APR Sept/Oct 2023 - 42

»
BIOPHARMACEUTICAL
»
Incubation Conditions
Incubation conditions should be suitable for the recovery of bioburden
and environmental isolates. It should be in the range of 20-37°C.
Incubation time should be not less than 14 days. A single incubation
temperature for 14 days or two temperatures for seven days each may
be used. If two incubation temperatures are used it is recommended to
start incubation at the lower temperature. Prior to start of incubation
all units should be inverted or manipulated so that the media comes
into contact with all internal surfaces.
Post-Incubation Inspection
After completion of incubation, all APS units are inspected visually
for the presence of microbial growth. Personnel trained to detect
low/high levels and different
types of microbial growth should
perform the inspection. The count of units is performed and verified
after inspection. If non-integral units are found an investigation
should be performed as these should have been detected during
pre-incubation inspection.
All these activities should have the oversight of the Quality unit.
Growth Promotion should be performed after final inspection. In
addition to ATCC cultures the most common environmental isolates
should be used.
Acceptance Criteria
The target acceptance criteria for APS study is zero contaminated units.
Per FDA Guidance for Aseptic Processing.
When filling <5000 units
* One contaminated unit is cause for revalidation.
When filling 5000 to 10,000 units
* One contaminated unit - investigation and possible repeat
aseptic process simulation
* Two contaminated units- revalidation following investigation
When filling > 10,000 units
* One contaminated unit - investigation
* Two contaminated units- revalidation following investigation
Investigation of an APS
Positive/Contamination
A thorough investigation should be performed and documented with
root cause and corrective/preventive actions clearly identified. At a
minimum, the investigation should include the following:
* Species level identification of the contaminant and comparison
to EM/personnel isolates
42 |
| September/October 2023
2.
3.
* Holistic look at all systems and engineering controls
* Environmental trend and recovery review
* Personnel activities and qualification
* Sanitization process review
* Review of batch record, sterilization processes and
any deviations
* Tracing the location of the contaminant and corelating to any
interventions
* Trend review of previous APS
References
1.
FDA Guidance for Industry- " Sterile Drug Products Produced by Aseptic Processing -
Current Good Manufacturing Practices. " September 2004. Guidance for Industry (fda.gov)
PDA Technical Report No. 22 - " Process Simulation for Aseptically Filled Products. " 2011.
GUIDELINES, The Rules Governing Medicinal Products in the European Union Volume 4
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and
Veterinary Use, Annex 1 Manufacture of Sterile Medicinal Products; Brussels, 22.8.2022.
20220825_gmp-an1_en_0.pdf (gmp-compliance.org)
4.
5.
6.
7.
8.
9.
10.
FDA GUIDANCE DOCUMENT, Aseptic process simulation s for Validation of Aseptic
Preparations for Positron Emission Tomography, APRIL 2012, Aseptic process simulation s
for Validation of Aseptic Preparations for Positron Emission Tomography | FDA
21 CFR Part 210, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part 210
-- Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding
of Drugs; General
21 CFR Part 211, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part 211
-- Current Good Manufacturing Practice for Finished Pharmaceuticals
21 CFR Part 600-610s, cGMP for finished Pharmaceuticals, 08/31/2023; eCFR :: 21 CFR Part
600 -- Biological Products: General
TITLE 21--FOOD AND DRUGS, CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT
OF HEALTH AND HUMAN SERVICES, SUBCHAPTER C - DRUGS: GENERAL, Section 501(a)(2)
(B), Jun 07, 2023; CFR - Code of Federal Regulations Title 21 (fda.gov)
EudraLex GMP Part IV section, 9.5.2, 2017_11_22_guidelines_gmp_for_atmps_0.pdf
(europa.eu).
ISO 18362:2016, Manufacture Of Cell-Based Health Care Products - Control Of Microbial
Risks During Processing, first edition 2016-02-01; ISO 18362:2016 - Manufacture of cellbased
health care products - Control of microbial risks during processing (ansi.org).
11. EU GMP, The Rules Governing Medicinal Products in the European Union Volume 4 EU
Guidelines for Good Manufacturing Practice for Medicinal Products for Human and
Veterinary Use, 22.8.2022; 20220825_gmp-an1_en_0.pdf (europa.eu).
12.
13.
14.
15.
16.
BS EN ISO 13408-1:2015, Aseptic processing of health care products General requirements;
2015-08-31; BS EN ISO 13408-1:2015 Aseptic processing of health care products General
requirements (en-standard.eu).
PDA Technical Report No. 22, (TR 22) Revised December 2011 Process Simulation for
Aseptically Filled Products.
PDA Technical Report No. 28 Revised September 2006, (TR 28) Process Simulation Testing
for Sterile Bulk Pharmaceutical Chemicals.
Stuart Russell, Peter Norvig, Artificial Intelligence a Modern Approach, Fourth Edition,
Pearson, 2022.
Johannes Ernesti, Peter Kaiser, Python 3 - the Comprehensive Guide; Rheinwerk
Computing, 2022, Boston, MA.

APR Sept/Oct 2023

Table of Contents for the Digital Edition of APR Sept/Oct 2023