Highlights of the new EU GMP Annex 1 Draft

A side-by-side comparison with the current Annex 1

The European Comission has published a proposed revised version of Annex 1: Manufacture of Sterile Medicinal Products. The proposed revised version was prepared in cooperation with the WHO and PIC/S. The document will be subject to parallel public consultation by the WHO and PIC/S.


Key Changes

The key changes in this new Annex are;

  • The introduction of new sections such as; Scope, Utilities, Environmental Monitoring, Process Monitoring as well as a Glossary.
  • Quality Risk Management (QRM) Principles are introduced.
  • The entire document has been restructured to provide a more logical flow.
  • Further clarity is provided to some of the old sections through more detailed descriptions.

The document itself has grown from 7,036 to 22,158 words, spread over 50 pages as opposed to 16 pages in the current Annex. "Risk" is mentioned 92 times in the new draft as opposed to 20 times in the current document. "Assessment" is mentioned 36 times in the new draft, it is not mentioned in the current document.


Scope

The current Annex 1 does not contain a scope, merely a principle.

The new scope covers a wide range of product types, (sterile active substance through to finished dosage form), batch sizes (single unit to multiple units), processes (from highly automated systems to manual processes), primary packaging materials and technologies (e.g., biotechnology, classical small molecule manufacturing and closed systems).

This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product.


The Principle

The manufacture of sterile products is subject to special requirements in order to minimize the risks of microbiological, particulate and pyrogen contamination.

Facility, equipment and process design should be according to Annex 11 and Annex 15 of the EU GMP.
Added to the draft that appropriate current technology should be used.

Principles on personnel remain the same; they must have appropriate skills, training, and attitudes with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes.


Pharmaceutical Quality System (PQS)

This section is new and adds to the current Chapter 1 of the EU GMP; it does not replace it. This section should ensure that the PQS of the producer is focused on sterile production to ensure that all activities are effectively controlled so that all final products are free from microbial and other contamination. The main theme in this revised section is risk management and assessment.

Additional requirements have been added including an effective risk management system, which should be integrated into the product lifecycle. The draft document also expects the manufacturer to have sufficient knowledge and expertise in relation to the manufactured products as well as the manufacturing methods employed. The new draft even states that the manufacturer correctly understands the risks to the product for root cause analysis (RCA).

Performed and current Risk Assessments should regularly be reviewed by the Quality Management during the execution of Change Controls and Product Quality Review (PQR). To ensure all these risk assessments and other required data such as Environmental Monitoring data are actually seen by those responsible for batch release the document requires those responsible for the quality release of sterile medicines should have appropriate access to manufacturing- and quality information. But also possess adequate knowledge and experience in the manufacture of sterile dosage forms and their Critical to Quality Attributes (CQA).

The section concludes with the requirement for investigations to focus on the potential impact to sterility of the respective batch, but also on other potentially impacted batches.


Personnel


A number of requirements have been added for personnel in this revision. Some of these requirements look familiar to those found in the EudraLex Volume IV such as the statement that; "the manufacturer is responsible for sufficient and appropriate personnel, suitably qualified and experienced".

Other requirements are extracted from the WHO Technical Report Series, the requirement for determining the maximum amount of operators allowed in a cleanroom (based on QRM) is an example of this.

Personnel - Training

Expanded training requirements for cleanroom staff have been implemented, these include; cleanroom practices, contamination control, aseptic techniques and safety implications to the patient. Besides the existing requirements for training on hygiene and microbiology. 

If you require training on any of these subjects, contact PCS to explore the possibilities.

Besides the expanded regular training program, the requirement for regular qualification has been added. 

The revised Annex 1 has new demands for personnel working in grade A and grade B cleanrooms. These requirements include;
- Compliance with aseptic gowning procedures should involve both visual and microbiological assessment.
- For personnel who passed gowning, APS is only allowed in grade A/B areas.
- Obligatory monitoring after a critical intervention, and upon each exit from the cleanroom.

Ongoing continuous monitoring programs for personnel must be implemented as well as periodic monitoring under the supervision of the Quality unit.

When employees are no longer qualified for entering the cleanroom (based on the aforementioned qualification program for example), they must officially be disqualified from entering the cleanroom. Which will result in re-training and re-qualification of the respective staff member(s).

Items which are not allowed in cleanrooms have now explicitly been named in the Annex to include; wristwatches, jewelry and other personal items such as smartphones.

When in cleanrooms, personnel are required by the guideline to move as little as possible, to adhere to aseptic techniques and not obstruct the LAF.

