EU GMP Annex 1 Revision Two Analysis

The second revision of the renewed Annex 1 has been published.

This second revision boasts a number of smaller and larger changes which we will explore in this post. Overall a greater emphasis has been put on QRM, Contamination Control Strategy (CCS) receives a lot more attention in revision 2. Additionally, several small errors have been fixed. We make a side-by-side comparison of revision one and revision two of the EU GMP Annex 1 - Manufacture of Sterile Products. 

Following the first revision of Annex 1 the European Commission has received a great number of comments from the industry; as such it is now allowing further comments to be submitted.

Due to widespread interest from industry following the first targeted consultation, and because of substantial modifications introduced in several sections, it was agreed to engage with stakeholders a second targeted consultation on the updated draft guidance (version 12) focused on the sections and/or significantly modified paragraphs that raised most concerns by stakeholders.

The second targeted consultation aims at collecting experience from the sectors on certain manufacturing steps. The European Commission therefore expect to receive contribution from the European associations representing the sectors.

There are a number of changes as opposed to the earlier draft of Annex 1. Even though the number of pages hasn’t changed much (50 pages in rev. 1 and 52 pages in rev. 2) over 350 lines were added to the second revision, they simply reduced the font size.

We're going to assess the revisions following the document's structure, starting with the scope.

Scope

The basic principles in the scope have not been altered in revision 2 of the EudraLex Volume IV Annex 1 on the Manufacture of Sterile Medicinal Products. However; the writers felt that Quality Risk Management (QRM) should receive additional attention. The following section was added:

“QRM applies to this document in its entirety and will not be referred to in specific paragraphs. Where specific limits or frequencies are written, these should be considered as a minimum requirement. They are stated due to regulatory historical experience of issues that have previously been identified and have impacted the safety of patients.”

Most of the minor alterations in the new revision follow the spirit of that last sentence; bad experiences which the industry and regulators are trying to avoid in the future. A sentence was also added at the end of the scope emphasizing that if you elect to apply certain parts of the Annex 1 to non-sterile products, you must clearly document which parts / principles have been applied. More importantly, if you decide to implement parts of Annex 1 to non-sterile products you must comply to these parts in full.

Principle 

One of the changes we’re especially happy with is a sentence that was not in the original revision of the Annex 1 on the Manufacture of Sterile Medicinal Products:

“QRM priorities should include good design of the facility, equipment and process in the first instance, then implementation of well-designed procedures, with monitoring systems as the final element that demonstrate that the design and procedures have been correctly implemented and continue to perform in line with expectations. Exclusively monitoring or testing does not give assurance of sterility.

We continue to observe organizations with near-perfect procedures but a complete absence of a solid understanding of the process, which choices were made during equipment validation or what the risk analysis was of the initial facility design. Even though this sole paragraph is not going to fix any of those problems, it does show that regulators actively encourage a deeper level of thought throughout the pharmaceutical industry when it comes to facility/equipment/process (and people).

Whereas “Contamination Control Strategy” was not abbreviated in the first revision, it has now received its own abbreviation; CCS. It is introduced in the “Principle” paragraph and used throughout the document thereafter. In revision 1, “control strategy” was used nineteen times, in revision 2 of Annex 1 on the Manufacture of Sterile Medicinal Products, CCS has forty-three instances.

Revision two has one additional requirement for the CCS as opposed to revision one:

“The CCS (Contamination Control Strategy) should be actively updated and should drive continuous improvement of the manufacturing and control methods.”

Minor changes were made in the subsequent paragraphs, namely;

  • In revision 1 the term “equipment and facilities” was used, this has been updated to reflect the more common GMP terminology: “premises and equipment”.
  • Single use systems have received its own abbreviation: SUS.
  • A sentence was added indicating that all aspects the CCS (Contamination Control Strategy) and it’s life cycle (with ongoing and periodic review) should result in updates within the quality system as appropriate.

The following two notes were removed from revision two which were present in revision one:

Note One:

This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards and Pharmacopoeial monographs for more detailed guidance.

Note Two: 

Where national legislation permits, additional guidance regarding the preparation of unlicensed sterile medicinal products normally performed by healthcare establishments for direct supply to patients, reference may be made to the Annex 1: “Guidelines on the standards required for the sterile preparation of medicinal products” of the PIC/S guide to good practices for the preparation of medicinal products in healthcare establishments, PE 010.

Premises 

The section which is now “Premises” (section four) used to be “Personnel” in the previous revision. Again, we’re seeing further alignment with the GMP terminology and expectations we’re seeing in other Annexes / EudraLex Volume IV chapters. Where revision one mentioned that sterile products should be manufactured in “clean area’s”, this version indicates that sterile products should be manufactured in cleanrooms.

Further changes in the paragraph are more significant, with further clarification on how we expect workers and materials to enter cleanrooms, where revision one stated:

“5.1 The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.”

Revision two leaves less room for interpretation:

“4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through changing rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and capable of evaluating the state of environmental conditions for cleanrooms, airlocks and pass-throughs used for material and equipment transfer.”

