APR Sept/Oct 2023 - 36

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BIOPHARMACEUTICAL
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isolator). More stringent when performing manual open processing
inside an ISO 5/Grade A Biological Safety Cabinets (BSC). Environmental
monitoring (EM) should be performed during setup activities.
A routine EM program with established methods, frequencies, and
sampling locations should be in place to demonstrate control over
environment. EM during APS should include non-viable air, viable air,
viable surface, viable personnel.
Cell and Gene Therapy Products -
Unique Considerations
Highly product-specific manufacturing processes with inherent
variability:
* Allogeneic versus autologous therapies
* Cryopreserved versus fresh final product
* Centralized versus near-patient manufacturing
Final product consists of viable cells or cell-derived matrices and are
not amenable to final sterilization/filtration. Aseptic techniques are
often required throughout the manufacturing process. Full test results
may not be available before final release.
Cryopreserved Product Versus
Fresh Product
Cryopreserved product
* Generally, a long product shelf life, but may require additional
processing steps
* May facilitate distribution, but requires cold-chain
shipping logistics
* Final container closure suitability and integrity must be
demonstrated after exposure to cryo-conditions (closure
might get adulterated due to lower temperature effect on
closure material)
Fresh product
* Generally, a short product shelf-life
* Final product may be sensitive to shipping conditions
* Full test results may not be available before release
* Demonstration of asepsis during product transportation (e.g.,
leak-proof) can be part of the validation strategy
Applicable Regulatory Requirements
Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act
(statutory cGMP). Title 21 Code of Federal Regulations. Parts 210s -211s
- cGMP for Finished Pharmaceuticals. Parts 600 - 610s - Additional
biological products standards.5-8
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Guidance; Guidance for Industry: Sterile Drug Products Produced
by Aseptic Processing, Current Good Manufacturing Practice
(September 2004).1
EU EudraLex GMP Guide Part IV section, 9.5.2 - Aseptic processing
validation. Describes in general terms some considerations for APS,
referred to as 'aseptic processing validation'. This supports reduced
processing times for closed processes such as incubation, and the use
of segmentation, it may be acceptable to split the process into key
stages and the use of bracketing. Section 9.5.2 also appears to support
the use of alternative approaches to operator participation in a full
process APS for qualification purposes. The manufacturer is required
to consider the relevance of the aseptic process simulation testing for
training of operators.9
EU Eudralex GMP Guide Annex 1, Sections 9.32-9.49 - Aseptic
process simulation (APS). Primarily focused on filling operations but
includes sterile active substances. General requirements for process
APS and qualification of personnel included. 9.39 states manual
processes require qualifying three times for operators and twice per
year thereafter with a batch size that mimics routine manufacturing.11
ISO 18362 Manufacture of cell-based health care products - Control
of microbial risks during processing, acknowledges the fact that not all
starting material may no longer be sterile or sterilized when ATMPs are
processed. To reflect on this, the concept of extrinsic versus intrinsic
contamination is introduced. To challenge the aseptic processing
capabilities of such starting material and processes, the simulation
exercise is split in two parts. One part is the conventional APS test.
This part will focus and challenge the process capability in preventing
contamination from extrinsic sources (classic re-contamination
challenge), while the other part is a process confirmation study to
challenge potential intrinsic contamination sources. Depending on
the starting material going into the process, one of the two or both
types of studies might be required. For process simulation studies for
process including non-sterile starting material, sterile surrogate needs
to be used. For process confirmation studies, necessary for non-sterile
starting material, the studies are to be done with the original material.
With the selection of media for APS studies, ISO 18362 goes beyond
conventional microbiological challenges. The media selected may
need to include growth support for prokaryotic and eukaryotic cells.
The simulation studies need to be designed on the basis of a related
challenge rationale.10
ISO 13408-1; Primarily focused on healthcare products that are
intended to be sterile, but sterilization of final product is not possible;
therefore, aseptic processing is required to control all possible
sources of contamination to maintain sterility of biological product
or systems. ISO 13408 provides general requirements and guidance
on processes, programs and procedures for the development,
validation and routine control of the manufacturing for aseptically
processed healthcare products.12
PDA Technical Reports, TR 22 addresses process capability assessment
for aseptic formulation and filling activities. TR 28 addresses process
simulations
for sterile bulk pharmaceutical chemicals. General
APS guidance beyond regulations, TR 22 covers more current APS
expectations compared to TR 28.13-14
APR Sept/Oct 2023

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