Issue link: http://www.e-digitaleditions.com/i/1222740
40 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m adds a section requiring a risk assessment of the drug sub- stance manufacturing process to evaluate the theoretical risk of N-nitrosamine impurities formation and, if needed, implement a control strategy to detect and limit these impu- rities (36). A comprehensive list of actions taken by EDQM can be found on their website (37). Containers/packaging. Impurities can be introduced from the primary packaging systems and materials used in the bio/pharmaceutical industry. USP is revising their gen- eral chapter <661> on plastic packaging systems (38) and created two new sub-chapters, <661.1> and <661.2>, that apply, respectively, to the resins used for manufacture of a packaging system and to the packaging systems as a whole. The new chapters become official in May 2020, with the current chapter becoming obsolete in December 2025. This example highlights the value in companies commenting when new drafts are proposed by the pharmacopoeia. The original requirements and timelines proposed by USP were unrealistic for the industry to adopt. After many public meetings where the industry explained the difficulty to comply in the specified timeframe, USP provided this de- layed implementation so that companies have five years to transition to the new requirements in 2025. USP has published other chapters applying the same risk manage- ment approach to elastomeric components used in pack- aging and delivery systems, including <382>, <1381>, and <1382>. Additionally, USP <661.2> and <1382> require a "suitability for use assessment" that could include testing for any packaging system that is at risk, with extractables and leachables among the tests that should be conducted. It is reasonable to expect other pharmacopoeias to up- date their requirements for containers and packaging. For example, based on recent surveillance, the ChP is expected to publish existing national standards for drug packag- ing containers (materials), commonly referred to as the YBB standards. Additionally, there is an informal working group focused on the creation of a new ICH Q3E guideline for the assessment and control of extractables and leach- ables for pharmaceuticals and biologics (39). Timing for the development of this ICH guideline is not currently known, nor is the manner in which it could eventually be incorporated into the pharmacopoeias, but industry should continue to monitor developments in this impact- ful area. Rapid microbiological testing. Rapid microbiological test- ing is an area where additional harmonization would fa- cilitate expanded use of the technology. New chapters in- troduced in the pharmacopoeia are beginning to address this topic, but they are not fully harmonized. There are differences in method validation requirements between general chapters in Ph. Eur. 5.1.6, USP <1223>, and ChP 9201 (40). Differences between the chapters, including the number of replicates needed for a validation test and the amount of an organism to be added for recovery in a test, lead to a problematic situation. The result is that multiple validations must be done by the company trying to im- plement the technology, with little value added to ensur- ing product quality. Companies utilizing this technology should ensure these topics are included in the compendial monitoring processes to enable possible advocacy and en- sure eventual compliance. Pharmacopoeias around the world In the past few years, the health authorities in Japan, China, Brazil, Russia, and Korea have begun requiring a com- pany to perform compliance checks for their registration files versus what is actually being performed. This points to the increasing importance of compliance with the na- tional pharmacopoeias in these countries, where gaps will inevitably become evident during this assessment. Before bringing an additional national pharmacopoeia into their monitoring program, a company must first ensure there is "baseline compliance" with the existing requirements in the pharmacopoeia. This baseline compliance will likely require a cross-functional project to identify any gaps with exist- ing requirements before routine monitoring of revisions to the pharmacopoeia can begin. There are several important points to consider (e.g., translations) when trying to consis- tently monitor national pharmacopoeias (6,7). These con- siderations also apply when performing gap evaluations for current filings, which must include the national pharmaco- poeia requirements. China. China is the largest potential healthcare market in the world based on the size of its population. Recent govern- ment reforms and a drive to ensure better healthcare for its people make it a country to focus on in the coming years. It is no longer to be considered an emerging market, but rather, will soon join the United States and Europe among the coun- tries/regions where new drug product registrations will occur first. Though this may be a shocking statement to some, the statement is supported by the rate of regulatory change and the availability of accelerated processes to bring newer ther- apies to China sooner, instead of several years after approval in other countries. Included in this change is the ChP and its practices. China joined ICH in 2017 (41) and is currently in the process of adopting and implementing several ICH quality guidance documents (42,43), many of which will have major impact on the pharmacopoeia, such as ICH Q3C (residual solvents) and Q3D (elemental impurities). Additionally, with the adoption of ICH M7 and Q3A and B, designation and reporting of impurities in ChP will potentially change. Pharmacopoeia Compliance Series It is reasonable to expect other pharmacopoeias to update their requirements for containers and packaging.