A section on Restricted Access Barrier Systems (RABS) and isolators and their role in assuring the right conditions was added to the Premises paragraph;

“4.3 Restricted Access Barrier Systems (RABS) and isolators are beneficial in assuring the required conditions and minimizing the microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.”

Following this paragraph, the document details cleanroom grades, their purpose and expectations in each zone. In the first revision, there was a guidance value for airspeed in Grade A zone unidirectional air flow systems (0.36 to 0.54 m/s), this guidance value is no longer present in revision two.

Two new paragraphs have been included in revision two, these paragraphs are concerned with the risk of contamination when moving equipment and material into cleanrooms and the need for unidirectional flows of materials and equipment:

“4.10 The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities with the potential to compromise the cleanliness of cleanrooms or the critical zone should be assessed and if they cannot be eliminated, appropriate controls should be implemented.”

“4.11 The transfer of materials, equipment, and components into an aseptic processing area should be carried out via a unidirectional process. Where possible, items should be sterilized and passed into the area through double-ended sterilizers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilization on transfer of the items is not possible, a procedure which achieves the same objective of not introducing contaminant should be validated and implemented, (e.g. using an effective transfer disinfection, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter).”

Other changes in the premises section include (but not limited to);

  • The requirement for personnel and material airlocks to be separated. Where this is not possible, time-based separation of movement should be considered, this should be proceduralized.
  • The use of separate changing rooms (one for staff entering, one for staff leaving) in class B cleanrooms is desirable. When risk assessment shows that the risk for cross contamination is high, separate changing rooms for entering and leaving production areas should be considered.
  • Hand washing facilities should be provided only in the first stage of the changing room and not be present in changing rooms directly accessing Grade B cleanrooms.
  • Pass through hatches should be designed to protect the higher grade environment, for example, by flushing with an active filtered air supply.
  • Pressure differential between adjacent rooms with different grades were recommended to be between 10 and 15 Pascals (guidance values), revision two indicates a minimum of 10 Pascals (guidance value).
  • A section was added stating that where containment requires air to flow into a critical zone, the source of air should be from an area of the same grade.
  • In revision one, the requirement for visualization of airflow patterns was only required for Grade A and Grade B. In revision two, the visualization of airflow patterns is required for all grades (A/B/C/D) and zones.
  • Air flow pattern studies were required to be performed in “dynamic” conditions in revision one. Revision two requires these studies to be performed both “at rest and in operation”.
  • A section on alarms, overriding these and alarm delays was added (line 308 to 312).
  • The requirement for the design of facilities to permit observation from outside production areas initially included all clean areas. In revision two this has been reduced to Grade A and Grade B.
  • In revision one, the document stated that “consideration should be given to designing facilities that permit observation”. Revision two states that this should also be considered during refurbishment, not only when constructing new facilities.

Barrier Technologies 

As opposed to the first revision there are a number of small changes in the Barrier Technology section, most notably from a risk assessment perspective. The changes include;

  1. Revision one stated that negative pressure isolators should only be used when containment of the product is considered essential. Revision two added that risk control measures must be applied to ensure the critical zone is not compromised as a result of this.
  2. Revision one indicated that when RABS are used for aseptic processing, the background environment should meet Grade B. Revision two requires “at least” Grade B.
  3. For the background environment for open isolators has been expanded to meet Grade C AND Grade D. In revision 1, this was only Grade D. Furthermore, this decision must be based on risk assessment.
  4. Integrity testing of barrier and isolator systems as well as leak testing were recommended in revision one to be performed through visual, mechanical and physical tests. In revision two, it must be demonstrated to be suitable for the task and criticality.
  5. The glove replacement frequency must be defined in the Contamination Control Strategy (CCS).
  6. More detail is included for the decontamination methods of RABS and isolator systems with two points (line 369 to line 377).
  7. The requirement for RABS or isolator clean hold time validation before use of these systems was added.

Cleanroom and Clean Air Equipment Qualification

Major changes to the text, accompanying tables and included items for qualification were made in the section on cleanroom and clean air equipment qualification. The first change as opposed to the first revision is the addition of a items that should be performed when qualifying cleanrooms and clean room equipment (not limited to):

  • Installed filter leakage and integrity testing,
  • Airflow measurement – volume and velocity,
  • Air pressure difference measurement,
  • Airflow direction and visualization,
  • Microbial airborne and surface contamination,
  • Temperature measurements,
  • Relative humidity (RH) measurements,
  • Recovery testing,
  • Containment leak testing. 

Extra particle measurement recommendations for Grade A and Grade B have been included in this latest revision. Revision one required particle measurements for particles with a size equal to or greater than 0.5 micrometer (μm). For Grade A and Grade B, at rest and in operation, measurement with a larger particle size of 1.0 micrometer (μm) may be considered.

The table for which displays the maximum permitted airborne particulate concentration during classification no longer displays the ISO classification as it did in revision one. A reference is now made to the ISO 14644 (Part 1) is now made further on in the text.

