

    Certification by the authorised person and then release by the sponsor for use in the trial, both documented, with the certification kept at least five years.

    Part IV §11.32, §11.35

  • A short shelf life means certification in stages

    Built in MALUTI

    Assessment by a designated person of the batch records, the environmental results and the analytical results available, allowing release for administration, then final certification once the rest arrive; the delegation and the procedure written down.

    Part IV §11.37, §11.40

  • An unexpected deviation can be certified through, in writing

    Built in MALUTI

    Where the finished product still meets its specification, certification despite an unexpected deviation is possible given an in-depth assessment of its impact and an evaluation of whether the batch belongs in the on-going stability programme.

    Part IV §11.52

  • A failing product may still be given, and every part of that is recorded

    1 of 2 built

    Where administration is needed to avoid an immediate significant hazard, the manufacturer supplies its evaluation of the risks to the treating physician, notifies them that the product is out of specification, records their confirmation to accept it, and informs the authorisation holder and the supervisory authority.

    Part IV §11.53, §11.54

  • In a trial, the sponsor hears first and the authority next

    Not built yet

    The manufacturer immediately notifies the sponsor when an out-of-specification product is supplied at the physician’s request, and the sponsor informs the competent authority.

    Part IV §11.54

After release

  • What the hospital does next is written down by us

    1 of 2 built

    The reconstitution process described — the equipment, the requirements at the site of administration, the waiting period, the rate of temperature change — and the solvents and materials it needs specified or provided.

    Part IV §16.14, §16.15

  • And for a marketed product, it is validated too

    1 of 2 built

    For an authorised product, the reconstitution process validated from the point of batch release to administration, showing it is robust enough not to damage the product on the way.

    Part IV §16.16

  • A defect found later reaches the people who hold the product

    Built in MALUTI

    Quality defects recorded and investigated, and recalls or other risk-reducing actions taken, with the people holding the product told.

    Part IV §14.10, §14.20

What the rules ask, and what is built.

EU GMP Part IV, and the path of a batch above. 24 of 34 record types kept in MALUTI · 10 not built yet.

A record type in our catalogue is one thing a clause asks a site to record. Each is counted once, even when two documents or a step of the path ask for it. “Kept in MALUTI” covers what MALUTI does itself and the record it keeps of work your site does. The count shows what we have mapped, not a share of the regulation.

Part IV itself points to four other documents, each for one case: Annex 1 for sterilisation methods (§9.67), Annex 12 where ionising radiation is used (§9.73), Annex 11 for the validation of computerised systems (§10.13, note 17) and the site master file notes of Part III (note 10). They are not counted here.

Not built yet (10)

  • Use only starting materials that Quality Control has released EU GMP Part IV §7.10
  • Keep the bank inventory, and record its temperature continuously EU GMP Part IV §8.16
  • Trace from the donor to the batch and from the batch to the point of use, and keep it for thirty years EU GMP Part IV §6.35, §6.37
  • Supply an out-of-specification product at the treating physician’s written request, and record every part of it EU GMP Part IV §11.53, §11.54
  • Release an investigational product in two steps: the qualified person certifies, then the sponsor releases it for the trial EU GMP Part IV §11.35
  • Describe and validate what the hospital does to the product after release EU GMP Part IV §16.14, §16.16
  • Hold the environmental risk assessment, the containment measures and the emergency plan for a modified organism EU GMP Part IV §15.10, §15.11, §15.14
  • Name the central site and what each decentralised site may do EU GMP Part IV §11.46, §11.48, §11.49, §11.51
  • Hold records for the required years EU GMP Part IV §6.32
  • Notify the authority of theft, loss or a discrepancy SAHPRA Annex B §3 · path step Part IV §15.14, §15.15

And one step of the path with nothing yet to record it — not counted above, because there is no record type for it in the catalogue yet:

  • Nobody carries the modified organism out with them Part IV §15.13
Built in MALUTI (23)ShowHide
  • Run an identity test on every batch received EU GMP Part IV §7.10
  • Hold seed lots and cell banks as master and working generations, and count the passages between them and the product EU GMP Part IV §8.10, §8.12
  • Quarantine a new bank, characterise it and release it EU GMP Part IV §8.17
  • Give the tissue an internal code, and keep its link to the donation code retrievable at once EU GMP Part IV §6.37, §6.39
  • Raise and close deviations EU GMP Part IV §11.52
  • Qualify equipment through URS, IQ, OQ, PQ EU GMP Part IV §10.21, §10.22, §10.52
  • Release a batch EU GMP Part IV §11.30, §11.31
  • Release in stages: transport under quarantine, then conditional certification, then final EU GMP Part IV §11.37, §11.40
  • Act on a failing result that arrives after dispatch and before expiry EU GMP Part IV §11.41
  • Tell the clinical responsible person, and be able to show whom and when EU GMP Part IV §11.54
  • Store records so they survive disaster, crime and neglect SAHPRA Annex B §1 · path step Part IV §6.39
  • Say what makes a batch, and treat a product made for one patient as its own batch EU GMP Annex 2 §27 · path step Part IV §11.27
  • Assemble a batch dossier EU GMP ch. 4 · path step Part IV §6.32
  • Examine each container: labels, damage, broken seals EU GMP Part II 7.20 · path step Part IV §7.10, §7.11
  • Approve a specification, every limit naming its method EU GMP Annex 7 §8 · path step Part IV §7.10, §7.11
  • Register equipment and its qualification SAHPRA §7 · path step Part IV §10.21, §10.22
  • Keep the risk matrix and the validation file ICH Q9 · path step Part IV §15.10, §15.11
  • Run CAPA through action and verification EU GMP ch. 1 §1.4(xiv) · path step Part IV §11.51
  • Monitor conditions in transit EU GMP Annex 15 §6 · path step Part IV §10.52
  • Run an on-going stability programme EU GMP ch. 6 §6.27–6.31 · path step Part IV §11.52
  • Approve and supersede procedures EU GMP ch. 4 · path step Part IV §16.14, §16.15
  • Raise an incident and find the batches around it EU GMP ch. 8 · path step Part IV §14.10, §14.20
  • Recall released product EU GMP ch. 8 §8.22–8.30 · path step Part IV §14.10, §14.20
Done by the site, recorded in MALUTI (1)ShowHide
  • Hold written contracts for outsourced work EU GMP ch. 7 §7.14–7.17 · path step Part IV §11.46, §11.48, §11.49

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