Personnel - Clothing

Clothing requirements have been added depending on the cleanroom grade. 

  • Grade D: Shoes must be disinfected
  • Grade C: Appropriately disinfected or sterilized shoes or over-shoes. Dedicated socks must be worn before entry to the change rooms for grade C and B.
  • Grade A/B: Face masks and eye covering should be sterile, footwear should be sterile instead of sterile/disinfected. Dedicated socks must be worn before entry to the change rooms for grade C and B.
  • Added: Garments should be packed and folded in such a way as to allow operators to change into the garments with contact to the outer surfaces of the garment reduced to a minimum.
  • Recommendation for facility suits has been added, including the requirement for dedicated socks to be worn before entry to the change rooms for grade C and B.
  • The term "mask" has been changed into "garments", which should be changed for every working session.

Besides the specific cleanroom grade requirements, the draft document states that garments should be checked for integrity after washing and before sterilization.


Premises

Plenty of changes were made to this section, stressing segregation and a clear emphasis on environmental monitoring.

The section starts out with the requirement of appropriate segregation of technical and operational activities for every operation.

Where the old revision stated that containers and materials that are liable to shed materials should be avoided, the new revision states that materials liable to generate fibers should not be permitted in clean areas.

If floor drains are allowed in lower grade rooms, they should be regularly cleaned and disinfected. 

A new paragraph on airlocks is included. Recommending a cascade concept for personnel airlocks. When moving materials, however, pass through hatches without an actively filtered air supply should be avoided.

Even more so, when you want to move materials into grade A and grade B areas via airlock/pass-through-hatches they must be on the qualification list. Moving materials from clean, not-classified (CNC) to grade C areas should be based on QRM principles. This means you should ensure your cleaning and disinfection are aligned with the risks.

Other big changes include the requirement for air flow patterns to be visualized in grade A/B areas. For other areas, the need for visualization should be based on a Risk Assessment. But also the requirement for camera's or windows with a complete view of the area and processes to allow observation and supervision without having to physically enter the area will pose a challenge for certain companies with very large processes.

Another section that has been added is; "Clean Room and Air Device Qualification".

It states qualification needs to be performed according to Annex 15 of the EudraLex Volume IV guidance, ISO 14644 is used as a reference.
Regarding the airborne particles during qualification, 5.0um particles are no longer required.
The values for 0.5um remain the same. This is only for qualification.

 

The minimum amount of sampling points remains the same as it is in the current Annex, in accordance with ISO 14644 part 1.

The microbial load of the clean rooms should be determined as part of the clean room qualification, the limit values are the same as the current revision of Annex 1, but a line has been added that if settle plates are open for a period shorter than 4 hours, no recalculation is necessary.

Clean room qualification (including classification) should be clearly differentiated from operational process environmental monitoring. Additionally, cleanrooms should be requalified periodically, after equipment change, facility or process based on QRM principles. Recommended is a period of six months for grade A and B. Once per year for grades C and D.

Premises - Disinfectants

The Disinfectants paragraph has grown from 1 to 4 paragraphs.

  • The revision of Annex 1 requires a written program, with more than one disinfectant. A sporicidal agent should be used periodically. Monitoring should be in place to monitor effectiveness and detect the development of resistance. The disinfectant should be effective during its shelf life. Effective removal of residues should also be included in the program.
  • Disinfectants should be shown to be effective when used on the specific facilities, equipment, and processes that they are used in.


Equipment

The equipment paragraph opens with the request for a detailed description of equipment design which should be prepared by the company, including diagrams where appropriate. These detailed descriptions should include and describe the product as well as any other critical gas and fluid pathways and controls in place.
Annex 1 currently requires alarms for particle monitoring in grade A & B.

The revised Annex requires a general equipment monitoring program. The requirements for which should be determined during qualification. Process alarm events should be reviewed, approved and evaluated for the purpose of trending.

New requirements include the validation of the cleaning process showing that cleaning;

  • Can remove any residues.
  • Prevents chemical and particulate contamination.

Other new requirements include that all critical surfaces which come into direct contact with sterile materials should be sterile themselves. All equipment should be subjected to qualification, monitoring, and planned maintenance. Before the equipment can be returned to operational use, approval is required.

Particle counters should also be qualified, including the sampling tubing.

If unplanned maintenance is required, the potential impact on the sterility of the product should be ASSESSED and RECORDED.


