Novel Medicinal Products Part II (The EMA’s Guidance)

For Novel Medicinal Products Part I (The FDA’s Guidance), click here.

The EMA and GMPs for Advance Therapy Medicinal Products

by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief

Manufacturing and testing of Advance Therapy Medicinal Products (ATMPs) is generally significantly different from processes used in chemical synthesis of small molecules or cell-based production of recombinant DNA therapeutic products.  The novelty and complexity of these new products prompted the need for rules to ensure that these products were safe/efficacious and that they could move within the markets of the European Community.  To this end, the European Commission adopted the 88-page Guideline on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products on November 22, 2017 to which manufacturers must comply no later than May 22, 2018.  Further, they developed an Action Plan on ATMPs to promote the development and use of these products.  The Guideline on GMPs is now the first document in the new Part IV of the EU Guide on Good Manufacturing Practice for Human and Veterinary Drugs.  More documents will follow governing ATMPs and will be collected in this Part.

This GMP guideline is analogous, in many respects, to 21CFR1271 — the regulations implemented by the the FDA in January 2001 to address ‘Human Cells, Tissues, and Cellular and Tissue-Based Products.’  The FDA recently published a series of guidelines providing clarity on aspects of the regulations, including many examples of product types and specific issues that sponsors may encounter.

Before going too far, it’s important to define what is meant by ATMPs.  Article 2 of the Regulation (EC) No 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 provides the lengthy definition of ATMPs.  This product type is far from homogeneous!  At a high level, the category includes gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products.  And within these categories are the additional complexities of potentially added “…cellular products, bio-molecules, bio-materials, chemical substances, scaffolds or matrices.”  Add to this the devices that may be necessary to isolate, purify, and deliver these products and the complexity only increases.

Many of the features of the GMPs are like those for other products addressed in the EU GMP Guide Chapters and Annexes.  The segment on risk assessment, however, addresses a variety of concerns for sponsors to consider along with provisions for both commercial and investigational ATMPs.  It would be prudent to expect a reasonably robust risk management program to be applied by sponsors from the beginning of the manufacturing of investigational products.  Risk management is important due to the general complexity of the manufacturing process and the variability in the biological materials.  As such, an appropriate level of flexibility must be permitted particularly during the investigational stages of the product lifecycle.  This will likely be unique to the specific product type and will evolve during clinical development as knowledge about both manufacturing and clinical performance grows.  Among the specific areas where risk assessments are clearly called out include:

• Raw Materials:  Sponsors should understand the level of risk posed by raw materials, particularly those that may have intrinsic biological activity.  Raw materials that are critical to product quality and to the manufacturing process should be given extra attention.  Where risks cannot be eliminated, controls should be sufficient to mitigate their impact to product quality and patient safety to an acceptable level.
• Testing Strategy:  Where products cannot be fully tested prior to release, a control strategy should be devised to consider testing of intermediates or in-process materials — tests that can reasonably be assumed to reflect the quality of the final product.  For product with a short shelf life, ‘real time’ testing should be considered as an option.  While process validation is generally not expected for investigational products, it may be appropriate for ATMP products when ‘routine in-process or release testing is limited or not possible.’  In all cases, the testing should be consistent with commitments in the marketing authorization or, for investigational products, in the clinical trial authorization.  The document provides some examples that may be useful to consider in sections 2.38 through 2.43.
• Extent of Manipulation:  Products that do not undergo ‘substantial manipulation’ pose less risk than those which are highly manipulated but are not to be considered risk free.  The sponsor should assess the manufacturing process to determine mitigation strategies that may be employed to bring the risk to an acceptable level.  The sponsor should be aware that the controls in other legislative frameworks may be acceptable for minimally manipulated products.

The GMPs for ATMPs also permit manufacturing in multi-product facilities where cross contamination and mix-ups can be prevented.  (Yes, they use the term ‘prevent’, see section 4.13).  Non-ATMPs can be manufactured in the same facility but manufacturing of the ATMPs may need to occur in a dedicated area.  Again, sound risk assessments should support any decisions regarding separation and segregation.  When infectious viral vectors are employed, these activities ‘…should take place in a segregated area.’  Further, ‘concurrent production of two different ATMPs/batches in the same area is not acceptable.’  Systems may be closed or contained to separate the activities for multiple products/batches including but not limited to the following type of controls (see sections 4.28 through 4.25):

• Use of closed isolators with appropriate controls over exhausted air for concurrent manufacturing of different viral vectors in two isolators may be conducted simultaneously if there is no air recirculation, 100% air exhaustion
• Use of multiple biosafety cabinets is an acceptable approach if material and personnel flows are strictly controlled to prevent crossing of material

Facility design and construction and concerns about the aseptic environment receive significant attention.  The document addresses environmental air quality, viable/non-viable monitoring, and air pressure differentials within the facility.  The document also addresses air vent filters on equipment and indicates that these should be replaced frequently with integrity testing when replaced.

The guideline includes a substantial section on documentation, particularly for receipt records and batch records.  Section 6.6 of the guideline addresses traceability of data from the point of donation to the delivery of the finished product to the patient.  For allogeneic products, the guideline provides a description of seed lots and the call bank system in Section 8.  Section 9 provides extensive description of the requirements for production, and Section 10 addresses qualification/validation.

The guidance includes many sections beyond those mentioned here and should be carefully assessed by manufacturers of this product type.  Like the FDA’s recent publication of guidance documents, the EMA describes similar publications in their action plans that will be developed throughout the next several years.  I would expect additional communications from both health authorities as new technologies are used for these novel product types.