EU IMPD Guideline for Biological Products

Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials

Current Guideline is available here:

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational_en.pdf

We highlight the impact of this guidance to CTD sections content.

Please consider the use of our templates for CMC Sections writing for your clinical trials.

---

Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials

Current Guideline available here:

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational_en.pdf

We highlight the impact of this guidance to CTD sections content.

Please consider the use of our templates for CMC Sections writing for your clinical trials.

S2:

· Guideline addition:

"Testing should focus on safety relevant IPC. Acceptance criteria for critical steps (e.g. ranges for process parameters of those steps involved in virus removal) should be available for manufacture of Ph I/II material"

· S2 content:

Include IPCs for pH target and temperature for low pH inactivation step. Filter integrity should be defined as IPC for virus removal step.

· Guideline addition:

"Reprocessing could be considered in exceptional circumstances. For biological products, these situations are usually restricted to certain re-filtration and re-concentration steps upon technical failure of equipment or mechanical breakdown of a chromatography column"

· S2 content:

"Reprocessing is normally not foreseen. If a filter fails to pass the integrity test then it will be necessary to repeat the filtration step for e.g. primary recovery filtration (step 1), virus reduction filtration (step 6) or final filtration (step 7). Currently, this type of reprocessing is limited to a single repetition for the entire purification procedure."

Guideline addition:

"Clonality of the cell banks should be addressed for mammalian cell lines"

· S2 content:

Normal procedure is to include such a justification

Guideline addition:

"If process changes are made to steps involved in viral clearance, justification should be provided as to whether a new viral clearance study is required, or whether the previous study is still applicable."

· S2 content:

Normal procedure is to include such a justification

S3:

no major changes to guideline, no impact on template

S4:

· Guideline addition:

"Tests and defined acceptance criteria are mandatory for quantity, identity and purity and a limit of ‘record’ or ‘report results’ will not be acceptable for these quality attributes".

There is some inconsistency in the guideline, since it also states "Product characteristics that are not completely defined at a certain stage of development (e.g. glycosylation, charge heterogeneity) or for which the available data is too limited to establish relevant acceptance criteria, should also be recorded. As a consequence, such product characteristics could be included in the specification, without pre-defined acceptance limits. In such cases, a limit of ‘record’ or ‘report results’ is acceptable. The results should be reported in the Batch Analyses section (S.4.4)."

There is no guidance regarding how to communicate that such tests are "not completely defined".

· S4 content:

normal procedure is to include limits, but some older products may not have numerical limits for some parameters.

· Guideline addition:

"If validation studies have been undertaken for early phase trials, a tabulated summary of the results of analytical method validation studies could be provided for further assurance."

· S4 content:

tabular summary of method validations is routinely provided

· Guideline addition:

Method validation previously expected for phase II and III studies, but now has been revised to only phase III studies. Method suitability should be demonstrated for phase I and II.

· Guideline addition:

"a statement should be included whether the batch analyses data presented are from the batches that will be used in the clinical trial, or whether additional batches not yet manufactured at time of submission of the Investigation Medicinal Product Dossier (IMPD) might be used."

· S4 content:

A statement such as that required by the revised guideline should be included in the S2 Section

S5:

· Guideline addition:

(new text underlined) "If available, an international or Ph. Eur. standard should be used as primary reference material. Each in-house working standard should be qualified against this primary reference material."

"If an international or Ph. Eur. standard is not available, an in-house standard should be established during development as primary reference material. The stability of the reference material should be monitored."

· S5 content :

stability of reference standards is monitored via routine retesting. When two-tiered RS is implemented, this is routinely qualified against the primary RS.

S6:

no major changes to guideline, no impact on content

S7:

· Guideline addition:

"The methods used for analyzing the stability-indicating properties of the active substance should be discussed, or cross-reference to S.4.3 made"

· S7 content:

cross-reference to S.4 is made

P1:

· Guideline addition:

"an outline of container and closure for the dosage form or any accompanying reconstitution diluent and devices, if applicable. A complete description should be provided in section P.7."

· P1 Content:

Container and closure for dosage form or reconstitute is described. Examples of pre-filled syringe in safety device or auto injector is also provided in the template.

P33:

· Guideline addition:

"A flowchart [...] should be provided accompanied by a brief process description

· P3 Content:

process description included

· Guideline addition

“The IPCs may be recorded as action limits or reported as preliminary acceptance criteria and the focus should be on safety relevant attributes. For other IPCs, monitoring might be appropriate and acceptance criteria and action limits do not need to be reported."

· P3 Content:

Examples of IPCs listed are bioburden, filter integrity and fill weight. The safety critical IPCs are not distinguished

P34:

· Removed from Guideline:

"depending on the volume to be filtered in relation to the diameter of the filter. If this requirement is not met, it is necessary to use a pre-filtration through a bacteria-retaining filter to obtain a sufficiently low bioburden. Due to limited availability of the formulated medicinal product, a pre-/filtration volume"

P54:

· Guideline addition:

"A statement should be included whether the batch analyses data presented are from the batches that will be used in the clinical trial, or whether additional batches not yet manufactured at time of submission of the IMPD might be used"

· P5 Template:

This should be included with extensive detail

P.7:

· Removed from Guideline:

If applicable, the CE mark for an additional medical device should be confirmed.

· Guideline addition:

If a medical device is to be used for administration it should be stated whether the device is CE marked for its intended purpose. In the absence of a CE mark for the intended purpose, a statement of compliance with the relevant essential requirements for medical devices with regards to safety and performance related device features is required. An integral device component of a drug-device combination product, as defined in the Medical Device Directive, is exempt from CE-marking.

· Other additions to the Guideline:

Information regarding comparator and placebo has been added to the guideline. Previously these were not covered.