Utilities

Consists of a completely new section of six paragraphs in total.
It introduces the requirement to use Risk Assessments to determine the nature and amount of controls associated with utilities.

  • General high-risk utilities include:
    • Materials which are directly in contact with the product.
    • Contact materials that ultimately will become part of the product.
    • Control contamination of surfaces that contact the product.
    • Or otherwise directly impact the product.
  • The requirement for trend analysis of critical parameters of high-risk utilities has been introduced.
  • (Technical) Drawings must be produced including critical utilities and their parameters, these must also be CURRENT.
  • For water systems, the relevant Pharmacopoeia is introduced.
  • To prevent the formation of biofilms, sterilization or disinfection or regeneration of water systems should be carried out according to a predetermined schedule and also when microbial counts exceed action and alert limits.


Production & Specific Technologies

This part constitutes the largest revision compared to the current Annex 1. In this revision, more details are provided for production and the specific technologies that are used. Details are provided for:

  • Terminally Sterilized Products and Aseptic Preparations.
  • The Finishing of Sterile Products.
  • Sterilization, including:
    • Sterilization by heat.
    • Moist heat sterilization.
    • Dry heat sterilization.
    • Sterilization by radiation.
    • Sterilization with ethylene oxide.
    • Filtration of medicinal products which cannot be sterilized in their final container.
  • Form-Fill-Seal.
  • Blow-Fill-Seal technology.
  • Lyophilization.
  • Closed systems.
  • Single-use systems.


Environmental Monitoring & Process Monitoring

This section is entirely new; it combines all monitoring requirements. It states that whenever aseptic production is performed, frequent monitoring should be performed. Additionally, the monitoring program should be part of the contamination control strategy.

The monitoring program should contain; non-viable monitoring, viable monitoring, and aseptic process simulation.
These elements are a source of information when you are determining the capabilities of your process and facility to maintain sterility assurance.

In order to establish a robust environmental program, you must conduct appropriate risk assessments based on detailed knowledge. 

Non-Viable Monitoring

  • Recommended limits for airborne particle remain the same, only for grade D during operation a limit should be set based on a risk assessment
  • Although monitoring of ≧0 µm particles is not required for room qualification and classification purposes, it is required for routine monitoring purposes as they are an important diagnostic tool for early detection of the machine, equipment, and HVAC failure.

Viable Monitoring 

  • Continuous monitoring in grade A and B areas should be undertaken for the full duration of critical processing, including equipment (aseptic set up) assembly and filling operation.
  • The old revision stated that sampling should not interfere with zone protection, the new revision states that sampling should not pose a risk of contamination.
  • Added is that the monitoring procedures should define the approach to trending.
  • Mirco organisms that are detected in grade A or B should be identified all the way down to the "species level".

 Aseptic Process Simulation (APS)

  • APS = Media fill
  • Periodic verification of the effectiveness of the controls in place for aseptic processing should include a process simulation test using a sterile nutrient media and/or placebo.
  • Risk management principles should be used when developing the Aseptic Process Simulation plan.
  • In case of a failed process simulation, there should be a prompt review of all appropriate records relating to aseptic production since the last successful process simulation.


Quality Control

 Some paragraphs which were included in the "processing" section in the current revision of Annex 1 were moved to the QC section in the new revision.

A number of principles are introduced, including the requirement that sterility test should be performed under aseptic conditions which are at least consistent with the clean room where it is manufactured.

Two examples have been added to the section regarding sampling:

10.7 Samples taken for sterility testing should be representative of the whole of the batch, but should in particular include samples taken from parts of the batch considered to be most at risk of contamination.
These examples include:

  • Each sterilized load should be considered as different batches and require a separate sterility test.
  • Products that have been lyophilized in different lyophilization loads.

One of the other new requirements includes the growth promotion for media which is used in Environmental Monitoring and Aseptic Production Simulation (read: Media Fill). Additionally, Environmental Monitoring should be included in the batch release process. If the Environmental Monitoring is found to Out-Of-Spec (OOS), a plan with actions should be readily available.

Finally, the use of rapid microbial methods can also be considered. These methods should be validated for the product(s) or processes concerned and be approved in the registered product testing specification.


Conclusion

The new EU GMP Annex 1  is not just a minor revision, it is a complete overhaul of the current Annex 1. It provides a great deal of guidance and detail to the industry which will benefit process understanding, the definition of "KPI's" in the form of monitoring and the overall safety of products and operators.

Do you require assistance in aligning your processes/ equipment/personnel/facility with this revision? Contact PCS to find out how we can help you!