The revised Annex 1 on sterile manufacturing includes incorrect and ambiguous statements that must be fixed before implementation.
The December 2017 revision of EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products (1), when finalized, will be legally binding. Non-compliance could result in regulatory action, refusal, or revocation of marketing authorizations and civil and criminal penalties. Given the revised Annex 1’s legal standing, it is vital that the document delineates appropriate regulatory expectations and accepts contemporary manufacturing and control procedures and practices.
The European Medicines Agency (EMA) has put forward Annex 1 for comment, but the document is so badly written that understanding it, much less commenting on it, is far more difficult than it should be. As it stands, this version of Annex 1 will inevitably generate thousands of comments that will be difficult for EMA to reconcile within the framework of the current document. Preliminary review of the document indicates that it is poorly worded, ambiguous, and technically incorrect in many areas. The following comments represent a fraction of those identified during our review. They are categorized by general areas of concern.
Inconsistent use of and undefined terminology
There are many instances where inconsistent use of terms or wording results in ambiguity and the inability to determine or demonstrate compliance, such as listed in the following:
The terms “medicines” and “medicinal products” are used interchangeably and neither is defined.
Line 188 instructs that “All personnel . . . in such areas should receive regular training,” but it is unclear to which areas this refers.
Line 207 mentions a “continuous monitoring program for personnel” without explaining what this is, or how continuous personnel monitoring is feasible, useful, or even safe.
Line 230 instructs that “Staff who have been engaged in the processing of human or animal tissue materials” should not enter “sterile product areas,” but none of these terms are defined.
“Grade A/B” used throughout the document is undefined.
At line 861, “time between the start of the preparation of a solution and its sterilization,” the word “solution” does not reflect the full range of medicinal products that should be subject to pre-sterilization time limits.
Incorrect application of technology
The use and application of airlocks, barrier systems, isolation technology, and environmental and personnel monitoring systems are incorrectly described or applied, such as:
Airlocks and pass-throughs vary in sophistication and design, but the document limits flexibility and informs at line 365 that “the final stage of the airlock should . . . be the same grade as the area into which it leads,” which is inappropriate for exit airlocks.
Barrier technologies, other than true closed restricted-access barrier systems (RABS), are substantially less capable than isolators, yet the document considers them near equal in performance.
Monitoring of large particles (≥ 5 µm) lacks accuracy and is inherently less sensitive than monitoring of smaller particles. Also, the prevalence of such particles in grade A/B areas is too low to make sampling for them statistically useful. And there is no evidence particles of this size range predict microbial risk. EMA should harmonize with International Organization for Standardization (ISO) 14644.
Personnel monitoring should never be performed in grade A as instructed at line 205. Such monitoring increases the biological load in critical environments with no product safety benefit.
Technical process errors
The following technical errors dot the pages of the document:
At line 1251, a liquid product is to be “terminally sterilized by a microbiocidal process” instead of “terminally sterilized.”
The use of traps for back flow prevention is specified at line 358, even though “traps” do not prevent back flow.
At line 351, “Materials liable to generate fibres should not be permitted in clean areas,” which would eliminate gowned personnel, who, studies have shown, continuously shed particles and fibers.
At line 839, the document instructs “The transfer of partially closed containers to a lyophilizer, should be done under grade A conditions (e.g., HEPA filtered positive pressure) at all times . . .” which is contradictory because grade A requires unidirectional airflow.
Application of risk analysis
There is a misdirected focus toward factors that do not increase patient safety or relate to the safety, identity, strength, quality, or purity of a drug product beyond the official or other established requirement:
The document incorrectly applies risk analysis (e.g., line 1331, integrity testing of a sterilized filter assembly before use [pre-use post-sterilization integrity testing, PUPSIT] and on-line integrity testing immediately after use). PUPSIT adds risk by potentially requiring manipulations downstream of sterilized filters.
Routine and intervention-related monitoring of personnel in grade A adds activity and increases contamination risk, line 205.
At line 883, “Containers closed by fusion, e.g., Form-Fill-Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject to 100% integrity testing.” This is akin to testing quality into the product as opposed to validating the sealing process and running confirmatory process checks. Annex 1 references quality by design, statistical process control, and process validation approaches and then undercuts the asserted value of these well-recognized quality management tools with a poorly considered focus on end-product testing.
Unusual concept of sterile product manufacture
The document presents a view of sterile product manufacture inconsistent with that developed elsewhere, as codified in regulations, international standards, and pharmaceutical compendia, such as:
US and Japanese guidance on sterile product manufacturing differ markedly from what is presented.
The cleanroom content in the draft does not conform to ISO 14644 and perpetuates the myths that cleanrooms can be classified microbiologically and that microbiological testing can enhance sterility assurance.
United States Pharmacopeia (USP) chapters <1211>, <1228>, and <1229> provide more contemporary and appropriate guidance for sterile product preparation (2–4).
There are also conflicts with current EMA guidance (e.g., the water for injections Q&A paper and Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products).
EMA should withdraw this draft of Annex 1. It should be significantly revised to include more contemporary and global content on sterile product manufacture and control and reissued for comment once its many faults have been corrected.
The cited examples represent only a fraction of the more than 130 issues we identified in the document and we plan to submit a comprehensive response to EMA by the comment deadline of March 20, 2018 in the event that the draft is not withdrawn.
1. European Commission, EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, December 2017.
2. USP, <1211> Sterilization and Sterility Assurance of Compendial Articles, USP 40-NF 35 (USP, 2017).