Other changes to this section include;

  • Revision one stated that personnel could not be in the facility when classifying cleanrooms. This has now been changed to; “without personnel in the room”.
  • Revision one stated that equipment should be “static” when classifying cleanrooms. This has now been changed to; “standing by for operation”.
  • The particulate limits should be achieved after a “clean up period” in the “at rest” state. Revision one did not provide a guidance limit on the duration of the “clean up period” Revision two provides a guidance value of 15 to 20 minutes.
  • A full paragraph was added on the air speed for unidirectional airflow systems (line 463 to 470).
  • A full paragraph was added on the determination of microbial concentration in cleanrooms during qualification (line 471 to 476).
  • The table containing limits for microbial contamination during qualification for Grade A are now defined as “no growth”. In revision one, the table displayed “1” in all three columns.
  • Requalification examples for cleanrooms have been included (line 509 to 513).
  • A new table has been added at line 497 on the minimum test requirements for the requalification of cleanrooms.

Old table:

Maximum permitted airborne particle concentration during classification (Revision 1)

New table: 

Maximum Limits for Particulates (Revision 2) 

Disinfection 

Two paragraphs have been added on the validation and the use of disinfectants in different Grades of cleanrooms.

“4.37 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and should support the in-use expiry periods of prepared solutions.”

“4.38 Disinfectants and detergents used in Grade A zone and Grade B areas should be sterile prior to use (disinfectants used in Grade C and D may also be required to be sterile). Where the disinfectants and detergents are made up by the sterile product manufacturer, they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers and should only be stored for defined periods. If the disinfectants and detergents are supplied “ready-made” then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.”

Equipment 

Although equipment has mostly stayed the same between revisions one and two, a few minor details have been added in this second revision.

The most notable change concerns the sterilization of equipment. Whereas revision one required only critical surfaces with direct impact to be sterilized, revision two required direct and indirect contact parts to be sterilized.

A smaller change is concerned with the requirement that equipment monitoring requirements should be defined in the User Requirement Specification (URS) as well as the early stages of development, to be confirmed during qualification.

One paragraph was removed from revision one:

“6.4 When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilized where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work.”

Utilities

Two paragraphs have been added to utilities regarding the trending of critical quality parameter results for high risk utilities and the requirement for utility installation records to be maintained (lines 614 to 626).

Where revision one stated that “Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.” The second revision takes a wholly different approach:

“Pipes, ducts and other utilities should not be present in cleanrooms. If unavoidable, then they should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean. Installation should allow cleaning and disinfection of outer surface of the pipes.”

Water Systems 

The following (in bold) was added in revision two:

“WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, (unless justified otherwise) as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk and the outcome of qualification.”

Heating and Cooling and Hydraulic Systems 

Heating systems were not present in revision one. Heating systems have been added throughout this paragraph. The old paragraph focused solely on cooling and hydraulic systems.

Personnel 

This used to be section four in revision one. In revision two personnel is the last section before production and specific technologies. It is also one of the longest sections, spanning three pages of the fifty-two-page document.

A few “common sense” items were added to this section, including:

  • The fact that non-essential processes should be conducted outside clean areas.
  • The level of training of personnel should be commensurate with the criticality of the function and area in which the personnel is working.
  • Outside staff has been renamed to the more appropriate; “unqualified personnel”.
  • Unqualified personnel may not enter Grade A or Grade B when in operation, unless there are exceptional circumstances, for which a procedure must be available (amongst others).
  • Where revision 1 banned all electronic and other personal items from the cleanrooms, revision 2 allows mobile phones and tablets supplied by the company for the sole use in cleanrooms. Obviously, cleanliness and the ability to disinfect must be guaranteed.

There is a large number of updates to the requirements for garments:

  • When clothing protects the operator from the product, the clothing may not affect the product.
  • Garments should be checked for cleanliness and integrity twice; once before gowning, once before entering the cleanroom.
  • Sterilized and decontaminated garments and eye coverings packaging must be visually inspected against integrity and replaced if damaged or at a set frequency.
  • Visual inspection alone may not be sufficient to identify damage, as such qualification should consider additional methods.
  • Clothing should be chosen to prevent shedding due to excessive movements from operators (when cold or sweating).
  • Revision one did not require a dedicated laundry facility for clean area clothing. Revision two says that “clean area clothing should be cleaned in a dedicated laundry facility using a qualified process”.
  • Revision two added the following section; “Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided. Airflow visualisation studies should be considered as part of the operator’s training programme.”

Conclusion 

Overall the Annex 1 on the Manufacture of Sterile Products has been increased in size and detail. Minor mistakes in the first revision have been corrected and a greater emphasis has been placed on the industry’s knowledge building, understanding of the process and analysis of the risks when producing sterile products.

The biggest changes could be found in the Premises section. The document has become more mature. We’re seeing a great deal of additions based on recent and historic inspection results which led to undesirable situations, the second revision tries to prevent these by introducing more specific guidance and involving Contamination Control Strategies and Risk Management to a greater extent.

Download the revised Annex 1 of the EU GMP here: https://ec.europa.eu/health/medicinal_products/consultations/2020_sterile_medicinal_products_en

Find our first blog post on the first revision of Annex 1 here: https://www.pcs-nl.com/gmp-blog/article/highlights-from-the-new-draft-annex-1